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Background: The effect of anti-viral treatment (AVT) initiated before surgery (pre-operative AVT) on HBV-related hepatocellular carcinoma (HCC) has been controversial. This study aimed to elucidate the prognostic significance of pre-operative AVT for HCC patients who received hepatectomy. Materials and Methods: A large-scale retrospective study was conducted based on a cohort consisting of 1937 HBV-related HCC patients who underwent R0 liver resection between January 2011 and December 2012. Propensity score matching (PSM) method was adopted to balance covariates and landmark survival analyses were performed to visualize effects in different phases after surgery. Results: After PSM, a total of matched 744 patients (372 in each group) were recruited. The patients in the pre-operative AVT group had lower HBV-DNA loading levels and better recurrence-free survival (RFS) than those in the non-AVT group. The 1, 3, 5-year RFS rates of two groups were 67.3%, 49.0%, and 43.1% vs. 66.7%, 41.1% and 18.5%, respectively (P5cm), esophageal and gastric varices, lymph node metastasis were independent risk factors of RFS, and larger tumor (>5cm) and ascites were independent risk factors of OS. Conclusions: Pre-operative AVT could significantly improve the RFS, and could not improve short-term OS (< 36 months) but could better long-term survival of the patients with HBV-HCC after surgery.

Background: This study developed a novel inflammation score system to predict survival outcomes using preoperational inflammatory markers in hepatocellular carcinoma (HCC) after surgery. Materials and Methods: An inflammation score system was developed using five preoperative inflammatory markers based on the clinical data of 455 HCC patients (training cohort) receiving radical resection in the Eastern Hepatobiliary Surgery Hospital. The system was validated using a cohort from a different hospital (external validation). Kaplan-Meier curves and log-rank test were used to compare the survival of patients with different inflammation scores. A nomogram including inflammation scores for survival prediction was created to exhibit the risk factors of overall survival (OS). Results: The patients in the low-score group showed better OS and recurrence-free survival (RFS) in the training and external validation cohorts than those from the high-score group. Subgroup analysis showed that compared with patients in the training cohort from the high-score group, stage I (eighth TNM stage) patients in the low-score group exhibited better prognosis results, whereas the findings for Stage II and III patients were different. Multivariate Cox analysis revealed that high inflammation score is an independent risk factor of OS and RFS. The nomogram established using the inflammation score with the C-index value of 0.661 (95% confidence interval=0.624-0.698) revealed a good three- and five-year calibration curves. Conclusions: The inflammation score system based on five preoperative inflammatory markers well predicted the survival of HCC patients after surgery, especially in those at the early stage (Stage I).

Background Inflammation is implicated in tumorigenesis and has been reported as an important prognostic factor in cancers. In this study, we aimed to develop and validate a novel inflammation score (IFS) system based on 12 inflammatory markers and explore its impact on intrahepatic cholangiocarcinoma (ICC) survival after hepatectomy. Methods Clinical data of 446 ICC patients undergoing surgical treatment were collected from the Primary Liver Cancer Big Data, and then served as a training cohort to establish the IFS. Furthermore, an internal validation cohort including 175 patients was used as internal validation cohort of the IFS. A survival tree analysis was used to divide ICC patients into three groups (low-, median-, and high- IFS-score groups) according to different IFS values. Kaplan-Meier (KM) curves were used to compare the overall survival (OS) and recurrence-free survival (RFS) rates among three different groups. Cox regression analyses were applied to explore the independent risk factors influencing OS and RFS. Results In the training cohort, 149 patients were in the low-IFS-score group, 187 in the median-IFS-score group, and 110 in the high-IFS-score group. KM curves showed that the high-IFS-score group had worse OS and RFS rates than those of the low- and median-IFS-score groups (P Conclusion Our results revealed the IFS was an independent risk factor for OS and RFS in patients with ICC after hepatectomy and could serve as an effective prognostic prediction system in daily clinical practice.

Background Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA. Method Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein–protein interaction (PPI) network analysis. Validation studies were conducted to detect the “real” hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments. Results A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway. Conclusions ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with aggressive biological behaviour. Its rapid proliferation and tumour growth require reprogramming of glucose metabolism or the Warburg effect. However, the association between glycolysis‐related genes with clinical features and prognosis of PDAC is still unknown. Here, we used the meta‐analysis to correlate the hazard ratios (HR) of 106 glycolysis genes from MSigDB by the cox proportional hazards regression analysis in 6 clinical data sets of PDAC patients to form a training cohort, and a single group of PDAC patients from the TCGA, ICGC, Arrayexpress and GEO databases to form the validation cohort. Then, a glycolysis‐related prognosis (GRP) score based on 29 glycolysis prognostic genes was established in 757 PDAC patients from the training composite cohort and validated in 267 ICGC‐CA validation cohort (all P

Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with high aggressiveness and extremely poor prognosis. The role of circular RNAs (circRNAs) in ICC carcinogenesis and progression remains to be determined.CircRNA microarray was performed to screen significantly upregulated circRNAs in paired ICC and non-tumor tissues. Colony formation, transwell, and xenograft models were used to examine the role of circRNAs in ICC proliferation and metastasis. RNA pulldown, mass spectrometry, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, chromatin isolation by RNA purification, electrophoretic mobility shift assay, and luciferase reporter assays were used to explore the molecular sponge role of the circRNA (via miRNA binding), and the interaction between circRNA and RNA-binding proteins.Hsa_circ_0050898, which originated from exon 1 to exon 20 of the ACTN4 gene (named circACTN4), was significantly upregulated in ICC. High circACTN4 expression was associated with enhanced tumor proliferation and metastasis in vitro and in vivo, as well as a worse prognosis following ICC resection. In addition, circACTN4 upregulated Yes-associated protein 1 (YAP1) expression by sponging miR-424-5p. More importantly, circACTN4 also recruited Y-box binding protein 1 (YBX1) to stimulate Frizzled-7 (FZD7) transcription. Furthermore, circACTN4 overexpression in ICC cells enhanced the interaction between YAP1 and β-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively.CircACTN4 was upregulated in ICC and promoted ICC proliferation and metastasis by acting as a molecular sponge of miR-424-5p, as well as by interacting with YBX1 to transcriptionally activate FZD7. These results suggest that circACTN4 is a potential prognostic marker and therapeutic target for ICC.Intrahepatic cholangiocarcinoma is a primary liver cancer associated with aggressiveness and extremely poor prognosis. It is essential for therapeutic development that we uncover relevant pathogenic pathways. Herein, we showed that a circular RNA (circACTN4) was highly expressed in intrahepatic cholangiocarcinoma and was positively associated with tumor growth and metastasis through key developmental signaling pathways. Thus, circACTN4 could be a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.

Additional file 2: Figure S1. (A) Analysis of the mean connectivity for various soft-thresholding powers (b). Mean connectivity (y-axis) is a strictly decreasing function of the power b (x-axis). (B) Clustering of MEs. MEDissTres was set as 0.24 to merge similar modules. The red and yellow modules were merged into the new red module, which was selected as the hub module in our research. (C) Heatmap of the adjacencies in the hub gene network. (D) PPI network of all genes in the red module. (E) qRT-PCR results for ESR1, A2M, S1PR1, HGF, VDR, RAPGEF4 and STAB2. (F) IHC results for A2M and RAPGEF4 in iCCA tissues and normal liver tissues based on the Human Protein Atlas database. A2M and RAPGEF4 were significantly overexpressed in normal liver tissue vs. iCCA tissue.

Long non-coding RNAs (lncRNAs) have extremely complex roles in the progression of intrahepatic cholangiocarcinoma (ICC) and remain to be elucidated. By cytological and animal model experiments, this study demonstrated that the expression of lncRNA MNX1-AS1 was remarkably elevated in ICC cell lines and tissues, and was highly and positively correlated with motor neuron and pancreas homeobox protein 1 (MNX1) expression. MNX1-AS1 significantly facilitated the proliferation, migration, invasion, and angiogenesis in ICC cells in vitro, and remarkably promoted tumor growth and metastasis in vivo. Further study revealed that MNX1-AS1 promoted the expression of MNX1 via recruiting transcription factors c-Myc and myc-associated zinc finger protein (MAZ). Furthermore, MNX1 upregulated the expression of Ajuba protein via binding to its promoter region, and subsequently, Ajuba protein suppressed the Hippo signaling pathway. Taken together, our results uncovered that MNX1-AS1 can facilitate ICC progression via MNX1-AS1/c-Myc and MAZ/MNX1/Ajuba/Hippo pathway, suggesting that MNX1-AS1 may be able to serve as a potential target for ICC treatment.

Background: This study aimed to establish a model predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) patients with cirrhosis before liver resection (LR). Methods: An Eastern Hepatobiliary Surgery Hospital (EHBH) model using the preoperative factors was established in a training cohort (305 patients from 2006 to 2011) and validated in an internal validation cohort (113 patients from 2012 to 2014). Predictive performance and discrimination were evaluated and compared with other staging systems. Results: The EHBH model containing preoperative factors of carbohydrate antigen 19-9 (CA19-9), radiological tumor diameter, tumor number, and satellite nodules outperformed other staging systems in predicting the prognosis of ICC. A contour plot of 3-year survival probability and a nomogram to form two differentiated groups of patients (high-risk group and low-risk group) were constructed based on the EHBH model to help surgeons predicting the overall survival (OS) before LR. Patients from the high-risk group (>86.56 points) in the training cohort had worse OS rates compared with those from the low-risk group (≤86.56 points). The one-, three-, and five-year OS rates were 50.4%, 29.0%, and 21.0% for the high-risk group and 68.2%, 45.5%, and 39.7% for the low-risk group, respectively (P

Background: Prognosis remains poor for hepatocellular carcinoma (HCC) patients with extrahepatic metastases (EHMs). This study aimed to develop a nomogram to predict EHMs in HCC patients who underwent adjuvant transarterial chemoembolization (TACE) following hepatectomy. Methods: Data of 578 HCC patients who underwent TACE after hepatectomy at the Eastern Hepatobiliary Surgery Hospital was retrospectively reviewed. Cox regression analyses was used to select variables to construct the nomogram. Predictive accuracy and discriminative ability of the model were performed using concordance index (C-index), calibration curve and the area under time-dependent receiver operating characteristic (ROC) curve. Results: Postoperative EHMs were detected in 89 and 31 patients in the training cohort (n = 453) and validation cohort (n = 125), respectively. Multivariate analysis showed that tumor size (HR, 1.099; 95% CI, 1.049-1.152), coarse beam type of tumor histopathological structure (HR, 2.382; 95% CI, 1.030-5.512), presence of satellite nodules (HR, 1.936; 95% CI, 1.156-3.244) and alpha-fetoprotein (AFP) (HR, 1.399; 95% CI, 1.098-1.783) were independent risk factors for EHMs (all p < 0.05). The nomogram incorporated these factors achieved good agreement between prediction and actual observation with a concordance index (C-index) of 0.73 (95% CI, 0.68 to 0.78) and 0.71 (95% CI, 0.63 to 0.79) in the training cohort and validation cohort, respectively. In addition, patients who had a nomogram score > 17 were considered to have higher risk for EHMs compared with those scored ≤ 12. Furthermore, the time-dependent area under the ROC curve indicated comparative stability and adequate discriminative ability of the model. Conclusions: This novel nomogram can identify those with high risk of EHMs after adjuvant TACE following hepatectomy. The validation cohort showed a good performance, suggesting it could benefit surgeons on decision-making.