Search Results (5,461)

Background/Objectives: Carbon-ion radiotherapy (CIRT) is now covered by Japan’s health insurance for patients with hepatocellular carcinoma (HCC) tumors measuring ≥4 cm. However, no studies have compared intrahepatic control between CIRT and hepatectomy in these patients. Methods: We retrospectively analyzed intrahepatic control in 51 patients with HCC tumors ≥4 cm. Among them, 38 underwent CIRT (60 Gy in four fractions), while 13 underwent systematic hepatectomy. Intrahepatic recurrence was classified as local or intrahepatic distant. We evaluated local, distant, and total intrahepatic control rates at 1 and 2 years. Results: In the CIRT group, the local control rates at 1 and 2 years were 81.5% and 76.3%, whereas the intrahepatic distant control rates were 68.5% and 63.2% (p = 0.0495), respectively. Among patients aged <80 years, the 2-year intrahepatic control rate did not significantly differ between CIRT and hepatectomy. However, it was significantly lower in patients aged ≥80 years treated with CIRT than in those aged <80 years (73.7% vs. 42.1%, p = 0.0100), with similar trends in local (92.3% vs. 63.2%, p = 0.0381) and distant control (78.9% vs. 47.3%, p = 0.0259). Conclusions: CIRT may be as effective as hepatectomy for HCC tumors ≥4 cm in patients aged <80 years, but its efficacy declines in older patients, warranting age-tailored strategies. Full article

In the modern era of HIV treatment, people co-infected with HIV and HBV still face poor liver outcomes, including liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. We investigated baseline characteristics and long-term liver function outcomes in 435 people living with HIV and HBV co-infection, focusing on HCC-associated point mutations (PMs) and PreS region deletion mutations. PMs were present in 72.9% of participants and were associated with male predominance, lower HBV genotype C prevalence, reduced HBV DNA and HBeAg levels, and higher HBsAg and HBeAb positivity. However, PMs did not significantly impact liver function or fibrosis progression over six years of ART follow-up. In contrast, PreS deletions were found in 21.8% of cases and stratified into PreS1, PreS2, and PreS1+2 deletions. PreS2 and PreS1+2 deletions were linked to older age, higher HBsAg and AFP levels, elevated liver enzymes, and lower platelet counts. These groups also exhibited significantly worse liver fibrosis markers (APRI and FIB-4), with PreS2 deletions consistently showing the highest values throughout the follow-up. Despite the initial improvement with ART, patients with PreS2 and PreS1+2 deletions maintained higher fibrosis and cirrhosis risks over six years. In summary, while PMs were not predictive of liver disease progression, PreS deletion mutations (especially in the PreS2 region) were associated with poorer liver outcomes, indicating their potential as biomarkers for fibrosis risk in co-infected individuals with long-term ART. Full article

Background/Objectives: Tumor-associated inflammation plays a crucial role in supporting tumorigenesis and the progression of oncological diseases. This study aimed to evaluate whether systemic inflammatory indices are associated with overall survival (OS) in patients with hepatocellular carcinoma (HCC) undergoing surgery. Methods: A retrospective cohort study was conducted on consecutive patients with HCC who underwent hepatic resection. Data were prospectively collected and retrospectively reviewed. The 5-year OS rate was used as the primary endpoint to stratify the values of inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), aspartate aminotransferase-to-neutrophil ratio index (ANRI), fibrinogen-to-albumin ratio (Fib-Alb), the systemic immune-inflammation index (SII), prognostic nutritional index (PNI), and aspartate aminotransferase-to-platelet ratio index (APRI), through receiver operating characteristic (ROC) curve analysis. The optimal albumin–bilirubin (ALBI) and platelet–ALBI (PALBI) cut-off points from the literature were also applied. Results: Patients included in the study were 153. The 1-, 3-, and 5-year OS rates were 81.7%, 65.2%, and 40.7%, respectively. Univariate Cox proportional hazards analysis showed that, in addition to several patient- and tumor-related characteristics and postoperative complications, elevated values of PLR, ANRI, Fib-Alb, SII, APRI, ALBI, and PALBI, as well as low PNI, were significantly associated with poorer overall survival (OS). Among these, only APRI and PNI emerged as independent prognostic factors in the multivariate analysis. Conclusions: PNI and APRI could serve as valuable inflammatory indices for predicting OS, helping to identify HCC patients who might benefit from hepatic resection. However, further prospective studies with larger cohorts are needed to validate the prognostic role of PNI and APRI. Full article

Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and cellular signaling in cancer. Their functions are primarily mediated through interactions with specific protein partners that modulate chromatin structure, epigenetic remodeling, transcription, and signal transduction. In this review, we explore reports and strategies for the proteomic characterization of lncRNA-associated proteins, particularly emphasizing high-throughput liquid chromatography–mass spectrometry (LC-MS)-based techniques. Affinity-based methods such as RNA pull-down, ChIRP MS, RAP-MS, BioID-MS, and SILAC-MS enable sensitive and specific mapping of lncRNA and protein complexes. These approaches reveal cancer-specific proteomic signatures, post-translational modifications, and mechanistic insights into tumor biology. The use of label-free quantification, bituminization, and crosslinking strategies further enhances the resolution of dynamic RNA–protein networks. Validation tools following bioinformatic analyses, such as Western blotting, immunohistochemistry, immunofluorescence, and ELISA, are used to prioritize and confirm findings. Candidate biomarkers from hepatocellular carcinoma to colorectal and prostate cancers, profiling lncRNA-associated proteins, hold promise for identifying clinically actionable biomarkers and therapeutic targets. This review highlights the translational relevance of lncRNA protein studies and advocates for their broader adoption in oncological research. In LC-MS workflows, proteins bound to lncRNAs are enzymatically digested into peptides, separated via nano-LC, and analyzed using high-resolution tandem MS. Label-free or isotope-labeled methods quantify differential enrichment, followed by bioinformatics-driven pathway annotation. Full article

Epithelial–mesenchymal transition (EMT) is a key process in cancer progression and fibrogenesis. In this study, EMT was induced in Huh7 hepatocellular carcinoma cells via TGF-β1 treatment, and the resulting lipidomic and metabolomic alterations were characterized. Morphological changes and protein marker analyses confirmed the transition to a mesenchymal phenotype, with reduced E-cadherin and increased vimentin and N-cadherin expression. Lipidomic profiling revealed a dose-dependent reorganization of membrane lipids, with a pronounced increase in the levels of ceramides, cholesteryl esters, and lysophospholipids, consistent with alterations in membrane structure, potential cellular stress, and modulation of inflammatory pathways. Changes in the content of phospholipid classes, including phosphatidylethanolamines and phosphatidylserines, indicate possible variations in membrane dynamics and potentially point to modifications in mitochondrial function, cellular stress responses, and redox balance. Metabolomic analysis further indicates an alteration of choline and phosphatidylcholine metabolism, consistent with a shift from de novo membrane synthesis toward lipid turnover. Reduced glycolytic capacity and modified acylcarnitine levels indicated impaired metabolic flexibility and mitochondrial efficiency. The integration of phenotypic, lipidomic, and metabolomic data suggests that TGF-β1 induces EMT and drives a coordinated metabolic reprogramming. These findings highlight the involvement of lipid and energy metabolism in sustaining EMT and suggest that specific metabolic reprogramming events characterize the mesenchymal shift in hepatocellular carcinoma. By exploring this process in a tumor-specific context, we aim to deepen our understanding of EMT complexity and its implications for tumor progression and therapeutic vulnerability. Full article

Hepatitis D virus (HDV) infection remains a major cause of severe liver disease among hepatitis B virus (HBV)-infected patients, contributing to accelerated progression to cirrhosis and hepatocellular carcinoma. Pegylated interferon-α remains the first-line therapy for chronic HDV infection in most cases. However, despite its approval for HBV and hepatitis C virus (HCV) infections, its use in HDV is largely driven by a lack of other options and is constrained by its limited efficacy, suboptimal durability of response, and a substantial side effect profile. Meanwhile, bulevirtide, an entry inhibitor, became the first agent to be approved for use in chronic HDV infections by the European Medicines Agency (EMA), and several other therapies are currently being investigated as well. In this review, we provide updates on recent advancements in HDV treatment and novel therapies. Full article

Background: Early diagnosis of hepatocellular carcinoma (HCC) and monitoring of therapeutic results remain clinical challenges. Methods: In a prospective study, we evaluated the diagnostic capabilities of the serum level of glypican-3 in 70 patients with chronic advanced compensated liver disease: 40 cases with confirmed HCC and 30 cases with chronic viral hepatitis with bridging fibrosis or cirrhosis as a control group. The glypican-3 concentration was analyzed in the context of the disease characteristics. Results: The mean level of glypican-3 in HCC patients was 50.84 ± 75.98 ng/mL, significantly higher compared to the control group of 5.69 ± 10.43 ng/mL. A progressive increase in alpha-fetoprotein in accordance with the stage of neoplastic disease was observed, but this tendency was not assessed for glypican-3. Two cut-off levels can be suggested for glypican-3: 2.5 ng/mL to exclude HCC with an optimal sensitivity of 85%, and 33.7 ng/mL for confirmation of HCC, with a specificity of 96.7%. The diagnostic accuracy of serum glypican-3 was 80.0% for HCC, 82.1% for alpha-fetoprotein, and 87.4% for both tumor markers. Conclusions: This pilot study suggests a complementary role of glypican-3 with alpha-fetoprotein and better diagnostic performance when combining tumor biomarkers. Full article

Background and Clinical Significance: Combined hepatocellular–cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy exhibiting both hepatocellular and cholangiocellular features. Due to overlapping clinical, imaging, and pathological characteristics with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCC), diagnosis remains challenging. Early and accurate differentiation is critical for optimal treatment planning. Case Presentation: We report three histologically confirmed cases of cHCC-CC with different imaging features, biomarker profiles, treatment strategies, and clinical outcomes. Patient 1, a 69-year-old female, presented with a large centrally located liver mass exhibiting iCC-like imaging features and mildly elevated AFP and CA 19-9 levels. Biopsy confirmed poorly differentiated cHCC-CC. Treatment involved palliative chemotherapy, with a survival of 16 months following diagnosis. Patient 2, an 80-year-old female with a small lesion in a cirrhotic liver, demonstrated an HCC-like enhancement pattern but normal AFP levels. Surgical resection was performed, and histology confirmed cHCC-CC with a dual phenotype. Despite initial remission, intrahepatic recurrence developed, treated with TACE and systemic therapy. The patient later transitioned to palliative care due to progression and survived 36 months. Patient 3, a 67-year-old male with chronic hepatitis C, presented with an HCC-like lesion and elevated AFP. Due to comorbidities, surgical resection was not feasible, and the patient was treated with percutaneous microwave ablation as a safer alternative. Biopsy during ablation confirmed cHCC-CC; follow-up was ongoing at submission. Conclusions: These cases highlight the diagnostic complexity and clinical variability of cHCC-CC. Imaging may be misleading, and tumor markers do not reliably predict subtype or prognosis. Histological confirmation is essential, particularly in patients with atypical imaging or discordant biomarker profiles. Individualized management, informed by tumor biology and patient condition, remains critical. Further research is needed to refine diagnostic criteria and develop tailored therapeutic strategies for this challenging tumor entity. Full article

Background/Objectives: As a noninvasive indicator of liver fibrosis and stiffness, liver stiffness measurement (LSM) has also shown significant value in differentiating focal liver lesions (FLLs). This study aimed to assess the characteristics of LSM values across different liver lesions and explore their value in differential diagnosis. Methods: A total of 8817 individuals with FLLs were assessed using liver stiffness measurements (LSMs). We evaluated the LSM characteristics across different FLL categories and further compared these values within subgroups based on their alpha-fetoprotein (AFP) and hepatitis B surface antigen (HBsAg). The LSM was visualized graphically. We compared two logistic regression models (with the LSM and without the LSM) in a cohort of 2271 patients who were both AFP-normal (<20 ng/mL) and HBsAg-negative. The differentiation value of the LSM was quantified by comparing the models’ area under the curves (AUCs) and through decision curve analysis (DCA). Results: The LSM showed significant differences (p < 0.001) among malignant lesions, benign lesions, and cirrhotic nodules (CN). Among benign lesions, only focal nodular hyperplasia (FNH) and simple hepatic cysts (SHC) showed a significant difference (p < 0.05). Among malignant lesions, significant differences in the LSM were observed between all pairs (p < 0.001) except between hepatocellular carcinoma (HCC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC). Patients with elevated AFP levels exhibited significantly higher LSM across most lesion types. HBsAg-positive patients also showed significantly increased LSM in all five lesion types, except for CN and cHCC-CC. The full model (with LSM) for differentiating primary malignant lesions from benign ones was built using six variables. The AUCs of the full model were 0.897 and 0.896 in the training and validation sets, significantly outperforming the comparison model (AUC: 0.882, p = 0.0002; 0.879, p = 0.017). Conclusions: The LSM can provide additional information on focal liver lesions. Full article

The liver’s susceptibility to age-related diseases, including hepatocellular carcinoma (HCC), is increasingly linked to progressive epigenetic alterations that disrupt gene regulation, promote fibrosis, and impair regeneration. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well-established in the treatment of type 2 diabetes and obesity, emerging evidence suggests they may also exert protective effects on the liver through the modulation of epigenetic pathways. In this perspective, we explore the hypothesis that GLP-1RAs may help restore a healthier epigenetic state in the aging liver by influencing mechanisms such as DNA methylation, histone modification, and non-coding RNA activity. These effects could reduce chronic inflammation, hepatic stellate cell activation, and fibrotic remodeling, key steps in the path to HCC. Preclinical studies have shown GLP-1RAs can affect transcriptional regulation and fibrotic markers, and early clinical data support improvements in liver function and structure in patients with metabolic liver disease. We highlight the need for further research to clarify these mechanisms in aging populations and propose that GLP-1RAs hold potential as a novel therapeutic strategy to reduce liver cancer risk by targeting the epigenetic contributors to disease progression. Full article

Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies characterized by a poor prognosis and resistance to conventional therapies. Mounting evidence suggests the pivotal role of epithelial–mesenchymal transition (EMT) in tumor progression, metastasis, and therapeutic resistance in these cancers. Protein induced by vitamin K absence II (PIVKA-II)—a valuable HCC detector—has ultimately emerged as a potentially relevant biomarker in PDAC, serving as both a serum biomarker and a prognostic indicator. This study investigates the putative link between PIVKA-II expression and the EMT process in HCC and PDAC. Using a Western blot analysis and electrochemiluminescence immunoassay (ECLIA), we quantified PIVKA-II serum levels alongside two canonical EMT markers—Vimentin and E-cadherin—in selected cohorts. Emerging data suggest a dual, context-dependent role for PIVKA-II. Beyond its diagnostic value in both malignancies, its co-expression with EMT markers points to a potential mechanistic involvement in tumor invasiveness and phenotypic plasticity. Notably, the selective detection of E-cadherin in HCC implies limited EMT activation and a preservation of the epithelial phenotype, whereas the higher expression of Vimentin in PDAC reflects a more substantial shift toward EMT. We provide a comprehensive analysis of key molecular markers, their involvement in EMT-driven pathophysiological mechanisms, and their potential as novel diagnostic tools. Full article

Background/Objectives: Inflammation-based markers have emerged as potential prognostic tools in hepatocellular carcinoma (HCC), but comparative data with classical prognostic factors in untreated HCC are limited. This study aimed to evaluate and compare the prognostic performance of inflammatory and conventional markers using Harrell’s concordance index (C-index). Methods: This retrospective study included 250 patients with untreated HCC. Prognostic variables included age, BCLC stage, Child–Pugh classification, Milan criteria, MELD score, AFP, albumin, Charlson comorbidity index, and the inflammation-based markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), Systemic Inflammation Response Index (SIRI), and Systemic Immune-inflammation Index (SIII). Survival was analyzed using Cox regression. Predictive performance was assessed using the C-index, Akaike Information Criterion (AIC), and likelihood ratio tests. Results: Among the classical markers, BCLC showed the highest predictive performance (C-index: 0.717), while NLR ranked highest among the inflammatory markers (C-index: 0.640), above the MELD score and Milan criteria. In multivariate analysis, NLR ≥ 2.3 remained an independent predictor of overall survival (HR: 1.787; 95% CI: 1.264–2.527; p < 0.001), along with BCLC stage, albumin, Charlson index, and Milan criteria. Including NLR in the model modestly improved the C-index (from 0.781 to 0.794) but significantly improved model fit (Δ–2LL = 10.75; p = 0.001; lower AIC). Conclusions: NLR is an accessible, cost-effective, and independent prognostic marker for overall survival in untreated HCC. It shows discriminative power comparable to or greater than most conventional predictors and may complement classical stratification tools for HCC. Full article

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article

Background/Objectives: Primary liver cancer (PLC), encompassing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constitutes a growing global health concern. Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) and Type 2 diabetes mellitus (T2DM) represent a recurrent epidemiological overlap. Individuals with MASLD and T2DM (MASLD-T2DM) are at a higher risk of PLC. This scoping review highlights the epidemiological burden, the classic and novel pathogenetic frontiers, and the potential strategies optimizing the management of PLC in MASLD-T2DM. Methods: A systematic search of the PubMed, Medline, and SCOPUS electronic databases was conducted to identify evidence investigating the pathogenetic mechanisms linking MASLD and T2DM to hepatic carcinogenesis, highlighting the most relevant targets and the relatively emerging therapeutic strategies. The search algorithm included in sequence the filter words: “MASLD”, “liver steatosis”, “obesity”, “metabolic syndrome”, “body composition”, “insulin resistance”, “inflammation”, “oxidative stress”, “metabolic dysfunction”, “microbiota”, “glucose”, “immunometabolism”, “trained immunity”. Results: In the MASD-T2DM setting, insulin resistance (IR) and IR-induced mechanisms (including chronic inflammation, insulin/IGF-1 axis dysregulation, and autophagy), simultaneously with the alterations of gut microbiota composition and functioning, represent crucial pathogenetic factors in hepatocarcinogenesis. Besides, the glucose-related metabolic reprogramming emerged as a crucial pathogenetic moment contributing to cancer progression and immune evasion. In this scenario, lifestyle changes, simultaneously with antidiabetic drugs targeting IR-related effects and gut-liver axis, in parallel with novel approaches modulating immunometabolic pathways, represent promising strategies. Conclusions: Metabolic dysfunction, classically featuring MASLD-T2DM, constitutes a continuously expanding global issue, as well as a critical driver in PLC progression, demanding integrated and personalized interventions to reduce the future burden of disease. Full article