Long-term surgical outcomes of bile duct tumor thrombus versus portal vein tumor thrombus for hepatocellular carcinoma: a propensity score matching analysis.

Background: Portal vein tumor thrombus (PVTT) seriously affects the prognosis of hepatocellular carcinoma (HCC). However, whether bile duct tumor thrombus (BDTT) significantly affects the prognosis of HCC as much as PVTT remains unclear. We aimed to compare the long-term surgical outcomes of HCC with macroscopic PVTT (macro-PVTT) and macroscopic BDTT (macro-BDTT). Methods: The data of HCC patients with macro-BDTT or macro-PVTT who underwent hemihepatectomy were retrospectively reviewed. A propensity score matching (PSM) analysis was performed to reduce the baseline imbalance. The recurrence-free survival (RFS) and overall survival (OS) rates were compared between the cohorts. Results: Before PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.043 and P = 0.008, respectively). Multivariate analyses identified PVTT (hazard ratio [HR] = 1.835, P = 0.016) and large HCC (HR = 1.553, P = 0.039) as independent risk factors for poor OS and RFS, respectively. After PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.037 and P = 0.004, respectively). The 3- and 5-year OS rates were significantly higher in the BDTT group (59.5% and 52.1%, respectively) than in the PVTT group (33.3% and 20.2%, respectively). Conclusion: Aggressive hemihepatectomy provides an acceptable prognosis for HCC patients with macro-BDTT. Furthermore, the long-term surgical outcomes of HCC patients with macro-BDTT were significantly better than those of HCC patients with macro-PVTT.

Surgical outcomes of hepatocellular carcinoma with extrahepatic bile duct tumor thrombus: a multicenter study.

Background: The long-term prognosis after surgery of patients with hepatocellular carcinoma (HCC) and extrahepatic bile duct tumor thrombus (Ex-BDTT) remains unknown. We aimed to identify the surgical outcomes of patients with HCC and Ex-BDTT. Methods: A total of 138 patients with Ex-BDTT who underwent hepatectomy with preservation of the extrahepatic bile duct from five large hospitals in China between January 2009 and December 2017 were included. The Cox proportional hazards model was used to analyze overall survival (OS) and recurrence-free survival (RFS). Results: With a median follow-up of 60 months (range, 1-127.8 months), the median OS and RFS of the patients were 28.6 and 8.9 months, respectively. The 1-, 3-, and 5-year OS rates of HCC patients with Ex-BDTT were 71.7%, 41.2%, and 33.5%, respectively, and the corresponding RFS rates were 43.5%, 21.7%, and 20.0%, respectively. Multivariate analysis identified that major hepatectomy, R0 resection, and major vascular invasion were independent prognostic factors for OS and RFS. In addition, preoperative serum total bilirubin ≥ 4.2 mg/dL was an independent prognostic factor for RFS. Conclusion: Major hepatectomy with preservation of the extrahepatic bile duct can provide favorable long-term survival for HCC patients with Ex-BDTT.

Early Tumor Marker Response Predicts Treatment Outcomes in Patients with Unresectable Hepatocellular Carcinoma Receiving Combined Lenvatinib, Immune Checkpoint Inhibitors, and Transcatheter Arterial Chemoembolization Therapy.

Purpose: Few reliable biomarkers for predicting the efficacy of triple therapy (lenvatinib + immune checkpoint inhibitors + transarterial chemoembolization) exist for patients with unresectable hepatocellular carcinoma (uHCC). This study explored the prognostic role of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) levels in patients with uHCC receiving triple therapy. Patients and Methods: This retrospective study included 93 patients with uHCC who received triple therapy at Fujian Provincial Hospital between August 2020 and November 2022. Depending on the respective baseline levels, the patients were divided into high-AFP and high-DCP groups. An early response was defined as an AFP or DCP concentration >50% less than the baseline concentration after 6 weeks of triple therapy. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: After 6 weeks of triple therapy, 75.3% (58/77) and 78.9% (60/76) of patients in the high-AFP and high-DCP groups achieved an objective response. Early AFP and DCP responses were positively associated with ORR (high-AFP group: odds ratio [OR]: 13.542; 95% confidence interval [CI]: 3.991-45.950, p<0.001; high-DCP group: OR: 17.853; 95% CI: 4.478-71.179, p<0.001). In the high-AFP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the AFP responders than those in the non-responders (PFS: 66.4%, 59.6%, 48.2% vs 42.3%, 19.3%, 0%, p<0.001; OS: 94.5%, 90.4%, 77.3% vs 75.6%, 66.2%, 49.6%, p=0.006). In the high-DCP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the DCP responders than those in the non-responders (PFS: 67.4%, 57.7%, 39.0% vs 38.9%, 8.1%, 0%, p<0.001; OS: 94.7%, 94.7%, 83.3% vs 77.0%, 53.9%, 36.0%, p<0.001). Conclusion: After 6 weeks of triple therapy, an AFP or DCP reduction of >50% predicts better treatment outcomes in uHCC patients.

Activin A stimulates the proliferation and differentiation of cardiac fibroblasts via the ERK1/2 and p38-MAPK pathways.

Activin A is a key regulator of cardiac fibrosis. However, little is known about the mechanisms by which it contributes to cardiac fibrosis. Our study explored the effects of activin A on proliferation and differentiation of adult rat cardiac fibroblasts (CFs) via the activin A receptor, activin receptor-like kinase 4 (ALK4). CF proliferation was measured by CCK8 and EdU assays, while differentiation, fibrosis and signaling were measured by western blot analysis of α-smooth muscle actin, collagen type I, phosphorylated extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38-MAPK) expression. Activin A levels were measured by ELISA and western blot analysis. We demonstrated that CFs express activin A and its expression was significantly enhanced by angiotensin II (Ang II), but follistatin (activin A inhibitor) significantly reversed Ang II-induced activin A upregulation, CF proliferation, differentiation, collagen type I expression as well as ERK1/2 and p38-MAPK pathways activation. Conversely, recombinant activin A largely increased these parameters in both the presence and absence of Ang II. Interestingly, p38-MAPK (SB203580) and ALK4 (SB431542) inhibitors significantly reduced all activin A-mediated responses; however, an ERK1/2 inhibitor (PD98059) could only significantly reduce CF proliferation and collagen type I expression but not differentiation. Importantly, the most significant effects were observed in the presence vs. absence of Ang II. Thus, activin A promotes basal and Ang II-induced CF proliferation and differentiation via ALK4, and the effects are partly mediated through the ERK1/2 and p38-MAPK pathways. These data suggest that activin A is a potential therapeutic target for cardiac fibrosis.

Ca(2+)-inactivated K+ current is modulated by endothelin-1 in B-16 murine melanoma cells.

It is well established that endothelin-1 (ET-1) plays a role in differentiation and proliferation in a variety of cells such as fibroblasts and human melanoma cells via a receptor-mediated mechanism. However, whether ET-1 modulates ion channel activity in these cell types is still unknown. In this report, we recorded the voltage-dependent outward K+ current in cultured B16 melanoma cells using the patch-clamp technique. Biophysical and pharmacological properties of the K+ current, and the effect of ET-1 on the K+ current were investigated. When cells were loaded with a Ca(2+)-chelating agent (EGTA or BAPTA), the K+ current amplitude gradually increased with time after establishment of the whole cell configuration. Replacement of Ca2+ with Co2+ in the extracellular medium caused no significant modulation of the K+ current amplitude. Addition of BaCl2 or quinidine to the extracellular solution reduced the K+ current amplitude, whereas the K+ current was insensitive to tetraethylammonium. ET-1 (10 nM) reversibly decreased the K+ current amplitude and accelerated the decay of the K+ current. The ET-1-induced inhibitory effect displayed no desensitization following repeated ET-1 application. Pretreatment with pertussis toxin (PTX) or perfusion of cells with the protein kinase C (PKC) inhibitor H-7 abolished the inhibitory effect of ET-1 on the K+ current. We conclude that the outward K+ current recorded in murine B-16 melanoma cells represents a Ca(2+)-inactivated K+ current, and that the inhibitory effect of ET-1 on the K+ current may reveal a novel mechanism to control the differentiation and proliferation of melanoma cells.