Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.

Since many people die of either cancers or cardiovascular diseases worldwide, it is important to find the clinical pitfall that provokes cardiovascular diseases and cancer overall. Since metabolic syndrome (MetS) is largely linked to cardiovascular diseases, we have come to consider that MetS, even in its early state, may prime the occurrence of cancers overall. Indeed, the importance of MetS in causing pancreatic cancer has been proved using our large medical database. We analyzed Japanese healthcare and clinical data in 2005, who were followed up until 2020 and we examined the incidence of major cancers. At the enrollment, we examined the presence or absence of MetS judged by either Japanese criteria or NCEP/ATPIII. Of 2.7 million subjects without missing data, 102,930; 200,231; 237,420; 63,435; 76,172; and 2,422 subjects suffered lung, stomach, colon, liver and prostate cancer, respectively, and myelogenous leukemia during follow-up. MetS, defined by Japanese criteria, increased (p < 0.005 each) the incidence of cancer with a hazard ratio (HR) of 1.03-1.47 for lung, stomach, colon, liver, prostate cancers, and myelogenous leukemia. According to Japanese criteria, cancer incidence in the pre-stage MetS group was comparable to the MetS group. The results were almost identical when we defined MetS using NCEP ATP III. Taken together, we conclude that MetS is linked to majority of cancers.

Biliary tract cancer (BTC) is becoming more common worldwide, with geographic differences in incidence and risk factors. In Europe, BTC may be associated with primary sclerosing cholangitis, lithiasis, and liver cirrhosis, but is more frequently observed as a sporadic disease. BTC increasingly affects patients under 60 years, resulting in a significant social and economic burden. Early diagnosis remains challenging due to vague symptoms in 50% of patients with BTC, and lack of specific biomarkers, resulting in late presentation and poor prognosis. The identification of patients at increased risk and reliable biomarkers require collaborative efforts to make faster progress. This Series paper highlights the disparities in access to diagnostic tools and multidisciplinary care in Europe, particularly in economically disadvantaged regions, while identifying priority areas for improvement. Addressing these inequities requires harmonised guidelines, accelerated pathways to curative treatments, and improved awareness among healthcare professionals and the public. Multidisciplinary teams (MDTs) are crucial for the diagnosis of BTC and for improving patient outcomes, yet inconsistencies exist in their implementation not only between different countries, but also between different centres within a country. Collaboration and standardisation of diagnostic and treatment protocols across Europe are essential to effectively address the management of patients with BTC.

Hepatocellular carcinoma (HCC) disproportionately affects Hispanic persons with higher age-specific incidence and increased mortality rates compared to non-Hispanic Whites. These high rates of incidence and mortality may be explained by the variation in risk factors. Given the high prevalence of type 2 diabetes mellitus (DM) among the Hispanic population, we aimed to assess the risk and prognosis of HCC in Mexican Americans with type 2 DM with consideration of treatment for DM.

A case-control study of 241 Mexican American HCC patients and 500 healthy controls in Texas was conducted. Multivariable logistic regression analysis was performed to determine the association between type 2 DM and HCC risk while adjusting for other risk factors. Also, a restricted analysis of patients with type 2 DM was conducted to determine the effects of age at onset and duration of DM on HCC risk. Interactions among DM, heavy alcohol consumption, and viral hepatitis infection were examined. Overall survival was examined, and multivariable Cox proportional hazards regression analysis was performed for HCC patients with type 2 DM.

The adjusted odds ratio (AOR) for DM was 2.74 (P < 0.01). Compared with patients who had DM for 2-10 years, those who had it for at least 20 years had an AOR of 4.60 (P = 0.04). Metformin use was associated with a reduced risk of death in HCC cases with type 2 DM, with a hazard ratio of 0.72 (P = 0.01) as compared with non-users.

Our results demonstrate that type 2 DM was independently associated with increased risk of HCC among Mexican Americans. Metformin use was associated with improved survival among HCC patients with type 2 DM. Type 2 DM significantly increased the risk of HCC alone and in conjunction with other parameters of metabolic syndrome in the Mexican American population after adjusting for other risk factors.

Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40-60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7-15%) and IDH1 mutations (10-20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies.

Traditional epidemiological studies are susceptible to confounding factors. To clarify the impact of metabolic syndrome and its diagnostic components on hepatocellular carcinoma, we conducted a preliminary mendelian randomization analysis with metabolic syndrome and its diagnostic components as exposures and hepatocellular carcinoma as the outcome. Another set of genetic data related to hepatocellular carcinoma was used as a validation cohort, repeating the mendelian randomization analysis and combining the two groups for a meta-analysis. Preliminary analysis showed that metabolic syndrome (P-value = 0.002) and waist circumference (P-value = 0.026) are significantly positively correlated with an increased risk of hepatocellular carcinoma. After multiple testing corrections, metabolic syndrome (PFDR-value = 0.013) remained significant, although the association between waist circumference (PFDR-value = 0.079) and hepatocellular carcinoma was considered suggestive, the meta-analysis further confirmed the impact of metabolic syndrome (P-value = 0.0002) and waist circumference (P-value = 0.0038) in increasing the risk of hepatocellular carcinoma. After adjusting for the genetic predictive effects of all exposures, waist circumference was found to be a key factor significantly influencing the relationship between metabolic syndrome and hepatocellular carcinoma. In summary, our study indicates that metabolic syndrome increases the risk of hepatocellular carcinoma, particularly among individuals with a larger waist circumference.

Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.

Alcohol-associated liver disease (ALD) poses a significant risk for hepatocellular carcinoma (HCC), comprising various liver conditions from steatosis to cirrhosis. Despite accounting for a third of global HCC cases and deaths, ALD-related HCC lacks characterization compared to viral hepatitis-related HCC. Proposed mechanisms for ALD-related HCC include acetaldehyde toxicity, increased reactive oxygen species, and inflammation. This review examines ALD-associated HCC epidemiology, co-factors like viral hepatitis and metabolic syndrome, surveillance, and treatment challenges. Despite advances in screening and management, ALD-related HCC often presents at advanced stages, limiting treatment options and survival.

BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.

Hepatocellular carcinoma (HCC) recurrence following surgical resection remains a significant clinical challenge, necessitating reliable predictive models to guide personalised interventions. In this study, we sought to harness the power of artificial intelligence (AI) to develop a robust predictive model for HCC recurrence using comprehensive clinical datasets.

Leveraging data from 958 patients across multiple centres in Australia and Hong Kong, we employed a multilayer perceptron (MLP) as the optimal classifier for model generation.

Through rigorous internal cross-validation, including a cohort from the Chinese University of Hong Kong (CUHK), our AI model successfully identified specific pre-surgical risk factors associated with HCC recurrence. These factors encompassed hepatic synthetic function, liver disease aetiology, ethnicity and modifiable metabolic risk factors, collectively contributing to the predictive synergy of our model. Notably, our model exhibited high accuracy during cross-validation (.857 ± .023) and testing on the CUHK cohort (.835), with a notable degree of confidence in predicting HCC recurrence within accurately classified patient cohorts. To facilitate clinical application, we developed an online AI digital tool capable of real-time prediction of HCC recurrence risk, demonstrating acceptable accuracy at the individual patient level.

Our findings underscore the potential of AI-driven predictive models in facilitating personalised risk stratification and targeted interventions to mitigate HCC recurrence by identifying modifiable risk factors unique to each patient. This model aims to aid clinicians in devising strategies to disrupt the underlying carcinogenic network driving recurrence.

Steatotic liver disease (SLD) is a new overarching term proposed to replace nonalcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease. Subclassification includes metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and cryptogenic SLD. This study aimed to investigate whether SLD and its subclassification could stratify hepatocellular carcinoma (HCC) risk.

A cohort of 85,119 adults without viral hepatitis or heavy alcohol intake was analyzed for the risk of HCC according to SLD and its subclassification. The fibrosis-4 (FIB-4) index was used to estimate the degree of liver fibrosis.

During a median follow-up of 11.9 years, HCC was diagnosed in 123 individuals. The incidence rate of HCC per 1,000 person-years was higher in individuals with SLD than in those without SLD (0.197 vs. 0.071, p < 0.001), with an adjusted hazard ratio of 2.02 (95% confidence interval: 1.40-2.92). The HCC incidence rate per 1,000 person-years was 0, 0.180, and 0.648 for cryptogenic SLD, MASLD, and MetALD, respectively. When participants with SLD was further stratified by the FIB-4 index, the HCC incidence rate per 1,000 person-years was 0.074 for SLD with FIB-4 < 1.3 and 0.673 for SLD with FIB-4 ≥ 1.3. Of note, HCC risk was substantially high (HCC incidence rate: 1.847 per 1,000 person-years) for MetALD with FIB-4 ≥ 1.3.

HCC risk was different by SLD and its subclassification. The utilization of SLD and its subclassification can aid in stratifying HCC risk and facilitate the identification of individuals requiring interventions to mitigate the risk of HCC.

Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with increasing incidence and poor survival rates. This study aims to evaluate the incidence and survival trends of iCCA patients over 20 years using a national cancer database, and assess the temporal association between survival and landmark clinical trials.

Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rates (AAIRs) were calculated from 2000 to 2020. Overall survival was analyzed based on diagnosis time and disease stage. Subgroup analysis was performed for patients diagnosed between 2015 and 2020. Landmark clinical trials were reviewed to determine temporal changes in survival.

In this analysis of 28,918 iCCA patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 [annual percent change (APC) 6.94, 95% confidence interval (CI): 6.32 to 7.56], with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted median overall survival (mOS) improved from 5.28 months in 2000 to 9.3 months in 2013, then stabilized between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 months in 2000-2010 to 9.06 months in 2010-2020. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3, 12.1, and 5.4 months for local, regional, and distant stages, respectively.

The study indicates a steady rise in iCCA incidence since 2000 across all subgroups. Survival rates improved since 2000 but stabilized after 2013, following the ABC-02 trial publication in 2010. The impact of more recent clinical trials on survival rates requires further analysis in the coming years.

Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed.

Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events.

In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002).

Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors.

Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Hepatocellular carcinoma ranks as the third leading cause of cancer-related mortality globally. We present a case of a rapidly progressive hepatocellular carcinoma in an 81-year-old female with metabolic abnormalities. The patient initially presented with non-specific signs and symptoms and was managed for sepsis of suspected urinary source. Unresolving laboratory markers led to repeat abdominal imaging demonstrating new hepatic lesions within six days. Biopsy confirmed moderately differentiated hepatocellular carcinoma. The patient received conservative inpatient treatment with recommendation for nutritional and performance status optimization prior to oncologic therapies, however continued to decline and passed away three months later.

Liver cancer is the world's sixth most prevalent cancer and the third most frequent cause of cancer-related mortality. Glucose metabolic disorders, indicated by a high fasting plasma glucose (HFPG) concentration, is a contributor to the etiology of liver cancer. With the rising prevalence of glucose metabolic disorders, an assessment of the global burden of liver cancer attributable to HFPG is warranted to inform global liver cancer prevention and control strategies.

We evaluated the global death and disability-adjusted life years (DALYs) of liver cancer and its subtypes attributable to HFPG at global, regional, and country level. The temporal trend and disparity across geographic regions, social development level, age groups and sex were assessed.

In 2019, HFPG-attributable liver cancer was estimated to have caused 4,729.49 deaths and to be responsible for 99,302.25 DALYs. The age-standardized mortality and DALY rate were 0.06 and 1.20 per 100,000 population, and displayed a significantly increasing temporal trend from 1990 to 2019. The age-standardized mortality rate of patients with liver cancer that was attributable to HFPG was higher in men than women. Sex-based disparity narrowed after the women reached menopause, but increased between 1990 and 2019.

The burden of liver cancer that are attributable to HFPG has been influenced by longitudinal changes in lifestyle, the etiology of liver disease, age demographics, and hormonal status in women. These findings suggest that comprehensive strategies could be implemented, especially for patients with NASH and hyperglycemia, to prevent liver cancer.

Plant-derived immunomodulators and antitumor factors have appealed lots of attention from natural product scientists for their efficiency and safety and their important contribution to well-designed targeted drug action and delivery mechanisms. Zerumbone (ZER), the chief component of Zingiber zerumbet rhizomes, has been examined for its wide-spectrum in the treatment of multi-targeted diseases. The rhizomes have been used as food flavoring agents in numerous cuisines and in flora medication. Numerous in vivo and in vitro experiments have prepared confirmation of ZER as a potent immunomodulator as well as a potential anti-tumor agent. This review is an interesting compilation of all the important results of the research carried out to date to investigate the immunomodulatory and anticancer properties of ZER. The ultimate goal of this comprehensive review is to supply updated information and a crucial evaluation on ZER, including its chemistry and immunomodulating and antitumour properties, which may be of principal importance to supply a novel pathway for subsequent investigation to discover new agents to treat cancers and immune-related sickness. In addition, updated information on the toxicology of ZER has been summarized to support its safety profile.

Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC.

Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis.

The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC).

The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Alcohol consumption and metabolic syndrome(MetS), both prevalent in the general population, frequently co-occur. They are recognized as significant contributors to liver dysfunction, yet their combined effect is often challenging to delineate. This study delves into the compounding influence of alcohol consumption and metabolic disorder on liver dysfunction within an elderly demographic in Zhejiang Province, China. Our findings spotlight a heightened risk of liver dysfunction among females, younger individuals, rural dwellers, those with minimal educational attainment, single individuals, and those diagnosed with MetS. We also discerned a positive correlation correlation between the number of MetS components and the propensity for liver dysfunction. Furthermore, the risk of liver dysfunction escalated in tandem with the frequency of alcohol consumption. Interestingly, a prolonged abstinence period (≥ 5 years) seemed to mitigate this risk. Our research underscores the significance of refraining from excessive alcohol consumption, embracing a healthy lifestyle, and managing MetS components-especially triglyceride levels-for effective prevention of liver dysfunction.

The prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing globally due to factors such as urbanization, obesity, poor nutrition, sedentary lifestyles, healthcare accessibility, diagnostic advancements, and genetic influences. Research on MAFLD and HCC risk factors, pathogenesis, and biomarkers has been conducted through a narrative review of relevant studies, with a focus on PubMed and Web of Science databases and exclusion criteria based on article availability and language. Steatosis marks the early stage of MASH advancement, commonly associated with factors of metabolic syndrome such as obesity and type 2 diabetes. Various mechanisms, including heightened lipolysis, hepatic lipogenesis, and consumption of high-calorie diets, contribute to the accumulation of lipids in the liver. Insulin resistance is pivotal in the development of steatosis, as it leads to the release of free fatty acids from adipose tissue. Natural compounds hold promise in regulating lipid metabolism and inflammation to combat these conditions. Liver fibrosis serves as a significant predictor of MASH progression and HCC development, underscoring the need to target fibrosis in treatment approaches. Risk factors for MASH-associated HCC encompass advanced liver fibrosis, older age, male gender, metabolic syndrome, genetic predispositions, and dietary habits, emphasizing the requirement for efficient surveillance and diagnostic measures. Considering these factors, it is important for further studies to determine the biochemical impact of these risk factors in order to establish targeted therapies that can prevent the development of HCC or reduce progression of MASH, indirectly decreasing the risk of HCC.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need.

This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs.

PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC.

In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels.

PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.

To measure the impact of socio-economic environment on the incidence of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA).

The study used data from the French Network of Cancer Registries (FRANCIM) between 2006 and 2016. Classification of patients into HCC and iCCA was performed according to the topographical and morphological codes of the 3rd edition of the International Classification of Diseases for Oncology. Patient addresses were geolocalized and assigned to an IRIS, the smallest French geographic unit. Socio-economic environment was assessed by the European Deprivation Index (EDI). Sex- and age-standardized incidence rates with 95% confidence intervals (CI) were estimated per 100 000 inhabitants, by national quintiles, for each IRIS, sex and age group. Quintile 1 (Q1) characterized the most affluent areas. A Poisson regression was performed to model the impact of deprivation.

We included 22 249 cases (79.64% HCC, 16.97% iCCA). Incidence rates were 11.46 and 2.39 per 100 000 person-years for HCC and iCCA, respectively. There was an over-incidence of HCC in quintiles 2, 3, 4 and 5 compared to quintile 1: Q1 10.28 [9.9-10.66] per 100 000 person-years, Q2 11.43 [10.48-12.47] (p < .0001), Q3 11.81 [10.82-12.89] (p < .0001), Q4 12.26 [11.25-13.37] (p < .001) and Q5 11.53 [10.57-12.57] (p < .0001). By contrast, there was no difference for iCCa. Deprivation was significantly associated with HCC in men (p = .0018) and women (p = .0009), but not with iCCA (p = .7407).

The incidence of HCC is related to socio-economic environment, unlike iCCA. HCC and iCCA should be studied separately in epidemiological studies.

To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS).

Liver resections for HCC on MS are associated with high perioperative morbidity and mortality. No data on the minimally invasive approach in this setting exist.

A multicenter study involving 24 institutions was conducted. Propensity scores were calculated, and inverse probability weighting was used to weight comparisons. Short-term and long-term outcomes were investigated.

A total of 996 patients were included: 580 in OLR and 416 in MILR. After weighing, groups were well matched. Blood loss was similar between groups (OLR 275.9±3.1 vs MILR 226±4.0, P =0.146). There were no significant differences in 90-day morbidity (38.9% vs 31.9% OLRs and MILRs, P =0.08) and mortality (2.4% vs 2.2% OLRs and MILRs, P =0.84). MILRs were associated with lower rates of major complications (9.3% vs 15.3%, P =0.015), posthepatectomy liver failure (0.6% vs 4.3%, P =0.008), and bile leaks (2.2% vs 6.4%, P =0.003); ascites was significantly lower at postoperative day 1 (2.7% vs 8.1%, P =0.002) and day 3 (3.1% vs 11.4%, P <0.001); hospital stay was significantly shorter (5.8±1.9 vs 7.5±1.7, P <0.001). There was no significant difference in overall survival and disease-free survival.

MILR for HCC on MS is associated with equivalent perioperative and oncological outcomes to OLRs. Fewer major complications, posthepatectomy liver failures, ascites, and bile leaks can be obtained, with a shorter hospital stay. The combination of lower short-term severe morbidity and equivalent oncologic outcomes favor MILR for MS when feasible.

Non-alcoholic fatty liver disease (NAFLD) and arterial hypertension (AH) are widespread noncommunicable diseases in the global population. Since hypertension and NAFLD are diseases associated with metabolic syndrome, they are often comorbid. In fact, many contemporary published studies confirm the association of these diseases with each other, regardless of whether other metabolic factors, such as obesity, dyslipidemia, and type 2 diabetes mellites, are present. This narrative review considers the features of the association between NAFLD and AH, as well as possible pathophysiological mechanisms.

Nearly 60% of patients with cancer have metabolic syndrome, which increases the risk of mortality, but there is no clear guidance for oncology providers about its management. Here, we report on the qualitative component of a larger mixed methods study that aimed to understand cancer patients' knowledge, attitudes, and preferences regarding metabolic syndrome.

Adult cancer patients with metabolic syndrome were recruited during 2022-2023 in the MD Anderson General Internal Medicine clinic and participated in semistructured interviews focused on metabolic syndrome and lifestyle interventions. Interviews were audio-recorded and transcribed verbatim. Participants' demographic information was collected. Interviews were analyzed using hybrid thematic analysis and constant comparison involving deductive and inductive coding. Researcher triangulation and debriefing were used to ensure rigor.

There were 19 participants, 12 female and 12 White. Eighteen had solid tumors, including gynecologic (n = 5), genitourinary (n = 4), colorectal (n = 3), and breast (n = 2). Analysis yielded 5 major themes: 1) patients' understanding of metabolic syndrome; 2) attitudes about and approaches to managing metabolic syndrome; 3) capacity and limitations regarding managing metabolic syndrome; 4) patient-led care; and 5) tailored intervention plans. Participants had limited knowledge of metabolic syndrome and its cancer-related consequences; most desired additional education. Many participants reported that their cancer or diabetes diagnosis motivated them to prioritize lifestyle Modifications. Participants expressed strong interest in personalized care plans focused on healthy lifestyle rather than simply weight loss. As part of their tailored intervention plans, participants desired clear communication with their medical team, coordination of care among team members, and collaboration with providers about treatment decisions.

Cancer patients with metabolic syndrome want collaborative, patient-centered care. Shared decision-making based on respect for patients' distinctive needs and preferences is an essential component of the development of such collaborative care. Tailored interventions, practical implementation strategies, and personalized care plans are needed for cancer patients with metabolic syndrome. The study findings contribute to filling the gap in knowledge regarding clear guidance for oncology providers on managing metabolic syndrome and will inform the development of future lifestyle interventions for patients diagnosed with metabolic syndrome.

To define sarcopenic obesity (SaO) among chronic liver disease (CLD) patients via CT and MRI, and assess its impact on liver disease severity.

CLD patients referred from the Gastroenterology and Hepatology Department diagnosed as chronic hepatitis B (N:101), cirrhosis (N:110), and hepatocellular carcinoma (N:169) with available information on body height, weight, Child-Pugh and MELD scores within 2 weeks of CT or MRI scanning were included in the study. Cross-sectional examinations were retrospectively evaluated for skeletal muscle index (SMI) and visceral adipose tissue area (VATA). The disease severity was assessed by Child-Pugh and MELD scoring.

The rate of sarcopenia and SaO in the cirrhotic patients was higher than that in the chronic hepatitis B patients (p <0.033 and p < 0.004, respectively). The rate of sarcopenia and SaO in HCC patients was higher than that in the chronic hepatitis B patients (p <0.001 and p <0.001, respectively). Sarcopenic patients in Chronic hepatitis B, cirrhotic, and HCC groups had higher MELD scores than nonsarcopenic patients (p <0.035, p <0.023, and p <0.024, respectively). Despite finding a similar increase in Child-Pugh scores in cirrhotic and HCC sarcopenic patients, results were statistically insignificant (p <0.597 and p <0.688). HCC patients with SaO had higher MELD scores than patients with other body composition catagories (p <0.006). Cirrhotic patients with SaO had higher MELD scores than nonsarcopenic obese patients (p <0.049). Chronic hepatitis B patients with obesity had low MELD scores (p <0.035). Cirrhotic and HCC patients with obesity had higher MELD scores (p <0.01 and p <0.024, respectively). Cirrhotic and HCC patients with obesity had higher Child-Pugh scores than nonobese patients but only HCC patients showed statistically significance (p <0.480 and p <0.001).

Radiologic evaluation of SaO and harmonizing body composition with MELD scoring is critical in CLD management.

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.

Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies.

Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.

Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for HCC in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications.

The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort.

The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index.

A total of 1087 patients were gathered from 24 centers between 2001 and 2021. Four hundred and eighty-four patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. Three hundred and seventy-six patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. Seven hundred and thirteen patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the nontumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% CI: 67.2%-78.2%) ( https://childb.shinyapps.io/NomogramMajorMorbidity90days/ ).

Patients undergoing liver resection for HCC and MS are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes.

Adiposity is associated with an increased risk of primary liver cancer (PLC). As the most commonly used indicator of adiposity, the body mass index (BMI) has been questioned for its limitations in reflecting visceral fat. This study aimed to investigate the role of different anthropometric indicators in identifying the risk of PLC by accounting for potential non-linear associations.

Systematic searches were conducted in the PubMed, Embase, Cochrane Library, Sinomed, Web of Science, and CNKI databases. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship was assessed using a restricted cubic spline model.

Sixty-nine studies involving more than 30 million participants were included in the final analysis. Regardless of the indicator used, adiposity was strongly associated with an increased risk of PLC. When comparing the HRs per 1-standard deviation increment across indicators of adiposity, the association was strongest for waist-to-height ratio (WHtR) (HR = 1.39), followed by waist-to-hip ratio (WHR) (HR = 1.22), BMI (HR = 1.13), waist circumference (WC) (HR = 1.12), and hip circumference (HC) (HR = 1.12). A strong non-linear association was observed between each anthropometric parameter and the risk of PLC, regardless of whether the original or decentralised value was used. The positive association between WC and PLC risk remained substantial after adjusting for BMI. The incidence of PLC was higher with central adiposity (52.89 per 100,000 person-years, 95% CI = 50.33-55.44) than general adiposity (39.01 per 100,000 person-years, 95% CI = 37.26-40.75).

Central adiposity seems to contribute more to the development of PLC than general adiposity. A larger WC, independent of BMI, was strongly associated with the risk of PLC and might be a more promising predictive indicator than BMI.