Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis.

PURPOSE: The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy. METHODS: Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl4). RESULTS: Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment. CONCLUSION: Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.

A novel remnant liver-first strategy for liver autotransplantation in patients with end-stage hepatic alveolar echinococcosis: a retrospective case series.

BACKGROUND: Ex vivo liver resection combined with autotransplantation is an effective therapeutic strategy for unresectable end-stage hepatic alveolar echinococcosis (HAE). However, ex vivo liver resection combined with autotransplantation is a technically demanding and time-consuming procedure associated with significant morbidity and mortality. The authors aimed to present our novel remnant liver-first strategy of in vivo liver resection combined with autotransplantation (IRAT) technique for treating patients with end-stage HAE. METHODS: This retrospective study included patients who underwent IRAT between January 2014 and December 2020 at two institutions. Patients with end-stage HAE were carefully assessed for IRAT by a multidisciplinary team. The safety, feasibility, and outcomes of this novel technique were analyzed. RESULTS: IRAT was successfully performed in six patients, with no perioperative deaths. The median operative time was 537.5 min (range, 501.3-580.0), the median anhepatic time was 59.0 min (range, 54.0-65.5), and the median cold ischemia time was 165.0 min (range, 153.8-201.5). The median intraoperative blood loss was 700.0 ml (range, 475.0-950.0). In-hospital complications occurred in two patients. No Clavien-Dindo grade III or higher complications were observed. At a median follow-up of 18.6 months (range, 15.4-76.0) , all patients were alive. No recurrence of HAE was observed. CONCLUSION: The remnant liver-first strategy of IRAT is feasible and safe for selected patients with end-stage HAE. The widespread adoption of this novel technique requires further studies to standardize the operative procedure and identify patients who are most likely to benefit from it.

Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury.

Oxygen-dependent preservation has been proposed to protect liver grafts from ischemia-reperfusion injury (IRI), but its underlying mechanism remains elusive. Here, we proposed an oxygen-carrying sequential preservation (OCSP) method that combined oxygenated static cold storage (SCS) and normothermic mechanical perfusion. We demonstrated that OCSP, especially with high oxygen partial pressure level (500-650mmHg) during the oxygenated SCS phase, was associated with decreased IRI of liver grafts and improved rat survival after transplantation. A negative correlation between autophagy and endoplasmic reticulum stress response (ERSR) was found under OCSP and functional studies indicated OCSP suppressed ERSR-mediated cell apoptosis through autophagy activation. Further data showed that OCSP-induced autophagy activation and ERSR inhibition were oxygen-dependent. Finally, activated NFE2L2-HMOX1 signaling was found to induce autophagy under OCSP. Together, our findings indicate oxygen-dependent autophagy mitigates liver graft's IRI by ERSR suppression and modulates NFE2L2-HMOX1 signaling under OCSP, providing a theoretical basis for liver preservation using a composite-sequential mode.

HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation.

BACKGROUND & AIMS: The contribution of abnormal metabolic targets to hepatocellular carcinoma (HCC) progression and the associated regulatory mechanisms are attractive research areas. High-density lipoprotein binding protein (HDLBP) is an important transporter that protects cells from excessive cholesterol accumulation, but few studies have identified a role for HDLBP in HCC progression. METHODS: HDLBP expression was determined in HCC tissues and published datasets. The biological roles of HDLBP in vitro and in vivo were examined by performing a series of functional experiments. RESULTS: An integrated analysis confirmed that HDLBP expression was significantly elevated in HCC compared with noncancerous liver tissues. The knockdown or overexpression of HDLBP substantially inhibited or enhanced, respectively, HCC proliferation and sorafenib resistance. Subsequently, a mass spectrometry screen identified RAF1 as a potential downstream target of HDLBP. Mechanistically, when RAF1 was stabilized by HDLBP, MEKK1 continuously induced RAF1Ser259-dependent MAPK signaling. Meanwhile, HDLBP interacted with RAF1 by competing with the TRIM71 E3 ligase and inhibited RAF1 degradation through the ubiquitin-proteasome pathway. CONCLUSIONS: Our study reveals that HDLBP is an important mediator that stabilizes the RAF1 protein and maintains its activity, leading to HCC progression and sorafenib resistance. Thus, HDLBP might represent a potential biomarker and future therapeutic target for HCC.

HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma.

Recent studies have suggested that exploring the potential mechanisms regulating ferroptosis vulnerability may contribute to improving the systemic therapeutic efficacy in HCC. High-density lipoprotein-binding protein (HDLBP), the largest RNA-binding protein, is an important transporter that protects cells from overaccumulation of cholesterol, but few studies have elucidated the role of HDLBP in the regulation of ferroptosis vulnerability in HCC. Our study suggests that HDLBP was markedly elevated in HCC compared with noncancerous liver tissues and that this elevation inhibited the ferroptosis vulnerability of HCC. Further experiments revealed that HDLBP bound to and stabilized the long noncoding RNA lncFAL (ferroptosis-associated lncRNA), which is derived from the plexin B2 gene. Moreover, our study suggests that the splicing of lncFAL was increased by YTH N6-methyladenosine (m6A) RNA-binding protein 2 (YTHDF2) in a m6A-dependent manner. Although HDLBP or lncFAL could not regulate the GPX4 antioxidant signalling pathway, lncFAL reduced ferroptosis vulnerability by directly binding to ferroptosis suppressor protein 1 (FSP1) and competitively abolishing Trim69-dependent FSP1 polyubiquitination degradation. More importantly, FSP1 inhibition promoted the antitumour activity of ferroptosis inducers both in vitro and in vivo. Collectively, our results provide a clinically promising demonstration that HDLBP stabilizes lncFAL, which mediates a FSP1-dependent anti-ferroptosis mechanism in HCC. These results support the enormous potential of disrupting FSP1 as a promising therapeutic approach for HCC patients with high HDLBP or lncFAL expression.

A novel medication decision gene signature predicts response to individualized therapy and prognosis outcomes in hepatocellular carcinoma patients.

Molecular targeted therapy has shown potential in hepatocellular carcinoma (HCC) patients, and immunotherapy applications are developing rapidly. However, clinical guidance for making individualized therapy decisions for HCC patients remains lacking. MDH (Medication Decision in HCC) gene signatures comprising 70 genes were screened using transcriptomic data from multikinase inhibitor (TKI)-resistant HCC cells and HCC patient-derived xenograft model (PDX) models. Four MDH subtypes with distinct biological and clinical characteristics were defined by unsupervised cluster analysis of HCC data from The Cancer Genome Atlas (TCGA) database. To facilitate individualized and reasonable clinical guidance for each HCC patient, we constructed the MDH score. Comprehensive analysis suggested high MDH scores were associated with TKI resistance, a high proportion of stromal cell infiltration and poor survival outcomes. We recommend concomitant stromal activity intervention and immunotherapy for this type of HCC. Moreover, low MDH scores indicate TKI sensitivity, and a combination of targeted and immunotherapy is recommended. The nomogram constructed by iteration least absolute shrinkage and selection operator (LASSO) Cox regression analysis successfully predicted 3- or 5-year survival outcomes and mortality risks of HCC patients. In conclusion, TKI resistance model-based MDH gene signatures provide novel insight into potential mechanisms of drug resistance and heterogeneity in HCC. Integrative analysis plus a simplified decision model may aid personalized treatment and prognostic assessment among HCC patients.

The lipid transporter HDLBP promotes hepatocellular carcinoma metastasis through BRAF-dependent epithelial-mesenchymal transition.

Tumor metastasis is a major cause of cancer mortality. However, little is known regarding the regulation of abnormal cholesterol metabolism in hepatocellular carcinoma (HCC) metastasis. Here, we show that the expression of high-density lipoprotein binding protein (HDLBP), a lipid transporter, is clinically correlated with tumor metastasis in HCC patients. Moreover, HDLBP was required for cholesterol-induced HCC metastasis. We revealed that knockdown and overexpression of HDLBP significantly inhibited and enhanced, respectively, the metastasis, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro and in vivo. Mechanistically, coimmunoprecipitation and mass spectrometry screening uncovered BRAF as a protein target of HDLBP. HDLBP was found to promote EMT signaling in a BRAF-dependent manner. Furthermore, HDLBP interacts with BRAF and inhibits its ubiquitinated degradation by abrogating BRAF-ITCH interactions. Notably, further studies suggest that dabrafenib exhibited a greater metastasis-suppressive effect in HDLBP knockout HCC than isolated treatment. Overall, our findings imply that cholesterol-induced HDLBP contributes to the metastasis and invasion of HCC through BRAF-dependent EMT signaling and that HDLBP may be applied as a biomarker and therapeutic target for HCC.

Double-Negative α-Fetoprotein and Carbohydrate Antigen 19-9 Predict a Good Prognosis in Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis.

INTRODUCTION: Carbohydrate antigen 19-9 (CA19-9) and α-fetoprotein (AFP) are routinely tested in patients with liver malignancies before surgery. However, few reports have explored the relevance of the expression pattern of these 2 tumor markers regarding the prognosis of intrahepatic cholangiocarcinoma (ICC). We herein combined these 2 tumor markers to investigate the influence on ICC malignancy and patient prognosis. METHODS: From March 2009 to December 2019, 519 consecutive patients with newly diagnosed ICC who underwent R0 resection were enrolled and followed. The relationships between clinicopathological parameters and these 2 tumor markers were analyzed. Propensity score matching was used to eliminate the baseline differences. RESULTS: A lower proportion of patients with double-negative AFP and CA19-9 had advanced tumor-node-metastasis stage, larger tumor diameter, multiple tumors, lymph node metastasis, microvascular invasion, and perineural invasion. With propensity score matching, patients were divided into double-negative and non-double-negative groups, with 128 patients in each group, and the 5-year recurrence-free survival and overall survival rates were 33.8 vs 15.2 (P < 0.001) and 45.3 vs 19.0, respectively (P < 0.001). In the multivariate Cox analyses, double negativity for the 2 tumor markers was an independent factor for recurrence-free survival (hazard ratios, 0.578; 95% CI, 0.442-0.755, P < 0.001) and overall survival (hazard ratios, 0.567; 95% CI, 0.434-0.741, P < 0.001). DISCUSSION: Double negativity for CA19-9 and AFP indicated less invasive tumor characteristics in patients with ICC. Patients with double-negative tumor markers achieved better outcomes than those with non-double-negative markers, which is meaningful for prognostic counseling and therapeutic triage.

The prognostic value of aspartate aminotransferase-to-lymphocyte ratio index in early-stage hepatocellular carcinoma after hepatectomy: A propensity-score matched analysis.

BACKGROUND: An elevated preoperative aspartate aminotransferase-to-lymphocyte ratio index (ALRI) may predict poor survival in various cancers. However, the prognostic value of aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma (HCC) remains to be determined. MATERIALS AND METHODS: A retrospective cohort study was conducted among 983 patients with HCC in our hospital from February 2007 to March 2016. A propensity-score matching (PSM) was performed to correct the selection bias and confounding factors. The risk of death and recurrence was plotted over aminotransferase-to-lymphocyte ratio index (ALRI) using the locally weighted scatterplot smoothing (LOWESS)-smoothed fit curve. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier method analysis was utilized to the role of aminotransferase-to-lymphocyte ratio index (ALRI) in HCC. Multivariate analysis was conducted to identify independent prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS: With the increase of aminotransferase-to-lymphocyte ratio index (ALRI), the risk of recurrence and death in HCC patients increases. In time-dependent ROC analysis, the AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year OS were 0.668 (95% CI: 0.596-0.740), 0.605 (95% CI: 0.560-0.649) and 0.613 (95% CI: 0.570-0.656), respective. The AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year RFS were 0.598 (95% CI: 0.555-0.641), 0.590 (95% CI: 0.552-0.628) and 0.604 (95% CI: 0.562-0.646), respectively. HCC patients with high aminotransferase-to-lymphocyte ratio index (ALRI) had a poor overall survival. Moreover, cox regression analysis revealed that aminotransferase-to-lymphocyte ratio index (ALRI) was an independent factor affecting the prognosis of HCC patients. CONCLUSIONS: Elevated preoperative aminotransferase-to-lymphocyte ratio index (ALRI) is a noninvasive, simple, and effective predictor in the prognosis of patients with HCC.

Diagnostic accuracy of midkine on hepatocellular carcinoma: A meta-analysis.

OBJECTIVE: To evaluate the dependability and accuracy of midkine (MK) in the diagnosis of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, Web of Science, China Biology Medicine disc and grey literature sources were searched from the date of database inception to January 2019. Two authors (B-H.Z. and B.L.) independently extracted the data and evaluated the study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were estimated using a bivariate model. Moreover, hierarchical summary receiver operating characteristic curves were generated. The diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled using a univariate model. RESULTS: Nine articles (11 studies) were included (1941 participants). The bivariate analysis revealed that the sensitivity and specificity of MK for HCC diagnosis were 0.85 (95% CI 0.78-0.91) and 0.83 (95% CI 0.76-0.88), respectively. We also found a LR+ of 5.05 (95% CI 3.33-7.40), a LR- of 0.18 (95% CI 0.11-0.28), a DOR of 31.74 (95% CI 13.98-72.09) and an AUC of 0.91 (95% CI 0.84-0.99). Subgroup analyses showed that MK provided the best efficiency for HCC diagnosis when the cutoff value was greater than 0.5 ng/mL. CONCLUSIONS: MK has an excellent diagnostic value for hepatocellular carcinoma.

The outcome of the HCC patients underwent ALPPS: Retrospective study.

The complete resection offers the best long-term survival for advanced hepatocellular carcinoma patients. ALPPS as a choice of resection, how is its outcome compared to one-stage resection, liver transplantation and TACE? This retrospective study included 20 ALPPS patients. To minimize the effect of confounding influences of measured covariates, PSM was performed. The overall survival (OS), morbidity, mortality and the increasing rate, KGR were analyzed. The OS in ALPPS group is 27.4 (±3.8 months) moths and the TACE group is 13.5(±1.2 months) (P < .001), LT group is 41.3 (±3.2 months) (P = .048), Resection group is 31.8 (±2.6 months) (P = .368). And the medium increasing volume is 209.5 cm (±61.5 cm) with the increasing ratio 52.4% (+26.9%). The ALPPS is a feasible treatment for HCC patients and it provides a better long-term survival than TACE and it is similar to Resection, less than LT.

A novel model for predicting posthepatectomy liver failure in patients with hepatocellular carcinoma.

Posthepatectomy liver failure (PHLF) is the most leading cause of mortality following hepatectomy in patients with hepatocellular carcinoma (HCC). Platelet count was reported to be a simple but useful indicator of liver cirrhosis and function of spleen. Spleen stiffness (SS) was used to evaluate the morphological change of spleen and was reported to be related to liver cirrhosis and portal hypertension. However, the predictive value of platelet to spleen stiffness ratio (PSR) on PHLF remains unknown. A retrospective study was performed to analyze 158 patients with HCC following hepatectomy from August 2015 to February 2016. Univariate and multivariate analyses were performed to evaluate the value of each risk factor for predicting PHLF. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve. PHLF occured in 23 (14.6%) patients. PSR (P<0.001, odds ratio (OR) = 0.622, 95% confidence interval (CI) 0.493~0.784), hepatic inflow occlusion (HIO) (P = 0.003, OR = 1.044, 95% CI 1.015~1.075) and major hepatectomy (P = 0.019, OR = 5.967, 95% CI 1.346~26.443) were demonstrated to be the independent predictive factors for development of PHLF in a multivariate analysis. Results of the present study suggested PSR is a novel and non-invasive model for predicting PHLF in patients with HCC.

miR-590-5p promotes liver cancer growth and chemotherapy resistance through directly targeting FOXO1.

miR-590-5p functions as an onco-miR or an anti-onco-miR in various types of cancers. However, the exact role of miR-590-5p in liver cancer remains to be elucidated. In the present study, we explored the predictive role of miR-590-5p expression in liver cancer patients. In addition, CCK-8 assay, colony formation assay, and analysis of xenograft tumors were performed to investigate the biological effects of miR-590-5p in liver cancer. A direct target of miR-590-5p was identified based on a luciferase assay and further molecular experiments. Our results demonstrated that miR-590-5p was upregulated in malignant tissues of liver cancer patients and in liver cancer cell lines. miR-590-5p expression was found to be inversely correlated with disease-free survival of liver cancer patients. Furthermore, both in vitro and in vivo experiments showed that miR-590-5p knockdown inhibited the growth of HepG2 and Bel-7404 tumor cells by promoting apoptosis and cell cycle arrest. We also demonstrated that increasing of miR-590-5p in 5-Fu resistant patients and liver cancer cells, and knockdown of miR-590-5p enhances chemosensitivity to 5-Fu in liver cancer. FOXO1 was identified as a direct and necessary target of miR-590-5p during regulating liver cancer growth. Taken together, our findings provide insights into the role of miR-590-5p in liver cancer. Moreover, it is suggested that miR-590-5p can serve as a novel therapeutic target and predictive biomarker for liver cancer.

Spleen stiffness and volume help to predict posthepatectomy liver failure in patients with hepatocellular carcinoma.

Posthepatectomy liver failure (PHLF) is the main cause of perioperative death, and liver cirrhosis is one of the most important risk factors for PHLF. Spleen stiffness (SS) is a novel ultrasonic indicator for liver cirrhosis and portal hypertension, however, it is not clear that whether it has a significant influence on PHLF. Future remnant liver volume (FRLV) is a significant factor for liver regeneration after hepatectomy, spleen volume (SV) could also predict the degree of liver cirrhosis, and recent literatures reported that SV to FRLV ratio (SV/FRLV) could predict small for size syndrome (SFSS) in liver transplantation, however, the relationship between SV/FRLV and PHLF in patients receiving hepatectomy is not known. Systemic inflammatory response (SIR) plays a significant role in the pathogenesis and progression of liver cirrhosis, however, it is not very clear about the exact relationship between SIR and PHLF.We prospectively collected the medical data of consecutive patients diagnosed with hepatocellular carcinoma (HCC) who underwent hepatectomy from August 2015 to February 2016. Preoperative measurements of SS, liver stiffness (LS), SV, FRLV, and SIR were performed on all patients. A univariate analysis was performed to find the risk factors of PHLF and a multivariate analysis was used to identify independent risk factors. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve.Twenty three (23) (14.6%) patients developed PHLF. Univariate analysis found several variables significantly related to PHLF, they were as follows: tumor diameter (P = .01), cirrhosis (P = .001), neutrophil to lymphocyte ratio (NLR) (P = .018), LS (P = .001), SS (P = .001), SV/FRLV (P < .001), operation duration (P = .003), transfusion (P = .009), hepatic inflow occlusion (HIO) (P = .001). Finally, SV/FRLV (P < .001, hazard ratio (HR) = 26.356, 95% confidence interval (CI) 1.627-425.21), SS (P = .009, HR = 1.077, 95%CI 1.017-1.141), and HIO time (P = .002, HR = 1.043, 95%CI 1.014-1.072) were determined as the independent risk factors of PHLF by multivariate analysis.SS and SV/FRLV help to predict the development of PHLF in patients with hepatocellular carcinoma.

Novel Prognostic Nomograms for Hepatocellular Carcinoma Patients with Microvascular Invasion: Experience from a Single Center.

Background/Aims: Microvascular invasion (MVI) is an established risk factor for hepatocellular carcinoma (HCC). However, prediction models that specifically focus on the individual prognoses of HCC patients with MVI is lacking. Methods: A total of 385 HCC patients with MVI were randomly assigned to training and validation cohorts in a 2:1 ratio. The outcomes were disease-free survival (DFS) and overall survival (OS). Prognostic nomograms were established based on the results of multivariate analyses. The concordance index (C-index), calibration plots and Kaplan-Meier curves were employed to evaluate the accuracy, calibration and discriminatory ability of the models. Results: The independent risk factors for both DFS and OS included age, tumor size, tumor number, the presence of gross vascular invasion, and the presence of Glisson's capsule invasion. The platelet-to-lymphocyte ratio was another risk factor for OS. On the basis of these predictors, two nomograms for DFS and OS were constructed. The C-index values of the nomograms for DFS and OS were 0.712 (95% confidence interval [CI], 0.679 to 0.745; p<0.001) and 0.698 (95% CI, 0.657 to 0.739; p<0.001), respectively, in the training cohort and 0.704 (95% CI, 0.650 to 0.708; p<0.001) and 0.673 (95% CI, 0.607 to 0.739; p<0.001), respectively, in the validation cohort. The calibration curves showed optimal agreement between the predicted and observed survival rates. The Kaplan-Meier curves suggested that these two nomograms had satisfactory discriminatory abilities. Conclusions: These novel predictive models have satisfactory accuracy and discriminatory abilities in predicting the prognosis of HCC patients with MVI after hepatectomy.

Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis.

Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. However, the mechanistic relationships among various genes and signaling pathways are still largely unclear. In this study, we aimed to elucidate potential core candidate genes and pathways in HCC. The expression profiles GSE14520, GSE25097, GSE29721, and GSE62232, which cover 606 tumor and 550 nontumour samples, were downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, HCC RNA-seq datasets were also downloaded from the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were filtered using R software, and we performed gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using the online databases DAVID 6.8 and KOBAS 3.0. Furthermore, the protein-protein interaction (PPI) network complex of these DEGs was constructed by Cytoscape software, the molecular complex detection (MCODE) plug-in and the online database STRING. First, a total of 173 DEGs (41 upregulated and 132 downregulated) were identified that were aberrantly expressed in both the GEO and TCGA datasets. Second, GO analysis revealed that most of the DEGs were significantly enriched in extracellular exosomes, cytosol, extracellular region, and extracellular space. Signaling pathway analysis indicated that the DEGs had common pathways in metabolism-related pathways, cell cycle, and biological oxidations. Third, 146 nodes were identified from the DEG PPI network complex, and two important modules with a high degree were detected using the MCODE plug-in. In addition, 10 core genes were identified, TOP2A, NDC80, FOXM1, HMMR, KNTC1, PTTG1, FEN1, RFC4, SMC4, and PRC1. Finally, Kaplan-Meier analysis of overall survival and correlation analysis were applied to these genes. The abovementioned findings indicate that the identified core genes and pathways in this bioinformatics analysis could significantly enrich our understanding of the development and recurrence of HCC; furthermore, these candidate genes and pathways could be therapeutic targets for HCC treatment.

Early postoperative controlling nutritional status (CONUT) score is associated with complication III-V after hepatectomy in hepatocellular carcinoma: A retrospective cohort study of 1,334 patients.

Postoperative complication III-V is closely related with hepatectomy-related mortality for hepatocellular carcinoma (HCC) patients. The aim of the study was to investigate the relationship between CONUTS and postoperative complication III-V. 1334 HCC patients who underwent hepatectomy were divided into two groups: high CONUTS group (early postoperative CONUTS ≥ 8, n = 659) and low CONUTS group (early postoperative CONUTS < 8, n = 675). The characteristics and clinical outcomes were compared and analyzed. Risk factors for postoperative complication III-V were evaluated by univariate and multivariate analysis. early postoperative CONUTS showed a good prediction ability for postoperative complication III-V (AUROC = 0.653, P < 0.001), with the cut-off value of 8. The high CONUTS group had higher incidence of postoperative pulmonary complications (12.0% vs 7.9%, P = 0.011), bile leakage (2.6% vs 0.9%, P = 0.018), intra-abdominal hemorrhage (4.9% vs 1.6%, P = 0.001), postoperative liver failure Grade C (3.6% vs 1.0%, P = 0.002), complication III-V (15.6% vs 6.2%, P < 0.001), length of ICU stay > 48 hours (9.4% vs 4.1%, P < 0.001) and mortality in 90 days (2.6% vs 0.4%, P = 0.001), longer period of postoperative hospitalization (10 (8-13) vs 9 (7-11) days, P < 0.001). Multivariable analysis revealed that early postoperative CONUTS ≥ 8 (OR = 2.054, 95%CI = 1.371-3.078, P < 0.001) was independently associated with postoperative complication III-V. Early postoperative CONUTS ≥ 8 was identified as a novel risk factor for postoperative complication III-V, and should be further evaluated as a predictive marker for who are to undergo liver resection.

Geriatric nutritional risk index predicts prognosis after hepatectomy in elderly patients with hepatitis B virus-related hepatocellular carcinoma.

Geriatric nutritional risk index (GNRI) is a novel and useful screening tool for evaluating nutritional status in elderly in-patients. We aimed to investigate whether the preoperative GNRI could be a predictive factor for outcomes in patients over 65 years of age with a diagnosis of hepatocellular carcinoma (HCC). We retrospectively enrolled 261 consecutive HCC patients after hepatectomy and classified them into four risk groups based on the GNRI values: high risk (GNRI, <82), moderate risk (GNRI, 82-92), low risk (GNRI, 92-98), and normal (GNRI, >98). We found that the lower GNRI value was significantly associated with severe postoperative complications (P < 0.001) and liver failure (P < 0.001). By multivariate logistic regression analysis, high risk- and moderate risk GNRI groups were identified as independent risk factors for postoperative serve complications and liver failure. Multivariate Cox regression analysis revealed preoperative GNRI (P < 0.001) adversely affected overall survival. In conclusion, preoperative GNRI could predict severe postoperative complications included liver failure, and the lower GNRI value was associated with worse overall survival after hepatectomy in elderly HCC patients.

The Impact of Tumor Differentiation on the Prognosis of HBV-Associated Solitary Hepatocellular Carcinoma Following Hepatectomy: A Propensity Score Matching Analysis.

AIM: The role of tumor differentiation in the prognosis of hepatocellular carcinoma (HCC) after hepatectomy remains controversial. The present study aimed to classify the impact of tumor differentiation on solitary hepatitis B viral (HBV)-associated HCC using propensity score matching analysis. METHODS: Between January 2009 and March 2015, the data of 721 HCC patients in West China Hospital were prospectively collected and analyzed. Propensity matching analysis was applied to overcome the imbalance in baseline characteristics. Survival analysis was performed using the Kaplan-Meier method. Risk factors were identified by the Cox proportional hazards model. RESULTS: All HCC patients were classified into the moderately well-differentiated HCCs group (group A, n = 442, 61.3%) or poorly differentiated HCCs group (group B, n = 279, 38.7%). Patients with poorly differentiated HCCs commonly had a larger tumor size, more advanced tumors, and a higher alpha-fetoprotein (AFP) level. Patients with poorly differentiated HCCs had a poorer recurrence-free survival and overall survival before and after propensity score matching analysis. Poorly differentiated tumors, positive serum hepatitis B viral e antigen, positive hepatitis B virus deoxyribonucleic acid load, tumor size, microvascular invasion, and AFP > 400 ng/ml were risk factors of a poor outcome. CONCLUSIONS: Our propensity model provided strong evidence that a poorly differentiated tumor had a negative impact on the recurrence and long-term survival of solitary HBV-associated HCCs after curative hepatectomy. Antiviral therapy might improve their prognosis.

The Prognostic Prediction Role of Preoperative Serum Albumin Level in Patients with Intahepatic Cholangiocarcinoma Following Hepatectomy.

BACKGROUND: There is little information regarding the role of preoperative serum albumin (ALB) in intrahepatic cholangiocarcinoma (ICC) patients who underwent liver resection. METHODS: Clinicopathological characteristics and survival rate of 91 ICC patients who underwent surgery between 2009 and 2013 were included in this study. The optimal cut-off for ALB were determined by plotting the receiver operating characteristics curves of ALB in predicting overall survival (OS) and utilizing the Youden index. Long-term outcome was calculated by Kaplan-meire method. RESULTS: The pathological characteristics were similar in both groups. The 1- and 3-year disease-free survival (DFS) rates between the high ALB group and the lower ALB group were 62.7 vs. 25.5% and 27.0 vs. 11.1% respectively (p < 0.001). The 1- and 3-year OS rates between the high ALB group and the lower ALB group were 78.4 vs. 57.5% and 42.6 vs. 6.7% respectively (p < 0.001). The ALB level as continuous variable in multivariate analysis remained a favorable factor for DFS and OS (p < 0.05). Furthermore, ALB could distinguish the prognoses in non-cirrhotic patients. Multivariate analysis showed other pathological risk factors like lymph node involvement, positive surgical margin, satellite lesions, and carbohydrate antigen 19-9 were associated with DFS and OS (p < 0.05 for all). CONCLUSIONS: A higher preoperative serum ALB level is associated with better long-term survival in ICC patients.