Background
Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent ...resections for hepatocellular carcinoma (HCC).
Methods
We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation.
Results
LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8
+
T-cell counts than low LCR patients.
Conclusions
Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.
Small-for-size graft (SFSG) syndrome after living donor liver transplantation (LDLT) is the dysfunction of a small graft, characterized by coagulopathy, cholestasis, ascites, and encephalopathy. It ...is a serious complication of LDLT and usually triggered by excessive portal flow transmitted to the allograft in the postperfusion setting, resulting in sinusoidal congestion and hemorrhage. Portal overflow injures the liver directly through nutrient excess, endothelial activation, and sinusoidal shear stress, and indirectly through arterial vasoconstriction. These conditions may be attenuated with portal flow modulation. Attempts have been made to control excessive portal flow to the SFSG, including simultaneous splenectomy, splenic artery ligation, hemi-portocaval shunt, and pharmacological manipulation, with positive outcomes. Currently, a donor liver is considered a SFSG when the graft-to-recipient weight ratio is less than 0.8 or the ratio of the graft volume to the standard liver volume is less than 40%. A strategy for transplanting SFSG safely into recipients and avoiding extensive surgery in the living donor could effectively address the donor shortage. We review the literature and assess our current knowledge of and strategies for portal flow modulation in LDLT.
Hepatocellular carcinoma (HCC) is a common and deadly cancer. The prognosis of HCC is poor and is related to tumor progression. The malignant potential of HCC is regulated by the tumor ...microenvironment (TME). As cancer-associated fibroblasts (CAFs) help regulate tumor progression, understanding how they function in HCC could improve patient outcomes. The aim of this study was to determine whether specific microRNAs (miRNAs) in exosomes derived from CAFs might be involved in HCC progression.
MiRNA microarray assay was used to analyze miRNA profiles of exosomes derived from CAFs and normal fibroblasts (NFs) in HCC. Migration and invasion assays were performed to examine the effects of miR-150-3p on HCC in vitro. In addition, the relationships between prognosis of HCC patients and miR-150-3p expression in HCC tissues and plasma exosomes were retrospectively analyzed.
MiR-150-3p was significantly reduced in CAFs-derived exosomes, and inhibited HCC migration and invasiveness. MiR-150-3p was transferred from CAFs transfected miR-150-3p to HCC cells through exosomes, and abrogated HCC migration and invasiveness. Furthermore, low miR-150-3p expression in HCC tissues was a significant risk factor for recurrence in HCC patients. More importantly, survival rate in patients with low miR-150-3p levels in plasma exosomes was significantly poor compared with that in patients with high miR-150-3p levels.
Overall, our findings suggest that the loss of antitumoral miR-150-3p in CAFs-derived exosomes greatly promotes HCC progression. Exosomal miR-150-3p is a potential prognostic biomarker, and transferring miR-150-3p-loaded exosomes to HCC cells might become a novel therapeutic option.
•MiR-150-3p is reduced in the exosomes of CAFs derived from HCC specimens.•Evaluation of exosomal miR-150-3p could help stratify risk in patients with HCC.•Transfer of exosomal miR-150-3p to HCC cells may have therapeutic applications.
The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, ...the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage‐independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β‐lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α‐fetoprotein, and des‐γ‐carboxy‐prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P = .0073) and was an independent risk factor for poor prognosis (P = .0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage‐independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy.
Downregulation of NADPH quinone oxidoreductase 1 (Nqo1) in suspended culture promoted intracellular reactive oxygen species production and induced anoikis, resulting in attenuated spheroid formation. Activation of Nqo1 by β‐lapachone showed a similar effect on anoikis sensitivity and diminished spheroid formation. Overexpression of Nrf2/Nqo1 was associated with intrahepatic recurrence and was an independent risk factor for poor prognosis.
Since a 1989 report demonstrating successful living donor liver transplantation (LDLT), living donors have been increasingly used to overcome the disparity between organ supply and demand, especially ...in the cases of pediatric patients. Although short-term graft outcomes after LDLT have improved significantly because of progress in surgical techniques and immunosuppression, biliary stricture (BS) remains the Achilles heel of pediatric LDLT and is the major cause of significant long-term morbidity. BS results in poor quality of life or even in graft loss after LDLT, with a reported incidence of BS after pediatric LDLT of 10% to 35%. The suggested risk factors for BS after LDLT are hepatic arterial thrombosis, bile duct ischemia, acute cellular rejection, older donor age, and ABO incompatibility. Duct-to-duct biliary reconstruction, which enables an endoscopic approach to be attempted after BS, is the preferred technique for LDLT. Endoscopic approaches are less invasive and more convenient for recipients than surgical and percutaneous interventions. However, the major cause of end-stage liver disease in pediatric recipients is biliary atresia, and hepaticojejunostomy is needed to reconstruct the bile duct because of the lack of recipient bile duct. Endoscopic approaches for BS are usually less favorable in patients with hepaticojejunostomy than in those with duct-to-duct biliary reconstruction. Treatment options for BS after hepaticojejunostomy at many centers thus involve interventional radiology or surgical reintervention. Although endoscopic approaches remain controversial in pediatric recipients, several reports have shown them to be safe and less invasive.
Background & Aims Although the Milan criteria (MC) have been used to select liver transplantation candidates among patients with hepatocellular carcinoma (HCC), many patients exceeding the MC have ...shown good prognosis. Preoperative neutrophil–lymphocyte ratio (NLR) is a predictor of patient prognosis, but its mechanism has never been clarified. Methods We assessed outcomes in 158 patients who had undergone living-donor liver transplantation (LDLT) for HCC. Recurrence-free survival (RFS) was determined in patients with high (⩾4) and low (<4) NLR. Levels of expression of vascular endothelial growth factor (VEGF), interleukin (IL)-8, IL-17, CD68, and CD163 were measured. Results The 5-year RFS rate was significantly lower in patients with high (n = 26) than with low (n = 132) NLR (30.3% vs . 89.0%, p < 0.0001), in patients with high (n = 15) than with low (n = 79) NLR who met the MC (73.6% vs. 100%, p = 0.0008) and in patients with high (n = 11) than with low (n = 53) NLR who exceeded the MC (0% vs. 76.1%, p = 0.0002). Tumor expression of VEGF, IL8, IL-17, CD68, and CD163 was similar in the high and low NLR groups, but serum and peritumoral IL-17 levels were significantly higher in the high-NLR group ( p = 0.01 each). The density of peritumoral CD163 correlated with the density of peritumoral IL-17-producing cells ( p = 0.04) and was significantly higher in the high-NLR group ( p = 0.005). Conclusions NLR predicts outcomes after LDLT for HCC via the inflammatory tumor microenvironment. Combined with the MC, NLR may be a new criterion for LDLT candidates with HCC.
The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron‐dependent accumulation of lethal lipid ...reactive oxygen species (ROS). Nuclear factor erythroid‐derived 2‐like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib‐induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib‐induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor‐4 (FGFR4) or Nrf2 and overexpressing‐Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system Xc− (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing‐FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2‐silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2‐overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low‐FGFR4 expression than in those with high‐FGFR4 expression. Patients with FGFR4‐positive HCC displayed significantly longer progression‐free survival than those with FGFR4‐negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.
Regulation of ferroptosis by fibroblast growth factor receptor 4 (FGFR4) and nuclear factor erythroid‐derived 2‐like 2 (Nrf2) in hepatocellular carcinoma GPX4, glutathione peroxidase 4.
Background
Virtual touch tissue quantification (VTTQ) based on acoustic radiation force impulse (ARFI) imaging has been developed as a noninvasive bedside method for the assessment of liver ...stiffness. In this study, we examined the diagnostic performance of ARFI imaging in 103 patients, focusing on the difference in VTTQ values between the right and left liver lobes.
Methods
We evaluated VTTQ values of the right and left lobes in 79 patients with chronic liver disease who underwent histological examination of liver fibrosis and in 24 healthy volunteers. The diagnostic accuracy of VTTQ was compared with several serum markers, including hyaluronic acid, type 4 collagen, and aspartate transaminase to platelet ratio index.
Results
The VTTQ values (meters per second) in the right and left lobes were 1.61 ± 0.51 and 1.90 ± 0.68, respectively, and the difference was statistically significant (
P
< 0.0001). The VTTQ values in both liver lobes were correlated significantly with histological fibrosis grades (
P
< 0.001). The standard deviations of the VTTQ values in the right lobe were significantly lower than those in the left lobe (
P
< 0.001). The area under the receiver-operating characteristic curve for the diagnosis of fibrosis (
F
≥ 3) using VTTQ values in both liver lobes was superior to serum markers, especially in the right lobe.
Conclusions
VTTQ is an accurate and reliable tool for the assessment of liver fibrosis. VTTQ of the right lobe was more accurate for diagnosing liver fibrosis than in the left lobe.
Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor ...microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = −0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.
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