Search Results (6,217)

Background: Ginsenoside Rh2 (Rh2), a bioactive metabolite of Panax ginseng, has documented anticancer effects, but its role in cancer–immune crosstalk remains incompletely defined. Thus, we aimed to investigate the role of Rh2 in hepatocellular carcinoma (HCC) cells and immune regulation. Methods: We used a co-culture system of murine Hepa1-6 hepatocellular carcinoma cells or nonmalignant AML12 hepatocytes with primary splenocytes to model cancer–immune interactions during Rh2 exposure. Readouts included cell viability, nuclear morphology, and multiparameter flow cytometry. Results: In a co-culture system of Hepa1-6 cells and splenocytes, Rh2 decreased bulk cell viability and increased apoptosis in Hepa1-6 cells. CD8⁺ T cells exhibited enhanced effector features, with increased CD107a and IFN-γ expression following Rh2 treatment. Rh2 reduced PD-L1 expression on Hepa1-6 cells and splenocytes, and PD-1 expression on CD8⁺ T cells. Rh2 also reduced TGF-β1 and IL-6 levels in both Hepa1-6 cells and splenocytes, and decreased IL-10 levels in splenocytes. This was accompanied by a reduction in CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs). Conclusions: In a physiologically relevant cancer–immune context, Rh2 reprograms suppressive interactions by enhancing CD8⁺ T cell effector function, dampening PD-L1/PD-1 signaling, and reducing key immunosuppressive cytokines and Tregs. These coordinated effects position Rh2 as a candidate multi-target immunomodulatory agent for enhancing anticancer immunity. Full article

Introduction: Hepatic fibrosis represents a critical intermediate stage in the progression from chronic liver disease to cirrhosis and ultimately hepatocellular carcinoma. Spirulina platensis, a microorganism rich in bioactive compounds, contains several functional components, among which are Spirulina polysaccharides and phycocyanin. Both have been demonstrated to exhibit multiple biological activities, including antioxidant, anti-inflammatory, and immunomodulatory effects. However, the intervention effects and mechanisms of Spirulina polysaccharides and phycocyanin on CCl₄-induced hepatic fibrosis remain unclear. 16S rRNA sequencing and non-targeted metabolomics technologies are employed to analyze bacterial taxa and metabolic pathways. Methods: Hepatic fibrosis (HF) was induced in male C57BL/6J mice via intraperitoneal injection of CCl₄. After 1 week of modeling, mice were intragastrically administered SPP or PC for 4 consecutive weeks. Gut microbiota composition and fecal metabolites were analyzed using 16S rRNA gene sequencing and metabolomics. Results: SPP showed more pronounced protective effects than PC under the experimental conditions used in this study. SPP treatment significantly alleviated hepatic fibrosis in mice. Compared with the model group, SPP administration markedly increased the abundance of bacterial taxa and modulated fecal metabolic profiles, including short-chain fatty acid metabolism. Conclusions: SPP treatment mitigates CCl₄-induced hepatic fibrosis in mice. These protective effects may be associated with the modulation of gut microbiota composition and fecal metabolic pathways, including those related to short-chain fatty acid metabolism. Full article

Background/Objectives: The glucocorticoid receptor (GR) is essential for regulating liver energy balance, metabolism, and inflammation. Stress and other factors can impair its function, resulting in glucocorticoid-resistant metabolic liver disease. GR mainly exists in two forms: the glucocorticoid-binding isoform, GRα, and the non-binding isoform, GRβ. The GRβ isoform typically exhibits minimal signaling activity beyond its role as a dominant-negative regulator of GRα, thereby decreasing glucocorticoid responsiveness and potentially causing resistance. Methods: To explore GRβ signaling independent of GRα, we developed mice with adenovirus-induced overexpression of GRβ (GRβ-Ad) and control mice with a vector (Vec-Ad). After five days on a standard diet, these mice received either vehicle or dexamethasone treatment. Liver tissues were collected, and we performed RNA sequencing and advanced PamGene kinome analysis to detect pathway changes in GRβ-Ad mice compared with controls. Results: Significant increases were observed in the expression of genes that inhibit fatty acid oxidation, inflammation, and liver cancer development. There was also a marked difference in serine/threonine kinase activity between GRβ-Ad and control mice. Conclusions: The findings suggest that elevated GRβ levels affect kinase pathways that modulate glucocorticoid signaling, disrupt liver lipid metabolism, and are associated with cancer pathways. Further research is needed to determine whether GRβ functions similarly in humans and to assess its potential contribution to hepatocellular carcinoma (HCC). Full article

Background/Objectives: Decreases in skeletal muscle mass affect the efficacy of and tumor response to various therapies for hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between changes in skeletal muscle mass during TACE-based combination therapy and tumor response and prognosis. Methods: This retrospective study analyzed 306 patients with unresectable HCC, divided into four groups according to the treatment received: TACE alone (n = 133), TACE plus targeted and immunotherapy combination (TACE + T + I, n = 68), TACE plus immunotherapy (TACE + I, n = 52), and TACE plus targeted therapy (TACE + T, n = 53). Skeletal muscle mass was assessed at the third lumbar vertebral level (L3) before treatment and at six months post-treatment using computed tomography (CT) scans. Patients were stratified based on changes in skeletal muscle index (SMI) values. Kaplan–Meier and Cox proportional hazards models were used to compare overall survival (OS) among groups classified by changes in SMI, while tumor response was assessed with univariate and multivariate analyses, using logistic regression analysis. Result: A total of 306 patients with unresectable HCC were included in this study. The median OS was 17.0 (0.9–83.0) months in the decreased-SMI group compared with 35.0 (2.0–113.0) months in the non-decreased-SMI group. The overall response rate (CR + PR) was 34.7% in the decreased-SMI group and 53.8% in the non-decreased group. Among different treatment regimens, significant differences in Kaplan–Meier survival curves were observed between the TACE and TACE + T + I groups. In multivariate analysis, decreased SMI remained an independent predictor of poor OS and tumor non-response, whereas a low-SMI pre-treatment was not an independent prognostic factor. Additionally, inadequate nutritional status and compromised liver function were associated with a greater decrease in SMI during comprehensive treatment. Conclusions: A decline in skeletal muscle index (SMI) among patients with unresectable hepatocellular carcinoma (HCC) undergoing TACE-based comprehensive treatment is associated with poor prognosis and unfavorable tumor response and is further linked to deteriorating nutritional status and impaired liver function. Monitoring SMI provides an effective approach for assessing overall patient condition and predicting clinical outcomes. Full article

Introduction: Multidisciplinary tumor boards (MTBs) are the standard for oncologic decision-making but require substantial time and personnel resources. Large language models (LLMs) may support MTBs by generating structured, guideline-based recommendations. We evaluated concordance between MTB decisions and LLM recommendations in newly diagnosed cholangiocellular adenocarcinoma (CCA) and hepatocellular carcinoma (HCC). Method: In this retrospective single-center study, MTB protocols from 2022–2023 were screened. After exclusions, 50 CCA and 50 HCC cases were analyzed. Institutional MTB recommendations were compared with outputs from ChatGPT and Claude using identical structured clinical summaries available at the time of MTB presentation. Agreement was assessed using Cohen’s kappa, and correlation using Spearman’s rank coefficient. Results: For CCA, exact concordance between MTB and ChatGPT was 80%, with substantial agreement (k = 0.688) and strong correlation (r = 0.725; both p < 0.001). Concordance with Claude was at 56%. For HCC, concordance between MTB and ChatGPT was 66%, with substantial agreement (k = 0.604) and moderate correlation (r = 0.484; both p < 0.001). Concordance with Claude was only 38%, with fair agreement (k = 0.314, p < 0.001) and weak correlation (r = 0.086, p = 0.551). Conclusions: LLM-derived recommendations varied markedly by model. ChatGPT demonstrated substantial concordance, whereas Claude showed limited agreement. MTBs appeared more individualized, while LLM outputs were more guideline-oriented. These findings highlight the potential role of LLMs as supportive tools for structured clinical reasoning and guideline adherence. Prospective multicenter studies should evaluate real-time LLM integration into MTB workflows, efficiency, decision quality, and patient outcomes safely. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the leading cause of hepatocellular carcinoma (HCC) globally. HCC surveillance is currently restricted to patients with cirrhosis, leaving those without cirrhosis, who present with more advanced disease and poorer outcomes without adequate risk stratification tools. This study compared lipid profiles across MAFLD and MAFLD-related HCC (MAFLD-HCC) patients, with and without cirrhosis, to characterise metabolic dysregulation underlying non-cirrhotic MAFLD-HCC (ncMAFLD-HCC). Plasma and liver lipidomic profiles were obtained from 221 patients (140 MAFLD, 66 cirrhotic MAFLD-HCC (cMAFLD-HCC), and 15 ncMAFLD-HCC) using untargeted liquid chromatography mass spectrometry. Univariate, multivariable and enrichment analyses were performed for statistically determining the lipid profile difference between the groups. Seventy percent of lipid classes were more abundant in MAFLD than in ncMAFLD-HCC and cMAFLD-HCC. Multivariate analysis revealed distinct lipid profiles across the three groups in both plasma and liver. Over 100 lipid species including diglyceride (DAG), sphingomyelin (SM), triglyceride (TG), dihydroceramide (DHCer), and linoleic acid derivatives were differentially expressed in ncMAFLD-HCC versus MAFLD, with enrichment in pathways such as glycerolipid metabolism, G-protein signalling, MAPK signalling, EGFR-TKI resistance pathway, implicated in HCC development. ncMAFLD-HCC exhibits a distinct lipid signature, offering preliminary mechanistic insight and a foundation for non-invasive biomarker development. Full article

Yttrium-90 (⁹⁰Y) is a pivotal pure beta-emitting radionuclide extensively employed in the targeted therapy of malignant tumors, such as hepatocellular carcinoma and lymphoma. The ⁹⁰Sr-⁹⁰Y generator system represents the most effective method for producing no-carrier-added (NCA) ⁹⁰Y to meet escalating clinical demands. However, safe clinical application necessitates the stringent separation of its parent isotope, ⁹⁰Sr, which poses significant radiotoxicological risks due to its long half-life and bone-seeking behavior. This review comprehensively summarizes recent advances in solid-phase adsorbent materials developed for the high-efficiency separation of Y³⁺ and Sr²⁺. We systematically analyze the design strategies, molecular recognition mechanisms, and performance evaluation metrics of various functional systems. Key materials discussed include extraction chromatography (EXC) resins based on organophosphorus extractants, diglycolamide (DGA) derivatives, and crown ethers, as well as inorganic ion exchangers such as antimony-based materials, manganese oxides, and zeolite-like molecular sieves. Special attention is given to composite modification strategies, including silica-based and polymer-matrix composites, and metal doping techniques aimed at enhancing radiation resistance, acid stability, and Sr-Y separation factors (SF). Finally, we provide an outlook on the future development of next-generation ⁹⁰Sr-⁹⁰Y generator materials, highlighting the imperative of transitioning from idealized simulated environments to robust, field-ready applications. Full article

Hepatocellular carcinoma (HCC) is a heterogeneous primary liver malignancy characterized by limited treatment options and low overall survival rates. Recent studies have explored the role of programmed death ligand 1 (PD-L1), tumor-associated macrophages (TAMs), and epithelial-mesenchymal transition (EMT) in modulating tumor progression and the response to immunotherapy. This study aimed to investigate the association among PD-L1 expression, TAMs, and EMT in HCC, highlighting the recently proposed immunophenotypic variant—gastric-type HCCs. A retrospective cohort of 50 surgically resected HCC patients was analyzed. Immunohistochemical staining was performed for PD-L1 (clones 28-8 and 22C3), CD68 (TAMs), and EMT markers (VSIG-1, TTF-1, and vimentin). PD-L1 expression was detected in 52% of the patients and was significantly associated with high TAM counts (p < 0.001). Compared with PD-L1-negative patients, those with gastric-type HCCs, which are characterized by VSIG-1 and TTF-1 co-expression and vimentin negativity, demonstrated improved survival outcomes (p = 0.03). Integration of immune and EMT profiling of tumor cells in routine diagnostics may guide prognosis and immunotherapeutic strategies in HCC. Further molecular validation is required to confirm the biological significance of the proposed gastric-type HCC immunophenotype. Full article

The widespread adoption of prostate-specific membrane antigen (PSMA)-targeted PET/CT has profoundly reshaped molecular imaging in prostate cancer and has substantially reduced the routine use of radiolabeled choline tracers. However, the transition from choline to PSMA imaging should not be interpreted simply as the replacement of one radiopharmaceutical by another, but rather as part of a broader evolution from metabolism-based imaging toward receptor-targeted and biology-driven imaging strategies. This narrative review critically reassesses the residual and emerging role of choline PET/CT in the PSMA era, with particular attention to the biological rationale of choline uptake, selected prostate cancer scenarios, and extra-prostatic applications. In prostate cancer, PSMA PET/CT remains the dominant imaging modality because of its superior diagnostic performance, particularly in biochemical recurrence; nevertheless, choline PET/CT may provide complementary metabolic information in highly selected settings, including PSMA-low or heterogeneous disease, aggressive or dedifferentiated variants, neuroendocrine transformation, equivocal PSMA findings, and limited PSMA availability. These prostate cancer applications, however, are supported mainly by biological rationale, indirect evidence, and limited clinical data and should therefore be regarded as exploratory rather than established indications. By contrast, ¹⁸F-fluorocholine PET/CT has emerged as a clinically established imaging modality in primary hyperparathyroidism, particularly after negative or inconclusive conventional imaging, with prospective studies and meta-analyses demonstrating high detection rates and superior performance compared with conventional scintigraphic techniques. Additional applications in hepatocellular carcinoma and selected neuro-oncologic settings remain exploratory and require further validation. Overall, choline PET/CT should not be considered obsolete in the PSMA era, but selectively repositioned within biology-driven and multiparametric imaging strategies, with its strongest evidence currently supporting primary hyperparathyroidism and its other applications requiring cautious interpretation and further prospective validation. Full article

Fibrosis is a common extracellular matrix pathology characterized by increased scarring, representing a critical checkpoint toward cirrhosis and hepatocellular carcinoma. Its onset involves coordinated interplay among hepatocytes, Kupffer, and hepatic stellate cells (HSCs). Extracellular ATP and its derivates act as crucial damage-associated molecular patterns when released by injured liver cells, binding to specific purinergic receptors (P2X, P2Y, and P1) to establish an autocrine–paracrine signaling loop. The hepatic fibrotic response underlies the activation of ATP receptors that generate second messengers and cationic conductance. In parallel, extracellular nucleotidases hydrolyze ATP towards less phosphorylated intermediates and adenosine. This review focuses on the role of P2X and P2Y receptors in liver injury. The P2X7 receptor regulates the NLRP3 inflammasome in Kupffer cells and HSCs, while the P2X4 receptor is upregulated in myofibroblasts, modulating migration and matrix synthesis. Among P2Y receptors, P2Y2 drives inflammation and steatosis but promotes HIF-1α-mediated DNA repair. The P2Y6 receptor promotes alcohol-induced injury but restrains metabolic-dysfunction-associated steatohepatitis. P2Y2 and P2Y4 receptors maintain biliary homeostasis in cholangiocytes, whereas the P2Y1 receptor preserves HSC quiescence by blocking YAP translocation. Finally, UDP-glucose–P2Y14 induces HSC activation. Targeting these specific purinergic receptors or ecto-nucleotidases represents a promising pharmacological frontier against hepatic fibrosis. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide and is characterized by extensive vascularization, aggressive progression, and limited therapeutic responsiveness. Angiogenesis plays a central role in HCC development by supporting tumor growth, metabolic adaptation, invasion, and metastatic dissemination. Although anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have improved clinical management, their overall survival benefit remains modest because of compensatory signaling, adaptive resistance, and the highly complex nature of the tumor microenvironment (TME). Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) has emerged as a multifunctional oncogene that functions by orchestrating interconnected angiogenic, inflammatory, metabolic, and immune-regulatory programs within the hepatic tumor microenvironment. AEG-1 regulates angiogenesis through modulation of VEGF-family signaling, NF-κB activation, hypoxia-responsive pathways, PI3K/AKT signaling, endothelial remodeling, and translational control of pro-angiogenic mediators. Emerging evidence further implicates AEG-1 in hypoxia adaptation, immune evasion, extracellular vesicle signaling, and metabolic reprogramming, supporting its role as a systems-level regulator of HCC angiogenesis. This review summarizes the current understanding of the molecular mechanisms through which AEG-1 regulates angiogenesis in HCC, discusses its interactions with the TME and anti-angiogenic resistance pathways, and highlights future translational opportunities for developing multi-targeted therapeutic strategies beyond conventional VEGF-centric approaches. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Background/Objectives: The prevalence and management options of bland (non-neoplastic) portal vein thrombosis (PVT) in patients with hepatocellular carcinoma (HCC) are poorly characterized and data remain limited. Methods: We performed a retrospective analysis of a prospectively collected single-center cohort of 638 patients with HCC. Bland PVT was identified at baseline or during follow-up. Treatment exposure was modeled as time-varying to account for differences in timing of anticoagulation initiation. Results: Bland PVT was identified in 39 patients (25 at baseline and 14 during follow-up). Patients with PVT showed features of more advanced portal hypertension (lower platelet count and higher prevalence of ascites) and had a higher tumor burden (more often outside the Milan criteria; higher AFP). A total of 30 patients received anticoagulation. Anticoagulation was associated with partial or complete recanalization in 30% of cases at three months and with decrease in bilirubin, but was not associated with improved 1 year survival. Bleeding events occurred in four anticoagulated patients (13.3%). Conclusions: Bland PVT in HCC is associated with more severe liver disease. Our data indicate that anticoagulation in patients with HCC and concomitant bland PVT was generally well-tolerated and was associated with thrombus regression in one-third of cases. However, we did not observe an improved survival in patients on anticoagulation. Full article

The new therapeutic options now available for patients with hepatocellular carcinoma (HCC) have made their assessment more complex, especially due to the different stages of liver cirrhosis typically associated with this tumor. The management of the disease therefore requires an interdisciplinary approach aimed at identifying the most appropriate treatment based on the risk–benefit profile and residual liver function, as well as in relation to the patient’s age and potential for a full or partial recovery, risk of complications, and cancer recurrence. Another factor to be carefully considered in patients with hepatocellular carcinoma is the frequent comorbidities and the associated socio-health variables (substance abuse, addictions, unfavorable economic or family circumstances), which can impact patient management or the possibilities for long-term monitoring, thus influencing the choice of the most appropriate therapeutic pathway. The healthcare services offered in the Province of Salerno (Campania Region, Southern Italy) to ensure all possible diagnostic and therapeutic options for these patients can be difficult to access due to the territorial extension of the Local Health Authority, characterized by clinics and hospitals located in distant locations, as well as the potential fragmentation of expertise between the University Hospital and ambulatorial facilities or small hospitals. An interdisciplinary consensus conference on the management of patients with HCC has been set with the aim of involving clinicians and surgeons working in healthcare facilities located in Salerno and its Province for the optimal care and effective management of these patients, taking into account all the clinical characteristics of the disease and individual health needs or expectations, from the perspective of personalized medicine. Full article

Background: Statins have pleiotropic anti-inflammatory, antifibrotic, and potential antineoplastic effects. Although several studies have linked statin exposure to lower hepatocellular carcinoma (HCC) incidence, their effect on survival after HCC diagnosis remains uncertain. We evaluated whether statin therapy before HCC diagnosis was associated with overall survival in a real-world cohort. Methods: We performed a retrospective single-center cohort study of consecutive patients with HCC managed at a tertiary referral center between January 2000 and January 2025. Demographic, clinical, laboratory, tumor-related, and treatment variables were collected at diagnosis and during follow-up. Patients were classified according to statin use before HCC diagnosis. Overall survival (OS) was assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Results: Overall, 190 patients were included; 172 (90.5%) were male, 136 (71.6%) had cirrhosis, and 42 (22.1%) received statins. Statin users more frequently had diabetes mellitus, elevated body mass index and arterial hypertension, but baseline liver function, alpha-fetoprotein levels, tumor burden, and treatment allocation were broadly comparable between groups. Among 159 patients with available survival data, statin users had longer OS than non-users (mean 82.5 vs. 41.7 months; median 57 vs. 31 months; log-rank p < 0.001). In univariate Cox analysis, statin therapy was associated with reduced mortality risk (HR 0.45, 95% CI 0.28–0.70, p < 0.001). This association remained significant across multivariable models adjusting for baseline liver function, tumor stage, vascular invasion, and diagnostic era. Conclusions: Pre-diagnostic statin therapy was independently associated with improved OS in patients with HCC. These hypothesis-generating findings warrant prospective multicenter validation and careful assessment of confounding by indication. Full article