miR-552 promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma by targeting FOXO1.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly malignant cancer. Few effective systemic targeted therapies are available for patients with unresectable ICC, but there exists an urgent need to explore mechanisms underlying the initiation and progression of ICC. MicroRNA (miRNA) plays vital roles in the initiation, progression, and drug resistance of different cancers. Recently, the biological function of a novel miRNA, miR-552, has been widely analyzed in hepatocellular carcinoma and colorectal, cervical, gastric, and other cancers. However, its role in ICC has not yet been elucidated. In this study, we found that miR-552 expression was upregulated in ICC and that miR-552 predicted poor prognosis. Using functional studies, we found that miR-552 enhanced the proliferation and invasion ability of ICC cells. Mechanistic research identified that forkhead box O1 (FOXO1) is the target of miR-552 in ICC. Moreover, the combined panels of miR-552 and FOXO1 exhibited a better prognostic value for ICC patients than did miR-552 alone. In conclusion, these findings demonstrated that the miR-552/FOXO1 axis drove ICC progression, further suggesting that targeting this axis could be a novel therapeutic strategy for ICC.

Postoperative Prognosis of Non-alcoholic Fatty Liver Disease-Associated Intrahepatic Cholangiocarcinoma: a Multi-center Propensity Score Matching Analysis.

BACKGROUND AND AIMS: The incidence of intrahepatic cholangiocarcinoma (ICC) in non-alcoholic fatty liver disease (NAFLD) is increasing gradually. The prognosis of NAFLD-ICC has not been well studied. We aim to investigate the prognosis of patients with NAFLD-ICC after curative-intent partial hepatectomy (PH). METHODS: Multi-center data from January 2003 to January 2014 were retrospectively analyzed. The prognosis of ICC was analyzed using PSM and compared with hepatitis B virus (HBV)-related ICC. RESULTS: A total of 898 patients with ICC were included in this study. Of them, 199 (22.2%) were NAFLD-ICC, and 699 (77.8%) were HBV-ICC. Multivariate analysis showed that CA19-9 ≥ 37 U/mL, microvascular invasion, tumor size > 5 cm, multiple tumors, and lymph node (LN) metastasis were independent risk factors for early recurrence (ER) in ICC patients. After a 1:1 PSM, NAFLD-ICC has worse 5-year overall survival (OS) (24.0% vs. 48.9%), 5-year recurrence (80.9% vs. 55.0%), and ER (58.5% vs. 30.0%) than that of HBV-ICC (all P < 0.01). Multivariable analysis showed NAFLD was an independent risk factor for OS (hazard ratio [HR] 2.26, 95% CI 1.63-3.13, P < 0.001), tumor recurrence (HR 2.24, 95%CI 1.61-3.10, P < 0.001) and ER (HR 2.23, 95%CI 1.60-3.09, P < 0.001) in patients with ICC after PH. The sensitivity analysis indicated that NAFLD-ICC patients were more likely to experience ER. CONCLUSION: Compared with HBV-ICC, NAFLD-ICC has a worse prognosis and was more likely to relapse early. More frequent surveillance should be considered.

Liver resection versus liver transplantation for hepatocellular carcinoma within the Milan criteria based on estimated microvascular invasion risks.

Background: Preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) may optimize individualized treatment decision-making. This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection (LR) and liver transplantation (LT) based on predicted MVI risks. Methods: We analysed 905 patients who underwent LR, including 524 who underwent anatomical resection (AR) and 117 who underwent LT for HCC within the Milan criteria using propensity score matching. A nomogram model was used to predict preoperative MVI risk. Results: The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT, respectively. Based on an optimal cut-off value of 200 points, the nomogram defined patients as high- or low-risk MVI groups. LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival (OS) rate than LR among the high-risk patients (23.6% vs 73.2%, P < 0.001; 87.8% vs 48.1%, P < 0.001) and low-risk patients (19.0% vs 45.7%, P < 0.001; 86.5% vs 70.0%, P = 0.002). The hazard ratios (HRs) of LT vs LR for recurrence and OS were 0.18 (95% confidence interval [CI], 0.09-0.37) and 0.12 (95% CI, 0.04-0.37) among the high-risk patients and 0.37 (95% CI, 0.21-0.66) and 0.36 (95% CI, 0.17-0.78) among the low-risk patients. LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients (24.8% vs 63.5%, P = 0.001; 86.7% vs 65.7%, P = 0.004), with HRs of LT vs AR for recurrence and OS being 0.24 (95% CI, 0.11-0.53) and 0.17 (95% CI, 0.06-0.52), respectively. The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients (19.4% vs 28.3%, P = 0.129; 85.7% vs 77.8%, P = 0.161). Conclusions: LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI. No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.

Effect of different PD-1 inhibitor combination therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). AIM: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC. METHODS: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. CONCLUSIONS: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo.

LncRNA HClnc1 facilitates hepatocellular carcinoma progression by regulating PKM2 signaling and indicates poor survival outcome after hepatectomy.

AIM: Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. METHODS: An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo-coupled mass spectrometry to identify HClnc1-interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull-down assay. RESULTS: HClnc1 levels were considerably greater in patients with advanced tumor-node-metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2-STAT3 signaling. CONCLUSIONS: HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis.

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial-mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster-related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.

A Novel Nomogram for Predicting Postoperative Liver Failure After Major Hepatectomy for Hepatocellular Carcinoma.

Background: Post-hepatectomy liver failure (PHLF) is the most common cause of mortality after major hepatectomy in hepatocellular carcinoma (HCC) patients. We aim to develop a nomogram to preoperatively predict grade B/C PHLF defined by the International Study Group on Liver Surgery Grading (ISGLS) in HCC patients undergoing major hepatectomy. Study Design: The consecutive HCC patients who underwent major hepatectomy at the Eastern Hepatobiliary Surgery Hospital between 2008 and 2013 served as a training cohort to develop a preoperative nomogram, and patients from 2 other hospitals comprised an external validation cohort. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to identify preoperative predictors of grade B/C PHLF. Multivariable logistic regression was utilized to establish a nomogram model. Internal and external validations were used to verify the performance of the nomogram. The accuracy of the nomogram was also compared with the conventional scoring models, including MELD and ALBI score. Results: A total of 880 patients who underwent major hepatectomy (668 in the training cohort and 192 in the validation cohort) were enrolled in this study. The independent risk factors of grade B/C PHLF were age, gender, prothrombin time, total bilirubin, and CSPH, which were incorporated into the nomogram. Good prediction discrimination was achieved in the training (AUROC: 0.73) and validation (AUROC: 0.72) cohorts. The calibration curve also showed good agreement in both training and validation cohorts. The nomogram has a better performance than MELD and ALBI score models. Conclusion: The proposed nomogram showed more accurate ability to individually predict grade B/C PHLF after major hepatectomy in HCC patients than MELD and ALBI scores.

Postoperative survival analysis of hepatocellular carcinoma patients with liver cirrhosis based on propensity score matching.

OBJECTIVE: Most hepatocellular carcinoma (HCC) patients in China have some degree of liver cirrhosis. The effect of cirrhosis on the long-term prognosis of HCC patients after hepatectomy is still unclear. This study aimed to investigate the effect of liver cirrhosis on the prognosis of HCC patients after hepatectomy. METHODS: Data from patients who underwent hepatectomy and had pathologically confirmed HCC were retrospectively collected. The patients' clinical pathological data were recorded. Propensity score matching (PSM) was used to eliminate the influence of potential confounding factors. The Kaplan-Meier method was used to calculate the recurrence-free survival (RFS) and overall survival (OS) rates, and Cox regression analysis was used to screen for independent risk factors affecting OS and RFS. RESULTS: A total of 1381 HCC patients who were initially treated with hepatectomy were included, including 797 patients with liver cirrhosis. The RFS and OS rates in the group with cirrhosis were significantly lower than those in the group without cirrhosis (after PSM, RFS: P < 0.001; OS: P = 0.001). Subgroup analysis showed that among patients with Barcelona Clinic Liver Cancer (BCLC) stage 0-B disease, RFS and OS were significantly lower in those with cirrhosis than in those without cirrhosis (both P < 0.05); while in patients with stage C disease, there was no significant difference between those with and without cirrhosis. In the group with cirrhosis, alpha-fetoprotein (AFP) > 400, intraoperative blood loss, tumor diameter > 5 cm, satellite lesions, and large vessel invasion were independent risk factors for RFS, while albumin-bilirubin (ALBI) grade, neutrophil-to-lymphocyte ratio (NLR), tumor diameter > 5 cm, satellite lesions, microvascular invasion, and macrovascular invasion were independent risk factors for OS. CONCLUSION: HCC with liver cirrhosis has specific characteristics. Compared with patients without cirrhosis, patients with cirrhosis have worse long-term survival after surgery. In addition, the independent risk factors for RFS and OS are different between patients with cirrhosis and without cirrhosis; liver cirrhosis is an independent risk factor for the long-term prognosis of HCC patients, especially patients with BCLC stage 0-B disease after hepatectomy.

A nomogram predicting severe COVID-19 based on a large study cohort from China.

BACKGROUND: The use of accurate prediction tools and early intervention are important for addressing severe coronavirus disease 2019 (COVID-19). However, the prediction models for severe COVID-19 available to date are subject to various biases. This study aimed to construct a nomogram to provide accurate, personalized predictions of the risk of severe COVID-19. METHODS: This study was based on a large, multicenter retrospective derivation cohort and a validation cohort. The derivation cohort consisted of 496 patients from Jiangsu Province, China, between January 10, 2020, and March 15, 2020, and the validation cohort contained 105 patients from Huangshi, Hunan Province, China, between January 21, 2020, and February 29, 2020. A nomogram was developed with the selected predictors of severe COVID-19, which were identified by univariate and multivariate logistic regression analyses. We evaluated the discrimination of the nomogram with the area under the receiver operating characteristic curve (AUC) and the calibration of the nomogram with calibration plots and Hosmer-Lemeshow tests. RESULTS: Three predictors, namely, age, lymphocyte count, and pulmonary opacity score, were selected to develop the nomogram. The nomogram exhibited good discrimination (AUC 0.93, 95% confidence interval [CI] 0.90-0.96 in the derivation cohort; AUC 0.85, 95% CI 0.76-0.93 in the validation cohort) and satisfactory agreement. CONCLUSIONS: The nomogram was a reliable tool for assessing the probability of severe COVID-19 and may facilitate clinicians stratifying patients and providing early and optimal therapies.

External Validation of Six Liver Functional Reserve Models to predict Posthepatectomy Liver Failure after Major Resection for Hepatocellular Carcinoma.

Objective: To validate and compare the predictive ability of albumin-bilirubin model (ALBI) with other 5 liver functional reserve models (APRI, FIB4, MELD, PALBI, King's score) for posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) who underwent major hepatectomy. Methods: Data of patients undergoing major hepatectomy for HCC from 4 hospitals between January 01, 2008 and December 31, 2019 were retrospectively analyzed. PHLF was evaluated according to the definition of the 50-50 criteria. Performances of six liver functional reserve models were determined by the area under the receiver operating characteristic curve (AUC), calibration plot and decision curve analysis. Results: A total of 745 patients with 103 (13.8%) experienced PHLF were finally included in this study. Among six liver functional reserve models, ALBI showed the highest AUC (0.64, 95% CI: 0.58-0.69) for PHLF. All models showed good calibration and greater net benefit than treating all patients at a limit range of threshold probabilities, but the ALBI demonstrated net benefit across the largest range of threshold probabilities. Subgroup analysis also showed ALBI had good predictive performance in cirrhotic (AUC=0.63) or non-cirrhotic (AUC=0.62) patients. Conclusion: Among the six models, the ALBI model shows more accurate predictive ability for PHLF in HCC patients undergoing major hepatectomy, regardless of having cirrhosis or not.

Preoperative Estimated Risk of Microvascular Invasion is Associated with Prognostic Differences Following Liver Resection Versus Radiofrequency Ablation for Early Hepatitis B Virus-Related Hepatocellular Carcinoma.

OBJECTIVES: The aim of this study was to examine prognostic differences between liver resection (LR) and percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC) based on preoperative predicted microvascular invasion (MVI) risk. METHODS: Data on consecutive patients who underwent LR (n = 1344) or PRFA (n = 853) for hepatitis B virus-related HCC within the Milan criteria (MC) were analyzed. A preoperative nomogram was used to estimate MVI risk. Overall survival (OS), time to recurrence, and patterns of recurrence were compared using propensity score matching. RESULTS: The concordance indices of the nomogram to predict MVI were 0.813 and 0.781 among LR patients with HCC within the MC or ≤ 3 cm, respectively. LR and PRFA resulted in similar 5-year recurrence and OS for patients with nomogram-predicted low-risk of MVI. LR provided better 5-year recurrence and OS versus PRFA for patients with high-risk of MVI (71.6% vs. 80.7%, p = 0.013; 47.9% vs. 34.0%, p = 0.002, for HCC within the MC; 62.3% vs. 78.8%, p = 0.020; 63.6% vs. 38.3%, p = 0.015, for HCC ≤ 3 cm). Among high-risk patients, LR was associated with lower recurrence and improved OS compared with PRFA, on multivariate analysis [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63-0.97, and HR 0.68, 95% CI 0.52-0.88, for HCC within the MC; HR 0.51, 95% CI 0.32-0.81, and HR 0.47, 95% CI 0.26-0.84, for HCC ≤ 3 cm], and resulted in less early and local recurrence than PRFA (42.4% vs. 54.8%, p = 0.007, and 31.2% vs. 46.1%, p = 0.007, for HCC within the MC; 27.9% vs. 50.8%, p = 0.016, and 15.6% vs. 39.5%, p = 0.046, for HCC ≤ 3 cm). CONCLUSIONS: LR was oncologically superior over PRFA for early HCC patients with predicted high-risk of MVI. LR was associated with better local disease control than PRFA in these patients.

Postoperative adjuvant transarterial chemoembolization for intrahepatic cholangiocarcinoma patients with microvascular invasion: a propensity score analysis.

BACKGROUND: Microvascular invasion (MVI) is an independent risk factor associated with tumor recurrence and poor survival in patients with intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy (PH). The potential impact of adjuvant TACE on the prognosis of patients with ICC involving MVI (ICC-MVI) remains uncertain. Our aim was to investigate the effectiveness of postoperative adjuvant transarterial chemoembolization (TACE) on ICC involving MVI. METHODS: Multicentric data consisted of 223 patients who underwent curative-intent PH for ICC-MVI from 2002-2015 were retrospectively analyzed. The impact of adjuvant TACE was evaluated using inverse probability of treatment weighting (IPTW) and propensity-score matched (PSM) analyses. RESULTS: No association between the TACE and the overall survival (OS) and recurrence rates was observed among the overall ICC-MVI patients. However, subgroup analyses revealed that adjuvant TACE favored OS (HR, 0.62; 95% CI, 0.39-0.99; P=0.047) and time to recurrence (TTR) (HR, 0.59; 95% CI, 0.36-0.97; P=0.037) among patients with elevated CA19-9 and those without lymphadenectomy (HR, 0.53; 95% CI, 0.30-0.93; P=0.027 for OS, and HR, 0.49; 95% CI, 0.28-0.87; P=0.015 for TTR, respectively). In the CA19-9 ≥39 U/L subgroup and Nx subgroup, adjuvant TACE was associated with higher 1-, 3-, and 5-year OS rates (P=0.033 and P=0.034, respectively) and lower corresponding recurrence rates (P=0.024 and P=0.023, respectively). CONCLUSIONS: Among the ICC-MVI patients undergoing curative-intent PH, only those have elevated CA19-9 or who did not undergo lymphadenectomy might be suitable for adjuvant TACE.

microRNA-454 promotes liver tumor-initiating cell expansion by regulating SOCS6.

Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response.

Long-term Effects of Repeat Hepatectomy vs Percutaneous Radiofrequency Ablation Among Patients With Recurrent Hepatocellular Carcinoma: A Randomized Clinical Trial.

Importance: Repeat hepatectomy and percutaneous radiofrequency ablation (PRFA) are most commonly used to treat early-stage recurrent hepatocellular carcinoma (RHCC) after initial resection, but previous studies comparing the effectiveness of the 2 treatments have reported conflicting results. Objective: To compare the long-term survival outcomes after repeat hepatectomy with those after PRFA among patients with early-stage RHCC. Design, Setting, and Participants: This open-label randomized clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital and the National Center for Liver Cancer of China. A total of 240 patients with RHCC (with a solitary nodule diameter of ≤5 cm; 3 or fewer nodules, each ≤3 cm in diameter; and no macroscopic vascular invasion or distant metastasis) were randomized 1:1 to receive repeat hepatectomy or PRFA between June 3, 2010, and January 15, 2013. The median (range) follow-up time was 44.3 (4.3-90.6) months (last follow-up, January 15, 2018). Data analysis was conducted from June 15, 2018, to September 28, 2018. Interventions: Repeat hepatectomy (n = 120) or PRFA (n = 120). Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included repeat recurrence-free survival (rRFS), patterns of repeat recurrence, and therapeutic safety. Results: Among the 240 randomized patients (216 men [90.0%]; median [range] age, 53.0 [24.0-59.0] years), 217 completed the trial. In the intention-to-treat (ITT) population, the 1-year, 3-year, and 5-year OS rates were 92.5% (95% CI, 87.9%-97.3%), 65.8% (95% CI, 57.8%-74.8%), and 43.6% (95% CI, 35.5%-53.5%), respectively, for the repeat hepatectomy group and 87.5% (95% CI, 81.8%-93.6%), 52.5% (95% CI, 44.2%-62.2%), and 38.5% (95% CI, 30.6%-48.4%), respectively, for the PRFA group (P = .17). The corresponding 1-year, 3-year, and 5-year rRFS rates were 85.0% (95% CI, 78.8%-91.6%), 52.4% (95% CI, 44.2%-62.2%), and 36.2% (95% CI, 28.5%-46.0%), respectively, for the repeat hepatectomy group and 74.2% (95% CI, 66.7%-82.4%), 41.7% (95% CI, 33.7%-51.5%), and 30.2% (95% CI, 22.9%-39.8%), respectively, for the PRFA group (P = .09). Percutaneous radiofrequency ablation was associated with a higher incidence of local repeat recurrence (37.8% vs 21.7%, P = .04) and early repeat recurrence than repeat hepatectomy (40.3% vs 23.3%, P = .04). In subgroup analyses, PRFA was associated with worse OS vs repeat hepatectomy among patients with an RHCC nodule diameter greater than 3 cm (hazard ratio, 1.72; 95% CI, 1.05-2.84) or an α fetoprotein level greater than 200 ng/mL (hazard ratio, 1.85; 95% CI, 1.15-2.96). Surgery had a higher complication rate than did ablation (22.4% vs 7.3%, P = .001). Conclusions and Relevance: No statistically significant difference was observed in survival outcomes after repeat hepatectomy vs PRFA for patients with early-stage RHCC. Repeat hepatectomy may be associated with better local disease control and long-term survival in patients with an RHCC diameter greater than 3 cm or an AFP level greater than 200 ng/mL. Trial Registration: ClinicalTrials.gov identifier: NCT00822562.

miR-219 regulates liver cancer stem cell expansion via E-cadherin pathway.

Liver cancer stem cells contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liverCSCs is not fully understood yet. Here we show that miR-219 is upregulated in liver CSCs. Knockdown of miR-219 attenuates the self-renewal and tumorigenicity of liver CSCs. Conversely, miR-219 overexpressing enhances the self-renewal and tumorigenicity of liver CSCs.Mechanistically,miR-219 downregulates E-cadherin via itsmRNA 3'UTR in liver CSCs. The correlation between miR-219 and E-cadherin is validated in human HCC tissues. Furthermore, the miR-219 expression determines the responses of hepatoma cells to sorafenib treatment. Our findings indicate that miR-219 plays a critical role in liver CSCs expansion and sorafenib response, rendering miR-219 as an optimal target for the prevention and intervention of HCC.Abbreviations: HCC: Hepatocellular carcinoma; CSCs: cancer stem cells; DMEM: Dulbecco's modified Eagle's medium; FBS: fetal bovine serum; OS: overall survival.

Modifications of the AJCC 8th edition staging system for intrahepatic cholangiocarcinoma and proposal for a new staging system by incorporating serum tumor markers.

BACKGROUND: Several studies have noted that the discriminatory ability and stratification performance of the AJCC 8th edition staging system is not entirely satisfactory. We aimed to improve the American Joint Committee on Cancer (AJCC) 8th edition staging system for intrahepatic cholangiocarcinoma (ICC). METHODS: A multicentric database from three Chinese mainland centers (n = 1601 patients) was used to modify the 8th edition staging system. This modified TNM (mTNM) staging system was then validated using the SEER database (n = 761 patients). A new TNM staging system, by incorporating serum tumor markers (TNMIS) into the mTNM staging system was then proposed. RESULTS: The 8th edition staging system did not provide an adequate stratification of prognosis in the Chinese multicentric cohort. The mTNM staging system offered a better discriminatory capacity in the multicentric cohort than the original 8th edition. External validation in the SEER cohort showed that the mTNM staging system also had a good stratification performance. After further incorporating a serum marker stage into the mTNM staging, the TNMIS staging system was able to stratify prognosis even better. CONCLUSION: The proposed mTNM staging system resulted in better stratification performance and the TNMIS staging system provided even more accurate prognostic classification than the conventional TNM system.

Coming of a precision era of the staging systems for intrahepatic cholangiocarcinoma?

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Appropriate treatment of this aggressive and heterogeneous cancer requires accurate staging and prognostic stratification, as does patient selection for clinical trials. Over the past two decades, several staging systems and prognostic models for ICC have been developed. Most include independent prognostic factors such as tumor extent, clinical parameters and histopathological features and are inaccurate. Accumulating findings offer new insights into the genetic and molecular basis of ICC progression. Hence, staging systems and prognostic models that incorporate in clinicalpathological factors, molecular and genomic information, and tumor biomarkers, and hence more accurately estimate prognosis, will become a reality. This review summarizes the current staging systems and prognostic models for ICC and highlights the need to establish more precise and personalized systems and models that incorporate tumor biologic factors.

Exosome-transmitted p120-catenin suppresses hepatocellular carcinoma progression via STAT3 pathways.

Hepatocellular carcinoma (HCC) is a fatal disease with increasing morbidity and poor prognosis due to surgical recurrence and metastasis. Moreover, the molecular mechanism of HCC progression remains unclear. Although the role of p120-catenin (p120ctn) in liver cancer is well studied, the effects of secreted p120ctn transported by exosomes are less understood. Here, we show that p120ctn in exosomes secreted from liver cancer cells suppresses HCC cell proliferation and metastasis and expansion of liver cancer stem cells (CSCs). Mechanically, exosome p120ctn inhibits HCC cell progression via the STAT3 pathway, and the STAT3 inhibitor S3I-201 abolishes the observed effects on growth, metastasis, and self-renewal ability between exosome p120ctn-treated HCC cells and control cells. Taken together, we propose that p120ctn-containing exosomes derived from cancer cells inhibit the progression of liver cancer and may offer a new therapeutic strategy.

Short-term and long-term outcomes of liver resection for HCC patients with portal vein tumor thrombus.

BACKGROUND: Portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) is a sign of advanced stage disease, which is associated with poor prognosis. Liver resection (LR) may provide better prognosis in selected patients. In the present study, we aimed to assess information from HCC patients with PVTT who died within 3 months or 2 years after LR in order to identify preoperative factors correlated to short-term or long-term survival, by which inappropriate selection of patients for LR might be avoided in the future. METHODS: A retrospective cohort study consisting of 487 consecutive cases of HCC patients with PVTT was performed from 2008 to 2010 at Eastern Hepatobiliary Surgery Hospital. Medical records, including laboratory values, imaging results and treatment information, were obtained from participants. Study endpoints were survival at 3 months and 2 years post-hepatectomy. Logistic regression analysis was utilized to determine the significant pre-operative factors influencing short-term or long-term survival. RESULTS: In multivariable analysis, α-fetoprotein, total bilirubin and radiologic ascites were significantly associated with short-term survival, while α-fetoprotein level, clinical significant portal hypertension, extent of PVTT and tumor differentiation were factors significantly associated with long-term survival. CONCLUSIONS: The independent risk factors of poor short-term survival were the liver function-associated, such as factors radiologic ascites and total bilirubin, while tumor differentiation indicating the tumor biology was associated with longer-term survival. In addition, α-fetoprotein was a risk factor associated with both short-term and longer-term survivals.

Impact of Anatomical Versus Non-anatomical Liver Resection on Short- and Long-Term Outcomes for Patients with Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The aim of this study was to examine the impact of anatomical resection (AR) versus non-anatomical resection (NAR) on the survival outcomes in patients with intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Data on 702 consecutive patients who underwent either AR (n = 319) or NAR (n = 383) for ICC were reviewed. Disease-free survival (DFS) and overall survival (OS) following AR versus NAR was compared using propensity score matching (PSM). Subgroups of patients who benefited from AR versus NAR were examined after being stratified by the 8th TNM staging of ICC. RESULTS: AR and NAR had similar complication rates (26.6% vs. 25.1%, p = 0.634). AR was associated with better 1-, 3-, and 5-year DFS and OS rates compared with NAR after PSM (58.1%, 35.7% and 28.1% vs. 44.1%, 23.9% and 18.0%; 72.9%, 45.7% and 36.0% vs. 62.0%, 30.8% and 25.3%; both p = 0.002). On multivariate analysis, NAR was associated with worse DFS and OS than AR [hazard ratio (HR) 1.461 and 1.488; 95% confidence interval (CI) 1.184-1.804 and 1.189-1.863, respectively]. Stratified analysis demonstrated similar outcomes following AR versus NAR for ICC at stages IA, II with vascular invasion, and III with visceral peritoneum perforation, local extrahepatic invasion and nodal metastasis, while NAR was associated with worse DFS and OS versus AR for stages IB (HR 1.897 and 2.321; 95% CI 1.179-3.052 and 1.376-3.914, respectively) or II ICC without vascular invasion (2.071 and 2.077; 95% CI 1.239-3.462 and 1.205-3.579, respectively). CONCLUSIONS: AR was associated with better survival outcomes compared with NAR in ICC patients with stage IB or II tumors without vascular invasion.