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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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are the preferred anti-viral agents used as first-line treatments for chronic hepatitis B. Despite many meta-analyses being conducted, it is still not clear whether TDF is more effective than ETV at reducing the risk of HCC due to the inconsistent statistical methodologies employed in previous observational studies. To reduce heterogeneity, we analysed only hospital cohort data studies with anti-viral naive patients. Additionally, unlike previous studies, we conducted subgroup analyses with enrolment criteria and socioeconomic factors that could not be corrected with statistical techniques. There is no difference between the two drugs in terms of reducing the risk of HCC in a pooled analysis of PS-matched patients. In the subgroup analysis, if there was interval of over three years from the start point of patient enrolment, we found that TDF was associated with significantly lower HCC risk. This result will provide new perspectives for future research. Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are the preferred anti-viral agents used as first-line treatments for chronic hepatitis B (CHB). However, the efficacy of these agents in reducing the incidence of hepatocellular carcinoma (HCC) remains unclear. We conducted this meta-analysis to assess the efficacy of anti-viral agent on preventing HCC in CHB. Two investigators independently searched all relevant studies that examined the efficacy of anti-viral agent for preventing HCC using MEDLINE, Embase, and Cochrane Library databases through August 2021. The extracted data were analysed using a random-effects meta-analysis model based on the inverse-variance method (DerSimonian–Laird) and expressed as hazard ratio (HR) and 95% confidence interval (95% CI). We included 19 retrospective studies in the analysis. Although there was substantial heterogeneity between the studies, the overall pooled HR indicated that TDF significantly lowered the risk of HCC (HR: 0.72, 95% CI: 0.58–0.90, I2 = 66.29%). However, the pooled analysis of propensity score (PS)-matched subpopulations showed no significant differences (HR, 0.83; 95% CI, 0.65–1.06; I2 = 52.30%) between TDF and ETV. In a subgroup analysis, an interval of over three years in the start point of patient enrolment and excluding alcoholic liver disease patients significantly lowered the HCC risk associated with TDF. In conclusion, TDF may be more effective than ETV at reducing HCC incidence in treatment-naive CHB patients, but this effect was not consistent in the PS-matched subpopulation that reduced heterogeneity. As a result of subgroup analysis, the conflicting findings of previous studies may result from heterogeneous inclusion criteria. Further studies with standardised protocols are needed to reduce the residual heterogeneity. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we developed novel bioresponsive HSA-binding nanoparticles co-delivering paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba) for the combined photo- and chemo-treatment of breast cancer. Extensive structural characterization allowed us to evaluate the size, stability and morphology of nanoparticles, which exhibited sustained and controlled drug release under the distinctive redox conditions of the tumor environment. HSA-binding PTX/Pba nanoparticles showed higher Pba uptake in human breast cancer cells and a synergistic antitumor effect upon light irradiation. Preliminary in vivo experiments using low drug doses showed the potential of our bioresponsive nanoparticles to reduce the primary tumor mass while diminishing the number of lung metastases, thus suggesting the effectiveness of this novel approach. Exploiting the tumor environment features (EPR effect, elevated glutathione, reactive oxygen species levels) might allow attaining a selective and responsive carrier capable of improving the therapeutic outcome. To this purpose, the in situ covalent binding of drugs and nanoparticles to circulating human serum albumin (HSA) might represent a pioneering approach to achieve an effective strategy. This study describes the synthesis, in vitro and in vivo evaluation of bioresponsive HSA-binding nanoparticles (MAL-PTX2S@Pba), co-delivering two different paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba), for the combined photo- and chemo-treatment of breast cancer. Stable and reproducible MAL-PTX2S@Pba nanoparticles with an average diameter of 82 nm and a PTX/Pba molar ratio of 2.5 were obtained by nanoprecipitation. The in vitro 2D combination experiments revealed that MAL-PTX2S@Pba treatment induces a strong inhibition of cell viability of MDA-MB-231, MCF7 and 4T1 cell lines, whereas 3D experiments displayed different trends: while MAL-PTX2S@Pba effectiveness was confirmed against MDA-MB-231 spheroids, the 4T1 model exhibited marked resistance. Lastly, despite using a low PTX-PDT regimen (e.g., 8.16 mg/Kg PTX and 2.34 mg/Kg Pba), our formulation showed to foster primary tumor reduction and curb lung metastases growth in 4T1 tumor-bearing mice, thus setting the basis for further preclinical validations. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver transplantation is the first-line treatment for patients diagnosed with unresectable early stage hepatocellular carcinoma in the setting of cirrhosis. Patients with tumours beyond this stage may benefit from liver transplantation if their tumours are successfully downstaged. Loco-regional therapies, including ablation, trans-arterial and radiotherapeutical approaches are commonly used to treat patients before transplant, with the aim of reducing the risk of drop off from the waiting list due to tumor progression for patients within transplantation criteria as well as decreasing tumour dimension to meet acceptable criteria. In this review, current evidence on the safety, efficacy and utility of locoregional therapies as neoadjuvant therapies before liver transplantation are summarized. Liver transplantation (LT) is the first-line treatment for patients diagnosed with unresectable early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. It is well known that HCC patients within the Milan criteria (solitary tumour ≤ 5 cm or ≤3 tumours, each <3 cm) could undergo LT with excellent results. However, there is a growing tendency to enlarge inclusion criteria since the Milan criteria are nowadays considered too restrictive and may exclude patients who would benefit from LT. On the other hand, there is a persistent shortage of donor organs. In this scenario, there is consensus about the role of loco-regional therapy (LRT) during the waiting list to select patients who would benefit more from LT, reducing the risk of drop off from the waiting list as well as decreasing tumour dimension to meet acceptable criteria for LT. In this review, current evidence on the safety, efficacy and utility of LRTs as neoadjuvant therapies before LT are summarized. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatitis C virus (HCV) is the major factor responsible for hepatocellular carcinoma (HCC). Currently available treatments for HCV infection are short, simple, effective and safe. Long-term monitoring of patients is essential to demonstrate the efficacy of antiviral therapy, including the risk of HCC development. Since highly effective treatment options only became available in the middle of the past decade, we evaluated patients treated during this period five years after treatment. We have shown that the risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful treatment. Therefore, longer follow-up is necessary to assess the long-term risk of developing HCC, especially in patients with cirrhosis. (1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2–3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of hepatocellular carcinoma (HCC) has not been well-controlled, even after the elimination of hepatitis C virus (HCV), especially for those with cirrhosis or of high-age. Fibrosis-related biomarkers have been recognized as useful predictors for the development of HCC; however, there are few analyses of the HCC incidence for the various regimens with direct-acting antivirals (DAA). We found that DAA treatment with sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, was not associated with the development of de novo HCC within five years by propensity score matched analysis. Moreover, the distribution of the early stage of HCC (the Barcelona Clinic Liver Cancer stage 0/A) was similar for all treatment regimens, irrespective of the use of sofosbuvir. Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75–2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98–4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC. [ABSTRACT FROM AUTHOR]

Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; p = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio [AHR], 2.10; p < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; p < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population. [ABSTRACT FROM AUTHOR]

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects' post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management. [ABSTRACT FROM AUTHOR]

Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with p < 0.0001 by using the log-rank test (noncirrhotic: the highest risk (n = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107–318.7; p <0.0001) and cirrhotic: the highest risk (n = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033–18.22; p < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, including small-molecule kinase inhibitors such as sorafenib, lenvatinib, cabozantinib, regorafenib, and monoclonal antibodies like ramucirumab, nivolumab, and pembrolizumab. Ideal use of these agents in clinics has improved the long-term outcome of patients with advanced HCC as well as introduced unique toxicities that can affect quality of life. These toxicities usually are thought to be partially related to cirrhosis, a major risk factor for the development of HCC and a pathophysiological barrier complicating the optimal delivery of antineoplastic therapy. Additionally, side effects of medications together with advanced HCC symptoms not only decrease quality of life, but also cause treatment interruptions and dose reductions that can potentially decrease efficacy. Physicians caring for patients with advanced HCC are called to optimally manage HCC along with cirrhosis in order to prolong life while at the same time preserve the quality of life. In this review, we aimed to summarize outcomes and quality of life with the use of modern systemic treatments in advanced HCC and provide a physician reference for treatment toxicity and cirrhosis management. [ABSTRACT FROM AUTHOR]