Objectives
This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its ...prognostic value.
Methods
For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients.
Results
The radiomics signature comprised eight LN-status–related features and showed significant association with LN metastasis in both cohorts (
p
< 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both
p
< 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival.
Conclusions
Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making.
Key Points
• The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup.
• Prognosis of high-risk patients remains dismal after curative-intent resection.
• The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.
Current guidelines recommend surgical resection as the first-line option for patients with solitary hepatocellular carcinoma (HCC); unfortunately, postoperative recurrence rate remains high and there ...is no reliable prediction tool. We explored the potential of radiomics coupled with machine-learning algorithms to improve the predictive accuracy for HCC recurrence.
A total of 470 patients who underwent contrast-enhanced CT and curative resection for solitary HCC were recruited from 3 independent institutions. In the training phase of 210 patients from Institution 1, a radiomics-derived signature was generated based on 3384 engineered features extracted from primary tumor and its periphery using aggregated machine-learning framework. We employed Cox modeling to build predictive models. The models were then validated using an internal dataset of 107 patients and an external dataset of 153 patients from Institution 2 and 3.
Using the machine-learning framework, we identified a three-feature signature that demonstrated favorable prediction of HCC recurrence across all datasets, with C-index of 0.633–0.699. Serum alpha-fetoprotein, albumin-bilirubin grade, liver cirrhosis, tumor margin, and radiomics signature were selected for preoperative model; postoperative model incorporated satellite nodules into above-mentioned predictors. The two models showed superior prognostic performance, with C-index of 0.733–0.801 and integrated Brier score of 0.147–0.165, compared with rival models without radiomics and widely used staging systems (all P < 0.05); they also gave three risk strata for recurrence with distinct recurrence patterns.
When integrated with clinical data sources, our three-feature radiomics signature promises to accurately predict individual recurrence risk that may facilitate personalized HCC management.
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•We identified a three-feature fusion signature using machine-learning framework.•The signature coupled with clinical sources accurately predicted HCC recurrence.•This signature may serve as an early detector of aggressive disease.•We highlight the complementary nature of radiomics and existing variables.
Background and Aims
Apolipoprotein A‐1 (ApoA‐1), the major apolipoprotein of high‐density lipoprotein, plays anti‐atherogenic role in cardiovascular diseases and exerts anti‐inflammation effect in ...various inflammatory and infectious diseases. However, the role and mechanism of ApoA‐1 in hepatic ischaemia–reperfusion (I/R) injury is unknown.
Methods
In this study, we measured ApoA‐1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA‐1 knockout mice, ApoA‐1 mimetic peptide D‐4F treatment mice and corresponding control mice to examine the effect of ApoA‐1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study.
Results
The results showed that ApoA‐1 expression was down‐regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA‐1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA‐1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA‐1 deficiency. Furthermore, the up‐regulated pyroptosis process was testified to be mediated by ApoA‐1 through TLR4–NF‐κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D‐4F ameliorated hepatic I/R injury.
Conclusions
Our study has identified the protective role of ApoA‐1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4–NF‐κB pathway. The effect of ApoA‐1 may provide a novel therapeutic approach for hepatic I/R injury.
Accurate prognosis assessment is essential for surgically resected intrahepatic cholangiocarcinoma (ICC) while published prognostic tools are limited by modest performance. We therefore aimed to ...establish a novel model to predict survival in resected ICC based on readily-available clinical parameters using machine learning technique.
A gradient boosting machine (GBM) was trained and validated to predict the likelihood of cancer-specific survival (CSS) on data from a Chinese hospital-based database using nested cross-validation, and then tested on the Surveillance, Epidemiology, and End Results (SEER) database. The performance of GBM model was compared with that of proposed prognostic score and staging system.
A total of 1050 ICC patients (401 from China and 649 from SEER) treated with resection were included. Seven covariates were identified and entered into the GBM model: age, tumor size, tumor number, vascular invasion, number of regional lymph node metastasis, histological grade, and type of surgery. The GBM model predicted CSS with C-Statistics ≥ 0.72 and outperformed proposed prognostic score or system across study cohorts, even in sub-cohort with missing data. Calibration plots of predicted probabilities against observed survival rates indicated excellent concordance. Decision curve analysis demonstrated that the model had high clinical utility. The GBM model was able to stratify 5-year CSS ranging from over 54% in low-risk subset to 0% in high-risk subset.
We trained and validated a GBM model that allows a more accurate estimation of patient survival after resection compared with other prognostic indices. Such a model is readily integrated into a decision-support electronic health record system, and may improve therapeutic strategies for patients with resected ICC.
Hypoxia is a hallmark of cancer, and is closely intertwined with tumor immune evasion. Circular RNAs (circRNAs) have been implicated in tumor response to immune checkpoint blockades. However, ...hypoxia-associated circRNAs that orchestrate the association between hypoxia and response to immunotherapy remain poorly understood. Here, we aimed to determine the roles of hypoxia-associated circRNAs in immune escape of hepatocellular carcinoma (HCC) cells.
Differentially expressed hypoxia-associated circRNAs were determined using high-throughput sequencing technology. HCC patients treated with PD-1 blockade were enrolled to assess the clinical significance of circPRDM4. RT-qPCR, western blotting, flow cytometry, T cell-mediated tumor cell killing assay, and enzyme linked immunosorbent assay were used to investigate the roles of circPRDM4 in immune escape of HCC cells in vitro. Patient-derived xenograft mouse models and adoptive human tumor infiltrating lymphocyte-CD8
T cell transfer were adopted to evaluate the effects of circPRDM4 in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin isolation by RNA purification, dual-luciferase reporter assays, dot blotting, DNA in situ hybridization, and immunoprecipitation were utilized to examine the interaction between circPRDM4, HIF-1α, and CD274 promoter.
We identified circPRDM4 as a hypoxia-associated circRNA in HCC. circPRDM4 was upregulated in responders to PD-1 blockade and associated with therapeutic efficacy. In vitro and in vivo experiments showed that circPRDM4 induced PD-L1 expression and promoted CD8
T cell-mediated immune escape under hypoxic conditions. Mechanistically, circPRDM4 acted as a scaffold to recruit HIF-1α onto CD274 promoter, and cemented their interaction, ultimately promoting the HIF-1α-mediated transactivation of PD-L1.
These findings illustrated that circPRDM4 promoted immune escape of HCC cells by facilitating the recruitment of HIF-1α onto the promoter of CD274 under hypoxia, thereby inhibiting CD8
T cell infiltration in the tumor microenvironment. This work may provide a novel prognostic biomarker and therapeutic candidate for HCC immunotherapy.
Background
This study aimed to compare clinical outcomes of the middle hepatic vein (MHV)‐oriented versus conventional hemihepatectomy for perihilar cholangiocarcinoma (PHC).
Methods
From 2008 to ...2017, medical records of patients undergoing hemihepatectomy with caudate lobectomy for advanced PHC were reviewed retrospectively. MHV‐oriented hepatectomy was defined as full exposure of the MHV on the dissection plane. Predictors of morbidity and survival were identified.
Results
A total of 125 patients were enrolled. MHV‐oriented and conventional hepatectomies were performed in 44 and 81 patients, respectively. The curative resection rate, blood loss, transfusion, and survival were comparable between two groups; however, severe morbidity rate was significantly lower in the MHV‐oriented group (9.1% vs 38.3%, P < 0.001). MHV‐oriented approach was an independent predictor of severe morbidity, as were the age, bilirubin level, and blood transfusion. Severe morbidity was associated with significantly decreased overall survival and recurrence‐free survival (RFS) (median 29.0 vs 46.9 months, P = 0.011 and 20.3 vs 31.1 months, P = 0.003, respectively). Multivariate analysis revealed that severe morbidity independently predicted shorter RFS (P = 0.025).
Conclusions
MHV‐oriented approach for advanced PHC is safe and associated with a significant decrease in severe morbidity. Severe morbidity adversely affects survival after surgery; therefore, optimal preoperative preparation and MHV‐oriented hepatectomy with meticulous dissection remain of critical importance.
The first human orthotopic liver transplantation was performed by Starzl in the 1960s.1 According to the U.S. Department of Health and Human Services Organ Procurement and Transplantation Network, ...>5000 orthotopic liver transplantations have been performed per year since 2000,2 and data from the China Liver Transplantation Registry suggest that more than 20000 liver transplantations have been performed in China to date. It is clear that liver transplantation,as the only curative therapeutic method for patients with end-stage liver disease, brings the hope of survival for a large number of patients. Due to the complexity of liver transplantation, the associated trauma and the influence of the primary disease, patients often need to stay in the intensive care unit (ICU) and hospital for long-term treatment postoperatively.Fast-track surgery was
•Caleosins in Arabidopsis are divided into two types, L-caleosin and H-caleosin.•L-caleosin may evolve from H-caleosin.•Segmental and tandem duplication are main reasons for caleosin family ...expansion.•The expression patterns of caleosins were investigated in silico.•Caleosin may be involved in signal transduction and lipid accumulation.
Caleosin is a common lipid-droplet surface protein, which has the ability to bind calcium. Arabidopsis (Arabidopsis thaliana) is considered a model organism in plant researches. Although there are growing researches about caleosin in the past few years, a systemic analysis of caleosins in Arabidopsis is still scarce. In this study, a comprehensive investigation of caleosins in Arabidopsis was performed by bioinformatics methods. Firstly, eight caleosins in Arabidopsis are divided into two types, L-caleosin and H-caleosin, according to their molecular weights, and these two types of caleosin have many differences in characteristics. Secondly, phylogenetic tree result indicates that L-caleosin may evolve from H-caleosin. Thirdly, duplication pattern analysis shows that segmental and tandem duplication are main reasons for Arabidopsis caleosin expansion with the equal part. Fourthly, the expression profiles of caleosins are also investigated in silico in different organs and under various stresses and hormones. In addition, based on promoter analysis, caleosin may be involved in calcium signal transduction and lipid accumulation. Thus, the classification and expression analysis of caleosin genes in Arabidopsis provide facilities to the research of phylogeny and functions in this gene family.
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