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Simple Summary: Decompensated patients with hepatocellular carcinoma (HCC) are a wide patient category with limited therapeutic options, and are often excluded from existing trials. Liver transplantation is the best treatment option for such patients but is affected by strict selection criteria and liver donor shortages. The data regarding locoregional treatments in patients with impaired liver function are scarce but indicate a possible survival benefit provided they are well tolerated. Perhaps the systemic treatments, and particularly immunotherapy, are the safest option for such patients based on the available real-life data. Regardless of the type of treatment, close adverse event monitoring is mandatory due to the high risk of hepatic disease deterioration. The aim of this review is to analyze the existing data regarding the administration of treatment in decompensated patients with HCC, evaluate the effect of therapy on overall survival, highlight the potential risks in terms of tolerability and elucidate the optimal therapeutic management. Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) associated with portal vein thrombosis (PVT) represents an advanced stage of the tumor, with a subsequently poor prognosis and reduced therapeutic perspectives. These patients could present severe complications such as ascites, metastases, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The intricate molecular patterns at the basis of the development of TVP could also represent possible biomarkers in the early detection of patients at high risk of PVT. Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of about 25–50% in HCC, determining poor prognosis and a remarkable reduction in therapeutic perspectives in these patients, leading to severe complications such as ascites, metastasis, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The aim of this review is to evaluate the molecular mechanisms that are at the basis of PVT development, trying to evaluate possible strategies in the early detection of patients at high risk of PVT. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous melanoma (CM) is an aggressive skin cancer that develops from melanocytic cells. The most important prognostic factor is still the vertical tumour thickness according to Breslow. Liver function is associated with better overall patient outcomes and is currently under increasing investigation in cancer patients. Current findings show that liver function is an important factor in different tumour entities and represents a potential biomarker. Therefore, we aimed to evaluate liver metabolism by using liver scores in CM. High tumour thickness (≥1.66 mm) and aspartate transaminase-to-platelet ratio index (APRI ≥ 0.2241) at the initial diagnosis were associated with a worse prognosis in stage I and II melanoma. Background: Neoadjuvant and adjuvant therapies are currently getting increasingly important in cutaneous melanoma (CM) management. However, there is still a lack of prognostic tools to identify which patients have a poor prognosis. There is increasing evidence that the liver score may be a potential prognostic parameter in different tumour types. The aim was to investigate whether established liver scores can establish the prognosis of CM. Methods: According to established methods, the APRI, the MELD score, the MELD-Na score and the De Ritis ratio were calculated from the laboratory values at the time of the initial diagnosis. Survival was compared with the Kaplan–Meier curve and tested with log-rank tests. Risk factors associated with cutaneous melanoma-specific survival (CMSS) and progression-free survival (PFS) were assessed by using the Cox proportional hazards regression model. To determine the diagnostic accuracy, we performed a time-dependent ROC analysis. Results: A total of 423 patients were included, including 141 patients in AJCC stage (2017) I (33.3%), 82 in stage II (19.4%), 128 in stage III (30.3%) and 72 in stage IV (17%). Median time until melanoma-specific death was 99 months (IQR: 37–126). In addition, 37.6% of patients relapsed with a median time to relapse of 88 months (IQR: 17.5–126). In all stages, tumour thickness and ulceration were independent markers for predicting CMSS and PFS (p < 0.05). The multivariable analysis with all stages showed no significant association with CM outcome for liver scores (p > 0.05). The subgroup analysis revealed that the APRI (≥0.2241) was associated with CMSS and PFS in melanoma stages I and II, independently of tumour thickness, age and ulceration (HR 2.57, 95% CI 1.14–5.75; HR 2.94, 95% CI 1.42–6.09, respectively). Conclusions: The 20-year prognosis of AJCC stage I and II CM was dependent on tumour thickness and the APRI. High tumour thickness and an APRI ≥ 0.2241 at the initial diagnosis were associated with a worse prognosis. Future studies should investigate the independent prognostic value of the APRI in low-stage CM. Furthermore, the APRI score could be a potential biomarker for nomograms. [ABSTRACT FROM AUTHOR]

Simple Summary: In the era of direct-acting antiviral (DAA) agents, chronic hepatitis C virus (HCV) infection has become a curable disease. Eradication of the virus remains a major goal for the World Health Organization (WHO) by 2030. Main obstacles seem to be the lack of national screenings and shortage of knowledge among patients and healthcare professionals. There also remain, scarcely described in the literature, specific groups of patients who, due to their comorbidities such as malignant tumors, may not be considered as candidates eligible for DAA treatment. In our study, we aimed to characterize and present treatment efficacy in individuals with chronic hepatitis C and an active malignancy treated in Poland in years 2015–2020 with DAAs and compare their outcomes with a treated population with no active malignancy. The obtained results indicate high effectiveness and a low number of premature treatment discontinuations for the majority of patients with active malignancies, with some concerns around HCCs. We believe that data provided by this study will lead to more efficient elaboration of the standard of care in this population. Background: Over the past years, the introduction of direct-acting antivirals (DAAs) revolutionized chronic hepatitis C treatment. We aimed to characterize and assess treatment efficacy in three specific groups of patients treated with DAAs: those with active solid malignant tumors (SMTs), hematological diseases (HDs) and hepatocellular carcinomas (HCCs). Methods: A total of 203 patients with active oncological disease (SMT n = 61, HD = 67, HCC n = 74) during DAA treatment in 2015–2020 selected from the EpiTer-2 database were analyzed retrospectively and compared to 12,983 patients without any active malignancy. Results: Extrahepatic symptoms were more frequent in HD patients (17.2% vs. SMT = 10.3%, HCC = 8.2%, without = 7.8%, p = 0.004). HCC patients characterized with the highest ALT activity (81 IU/L vs. SMT = 59.5 IU/L, HD = 52 IU/L, without = 58 IU/L, p = 0.001) more often had F4 fibrosis as well (86.11% vs. SMT = 23.3%, HD = 28.8%, controls = 24.4%, p = 0.001). A significant majority of subjects in HCC, HD and SMT populations completed the full treatment plan (HCC = 91%; n = 67, HD = 97%; n = 65, SMT = 100%; n = 62). Concerning the treatment efficacy, the overall sustained virologic response, excluding non-virologic failures, was reported in 93.6% HD, 90.16% SMT and 80.6% in HCC patients. Conclusions: As presented in our study, DAA therapy has proven to be highly effective and safe in patients with active SMTs and HDs. However, therapy discontinuations resulting from liver disease progression remain to be the major concern in HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Single small primary liver cancers are curable with treatments such as surgical resection, ablation, and liver transplant; however, many patients initially receive trans-arterial chemo-embolisation (TACE), which is generally not considered a curative treatment in itself, and often go on to receive further follow-up treatments. Little is known regarding the outcomes of such patients compared to those who receive upfront ablation. Our real-world multi-centre study demonstrates that key survival outcomes are similar between those initially undergoing TACE and those receiving ablation after controlling for other key clinical variables and allowing for subsequent individualised treatment selection. Percutaneous ablation is recommended in Barcelona Clinic Liver Cancer (BCLC) stage 0/A patients with HCC ≤3 cm as a curative treatment modality alongside surgical resection and liver transplantation. However, trans-arterial chemo-embolisation (TACE) is commonly used in the real-world as an initial treatment in patients with single small HCC in contrast to widely accepted clinical practice guidelines which typically describe TACE as a treatment for intermediate-stage HCC. We performed this real-world propensity-matched multi-centre cohort study in patients with single HCC ≤ 3 cm to assess for differences in survival outcomes between those undergoing initial TACE and those receiving upfront ablation. Patients with a new diagnosis of BCLC 0/A HCC with a single tumour ≤3 cm first diagnosed between 1 January 2016 and 31 December 2020 who received initial TACE or ablation were included in the study. A total of 348 patients were included in the study, with 147 patients receiving initial TACE and 201 patients undergoing upfront ablation. After propensity score matching using key covariates, 230 patients were available for analysis with 115 in each group. There were no significant differences in overall survival (log-rank test p = 0.652) or liver-related survival (log-rank test p = 0.495) over a median follow-up of 43 months. While rates of CR were superior after ablation compared to TACE as a first treatment (74% vs. 56%, p < 0.004), there was no significant difference in CR rates when allowing for further subsequent treatments (86% vs. 80% p = 0.219). In those who achieved CR, recurrence-free survival and local recurrence-free survival were similar (log rank test p = 0.355 and p = 0.390, respectively). Our study provides valuable real-world evidence that TACE when offered with appropriate follow-up treatment is a reasonable initial management strategy in very early/early-stage HCC, with similar survival outcomes as compared to those managed with upfront ablation. Further work is needed to better define the role for TACE in BCLC 0/A HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction of direct-acting antivirals (DAAs) has significantly improved the treatment of Hepatitis C, achieving high success rates and reducing complications and deaths. Despite their success, there are concerns about the potential risk of developing liver tumors after DAA treatment. This study analyzed data from the Swiss Hepatitis C Cohort to compare the risk of liver tumors and death among patients treated with DAAs, those treated with interferon (IFN)-based therapy, and untreated patients. The findings suggest that, while DAAs reduce the risk of death and do not increase the risk of non-liver tumors, there is a higher risk of liver tumors in patients treated with DAAs compared with untreated patients. This highlights the importance of ongoing liver cancer screening for patients who have undergone DAA treatment. Introduction: The use of direct-acting antivirals (DAAs) has drastically changed the management of HCV-infected patients by achieving a 95–98% sustained virologic response (SVR) and reducing morbidity and mortality in this population. However, despite their effectiveness, controversy exists concerning the occurrence of oncologic events following DAA therapy. Aims and Methods: A retrospective analysis was conducted on data from the Swiss Hepatitis C Cohort Study, a prospective cohort involving patients with positive HCV viremia upon inclusion, enrolled in various Swiss centers from September 2000 to November 2021. To examine potential differences in the risk of intrahepatic tumor (IHT) occurrence and death among patients treated with direct-acting antivirals (DAAs), untreated patients, and those receiving interferon (IFN)-based therapy, a semiparametric competing risk proportional hazards regression model was used. Results: Among 4082 patients (63.1% male, median age 45 years; genotype 1: 54.1%; cirrhosis: 16.1%), 1026 received exclusive treatment with IFN-based regimens, and 1180 were treated solely with DAAs. Over a median follow-up of 7.8 years (range: 3.8–11.9), 179 patients (4.4%) developed intrahepatic tumors (IHT), and 168 (4.1%) experienced extrahepatic tumors (EHT). The 5-year cumulative incidence of IHT was 1.55% (95% CI 0.96–2.48) for IFN-based therapy, 4.27% (95% CI 2.93–6.2) for DAA and 0.89% (95% CI 0.4–1.99) for untreated patients. There was no statistically significant difference in the risk of developing IHT (HR = 1.34; 95% CI = [0.70; 2.58]; p = 0.380) or death (HR = 0.66; 95% CI = [0.43; 1.03]; p = 0.066) between patients treated with DAAs and those treated with IFN. Conclusions: The DAAs reduced the risk of death and were not associated with an increased risk of extrahepatic tumors (EHT). In the adjusted model, accounting for cirrhosis and high liver stiffness, the DAA treatment was associated with a higher risk of IHT occurrence compared with untreated patients, emphasizing the relevance of implementing standardized hepatocellular carcinoma (HCC) screening post-DAA treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic hepatis B still remains a global epidemic and one of the leading causes of hepatocellular carcinoma worldwide. We aimed to find out possible factors that could predict hepatocellular carcinoma development, as well as to compare the predictive performance of various, well-known, risk models in 632 patients with chronic hepatitis B. In our cohort, 34 patients developed hepatocellular carcinoma during follow-up. We found that patients that had cirrhosis, were males, had increased alcohol consumption and were older, had increased risk for cancer development in the multivariate analysis. Of the various risk models that were tested, Core promoter mutations and cirrhosis-HCC (GAG-HCC) and Platelet Age Gender–HBV (PAGE-B) risk models had the greatest performance; however, this performance significantly declined in the subgroup of patients with cirrhosis. In conclusion, certain baseline factors and risk models seem to predict the development of hepatocellular carcinoma in patients with chronic hepatitis B; however, this prediction declines in the subgroup of patients with cirrhosis and thus, we need novel risk models to be developed specifically for these patients. Chronic hepatitis B (CHB) infection constitutes a leading cause of hepatocellular carcinoma (HCC) development. The identification of HCC risk factors and the development of prognostic risk scores are essential for early diagnosis and prognosis. The aim of this observational, retrospective study was to evaluate baseline risk factors associated with HCC in CHB. Six hundred thirty-two consecutive adults with CHB (n = 632) [median age: 46 (IQR: 24)], attending the outpatients' Hepatology clinics between 01/1993–09/2020 were evaluated. Core promoter mutations and cirrhosis-HCC (GAG-HCC), Chinese University-HCC (CU-HCC), risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B), Fibrosis-4 (FIB-4), and Platelet Age Gender–HBV (PAGE-B) prognostic scores were calculated, and receiver operating curves were used to assess their prognostic performance. HCC was developed in 34 (5.38%) patients. In the multivariable Cox regression analysis, advanced age (HR: 1.086, 95% CI: 1.037–1.137), male sex (HR: 7.696, 95% CI: 1.971–30.046), alcohol abuse (HR: 2.903, 95% CI: 1.222–6.987) and cirrhosis (HR: 21.239, 95% CI: 6.001–75.167) at baseline were independently associated with the development of HCC. GAG-HCC and PAGE-B showed the highest performance with c-statistics of 0.895 (95% CI: 0.829–0.961) and 0.857 (95% CI: 0.791–0.924), respectively. In the subgroup of patients with cirrhosis, the performance of all scores declined. When treated and untreated patients were studied separately, the discriminatory ability of the scores differed. In conclusion, HCC development was independently associated with advanced age, male sex, alcohol abuse, and baseline cirrhosis among a diverse population with CHB. GAG-HCC and PAGE-B showed high discriminatory performance to assess the risk of HCC development in these patients, but these performances declined in the subgroup of patients with cirrhosis. Further research to develop scores more specific to certain CHB subgroups is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, comprising 90% of liver cancer cases worldwide, with a five-year survival rate of less than 20%. Standard treatments for early-stage HCC include surgical resection and liver transplantation, but many patients are diagnosed at later stages and are ineligible for these interventions. For such patients, transarterial chemoembolization (TACE) is an alternative treatment that delivers chemotherapy directly to the tumor and blocks its blood supply. TACE can be used to help patients maintain eligibility for transplants, improve liver function, and alleviate symptoms. It is particularly effective for intermediate-stage HCC but also shows promise in the early and advanced stages when combined with other therapies. While generally safe, TACE can cause post-embolization syndrome (PES) and other complications in a minority of cases. The efficacy of TACE is continually being improved through advancements in techniques and the integration of novel systemic therapies and artificial intelligence for better patient selection and outcomes. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancer cases worldwide and is currently the most quickly increasing cause of cancer-related deaths in the United States. The 5-year survival rate for primary liver cancer is estimated to be below 20%, and HCC mortality is expected to increase by 41% by 2040. Currently, surgical resection is the first-line approach to definitive treatment of early-stage HCC. However, the majority of patients present with late-stage, unresectable disease due to the asymptomatic nature of early HCC. For patients who present with unresectable HCC, locoregional therapies such as transarterial chemoembolization (TACE) represent an alternative approach to HCC treatment. TACE is a minimally invasive, catheter-based technique that allows for targeted delivery of chemotherapy to tumor sites while occluding tumor-feeding blood vessels. In appropriately selected patients, outcomes for TACE therapy have been shown to be more favorable than supportive care or conservative management. The increasing incidence and mortality of HCC, in addition to the late-stage presentation of most HCC patients, demonstrates the need to expand the role of locoregional therapies in the treatment of HCC. TACE represents an appealing approach to HCC management, including disease control, palliation, and potentially curative-intent strategies. In this review, we will describe the current utility of TACE in the treatment of HCC, characterize the outcomes of patients treated with TACE across different HCC stages, and outline future applications of TACE in the treatment paradigm. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has evolved as a leading therapeutic modality for several malignancies, and increasing evidence has shown its utility in the treatment of hepatocellular carcinoma. Specifically, immune checkpoint inhibitors have shown promise as an alternative treatment for this neoplasm. However, given their ability to reactivate the immune system, these treatments pose significant risks, specifically hepatitis viral reactivation, autoimmune hepatitis, and hepatotoxicity. Here, we aim to review the potential hepatic side effects associated with immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. In doing so, we hope to provide an effective summary detailing our current understanding of the true risk of developing these side effects for providers considering immune checkpoint inhibitor therapy for their patients with hepatocellular carcinoma. Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors have become widely used against malignant tumors. The neutrophil-to-lymphocyte ratio, an index focusing on immune cells, has been reported as a marker to predict the efficacy and side effects of anti-tumor drugs. In the present study, we found that the neutrophil-to-lymphocyte ratio shows an altered predictability of anti-tumor efficacy and side effects due to changes in nutritional status. Patients with carcinoma in situ are prone to changes in nutritional status depending on the progression of the cancer and the age of the patient. We believe that the results of this study are important findings in predicting the course of treatment for cancer patients. The neutrophil -to-lymphocyte ratio (NLR) is useful for predicting the effectiveness of treatment with immune checkpoint inhibitors (ICIs) and immune-related adverse events (irAEs). Because a growing body of evidence has recently shown that the number of lymphocytes that comprise NLR fluctuates according to nutritional status, this study examined whether the usefulness of NLR varies in ICI treatment due to changes in nutritional status. A retrospective analysis was performed on 1234 patients who received ICI treatment for malignant tumors at our hospital. Progression-free survival (PFS) was significantly prolonged in patients with NLR < 4. Multivariate analysis revealed that the factors associated with the occurrence of irAE were NLR < 4 and the use of ipilimumab. However, when limited to cases with serum albumin levels <3.8 g/dL, lymphocyte counts significantly decreased, and the associations between NLR and PFS and between NLR and irAE occurrence disappeared. In contrast, when limited to the cases with serum albumin levels ≥3.8 g/dL, the associations remained, with significantly prolonged PFS and significantly increased irAE occurrence at NLR < 4. NLR may be a good predictive tool for PFS and irAE occurrence during ICI treatment when a good nutritional status is maintained. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the increasing incidence of HCC related to metabolism-associated steatotic liver disease (MASLD), viral hepatitis remains the major driver in liver carcinogenesis. Both HCV and HBV viruses have direct oncogenic properties that promote carcinogenesis, especially in active infections. The aim of this review is to summarize the viral mechanisms involved in liver cancer and to evaluate the changing incidence of HCC after antiviral treatment. Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28–30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Portal hypertension (PH) and hepatocellular carcinoma (HCC) are major complications of liver cirrhosis with a detrimental impact on patient outcomes that share common mechanisms. The incidence of PH in patients with advanced HCC is increasing due to the significant improvement of survival outcomes due to systemic therapies, so the management of the complications associated with clinically significant portal hypertension (such as variceal bleeding and ascites) becomes crucial. Moreover, the administration of systemic treatment presents challenges due to the drug-related bleeding risks. This review aims to elucidate the common pathophysiology of PH and HCC, with a specific focus on the influence of systemic therapies on PH. Moreover, we summarize the available evidence regarding PH management in HCC patients. Finally, we discuss potential new strategies for addressing the coexistence of CSPH and HCC. The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors originating in the liver and biliary system remain a significant health concern globally. The majority are cancers originating in liver cells known as hepatocellular carcinomas. Chronic liver disease including cirrhosis is a major risk factor for this type of cancer. For many patients, surgery is not an option due to the size of the tumor or the severity of liver disease. Established alternatives to surgery include chemoembolization, radioembolization, and ablation. These can be offered to a wide range of patients and produce similar outcomes to surgery for small tumors. A large majority of primary hepatobiliary tumors are hepatocellular carcinomas (HCC), with the remainer being cholangiocarcinoma. While surgical resection remains the gold standard treatment for hepatobiliary tumors, relatively few patients are operative candidates, and systemic treatments have limited effectiveness. Locoregional therapies offer significant promise in the management of HCC. Ablation and radioembolization may offer similar outcomes to surgery for early-stage hepatocellular carcinoma while radioembolization and chemoembolization are valuable in the management of advanced disease. There is significantly less evidence for the role of locoregional therapy in the treatment of cholangiocarcinoma, although it appears to be well tolerated. [ABSTRACT FROM AUTHOR]

Simple Summary: This study conducted a cost–utility analysis comparing tenofovir alafenamide (TAF) and entecavir (ETV) as first-line treatments for chronic hepatitis B. The TAF group exhibited an incremental cost effectiveness ratio (ICER) of −NT$23,878 per quality-adjusted life year (QALY) compared to the ETV group. Additionally, TAF demonstrated superior cost effectiveness, suggesting potential annual savings of over NT$500 million (approximately US$18 million). These findings support the consideration for expanding health insurance coverage for TAF in hepatitis B treatment. From the perspective of health economics, the evaluation of drug-related cost effectiveness and clinical utility is crucial. We conducted a cost–utility analysis of two first-line drugs, tenofovir alafenamide (TAF) and entecavir (ETV), in the treatment of chronic hepatitis B (CHB) patients. We performed inverse probability of treatment weighting (IPTW) to match the independent variables between the two treatment groups. The incremental cost effectiveness ratio (ICER) of the two treatment groups was simulated using a decision tree with the Markov annual-cycle model. A total of 54 patients treated with TAF and 98 with ETV from January 2016 to December 2020 were enrolled. The total medical cost in the TAF group was NT$76,098 less than that in the ETV group, and TAF demonstrated more effectiveness than ETV by 3.19 quality-adjusted life years (QALYs). When the time horizon was set at 30 years, the ICER of the TAF group compared with the ETV group was −NT$23,878 per QALY, suggesting more cost savings for TAF. Additionally, with the application of TAF, over NT$366 million (approximately US$12 million) can be saved annually. TAF demonstrates cheaper medical costs and more favorable clinical QALYs than ETV. To balance health insurance benefits and cost effectiveness, TAF is the optimal treatment for CHB. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the mortality rates and causes of death in patients with chronic hepatitis B (CHB) according to cirrhosis. Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver related causes, and mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years). Considering that mortality related to HCC decreased and mortality related to extrahepatic malignancies increased in the antiviral era of CHB, it will be important to develop customized strategies for aging CHB cohort to reduce mortality. (1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Research on the clinical impact of body composition parameters, such as myosteatosis, in patients with hepatocellular carcinoma (HCC) is limited. Our study examined the effects of computed tomography-based body composition measurements and traditional risk factors on the survival outcomes of sorafenib-treated HCC patients. Myosteatosis, evaluated using Hounsfield units, is associated with unfavorable survival outcomes, independent of traditional risk factors including vascular invasion, extrahepatic metastasis, and high alpha-fetoprotein levels. Two or more of these risk factors are associated with adverse outcomes. Thus, myosteatosis could serve as a prognostic factor in sorafenib-treated HCC patients. The role of body composition parameters in sorafenib-treated hepatocellular carcinoma (HCC) patients is still not fully elucidated. Here, we aimed to evaluate the impact of computed tomography (CT)-based body composition parameters on the survival of such patients. In this multicenter study, we analyzed the data of 245 sorafenib-treated HCC patients from January 2008 to December 2019. Sarcopenia, visceral obesity, and myosteatosis were defined by using cross-sectional CT images at the third lumbar vertebra level. The effects of these parameters on overall survival (OS) and progression-free survival (PFS) were evaluated. The median age was 67.0 years (interquartile range: 61.0–78.0 year), and 211 patients (86.1%) were male. The median OS and PFS were 7.9 months and 4.8 months, respectively. Vascular invasion (hazard ratio (HR), 1.727; 95% confidence interval (CI), 1.258–2.371; p = 0.001), extrahepatic metastasis (HR, 1.401; 95% CI, 1.028–1.908; p = 0.033), alpha-fetoprotein level > 200 ng/mL (HR, 1.559; 95% CI, 1.105–2.201; p = 0.012), and myosteatosis (HR, 1.814; 95% CI, 1.112–2.960; p = 0.017) were associated with OS. Patient mortality was significantly higher in the group with two or more risk factors than in the group with fewer risk factors. In conclusion, myosteatosis may be a novel prognostic CT-based radiological biomarker in sorafenib-treated HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic-dysfunction-associated steatotic liver disease (previously known as non-alcoholic fatty liver disease) is a term for a range of liver conditions in which excess fat builds up in the liver. This can eventually lead to liver inflammation, chronic liver disease and, in some cases, a form of liver cancer (hepatocellular carcinoma). This condition is increasing worldwide, with patients most at risk being overweight or obese or having type 2 diabetes. Hepatocellular carcinoma is seen in patients with this condition at different stages, and research is ongoing to identify why some patients appear to develop cancer at an earlier stage of liver disease than others, and how to best treat them, as there appear to be variations in how well patients respond depending on what caused the liver inflammation initially. Here, we summarise the research to date and discuss the potential rationale for what has been observed. Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an earlier stage of fibrosis compared to other causes of chronic liver disease, presenting challenges in how to risk-stratify patients to set up effective screening programmes. Therapeutic decision making for MASLD-HCC is also complicated by medical comorbidities and disease presentation at a later stage. The response to treatment, particularly immune checkpoint inhibitors, may vary by the aetiology of the disease, and, in the future, patient stratification will be key to optimizing the therapeutic pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-alcoholic fatty liver disease affects up to a quarter of the adult population in many developed and developing countries. This disease has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of hepatocarcinoma varies between patients with cirrhosis and noncirrhotic patients. In this review, HCC associated with non-alcoholic fatty liver disease will be described, considering its epidemiology, risk factors, and management, including preventive strategies and therapeutic approaches. Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the third main cause of cancer-related deaths worldwide, posing a significant global health problem. Surgical management offers the best chance of cure, making it crucial to accurately identify eligible patients and ensure optimal treatment. This paper discusses the ongoing debate regarding criteria expansion and highlights novel techniques for downstaging the tumor and optimizing the future liver remnant, aiming to enable patients to become eligible for surgical therapy. Moreover, the exploration of minimally invasive surgery, improved visualization techniques, and improved hemorrhage prevention techniques showcase promising advancements in HCC surgery that may reduce operative time, surgical stress, and morbidity. This review provides valuable updates for researchers and healthcare professionals, and the findings may shape future research directions, leading to improved outcomes and potentially expanding the pool of eligible patients for curative surgical interventions. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in the field. Treatment selection relies on the BCLC staging system, with surgical therapies primarily recommended for early-stage disease. Recent studies have shown that patients previously considered unresectable, such as those with portal vein tumor thrombus and uncomplicated portal hypertension, may benefit from hepatic resection. Minimally invasive surgery and improved visualization techniques are also explored, alongside new techniques for optimizing future liver remnant, ex vivo resection, and advancements in hemorrhage control. Liver transplantation criteria, particularly the long-standing Milan criteria, are critically examined. Alternative criteria proposed and tested in specific regions are presented. In the context of organ shortage, bridging therapy plays a critical role in preventing tumor progression and maintaining patients eligible for transplantation. Lastly, we explore emerging ablation modalities, comparing them with the current standard, radiofrequency ablation. In conclusion, this comprehensive review provides insights into recent trends and future prospects in the surgical management of HCC, highlighting areas that require further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic chemotherapies have revolutionized therapeutic paradigms for hepatocellular carcinoma (HCC) over the past decade. Various regimens have progressively become standard-of-care in clinical practice. However, there are no reports regarding the impact of multiple sequential therapies including immune-oncologic agents on their outcomes. This study investigated the change, over three time periods, in survival for patients with unresectable HCC, and the effects of sequential treatments on their outcomes. The results showed that the number of patients who received more than two lines steadily increased, and the overall survival significantly improved over time. Surprisingly, the 3-year survival rate increased from 12.1% in the early period to 44.4% for the most recent period. Using less than three lines, the non-objective response of the first line and extrahepatic metastasis were identified as the strongest drivers of a worse prognosis. Sequential treatment post-progression is valuable for prolonging survival. Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a type of primary liver malignancy. Worldwide, HCC is one of the leading causes of cancer-related deaths in adults. Liver cancer is currently the sixth most common cancer worldwide. Many changes in the epidemiology and underlying etiology of HCC have taken place in recent years. In industrialized countries, NAFLD/NASH has been playing an increasingly important role in the development of HCC. Despite major advances in the systemic medical management and availability of immunotherapy, no marked improvement in overall survival time has been found over the past decade. Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths and remains a major burden on healthcare systems worldwide. The incidence of HCC continues to rise globally, despite preventative efforts being made. Aims: This study aimed to investigate epidemiological changes observed in the etiology and survival outcomes of HCC patients at Klinikum Klagenfurt am Wörthersee between 2012 and 2023. Methods: This was a retrospective, single-center cohort study. Two time-periods (2012–2017 and 2018–2023) were created to enable comparison between the respective intervals. IBM SPSS was used to analyze statistical data. Results: More patients were diagnosed with HCC during the second time period (n = 128, n = 148). The median age of diagnosis was 72.5 years (SD 8.6). Patients were on average 2 years younger in the second time period compared to the first (p = 0.042). Alcohol remained the leading underlying etiology of HCC and no statistically significant change was seen over time (p = 0.353). Nevertheless, a clear upward trend in the number of NASH cases was evident over time (n = 15, n = 28, respectively). Nearly half of the patient population had a normal AFP (<7 µg/L) level at the time of diagnosis (n = 116, 42.6%). The survival time for HCC patients remained similar between time periods, with a median overall survival time of 20.5 months (95% CI 16.8–24.2, p = 0.841), despite improvements in management strategies and the availability of new systemic treatments. More advanced-stage HCC cases were documented in the second period (BCLC-C, n = 23 to n = 46, p = 0.051). An increased number of HCC patients without liver cirrhosis were identified during the second time period (n = 22, n= 47, respectively, p = 0.005). NASH was the most common underlying etiology in patients without liver cirrhosis (50%) compared to alcohol use in being the primary cause in cirrhotic patients (65%, p < 0.001). Conclusion: HCC continues to be an important health concern in our society. The number of HCC patients without liver cirrhosis is steadily increasing, with NAFLD/NASH, due to underlying lifestyle diseases playing an important etiological role. Continued efforts should be made to prevent HCC and to screen at-risk population groups. Preventative strategies and screening techniques should be adjusted in light of the changing epidemiological landscape of HCC, where more focus will have to be placed on detecting HCC in patients without underlying cirrhosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aimed to compare the outcomes of primary liver transplantation (PLT) and salvage liver transplantation (SLT) for hepatocellular carcinoma (HCC). The aim was to determine which approach offers better oncological outcomes and whether SLT after previous curative treatments such as liver resection (LR) or radiofrequency ablation (RFA) is as effective as PLT. Data analyzed from 141 patients who underwent liver transplantation for HCC found that PLT resulted in significantly longer disease-free survival, overall survival, and cancer-specific survival (CSS) compared to SLT. However, within the SLT group, there was no significant difference in DFS between SLT-LR and SLT-RFA. These findings suggest that PLT may provide superior long-term oncological outcomes, and a shift towards PLT rather than SLT may be worth considering. Further research is needed to confirm these results, but this study provides valuable insights for the research community regarding optimal transplantation strategies for HCC patients. Liver transplantation for hepatocellular carcinoma (HCC) may be performed ab initio, primary liver transplantation (PLT), or for HCC recurrence after previous treatments such as liver resection (LR) or radiofrequency ablation (RFA), salvage liver transplantation (SLT). The aim of this study was to evaluate the oncological outcomes of SLT vs. PLT. For this, a retrospective study was carried out on patients undergoing liver transplantation for HCC. The outcomes of PLT were compared with those of SLT. The primary outcome was disease-free survival (DFS). The secondary outcomes included overall survival (OS), cancer-specific survival (CSS), and major postoperative complications. A sub-analysis of SLT-LR and SLT-RFA was also performed. In total, 141 patients were included: 96 underwent PLT and 45 SLT. Among the SLT group, 25 patients had undergone previous LR while 20 had had RFA. There were no differences in the major postoperative complications. Unadjusted DFS was significantly longer in the PLT group (p = 0.02), as were OS (p = 0.025) and CSS (p = 0.001). There was no difference in DFS between PLT and SLT-LR groups, while a significant difference was found between the PLT and SLT-RFA groups (p = 0.035). Nonetheless, DFS was no different between the SLT-LR and SLT-RFA groups. PLT appears to offer superior long-term oncological outcomes to SLT. Both SLT-LR and SLT-RFA offer acceptable OS and CSS. Further prospective studies are needed to confirm these results, but the re-direction of grafts and transplant philosophy towards PLT rather than SLT may need to be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: The microbiome emerges as a crucial participant in gastric cancer (GC), a severe cancer burden worldwide. Current understanding has primarily focused on the impact of H. pylori and Epstein-Barr virus (EBV) on GC. Still, recent evidence suggests that other influences like microbiota and viral and fungal infections also contribute. This review highlights established factors like H. pylori and EBV and other microbes like Lactobacillus, Streptococcus, hepatitis B virus, hepatitis C virus, and Candida albicans. Improved understanding of the gut microbiome may lead to advanced diagnosis and therapies for GC. While previous research has primarily focused on the impact of H. pylori and Epstein-Barr virus (EBV), emerging evidence suggests that other microbial influences, including viral and fungal infections, may also contribute to gastric cancer (GC) development. The intricate interactions between these microbes and the host's immune response provide a more comprehensive understanding of gastric cancer pathogenesis, diagnosis, and treatment. The review highlights the roles of established players such as H. pylori and EBV and the potential impacts of gut bacteria, mainly Lactobacillus, Streptococcus, hepatitis B virus, hepatitis C virus, and fungi such as Candida albicans. Advanced sequencing technologies offer unprecedented insights into the complexities of the gastric microbiome, from microbial diversity to potential diagnostic applications. Furthermore, the review highlights the potential for advanced GC diagnosis and therapies through a better understanding of the gut microbiome. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of intrahepatic cholangiocarcinoma continues to rise, but survival remains dismal. Because malignancy often remains clinically indolent, treatment of the neoplasm becomes challenging. In advanced disease, locoregional therapies may be employed as a means of reducing toxicity and gaining disease control. A thorough understanding of these locoregional therapies will allow for optimal, individualized treatment. The intent of this review is to describethe role of intra-arterial therapies in the management of intrahepatic cholangiocarcinoma. Intrahepatic cholangiocarcinoma (ICC) is a rare disease with a rising incidence. While surgical resection is the only curative option, the disease process is often identified in advanced stages, as this malignancy often remains clinically silent in early development. Only one-third of patients are eligible for resection at the time of diagnosis. For patients who cannot undergo resection, intra-arterial therapies are reasonable palliative treatment options; in rare occasions, these may be bridging therapies, as well. The premise of bland embolization and most chemoembolization intra-arterial therapies is that the arterial supply of the tumor is occluded to induce tumor necrosis, while radioembolization utilizes the arterial flow of the tumor to deliver radiation therapy. In this review, we discuss the use of transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy for the treatment of ICC. Phase III randomized controlled clinical trials are difficult to tailor to this extremely rare and aggressive disease, but ultimately, further investigation should be pursued to define the patient population that will derive the greatest benefit from each modality. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) represents one of the main indications for liver transplantation. Over recent years, immune checkpoint inhibitor (ICI) therapy has improved its management, making patients with more advanced HCC potential candidates for transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize and discuss the preclinical and clinical data exploring the use of ICI prior to and after liver transplantation. We identify a three-month ideal minimum period between ICI and transplantation to decrease the risk of rejection. We also warn about its use after liver transplantation and speak about the need for more robust prospective data in the field. Immune checkpoint inhibitors (ICIs) have improved the management of patients with intermediate- and advanced-stage HCC, even making some of them potential candidates for liver transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize the key basic impact of immune checkpoints on HCC and liver transplantation. We analyze the available case reports and case series on the use of ICI therapy prior to and after liver transplantation. A three-month washout period is desirable between ICI therapy and liver transplantation to reduce the risk of acute rejection. Whenever possible, ICIs should be avoided after liver transplantation, and especially so early after a transplant. Globally, more robust prospective data in the field are required. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-alcoholic fatty liver disease (NAFLD) has become a significant public health concern, affecting over 30% of the population. The incidence of NAFLD-related hepatocellular carcinoma (HCC) has been rising, with unique pathogenic factors compared to other causes of HCC. Early detection is crucial for better outcomes. Currently, it is still unclear which subset of non-cirrhotic NAFLD-patients could benefit from HCC screening, and a better characterization and stratification of this population is required. This review underscores the potential of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential insights that could enable readers to enhance the personalized assessment of NAFLD-related HCC risk in a more systematic manner. Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach. [ABSTRACT FROM AUTHOR]

Simple Summary: It is still controversial whether tenofovir disoproxil fumarate (TDF) has a lower risk of hepatocellular carcinoma (HCC) development than entecavir (ETV) in patients with chronic hepatitis B (CHB). Furthermore, other antiviral treatment-related outcomes need to be evaluated between the two antivirals to provide essential information for clinical practice. Using a multicenter cohort of 4210 CHB patients, we demonstrated that ETV and TDF are comparable in terms of HCC development as well as mortality, incidence of liver-related outcome, extrahepatic malignancy or new decompensation events, and seroconversion rates. Patients treated with TDF experienced more side effects than those treated with ETV. The results of this study can be applied to the development of a personalized antiviral treatment strategy for CHB patients. Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) in preventing hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients; however, it remains controversial. This study aimed to conduct comprehensive comparisons between the two antivirals. CHB patients initially treated with ETV or TDF between 2012 and 2015 at 20 referral centers in Korea were included. The primary outcome was the cumulative incidence of HCC. The secondary outcomes included death or liver transplantation, liver-related outcome, extrahepatic malignancy, development of cirrhosis, decompensation events, complete virologic response (CVR), seroconversion rate, and safety. Baseline characteristics were balanced using the inverse probability of treatment weighting (IPTW). Overall, 4210 patients were enrolled: 1019 received ETV and 3191 received TDF. During the median follow-ups of 5.6 and 5.5 years, 86 and 232 cases of HCC were confirmed in the ETV and TDF groups, respectively. There was no difference in HCC incidence between the groups both before (p = 0.36) and after IPTW was applied (p = 0.81). Although the incidence of extrahepatic malignancy was significantly higher in the ETV group than in the TDF group before weighting (p = 0.02), no difference was confirmed after IPTW (p = 0.29). The cumulative incidence rates of death or liver transplantation, liver-related outcome, new cirrhosis development, and decompensation events were also comparable in the crude population (p = 0.24–0.91) and in the IPTW-adjusted population (p = 0.39–0.80). Both groups exhibited similar rates of CVR (ETV vs. TDF: 95.1% vs. 95.8%, p = 0.38), and negative conversion of hepatitis B e antigen (41.6% vs. 37.2%, p = 0.09) or surface antigen (2.8% vs. 1.9%, p = 0.10). Compared to the ETV group, more patients in the TDF group changed initial antivirals due to side effects, including decreased kidney function (n = 17), hypophosphatemia (n = 20), and osteoporosis (n = 18). In this large-scale multicenter study, ETV and TDF demonstrated comparable effectiveness across a broad range of outcomes in patients with treatment-naïve CHB during similar follow-up periods. [ABSTRACT FROM AUTHOR]

Simple Summary: Overview of the onset and progression of B-cell lymphoma under infection with the hepatitis C virus, and a review of the current status of biomarkers related to treatment efficacy and prognosis under the progress of DAA therapy. The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed. [ABSTRACT FROM AUTHOR]

Simple Summary: The correlation between Child–Pugh class (CP) and hepatocellular carcinoma (HCC) stage, and between HCC stage and sarcopenia is still not clear. Interleukin 6 (IL-6) promotes the growth of the HCC microenvironment and could promote sarcopenia. We investigated whether IL-6 is correlated with HCC stage and could represent a diagnostic marker for sarcopenia. IL-6 appears to be an effective biomarker for the diagnosis of advanced HCC patients. In addition, IL-6 could be considered a marker of cirrhotic HCC-related sarcopenia, suggesting further investigation with BIA- or CT-dedicated software. Hepatocellular carcinoma (HCC) is the major cause of liver-related death worldwide. Interleukin 6 (IL-6) promotes the growth of the HCC microenvironment. The correlation between Child–Pugh (CP) and HCC stage and between HCC stage and sarcopenia is still not clear. Our aim was to investigate whether IL-6 is correlated with HCC stage and could represent a diagnostic marker for sarcopenia. Ninety-three HCC cirrhotic patients in different stages, according to BCLC-2022 (stages A, B, and C), were enrolled. Anthropometric and biochemical parameters, comprehensive of IL-6, were collected. The skeletal muscle index (SMI) was measured using dedicated software on computer tomography (CT) images. IL-6 level was higher in advanced (BCLC C) compared to the early-intermediate (BCLC A-B) stages (21.4 vs. 7.7 pg/mL, p < 0.005). On multivariate analysis, IL-6 levels were statistically dependent on the degree of liver disease severity (CP score) and HCC stages (p = 0.001 and p = 0.044, respectively). Sarcopenic patients presented lower BMI (24.7 ± 5.3 vs. 28.5 ± 7.0), higher PMN/lymphocyte ratio (2.9 ± 2.4 vs. 2.3 ± 1.2) and increased values of log (IL-6) (1.3 ± 0.6 vs. 1.1 ± 0.3). Univariate logistic regression between sarcopenia and log (IL-6) showed a significant odds ratio (OR 14.88, p = 0.044) with an AUC of 0.72. IL-6 appears to be an effective biomarker for the diagnosis of advanced cirrhotic HCC. In addition, IL-6 could be considered a marker of cirrhotic HCC-related sarcopenia, suggesting further investigation with BIA- or CT-dedicated software. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of liver cancer is rising globally and is estimated to reach >1 million cases by 2025. Hepatocellular carcinoma (HCC) accounts for ~90% of the cases of liver cancer and is associated with a high healthcare expenditure and death rate. The most prominent risk factors for HCC include hepatitis B and C viral infections and non-alcoholic steatohepatitis associated with metabolic syndrome or type 2 diabetes. There has been a steady increase in the diagnosis of liver cancer in the Arabian Gulf region, possibly due to the high incidence of obesity, diabetes, and viral hepatitis. The diversity of the Gulf population makes it imperative to develop and implement effective screening programs for the early diagnosis and treatment of HCC. In this review, we discuss the available literature on the epidemiology, screening, and management of HCC in the Gulf region. The burden of hepatocellular carcinoma (HCC) is on the rise in the Gulf region, with most patients being diagnosed in the intermediate or advanced stages. Surgery is a treatment option for only a few, and the majority of patients receive either locoregional treatment (percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization [TACE], radioembolization, radiotherapy, or transarterial radioembolization) or systemic therapy (for those ineligible for locoregional treatments or who do not benefit from TACE). The recent emergence of novel immunotherapies such as immune checkpoint inhibitors has begun to change the landscape of systemic HCC treatment in the Gulf. The combination of atezolizumab and bevacizumab is currently the preferred first-line therapy in patients not at risk of bleeding. Additionally, the HIMALAYA trial has demonstrated the superiority of the durvalumab plus tremelimumab combination (STRIDE regimen) therapy in efficacy and safety compared with sorafenib in patients with unresectable HCC. However, there is a lack of data on post-progression treatment after first-line therapy with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab regimens, highlighting the need for better-designed studies for improved management of patients with unresectable HCC in the Gulf region. [ABSTRACT FROM AUTHOR]

Simple Summary: It is essential to consider the specific impact that conversion can have in a context where MILR is so positively determinant, that is, hepatocellular carcinoma. It has not yet been specifically investigated what impact conversion may have in case of advanced cirrhosis, which is the central risk factor for specific postoperative complications and the context in which the loss of minimally invasive benefits can be particularly harmful. This study showed that conversion in the setting of advanced cirrhosis can be associated with non-inferior outcomes compared to compensated cirrhosis, provided careful patient selection is applied. Difficulty scoring systems may help in identifying the most appropriate candidates to maintain satisfactory outcomes, even in case of conversion, and become helpful in multidisciplinary treatment decisions. Background: Minimally invasive liver resections (MILRs) in cirrhosis are at risk of conversion since cirrhosis and complexity, which can be estimated by scoring systems, are both independent factors for. We aimed to investigate the consequence of conversion of MILR for hepatocellular carcinoma in advanced cirrhosis. Methods: After retrospective review, MILRs for HCC were divided into preserved liver function (Cohort-A) and advanced cirrhosis cohorts (Cohort-B). Completed and converted MILRs were compared (Compl-A vs. Conv-A and Compl-B vs. Conv-B); then, converted patients were compared (Conv-A vs. Conv-B) as whole cohorts and after stratification for MILR difficulty using Iwate criteria. Results: 637 MILRs were studied (474 Cohort-A, 163 Cohort-B). Conv-A MILRs had worse outcomes than Compl-A: more blood loss; higher incidence of transfusions, morbidity, grade 2 complications, ascites, liver failure and longer hospitalization. Conv-B MILRs exhibited the same worse perioperative outcomes than Compl-B and also higher incidence of grade 1 complications. Conv-A and Conv-B outcomes of low difficulty MILRs resulted in similar perioperative outcomes, whereas the comparison of more difficult converted MILRs (intermediate/advanced/expert) resulted in several worse perioperative outcomes for patients with advanced cirrhosis. However, Conv-A and Conv-B outcomes were not significantly different in the whole cohort where "advanced/expert" MILRs were 33.1% and 5.5% in Cohort A and B. Conclusions: Conversion in the setting of advanced cirrhosis can be associated with non-inferior outcomes compared to compensated cirrhosis, provided careful patient selection is applied (patients elected to low difficulty MILRs). Difficulty scoring systems may help in identifying the most appropriate candidates. [ABSTRACT FROM AUTHOR]

Simple Summary: The CAM model is a promising alternative to murine models in terms of the 3Rs principles. However, its value for the noninvasive assessment of the biodistribution and accumulation of radiolabeled macromolecules by PET and MR imaging needs further evaluation. Thus, we analyzed the biodistribution and nonspecific tumor accumulation based on the EPR effect of 89Zr-labeled human serum albumin by PET and MRI in the xenograft CAM model. The results were correlated to in vivo results from the xenografted mouse model as the standard of reference. In both models, the xenografted TZM-bl and PC-3 tumors were visualized by PET imaging after 24 h. Furthermore, no significant differences were detected concerning the influx kinetics of 89Zr-labeled albumin into the two tumors. Therefore, the chicken model is a potential alternative to the animal model for initial PET studies on the characteristics of EPR-dependent target accumulation of radiolabeled macromolecules. Mouse models are commonly used to study the biodistribution of novel radioligands, but alternative models corresponding to the 3Rs principles, such as the chorioallantoic membrane (CAM) model, are highly required. While there are promising data from the CAM model regarding target-specific radiolabeled compounds, its utility for assessing macromolecule biodistribution and analyzing the EPR effect remains to demonstrated. Using 89Zr-labeled human serum albumin, the accumulation of nontarget-specific macromolecules in CAM and mouse xenograft models was studied using PET and MRI. Therefore, the radioligand [89Zr]Zr-DFO-HSA was analyzed in both chicken embryos (n = 5) and SCID mice (n = 4), each with TZM-bl and PC-3 tumor entities. Dynamic PET and anatomical MRI, as well as ex vivo biodistribution analyses, were performed to assess ligand distribution over 24 h. Histological staining and autoradiography verified the intratumoral accumulation. The tumors were successfully visualized for CAM and mouse models by PET, and the albumin influx from the blood into the respective tumors did not differ significantly. The accumulation and retention of HSA in tumors due to the EPR effect was demonstrated for both models. These results highlight that the CAM model is a potential alternative to the mouse model for initial studies with novel radiolabeled macromolecules with respect to the 3Rs principles. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides a comprehensive summary of the literature published thus far to highlight the prognostic significance of serum albumin (ALB) level and various ALB-based mono- and combination biomarkers in predicting the prognosis of patients with hepatocellular carcinoma (HCC) treated with different therapies. Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of branched-chain amino acid (BCAA) supplements in patients with cirrhosis and liver cancer has been investigated by numerous studies, with multiple reported benefits including improvements in survival rates and hepatic functional reserve. Although locoregional therapies for liver cancer have gained momentum over the past few decades, the potential role of BCAA supplementation in conjunction with these procedures has not yet been elucidated. In this study, we systematically analyze articles investigating the role of BCAA supplementation in patients with hepatocellular carcinoma undergoing interventional radiology procedures. Our systematic review and meta-analysis reveals that BCAA supplementation is associated with significantly higher post-treatment albumin levels, which may support their use in combination with locoregional treatments for HCC. There is a tendency for improved overall survival, mortality and recurrence rates; however, current data are insufficient to support additional benefits. Background: Branched-chain amino acid (BCAA) supplementation has been linked with favorable outcomes in patients undergoing surgical or palliative treatments for hepatocellular carcinoma (HCC). To date, there has been no systematic review investigating the value of BCAA supplementation in HCC patients undergoing locoregional therapies. Materials and Methods: A systematic search of the literature was performed across five databases/registries using a detailed search algorithm according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The search was conducted on 23 March 2022. Results: Sixteen studies with a total of 1594 patients were analyzed. Most patients were male (64.6%) with a mean age of 68.2 ± 4.1 years, Child–Pugh score A (67.9%) and stage II disease (40.0%). Locoregional therapy consisted of radiofrequency ablation, transarterial chemoembolization or hepatic artery infusion chemotherapy. BCAA supplementation was in the form of BCAA granules or BCAA-enriched nutrient. Most studies reported improved albumin levels, non-protein respiratory quotient and quality of life in the BCAA group. Results pertaining to other outcomes including overall survival, recurrence rate, and Child–Pugh score were variable. Meta-analysis showed significantly higher levels of post-treatment serum albumin in the BCAA group (SMD = 0.54, 95% CI 0.20–0.87) but no significant differences in mortality rate (RR = 0.81, 95% CI: 0.65–1.02) and AST (SMD = −0.13, 95% CI: −0.43–0.18). Conclusion: BCAA supplementation is associated with higher post-treatment albumin levels. There are currently not sufficient data to support additional benefits. Further studies are needed to elucidate their value. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common form of liver cancer with a low survival rate worldwide. The number of new cases and deaths from HCC is increasing globally, thus, we investigated the clinical conditions and survival of patients in Ethiopia to understand the extent of the problem and develop prevention and control strategies. Our analysis showed that hepatitis B virus (HBV) is an important risk factor associated with HCC. Half of the patients involved in our study survived only for about 5 months after their diagnosis. Patients who had been given antiviral therapy for an HBV infection survived longer than those who were not treated. By the year 2040, there will be a two-fold increase in the number of cases and deaths from HCC in Ethiopia. Therefore, since HBV is a major underlying factor for HCC, it is crucial to increase the vaccination coverage and access to antiviral drugs against hepatitis to lessen the devastation. (1) Background: Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally, killing over 700,000 people each year. Despite the rising incidence and mortality rates of HCC in Ethiopia, only few single-centered studies have been conducted; therefore, we aimed to explore the clinicopathological characteristics and survival of patients with HCC in multicenter settings. (2) Methods: We conducted a retrospective analysis of 369 patients with confirmed HCC diagnosed between 2016 and 2021. The survival of patients weas determined using the Kaplan–Meier method, and hazard ratios of the prognostic factors were estimated in Cox proportional hazard models. (3) Results: Majority patients were male (67%) and had a mean age of 52.0 ± 15.6 years. The majority of patients (87%) had a large tumor size (>5 cm) at diagnosis and presented with an advanced-stage condition. Cirrhosis (58%) and viral hepatitis (46.5%) were the main risk factors associated with HCC. The median overall survival was 141 days (95% CI: 117–165). Patients who took antivirals for HBV had a higher survival benefit compared to the untreated group (469 vs. 104 days; p < 0.001). The risk of death was 12 times higher in patients with Barcelona Clinic Liver Cancer-D (BCLC-D) terminal stage HCC compared to patients with an early stage (BCLC-A) HCC. The stage of HCC and treatment against HBV are the most significant survival predictors. (4) Conclusions: The overall survival of HCC patients in Ethiopia is poor. Cirrhosis and viral hepatitis are the primary risk factors linked with HCC. Patients who received antiviral therapy for HBV had a better survival outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is an aggressive human cancer and is caused as consequences of chronic liver diseases. Although HCC is more common in patients with cirrhosis, there is increasing evidence that this cancer may develop in the setting of noncirrhotic nonalcoholic steatohepatitis (NASH), even simple hepatic steatosis may progress to carcinogenesis development. NASH is associated with obesity, hyperlipidemia, insulin resistance, and type 2 diabetes (T2D), which are becoming emerging risk factors for the development of HCC, as well as for cardiovascular disease. In this review, we discuss the current molecular data supporting the link between HCC and NASH, with a focus on metabolic alterations, genetic and epigenetic drivers, including current therapeutic strategies for NASH and HCC prevention and treatment. Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of magnetic resonance imaging (MRI) for liver radiation treatment planning, adaptation and response assessment is an active area of clinical research. Particularly, research on the use of functional MRI to optimise radiation dose distribution and perform mid-treatment adaptation has grown in recent times. The aim of this review is to provide the current state of evidence on the most relevant functional MRI methods being investigated for liver radiation therapy applications aimed at the development of individualised, adaptive treatments for patients with liver cancer. Stereotactic body radiation therapy (SBRT) is an emerging treatment for liver cancers whereby large doses of radiation can be delivered precisely to target lesions in 3–5 fractions. The target dose is limited by the dose that can be safely delivered to the non-tumour liver, which depends on the baseline liver functional reserve. Current liver SBRT guidelines assume uniform liver function in the non-tumour liver. However, the assumption of uniform liver function is false in liver disease due to the presence of cirrhosis, damage due to previous chemo- or ablative therapies or irradiation, and fatty liver disease. Anatomical information from magnetic resonance imaging (MRI) is increasingly being used for SBRT planning. While its current use is limited to the identification of target location and size, functional MRI techniques also offer the ability to quantify and spatially map liver tissue microstructure and function. This review summarises and discusses the advantages offered by functional MRI methods for SBRT treatment planning and the potential for adaptive SBRT workflows. [ABSTRACT FROM AUTHOR]

Simple Summary: The liver maximum capacity test (LiMAx) represents a useful tool to estimate liver function in patients with chronic liver disease. LiMAx results correlate with short-term survival in patients with early stage HCC after transarterial chemo- or radioembolization. Low LiMAx levels might enable the identification of patients with poor hepatic function and decreased short-term survival after treatment. Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are recommended to treat patients with early or intermediate hepatocellular carcinoma (HCC). The liver maximum capacity test (LiMAx) has been supposed to predict the risk of post-interventional liver failure. We investigated the correlation of LiMAx with short-term survival as primary endpoint and the occurrence of adverse events after therapy as secondary endpoint. Our study cohort prospectively included 69 patients receiving TACE (n = 57) or TARE (n = 12). LiMAx test and serological analyses were performed on the day before and 4 weeks after treatment. Hepatic and extrahepatic complications were monitored for 4 weeks. The LiMAx results were not associated with altered liver function and the occurrence of adverse events. The survival rates of patients with BCLC A with LiMAx ≤ 150 μg/kg/h were lower after 30 days (75.0 ± 15.3% vs. 100%, p = 0.011), 90 days (62.5 ± 17.7% vs. 95.8 ± 4.1%, p = 0.011) and 180 days (50.0 ± 17.7% vs. 95.8 ± 4.1%, p = 0.001) compared to those with higher LiMAx levels. The LiMAx test is not suitable to predict liver function abnormalities or the occurrence of complications 4 weeks after therapy but enables the identification of patients with early stage HCC and reduced short-term survival after treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Intermittent fasting has the potential to beneficially act upon several pathways that are involved in hepato-cellular carcinoma pathogenesis. Especially among non-alcoholic steatohepatitis patients (NASH), intermittent fasting could effectively reduce the chance of progression to advanced liver disease and hepatocellular carcinoma. Although intermittent fasting activates similar pathways among those without NASH, the altered metabolism in cirrhotic patients may make them exceptionally vulnerable to malnutrition and increase the risk of liver-related adverse events. Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide, is a multistep process that usually develops in the background of cirrhosis, but also in a non-cirrhotic state in patients with non-alcoholic fatty liver disease (NAFLD) or viral hepatis. Emerging evidence suggests that intermittent fasting can reduce the risk of cancer development and could improve response and tolerance to treatment through the metabolic and hormonal adaptations induced by the low energy availability that finally impairs cancer cells' adaptability, survival and growth. The current review will outline the beneficial effects of fasting in NAFLD/NASH patients and the possible mechanisms that can prevent HCC development, including circadian clock re-synchronization, with a special focus on the possibility of applying this dietary intervention to cirrhotic patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Mac-2 binding protein glycosylation isomer (M2BPGi) has not been used in a risk score to predict hepatocellular carcinoma (HCC). We enrolled 1003 cirrhotic patients receiving entecavir or tenofovir monotherapy to construct an HCC risk score. The ASPAM-B score, based on age, sex, platelet count, AFP and M2BPGi at 12 months of treatment, was developed. The ASPAM-B scores accurately classified patients into low (0–3.5), medium (4–7) and high (>7) risk (p < 0.001). The values of AUROC for predicting 3-, 5- and 9-year risks of HCC were 0.742, 0.728 and 0.719, respectively. All AUROCs between the ASPAM-B and APA-B, PAGE-B, RWS-HCC and THRI scores at 3–9 years were significantly different. The M2BPGi-based risk model exhibited good discriminant function in predicting HCC in cirrhotic patients who received antiviral treatment. Mac-2 binding protein glycosylation isomer (M2BPGi) has not been used in a risk score to predict hepatocellular carcinoma (HCC). We enrolled 1003 patients with chronic hepatitis B and cirrhosis receiving entecavir or tenofovir therapy for more than12 months to construct an HCC risk score. In the development cohort, Cox regression analysis identified male gender, age, platelet count, AFP and M2BPGi levels at 12 months of treatment as independent risk factors of HCC. We developed the HCC risk prediction model, the ASPAM-B score, based on age, sex, platelet count, AFP and M2BPGi levels at 12 months of treatment, with the total scores ranging from 0 to 11.5. This risk model accurately classified patients into low (0–3.5), medium (4–7), and high (>7) risk in the development and validation groups (p < 0.001). The areas under the receiver operating characteristic curve (AUROC) of 3-, 5- and 9-year risks of HCC were 0.742, 0.728 and 0.719, respectively, in the development cohort. All AUROC between the ASPAM-B and APA-B, PAGE-B, RWS-HCC and THRI scores at 3–9 years were significantly different. The M2BPGi-based risk model exhibited good discriminant function in predicting HCC in cirrhotic patients who received long-term antiviral treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic liver diseases commonly cause severe scarring of the liver (cirrhosis) and liver cancer. The eventual progression of this scarring process to liver cancer is influenced by a variety of factors, including inflammatory cytokines (soluble mediators of cell communication). In order to increase our understanding of these mediators we studied them in the blood of patients with hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. We studied more than a 100 cytokines in up to 400 patients. We discovered that patients with cirrhosis had a vast upregulation of a wide variety of immune mediators, which stimulated inflammation and were linked with tumor-promoting roles. In contrast to prevailing assumptions, each type of underlying liver disease exhibited a unique immune mediator profile in blood, which is likely to impact how we will study these markers in the future. Patients with HBV cirrhosis had the largest number of upregulated inflammation-inducing mediators, compared to HCV, ALD and NAFLD. Next, we related blood immune mediator levels with liver cancer. To do so, we studied cytokine profiles in patients with small tumors, thus, those qualified for surgical curative strategies. We observed unique sets of cytokines in serum in each liver cancer group, indicating a role for these mediators in detecting liver cancer. In conclusion, our findings underscore the impact of different liver diseases on circulating immune mediators. Future studies that aim to study them as diagnostic tools will need to correct for this important effect accordingly. Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease driven in part by the rising obesity epidemic. Obesity causes HCC by initiating and progressing fatty liver disease. As such, weight reduction with the intention to treat fatty liver disease appears ideal for the primary prevention of HCC, but evidence is limited. This review covers recent advances in the treatment and management of obesity and fatty liver disease as it pertains to HCC risk and prevention. We conclude that combinatorial lifestyle, behavioral, medical, and surgical therapies that maximize whole body and liver fat reduction have the greatest potential to prevent HCC; however, prospective studies are required to demonstrate effectiveness. Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal. [ABSTRACT FROM AUTHOR]

Simple Summary: An increase in serum bile acids can generate a chronic inflammatory state and has been associated with the risk of developing hepatobiliary cancers. Progressive familial intrahepatic cholestasis, other forms of inherited cholestasis, and microbiota dysbiosis lead to an increase in bile acids in the blood, liver and gut. However, mutations in the genes responsible for cholestatic disorders can also be accountable for non-progressive and clinically mild phenotypes. This review summarizes the relationship between inherited cholestasis, bile acids, gut microbiota and the risk occurrence of hepatobiliary tumours. The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma is the most common liver cancer, leading to approximately 700,000 deaths worldwide and 30,000 deaths in the United States every year. Transarterial therapies play a crucial role in the management of these patients, with significant development in techniques over the last couple of decades. The aim of this review is to discuss the different types of transarterial therapies with regards to the pre-procedure, procedural, and post-procedural patient management, along with giving a review of evidence from the literature. Image-guided locoregional therapies play a crucial role in the management of patients with hepatocellular carcinoma (HCC). Transarterial therapies consist of a group of catheter-based treatments where embolic agents are delivered directly into the tumor via their supplying arteries. Some of the transarterial therapies available include bland embolization (TAE), transarterial chemoembolization (TACE), drug-eluting beads–transarterial chemoembolization (DEB–TACE), selective internal radioembolization therapy (SIRT), and hepatic artery infusion (HAI). This article provides a review of pre-procedural, intra-procedural, and post-procedural aspects of each therapy, along with a review of the literature. Newer embolotherapy options and future directions are also briefly discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Radical treatment combined with synchronous splenectomy has recently emerged as an effective therapy for patients with hepatocellular carcinoma (HCC), in the setting of portal hypertension secondary to liver cirrhosis, but its survival benefits remain to be elucidated. We retrospectively analyzed a longitudinal cohort of 96 patients receiving HCC radical treatment combined with splenectomy and a control group comprising 42 patients receiving radical treatment alone, comparing the oncological outcomes of the synchronous splenectomy for the two subgroups. Our analysis highlighted better recurrence-free survival (RFS), particularly in stage T1 patients. Cox multivariate analysis showed that preoperative irregular anti-viral therapy, Child-Pugh grade B liver function, vascular invasion, and microvascular invasion (MVI) were independent risk factors for early postoperative RFS (within 2 years), and preoperative irregular anti-viral therapy and vascular invasion were independent risk factors for 5-year overall survival (OS). Background: The survival benefits of radical treatment (resection or radiofrequency ablation) combined with splenectomy for primary hepatocellular carcinoma (HCC) in patients with liver-cirrhosis-associated portal hypertension (PH) remain to be clarified. Methods: 96 patients undertaking HCC radical treatment combined with splenectomy (HS group) were retrospectively analyzed, 48 of whom belonged to HCC stage T1 (HSS group). Another 42 patients at stage T1 with PH who received hepatectomy (or radiofrequency ablation) alone (HA group) during the same period served as the control group. Recurrence-free survival (RFS) and overall survival (OS) were compared at each time point between the HSS and HA group. The risk factors affecting early RFS and OS were confirmed through COX multivariate analysis. Results: The median RFS was 22.3 months and the mean median OS was 46 months in the HS group. As such, 1-year, 2-year, 3-year, and 5-year RFS rates in the HSS and HA group were 95% and 81% (p = 0.041), 81% and 67% (p = 0.05), 64% and 62% (p = 1.00), and 29% and 45% (p = 0.10), respectively. Further, 1-year, 3-year, and 5-year OS rates in the HSS and HA group were 98% and 98% (p = 1.00), 79% and 88% (p = 0.50), and 60% and 64% (p = 0.61), respectively. Cox multivariate analysis showed that preoperative irregular anti-viral therapy, Child-Pugh grade B liver function, vascular invasion, and microvascular invasion (MVI) were independent risk factors for early postoperative RFS (within 2 years), and preoperative irregular anti-viral therapy and vascular invasion were independent risk factors for 5-year OS. Conclusions: Radical treatment of HCC combined with synchronous splenectomy, especially applicable to patients with Child-Pugh grade A liver function, can significantly improve early postoperative RFS in patients with stage T1 HCC and liver-cirrhosis-associated portal hypertension, but fail to improve OS. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver transplantation (LT) is considered the only curative therapeutic option for early, unresectable, and unablatable hepatocellular carcinoma (HCC), particularly in the setting of chronic liver disease. The criteria for selecting patients for LT for HCC have evolved since the description of the Milan Criteria by Professor Mazzaferro. In Australia and New Zealand (ANZ), the choice of criteria has expanded over the last 24 years from the Milan to the University of California San Francisco (UCSF) criteria and, more recently, to Metroticket 2.0 (MT2). This study analysed the overall and HCC-related deaths following LT in ANZ through the last 24 years to clarify the impact of the expansion of these criteria. Our data confirm that overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, the expansion of criteria to MT2 is justifiable. Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997–2006) and the UCSF era (2007–July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable. [ABSTRACT FROM AUTHOR]

Simple Summary: The optimal management of non-metastatic hepatocellular carcinoma (HCC) remains debated. The association between HCC and cirrhosis influences prognosis and therapeutic choices between curative and palliative treatments. The goal of our retrospective study was to evaluate the cost-effectiveness of the extended use of ablation for the treatment of HCC with cirrhosis in an expert ablation center when compared to the non-extended use of ablation in equivalent tertiary care centers. In a propensity-score matched cohort of 532 patients with naïve HCC, the extended use of ablation led to better compliance with the Barcelona Clinic Liver Classification (BCLC) guidelines (80% vs. 67%) and was more effective and less expensive than the non-extended use of ablation strategy, particularly at an earlier stage of the disease. The shift from curative to palliative treatments was noted in a considerable percentage of patients; therefore, this needs to be redefined as the wide choice of ablation techniques and technical advances in imaging guidance increase the curative options available to treat a maximum of patients with HCC. Background: To evaluate the cost-effectiveness of the extended use of ablation for the treatment of hepatocellular carcinoma (HCC) with cirrhosis in an expert ablation center when compared to the non-extended use of ablation in equivalent tertiary care centers. Methods: Consecutive cirrhotic patients with non-metastatic HCC, no prior treatment, and referred to three tertiary care centers between 2012 and 2016 were retrospectively identified. The Bondy group, including all of the patients treated at Jean Verdier Hospital, where the extended use of ablation is routinely performed, was compared to the standard of care (SOC) group, including all of the patients treated at the Beaujon and Mondor Hospitals, using propensity score matching. A cost-effectiveness analysis was carried out from the perspective of French health insurance using a Markov model on a lifetime horizon. Results: 532 patients were matched. The Bondy group led to incremental discounted lifetime effects of 0.8 life-years gained (LYG) (95% confidence interval: 0.4, 1.3) and a decrease in lifetime costs of EUR 7288 (USD 8016) (95% confidence interval: EUR 5730 [USD 6303], EUR 10,620 [USD 11,682]) per patient, compared with the SOC group, resulting in a dominant mean incremental cost-effectiveness ratio (ICER). A compliance with the Barcelona Clinic Liver Classification (BCLC) guidelines for earlier stage contributed to the greater part of the ICER. Conclusion: The extended use of ablation in cirrhotic patients with HCC was more effective and less expensive than the non-extended use of the ablation strategy. [ABSTRACT FROM AUTHOR]