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Object. To identify and explore the key transcription factors in hepatocellular carcinoma (HCC) progression. Methods. Differentially transcription factors (DETFs) were identified from differentially expressed genes (DEGs) in GSE62232 and transcription factors. Then, they were analyzed by regulatory networks, prognostic risk model, and overall survival analyses to identify the key DETF. Combined with the regulatory networks and binding site analysis, the target mRNA of key DETF was determined, and its prognostic value in HCC was evaluated by survival, clinical characteristics analyses, and experiments. Finally, the expressions and functions of the key DETF on the DEmRNAs were investigated in HCC cells. Results. Through multiple bioinformatics analyses, ASCL1 was identified as the key DETF, and SLC6A13 was predicted to be its target mRNA with the common binding site of CCAGCAACTGGCC, both downregulated in HCC. In survival analysis, high SLC6A13 was related to better HCC prognosis, and SLC6A13 was differentially expressed in HCC patients with clinical characteristics. Furthermore, cell experiments showed the mRNA expressions of ASCL1 and SLC6A13 were both reduced in HCC, and their overexpressions suppressed the growth, invasion, and migration of HCC cells. Besides, over-ASCL1 could upregulate SLC6A13 expression in HCC cells. Conclusion. This study identifies two suppressor genes in HCC progression, ASCL1 and SLC6A13, and the key transcription factor ASCL1 suppresses HCC progression by targeting SLC6A13 mRNA. They are both potential treatment targets and prognostic biomarkers for HCC patients, which provides new clues for HCC research.

The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine.A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted.Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target.This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.

Background and objectives: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a poor prognosis. Long noncoding RNAs (lncRNAs) are now considered as key gene expression regulators and play important roles in different types of cancer. This study aimed to identify potential lncRNAs and uncover vital molecular mechanisms guiding clinical therapy for HCC. Methods Based on four microarray datasets (GSE112613, GSE84004, GSE67260, and GSE101728) from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database of lncRNAs expression in patients with HCC, quantitative real-time PCR (qRT-PCR), cell transfection, cell proliferation assay, scratch wound healing, transcriptome sequencing, and immunofluorescence assays were used to analyze the clinical value and molecular mechanism of LINC02362 in HCC. Results High LINC02362 expression was positively correlated with longer overall survival (OS) and exhibited excellent diagnostic accuracy, suggesting that LINC02362 may inhibit HCC progression. Increased LINC02362 expression in HCC cell lines (Hep 3B and Huh 7) after lentiviral infection, overexpression of LINC02362 inhibits hepatocellular carcinoma cell proliferation, migration and invasion and then transcriptome sequencing was performed. Potential molecular LINC02362 pathways in HCC were determined using ClusterProfiler R package in enrichment analyses. Protein–protein interaction networks (PPI) were used to screen hub genes. PPI networks and OS data confirmed that EFNA5 was a downstream target positively regulated by LINC02362. Conclusions The LINC02362–EFNA5 axis appears to inhibit HCC progression; thus, it can be used to diagnose, prognose, and treat HCC.

To clarify the significance of circulating tumor cells (CTC) undergoing epithelial–mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal–CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis.Significance: In liver cancer, CTC examination may represent an important “liquid biopsy” tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. Cancer Res; 78(16); 4731–44. ©2018 AACR.

A detailed description of the "Pathways in cancer" KEGG cluster related to differentially expressed genesï¼^made by the ClusterProfiler Package）. This cluster (Pathways in cancer) includes nine important canonical cancer pathways, such as the Wnt, FAK, and PI3K-AKT signaling pathways, and many differentially expressed cancer-related genes/ gene clusters are found in these nine canonical pathways.

Primer design for the BCAT1 gene and EMT markers

legends

DNA sequencing analysis of three other patients who had the R249S mutation in the P53 gene in the primary tumor but not in non-tumor liver tissues.

Imaging modalities and cumulative total CTC count by each CTC type for the other seven patients who had increased CTC counts 1 to 2 months before detectable recurrence or the appearance of metastatic lesions; six of these patients also had increased M-CTC percentage (i.e., patients 1, 2, 3, 4, 5 and 7).

Objective To establish a new surgical scheme defining risk classes of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among hepatocellular carcinoma (HCC) patients combined with clinically significant portal hypertension (CSPH). Backgrounds: Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC. Methods Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram. Results The analysis included 924 patients, of whom 721(78.0%) were without CSPH, 137(14.8%) with mild-CSPH, and 66(7.1%) with severe-CSPH. The nomogram incorporated preoperative prolonged prothrombin time (PT), total bilirubin (T-Bil), indocyanine green retention rate at 15 min (ICG-R15), CSPH grade, and standard future liver remnant (sFLR) volume, and achieved good prediction performance in the training (C index = 0.891, 95%CI: 0.855–0.920), internal validation (C index = 0.850, 95%CI: 0.786–0.901), and external validation (C index = 0.872, 95%CI: 0.835–0.904) cohorts, with well-fitted calibration curves. Calculations of total points of diagnostic errors with 95%CI were concentrated in 110.5(range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR. Conclusion This new surgical scheme is practical to stratify risk classes in severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.

Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear. We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies. The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI. Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

To improve rate and cycling performance of manganese oxide anode material, a precipitation method was combined with thermal annealing to prepare the MnO/Mn3O4/SeOx (x=0, 2) hybrid anode by controlling the reaction temperature of Mn2O3 and Se powders. At 3 A/g, the synthesized MnO/Mn3O4/SeOx anode delivers a discharge capacity of 1007 mA·h/g after 560 cycles. A cyclic voltammetry quantitative analysis reveals that 89.5% pseudocapacitive contribution is gained at a scanning rate of 2.0 mV/s, and the test results show that there is a significant synergistic effect between MnO and Mn3O4 phases.

Dysregulation of genes involved in alternative splicing contributes to hepatocarcinogenesis. SNRPB, a component of spliceosome, is implicated in human cancers, yet its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. Here, we show that SNRPB expression is increased in HCC tissues, compared with the nontumorous tissues, at both messenger RNA and protein levels in two independent cohorts. High expression of SNRPB is significantly associated with higher pathological grade, vascular invasion, serum alpha-fetoprotein level, tumor metastasis, and poor disease-free and overall survivals. Luciferase reporter and chromatin immunoprecipitation assays demonstrate that SNRPB upregulation in HCC is mediated by c-Myc. Positive correlation is found between SNRPB and c-Myc expression in clinical samples. In vitro studies show that ectopic expression of SNRPB promotes HCC cell proliferation and migration, whereas knockdown of SNRPB results in the opposite phenotypes. Collectively, our data suggest SNRPB function as an oncogene and serve as a potential prognostic factor in HCC.

Accurate preoperative assessment of hepatic functional reserve is essential for conducting a safe hepatectomy. In recent years, aspartate aminotransferase-to-platelet ratio index (APRI) has been used as a noninvasive model for assessing fibrosis stage, hepatic functional reserve, and prognosis after hepatectomy with a high level of accuracy. The purpose of this research was to evaluate the clinical value of combining APRI with standardized future liver remnant (sFLR) for predicting severe post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). Six hundred thirty-seven HCC patients who had undergone hepatectomy were enrolled in this study. The performance of the Child-Pugh (CP) grade, model for end-stage liver disease (MELD), APRI, sFLR, and APRI-sFLR in predicting severe PHLF was assessed using the area under the ROC curve (AUC). Severe PHLF was found to have developed in 101 (15.9%) patients. Multivariate logistic analyses identified that prealbumin, cirrhosis, APRI score, sFLR, and major resection were significantly associated with severe PHLF. The AUC values of the CP, MELD, APRI, and sFLR were 0.626, 0.604, 0.725, and 0.787, respectively, indicating that the APRI and sFLR showed significantly greater discriminatory abilities than CP and MELD (P

Objectives: Procalcitonin (PCT) has long been proved as an early diagnostic signal for postoperative outcomes. The purpose of this study is to explore the value of serum procalcitonin levels in predicting post-hepatectomy liver failure (PHLF), and further to declarethe relationship between postoperative PCT and short-term prognosis in patients after hepatectomy.Methods: Clinical data of patients with hepatocellular carcinoma (HCC) who underwent hepatectomy from June 1st, 2019 to September 31st, 2020 at Shanghai Eastern Hepatobiliary Surgery Hospital had been retrospectively analyzed. Logistic regression analysis was used to evaluate the risk factors related to PHLF. The Kaplan-Meier method was used to calculate the PHLF rate and 30-day survival after surgery.Results: A total of 885 patients with complete data were finally included in analysis, 311 of them with elevated serum PCT (≥1 ng/ml). Results of the logistic regression analysis suggested a significant association between PCT and PHLF [HR, 95%CI; 3.801 (1.825, 7.917), p < 0.001]. Other significant risk factors for PHLF included portal hypertension, portal blocking time (>30 min) and blood transfusion (>200 ml). Kaplan-Meier analysis also suggested a higher PHLF rate in elevated PCT patients [9.0% (95% CI, 7.3 to 12.8 VS. 1.9% (95% CI, 1.1–4.3)); p < 0.001]. For secondary outcomes, elevated PCT was also highly associated with postoperative sepsis, ICU admission, 30-day mortality and 3-month mortality.Conclusion: Elevated procalcitonin level in patients after hepatectomy is related to higher PHLF rate, with lower 30-day survival and poor short-term postoperative outcomes.

Background Epithelial–mesenchymal transition (EMT) promotes migration, invasion, and metastasis of hepatocellular carcinoma (HCC) cells. The molecular mechanisms behind EMT and metastasis in HCC remain unclear. Methods Microarray analysis was used to identify lncRNAs expression during polarization of U937 macrophages from M2 to M1 phenotype. The expression of the identified lncRNA was compared between clinical samples of HCC tissues or adjacent normal tissues, as well as between HCC and normal liver cell lines. lnc-Ma301 was overexpressed or knocked-down in HCC cell lines, and the effects were assessed in vitro and in vivo. Interactions among lnc-Ma301 and its potential downstream targets caprin-1 were investigated in HCC cell lines. Effects of lnc-Ma301 over- and underexpression on the Akt/Erk1 signaling pathways were examined. Results Microarray analyses identified lnc-Ma301 as one of the most overexpressed long non-coding RNAs during polarization of U937 macrophages from M2 to M1 phenotype. Lnc-Ma301 showed lower expression in HCC tissues than in adjacent normal tissues, and lower expression was associated with worse prognosis. Activation of lnc-Ma301 inhibited cell proliferation, migration and EMT in HCC cell cultures, and it inhibited lung metastasis of HCC tumors in mice. Mechanistic studies suggested that lnc-Ma301 interacts with caprin-1 to inhibit HCC metastasis and EMT through Akt/Erk1 pathway. Conclusions Lnc-Ma301 may help regulate onset and metastasis of HCC.

Purpose Post-hepatectomy liver failure (PHLF) is a severe complication in hepatocellular carcinoma (HCC) patients who have undergone hepatectomy. This research aimed to investigate the combination of albumin-bilirubin (ALBI) score and aspartate aminotransferase-platelet ratio index (APRI) as a novel approach in predicting PHLF risk in hepatitis B virus (HBV)-related HCC patients. Patients and methods HBV-related HCC patients who underwent hepatectomy from January 2006 to October 2013 were enrolled in this study. A novel model was constructed using a combination of ALBI and APRI scores to predict PHLF risk, and the prognostic value of the model was evaluated and compared with Child-Pugh (C-P) grade, ALBI score and APRI score. Results A total of 1,055 HCC patients were retrospectively studied, which included 151 experienced PHLF. Univariable and multivariate analyses showed that the ALBI and APRI scores were independent predictors of PHLF. The area under the ROC curve (AUC) of the ALBI score, APRI score, and C-P grade was 0.717, 0.720, and 0.602, respectively, with AUC (ALBI) > AUC (C-P) (P AUC (C-P) (P AUC (ALBI) (P AUC (APRI) (P =0.047). Our results indicated that ALBI and APRI scores had higher discriminatory abilities than C-P grade in predicting the risk of PHLF, and the ALBI-APRI model could enhance the capability of predicting PHLF compared to ALBI or APRI alone. Conclusion ALBI-APRI score is a novel and effective predictive model of PHLF for HBV-related HCC patients, and its accuracy in predicting the risk of PHLF is better than that of C-P, ALBI and APRI scores.

Background: There is no guideline recommendation for preventing hepatocellular carcinoma (HCC) recurrence after hepatic resection. Moreover, an unmet need exists on the effectiveness of sorafenib therapy in recurrent HCC. Purpose: We therefore assessed the efficacy and safety of sorafenib in Chinese HCC patients with high risk of recurrence. Patients and methods: Data were collected retrospectively from 15 Chinese research centers from January 1, 2012 to November 15, 2013, by chart reviews of patients with moderate-advanced HCC who received hepatic carcinectomy. The primary end point was recurrence-free survival rate at 1 year in patients with a high recurrence risk. Secondary end points included 1-year survival rate, time to recurrence and safety assessment. Results: A total of 209 high-risk patients (sorafenib, n=98; control, n=111) who underwent carcinectomy were analyzed. There was no significant difference in the proportion of patients with recurrence-free survival at 1 year between the sorafenib and control (70.43% vs 68.90%: χ2=0.007, P=0.934). One-year survival rate was significantly higher with sorafenib than observed with control (95.5% vs 83.35%; χ2=7.441, P=0.006). Time to recurrence between sorafenib and control groups was similar. Incidences of all the adverse events (AEs) were similar in both the groups and transaminase elevation was most common in both groups (20.37% vs 24.79%). Thrombocytopenia incidence was significantly lower with the sorafenib group than with control (1.85% vs 9.40%; P=0.015). Conclusion: Sorafenib may be considered as a feasible option in the treatment of HCC recurrence.

Rong-Yun Mai, Jia-Zhou Ye, Zhong-Rong Long, Xian-Mao Shi, Tao Bai, Jie Chen, Le-Qun Li, Guo-Bin Wu, Fei-Xiang Wu Department of Hepatobiliary and Pancreatic Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuangzu 530021, China Purpose: This study aimed to investigate the efficacy of preoperative aspartate aminotransferase-to-platelet-ratio index (APRI) score to predict the risk of posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) after liver resection, and to compare the discriminatory performance of the APRI with the Child–Pugh score, model for end-stage liver disease (MELD) score, and albumin–bilirubin (ALBI) score. Patients and methods: A total of 1,044 consecutive patients with HCC who underwent liver resection were enrolled and studied. Univariate and multivariate analyses were performed to investigate risk factors associated with PHLF. Predictive discrimination of Child–Pugh, MELD, ALBI, and APRI scores for predicting PHLF were assessed according to area under the ROC curve. The cutoff value of the APRI score for predicting PHLF was determined by ROC analysis. APRI scores were stratified by dichotomy to analyze correlations with incidence and grade of PHLF. Results: PHLF occurred in 213 (20.4%) patients. Univariate and multivariate analyses revealed that Child–Pugh, MELD, ALBI, and APRI scores were significantly associated with PHLF. Area under the ROC analysis revealed that the APRI score for predicting PHLF was significantly more accurate than Child–Pugh, MELD, or ALBI scores. With an optimal cutoff value of 0.55, the sensitivity and specificity of the APRI score for predicting PHLF were 72.2% and 68.0%, respectively, and the incidence and grade of PHLF in patients with high risk (APRI score >0.55) was significantly higher than in the low-risk cohort (APRI score

Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear.We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies.The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI.Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

Neonatal jaundice is a common symptom that occurs in neonates during the first month of their life and is generally divided into physiological and pathological subtypes. In serious cases, pathological neonatal jaundice frequently shows complications including seizures, cerebral palsy, and kernicterus. However, due to the unclear pathogenesis of pathological neonatal jaundice, effective drugs for this disease remain unsatisfied. In the present study, we first estimated the protective effects of folic acid (FA) on phenylhydrazine (PHA) or homocysteine (Hcy)-injected neonatal rats (2-3 days aged). Intriguingly, we found that FA significantly decreased the elevated total bilirubin (TBIL) and direct bilirubin (DBIL) concentration, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity in PHA- or Hcy-injected rats, indicating that FA improves liver functions. Meanwhile, our results also showed that the plasma Hcy level and N-homocysteinylation (N-Hcy) modification of albumin were significantly elevated in the jaundice rats, which were obviously reversed after FA administration. Furthermore, we identified a novel N-Hcy modification site K

To clarify the significance of circulating tumor cells (CTC) undergoing epithelial–mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal–CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis. Significance: In liver cancer, CTC examination may represent an important “liquid biopsy” tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. Cancer Res; 78(16); 4731–44. ©2018 AACR.

AIM To investigate the efficacy and safety of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in preventing tumor recurrence and improving survival in Barcelona Clinic Liver Cancer (BCLC) early (A) and intermediate (B) stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). METHODS A total of 519 BCLC A or B HCC patients treated by liver resection alone or followed by PA-TACE between January 2012 and December 2015 were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors for recurrence-free survival (RFS) and overall survival (OS). Multiple logistic regression was used to identify the clinicopathological characteristics associated with MVI. The rates of RFS and OS were compared among patients with or without MVI treated with liver resection alone or followed by PA-TACE. RESULTS Univariate and multivariate analyses demonstrated that serum AFP level > 400 ng/mL, tumor size > 5 cm, tumor capsule invasion, MVI, and major hepatectomy were risk factors for poor OS. Tumor capsule invasion, MVI, tumor size > 5 cm, HBV-DNA copies > 1 x 104 IU/mL, and multinodularity were risk factors for poor RFS. Multiple logistic regression identified serum AFP level > 400 ng/mL, tumor size > 5 cm, and tumor capsule invasion as independent predictors of MVI. Both OS and DFS were significantly improved in patients with MVI who received PA-TACE as compared to those who underwent liver resection alone. Patients without MVI did not show a significant difference in OS and RFS between those treated by liver resection alone or followed by PA-TACE. CONCLUSION PA-TACE is a safe adjuvant intervention and can efficiently prevent tumor recurrence and improve the survival of BCLC early- and intermediate-stage HCC patients with MVI.

AIM To develop and validate a risk estimation of tumor recurrence following curative resection of operable hepatocellular carcinoma (HCC). METHODS Data for 128 patients with operable HCC (according to Barcelona Clinic Liver Cancer imaging criteria) who underwent preoperative computed tomography (CT) evaluation at our hospital from May 1, 2013 through May 30, 2014 were included in this study. Follow-up data were obtained from hospital medical records. Follow-up data through May 30, 2016 were used to retrospectively analyze preoperative multiphasic CT findings, surgical histopathology results, and serum α-fetoprotein and thymidine kinase-1 levels. The χ2 test, independent t-test, and Mann-Whitney U test were used to analyze data. A P-value of < 0.05 was considered statistically significant. RESULTS During the follow-up period, 38 of 128 patients (29.7%) had a postoperative HCC recurrence. Microvascular invasion (MVI) was associated with HCC recurrence (χ2 = 13.253, P < 0.001). Despite postoperative antiviral therapy and chemotherapy, 22 of 44 patients with MVI experienced recurrence after surgical resection. The presence of MVI was 57.9% sensitive, 75.6% specific and 70.3% accurate in predicting postoperative recurrence. Of 84 tumors without MVI, univariate analysis confirmed that tumor margins, tumor margin grade, and tumor capsule detection on multiphasic CT were associated with HCC recurrence (P < 0.05). Univariate analyses showed no difference between groups with respect to hepatic capsular invasion, Ki-67 proliferation marker value, Edmondson-Steiner grade, largest tumor diameter, necrosis, arterial phase enhanced ratio, portovenous phase enhanced ratio, peritumoral enhancement, or serum α-fetoprotein level. CONCLUSION Non-smooth tumor margins, incomplete tumor capsules and missing tumor capsules correlated with postoperative HCC recurrence. HCC recurrence following curative resection may be predicted using CT.

// Jia-Zhou Ye 1 , Yan-Yan Wang 1, * , Tao Bai 1, * , Jie Chen 1 , Bang-De Xiang 1 , Fei-Xiang Wu 1, ** and Le-Qun Li 1 1 Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, PR China * Co-first authors ** Co-corresponding author Correspondence to: Le-Qun Li, email: Lequn_li001@163.com Keywords: hepatocellular carcinoma; portal vein tumor thrombus; surgical resection Received: January 28, 2017 Accepted: April 25, 2017 Published: June 27, 2017 ABSTRACT Portal vein tumor thrombus (PVTT) usually worsens prognosis of hepatocellular carcinoma (HCC), as characterized by aggressive disease progression, impaired liver function and tolerance to treatment. Conventionally, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) accepted the Barcelona Clinical Liver Cancer (BCLC) treatment algorithms, identifying PVTT as an absolute contra-indication of surgical resection for HCC. HCC-PVTT patients are offered sorafenib as the standard treatment. Evidently, SHARP and Asia-Pacific trials demonstrated that sorafenib only improves overall survival by approximately 3 months in patients with advanced HCC. Besides, BCLC treatment algorithm does not provide different therapeutic recommendations for different degree of PVTT, and only supports single treatment option for each stage of HCC rather than a combination of comprehensive treatments, which limited individual and best care for every HCC-PVTT patients. In the past few years, many surgeons do not restrict surgical resection to HCC with PVTT. There have been new reports demonstrated that surgical treatment is feasible for selected HCC-PVTT patients with resectable tumor and moderate liver function to prolong survival period and elevate life quality as long as PVTT limited to the first-order branch, whereas non-surgical treatments fail to provide comparable therapeutic effects. At present, guidelines on HCC management from mainland China, Japan, and Hong Kong have been updated and a consensus of Asia-Pacific experts has established that portal venous invasion is not an absolute contradiction of surgical resection for HCC. This review summarized the emerging data on surgical resection for HCC-PVTT patients beyond the BCLC treatment algorithms and discussed recent therapeutic conceptualchanges in the Asia-Pacific region.

// Jian-Hong Zhong 1, 2, * , Ning-Fu Peng 1, 2, * , Xue-Mei You 1, 2, * , Liang Ma 1, 2, * , Xiao Xiang 1 , Yan-Yan Wang 1 , Wen-Feng Gong 1, 2 , Fei-Xiang Wu 1, 2 , Bang-De Xiang 1, 2 , Le-Qun Li 1, 2 1 Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China 2 Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China * These authors have contributed equally to this work Correspondence to: Le-Qun Li, email: xitongpingjia@163.com Bang-De Xiang, email: xiangbangde@gmail.com Keywords: hepatic resection, hepatocellular carcinoma, transarterial chemoembolization, treatment selection, tumor stage Received: December 01, 2016 Accepted: January 18, 2017 Published: February 17, 2017 ABSTRACT The current clinical reality of tumor stages and primary treatments of hepatocellular carcinoma (HCC) is poorly understood. This study reviewed the distribution of tumor stages and primary treatment modalities among a large population of patients with primary HCC. Medical records of patients treated between January 2003 and October 2013 for primary HCC at our tertiary hospital in China were retrospectively reviewed. A total of 6241 patients were analyzed. The distribution of Barcelona Clinic Liver Cancer (BCLC) stages was as follows: stage 0/A, 28.9%; stage B, 16.2%; stage C, 53.6%; stage D, 1.3%. The distribution of Hong Kong Liver Cancer (HKLC) stages was as follows: stage I, 8.4%; stage IIa, 1.5%; stage IIb, 29.0%; stage IIIa, 10.0%; stage IIIb, 33.6%; stage IVa, 3.4%; stage IVb, 2.5%; stage Va, 0.2%; stage Vb, 11.4%. The most frequent therapy was hepatic resection for patients with BCLC-0/A/B disease, and transarterial chemoembolization for patients with BCLC-C disease. Both these treatments were the most frequent for patients with HKLC I to IIIb disease, while systemic chemotherapy was the most frequent first-line therapy for patients with HKLC IVa or IVb disease. The most frequent treatment for patients with HKLC Va/Vb disease was traditional Chinese medicine. In conclusion, Prevalences of BCLC-B and -C disease, and of HKLC I to IIIb disease, were relatively high in our patient population. Hepatic resection and transarterial chemoembolization were frequent first-line therapies.

Purpose Post-hepatectomy liver failure (PHLF) is a severe complication in hepatocellular carcinoma (HCC) patients who have undergone hepatectomy. This research aimed to investigate the combination of albumin–bilirubin (ALBI) score and aspartate aminotransferase-platelet ratio index (APRI) as a novel approach in predicting PHLF risk in hepatitis B virus (HBV)-related HCC patients. Patients and methods HBV-related HCC patients who underwent hepatectomy from January 2006 to October 2013 were enrolled in this study. A novel model was constructed using a combination of ALBI and APRI scores to predict PHLF risk, and the prognostic value of the model was evaluated and compared with Child-Pugh (C-P) grade, ALBI score and APRI score. Results A total of 1,055 HCC patients were retrospectively studied, which included 151 experienced PHLF. Univariable and multivariate analyses showed that the ALBI and APRI scores were independent predictors of PHLF. The area under the ROC curve (AUC) of the ALBI score, APRI score, and C-P grade was 0.717, 0.720, and 0.602, respectively, with AUC (ALBI) > AUC (C-P) (P AUC (C-P) (P AUC (ALBI) (P AUC (APRI) (P =0.047). Our results indicated that ALBI and APRI scores had higher discriminatory abilities than C-P grade in predicting the risk of PHLF, and the ALBI-APRI model could enhance the capability of predicting PHLF compared to ALBI or APRI alone. Conclusion ALBI-APRI score is a novel and effective predictive model of PHLF for HBV-related HCC patients, and its accuracy in predicting the risk of PHLF is better than that of C-P, ALBI and APRI scores.

Fei-Xiang Wu,1–3,* Hui-Rong Lu,4,* Shao-Liang Zhu,1,* Zi-Hui Li,1 Ling Zou,1 Tao Bai,1 Jie Chen,1 Tian-Bo Yang,1 Shi-Xiong Liang4,51Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 2Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 3Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Shanghai, 4Department of Radiation Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 5Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workObjective: The current study aimed to evaluate the efficacy and outcomes of three-dimensional conformal radiotherapy (3DCRT) combined with transarterial chemoembolization (TACE) for treating patients with hepatocellular carcinoma involving portal vein tumor thrombus.Methods: During 2000 and 2013, a total of 182 hepatocellular carcinoma patients with portal vein tumor thrombus were retrospectively analyzed: 68 patients were treated by 3DCRT alone (group A), 74 by TACE alone (group B), and 40 by a combination of 3DCRT + TACE (group C). The overall survival (OS) of the three groups was compared using the Kaplan–Meier method. The independent predictors of survival were identified using multivariate analysis.Results: The total effective rate (complete response + partial response) among all patients was 44% (80/182). The objective response rate (complete response + partial response) was higher in group C than in group A or B, but the differences were not significant. OS rates at 1, 2, and 3years were significantly higher in group C than in group A or B (P

Background Postoperative hepatitis B virus (HBV) reactivation (PHR) is associated with resection-induced immunosuppression in patients with HBV-related hepatocellular carcinoma (HCC). Controlling Nutritional Status (CONUT) score is an effective index for evaluating immune-nutrition function. However, the value of COUNT in predicting PHR in HBV-HCC patients remains unknown. Methods Totally, 209 HCC patients were enrolled. Results Preoperative immune function (CD3+CD4+, CD3+CD8+, IgG and IgM) in patients with high CONUT score was significantly worse than that in patients with low CONUT score (P Conclusion CONUT score is an effective indicator predicting survival and PHR in HBV-HCC patients, especially in those with HBV-DNA levels

Background Misregulation of the p53-mdm2 loop function is a major mechanism to promote hepatocellular carcinoma (HCC). RBM38, a member of the RNA recognition motif (RRM) family of RNA binding proteins (RBPs), plays a fundamental role in the posttranscriptional control of gene expression and regulatory functions in human tumors. A novel RBM38-p53-mdm2 autoregulatory feedback loop has been demonstrated. However, its mechanistic role in HCC remains unclear. Methods In the present study, we investigated the role and molecular mechanism of misregulation in the p53-mdm2 loop function by RBM38 in HCC. First we investigated the correlation of RBM38 activity and p53-mdm2 loop function in liver cancer cells and HCC tissues by western blot and quantitative RT-PCR. We then conducted functional assays to investigate the molecular roles of RBM38 in inhibiting liver cancer cells aggressiveness in vitro and suppressing tumorigenicity in vivo. Results We observed RBM38 protein expression was commonly silenced coupled with increased mdm2 and decreased wild type (wt) p53 in liver cancer cells and HCC tissues compared to the corresponding normal liver cells and adjacent liver tissues. RBM38 mRNA level was significantly lower in HCC than adjacent liver tissues, whereas mdm2 and wtp53 mRNA levels were similar between HCC and adjacent liver tissues. This implied that deactivation of RBM38 could disrupt the p53-mdm2 loop and promote HCC, even though p53 and mdm2 transcript amounts were stable. Then, we generated stable liver cancer cell lines with overexpressed RBM38 (RBM38-OE) and found that up-regulation of RBM38 could inhibit mdm2 and restore wtp53 expression. Luciferase assay shown that RBM38 destabilized the mdm2 transcript through binding to multiple AU-/U-rich elements in mdm2 3’-UTR. Furthermore, functional assays showed that ectopic expression of RBM38 could induce liver cancer cell apoptosis and senescence, inhibit proliferation and colony growth, and suppress migration and invasion in vitro. Lastly, RBM38 could suppress HCC tumorigenicity in vivo. Conclusion Our findings suggested that RBM38 may be a core contributor in stabilizing the p53-mdm2 loop function to prevent HCC, and a potential novel target to provide a therapeutic strategy for HCC by inhibiting mdm2 and rescuing p53 from inactivation. Electronic supplementary material The online version of this article (10.1186/s13046-018-0852-x) contains supplementary material, which is available to authorized users.

The present study aimed to investigate the prognostic factors for recurrence of hepatocellular carcinoma (HCC) following curative resection, and evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (TACE) in improving prognosis. A total of 166 patients who underwent curative resection followed by adjuvant TACE, and 190 patients who underwent curative resection alone were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors of recurrence. Separated based on risk factors, subgroup studies were conducted and the association between TACE and recurrence rates was examined. Postoperative overall survival rates were determined using the Kaplan-Meier method and differences between the two therapeutic strategies were identified through log-rank analysis. Computerized tomography (CT)/magnetic resonance imaging (MRI) images were used to evaluate the function of postoperative adjuvant TACE for enhancing the efficacy of CT/MRI in detecting recurrence. The results of the univariate and multivariate analyses revealed that tumor capsule invasion, vascular invasion, and multiple nodules were risk factors of early recurrence. For patients with these risk factors, recurrence rates were markedly decreased at 6 and 12 months, but not at 18 and 24 months, if TACE was added to curative resection. The hepatitis B virus (HBV) was a risk factor for late recurrence. Postoperative TACE was not effective in reducing the recurrence rate in patients with HBV. Survival increased following curative resection with TACE compared with curative resection alone. Furthermore, adjuvant TACE enhanced the efficacy of CT/MRI in detecting recurrence. Postoperative adjuvant TACE may improve the prognosis of HCC following curative resection.