The Effect of Microvascular Invasion on Hepatocellular Carcinoma With Portal Vein Tumor Thrombus After Hepatectomy: A Retrospective Study.

BACKGROUND: There is no report resolving whether microvascular invasion (MVI) affects the prognosis of hepatectomy for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). The present study aimed to investigate the effect of MVI on HCC with PVTT after hepatectomy. METHODS: 362 HCC patients with PVTT were included in this retrospective study. Diagnostic criteria of PVTT in HCC patients were based on typical preoperative radiological features on imaging studies. The log-rank test was utilized to differentiate overall survival (OS) and recurrence-free survival (RFS) rates between the two groups. Univariate and multivariate Cox proportional hazard regression was utilized to detect independent factors. RESULTS: PVTT without MVI accounted for 12.2% (n = 44). PVTT without MVI groups was significantly superior to PVTT with MVI groups in OS (the median survival = 27.1 months vs 13.7 months) and RFS (the median survival = 6.4 months vs 4.1 months). The 1-, 3-, and 5-year OS rates (65.5%, 36.8%, 21.7% vs 53.5%, 18.7%, 10.1%, P = .014) and RFS rates (47.0%, 29.7%, 19.2% vs 28.7%, 12.2%, 6.9%, P = .005) were significant different between two groups. Multivariate analysis showed that MVI was an independent risk factor for OS (hazard ratio (HR) = 1.482; P-value = .045) and RFS (HR = 1.601; P-value = .009). CONCLUSIONS: MVI was an independent prognostic factor closely linked to tumor recurrence and poorer clinical outcomes for HCC patients with PVTT after hepatectomy. MVI should be included in current PVTT systems to supplement to the PVTT type.

The effect of adjuvant transarterial chemoembolization for hepatocellular carcinoma after liver resection based on risk stratification.

BACKGROUND: There is currently no standard adjuvant treatment proven to prevent hepatocellular carcinoma (HCC) recurrence. Recent studies suggest that postoperative adjuvant transarterial chemoembolization (PA-TACE) is beneficial for patients at high risk of tumor recurrence. However, it is difficult to select the patients. The present study aimed to develop an easy-to-use score to identify these patients. METHODS: A total of 4530 patients undergoing liver resection were recruited. Independent risk factors were identified by Cox regression model in the training cohort and the Primary liver cancer big data transarterial chemoembolization (PDTE) scoring system was established. RESULTS: The scoring system was composed of ten risk factors including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, operative bleeding loss, resection margin, tumor capsular, satellite nodules, tumor size and number, and microvascular and macrovascular invasion. Using 5 points as risk stratification, the patients with PA-TACE had higher recurrence-free survival (RFS) compared with non-TACE in > 5 points group (P < 0.001), whereas PA-TACE patients had lower RFS compared with non-TACE in ≤ 5 points group (P = 0.013). In the training and validation cohorts, the C-indexes of PDTE scoring system were 0.714 [standard errors (SE) = 0.010] and 0.716 (SE = 0.018), respectively. CONCLUSIONS: The model is a simple tool to identify PA-TACE for HCC patients after liver resection with a favorable performance. Patients with > 5 points may benefit from PA-TACE.

Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation.

Although a variety of molecular targets have been identified, hepatocellular carcinoma (HCC) remains among the leading causes of death. As functions of they deubiquitinating enzyme Josephin domain containing 2 (JOSD2) in cancers are still poorly understood, we investigated its function and molecular mechanism in the regulation of HCC progression. Here, we indicated that JOSD2 expression is elevated in patient samples with HCC and positively associated with poor prognosis. Moreover, the promoting roles of JOSD2 in HCC cell survival, migration, and invasion were determined using in vitro models. Importantly, a mechanistic study revealed that JOSD2 binds to and decreases the ubiquitination level of catenin beta 1 (CTNNB1), a key component of Wnt signaling, thereby augmenting Wnt pathway transduction. Furthermore, a series of rescue experiments confirmed the significance of CTNNB1 in the modulation of HCC progression by JOSD2. Our study uncovered JOSD2 as a novel prognostic marker for patients with HCC and identified CTNNB1 as a pivotal partner and downstream target protein of JOSD2, which may aid in the development of JOSD2 as a promising molecular target for HCC treatment.

Antiviral Therapy Improves Survival in Hepatocellular Carcinoma with Microvascular Invasion: A Propensity Score Analysis.

BACKGROUND AND AIMS: To investigate the effect of postoperative adjuvant antiviral therapy (AVT) on hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after R0 liver resection. METHODS: A total of 1008 patients with HBV-related HCC with MVI were recruited, which comprises 378 non-AVT groups and 630 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis. RESULTS: After PSM, the 1-, 3-, and 5-year overall survival rates in the AVT group and non-AVT group were 89.2%, 62.4%, 42.1%, and 73.3%, 46.3%, 22.1%, (p < 0.01), respectively. The 1-, 3-, and 5-year recurrence-free survival rates in the AVT group and non-AVT group were 52.5%, 30.4%, 22.1%, and 46.3%, 26.8%, 13.2% (p = 0.02), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.55, 95%CI = 0.46-0.67, p < 0.01) and tumor recurrence (HR = 0.81, 95%CI = 0.69-0.96, p = 0.01). CONCLUSIONS: Among patients who underwent curative hepatectomy for HBV-related HCC with MVI, postoperative adjuvant AVT was the independent protective factor associated with mortality and tumor recurrence. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC with MVI, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Development and validation of nomogram to predict very early recurrence of combined hepatocellular-cholangiocarcinoma after hepatic resection: a multi-institutional study.

BACKGROUND AND OBJECTIVES: Combined hepatocellular cholangiocarcinoma (cHCC) has a high incidence of early recurrence. The objective of this study is to construct a model predicting very early recurrence (VER) (i.e., recurrence within 6 months after surgery) of cHCC. METHODS: One hundred thirty-one consecutive patients from Eastern Hepatobiliary Surgery Hospital served as a development cohort to construct a nomogram predicting VER by using multi-variable logistic regression analysis. The model was internally and externally validated in a validation cohort of 90 patients from Mengchao Hepatobiliary Hospital using the C concordance statistic, calibration analysis, and decision curve analysis (DCA). RESULTS: The VER nomogram contains microvascular invasion (MiVI), macrovascular invasion (MaVI), and CA19-9 > 25 mAU/mL. The model shows good discrimination with C-indexes of 0.77 (95% CI: 0.69-0.85) and 0.76 (95% CI: 0.66-0.86) in the development cohort and validation cohort respectively. Decision curve analysis demonstrated that the model is clinically useful and the calibration of our model was favorable. Our model stratified patients into two different risk groups, which exhibited significantly different VER. CONCLUSIONS: Our model demonstrated favorable performance in predicting VER in cHCC patients.

Development of pre and post-operative nomograms to predict individual survival for ideal liver resection candidates with hepatocellular carcinoma.

BACKGROUND: Liver resection is currently the only recommended treatment option for solitary hepatocellular carcinoma (HCC) at an early stage, with well-preserved liver function and no clinically significant portal hypertension. However, this population is heterogeneous, rendering it crucial to develop a risk stratification tool. Therefore, this study aimed to develop preoperative and post-operative nomograms to predict individual survival and stratify patient risk in the ideal candidates for liver resection. METHODS: A total of 1405 ideal liver resection candidates were recruited. Independent risk factors were identified by Cox regression model and used to establish two ideal liver resection for overall survival (IROS) nomograms in training cohort. Model performance was assessed by discrimination, calibration, clinical usefulness. The two model also compared with six other prognostic nomograms and six other staging systems. RESULTS: Multivariate COX analysis revealed that ALP, ln(AFP), NrLR, PNI, ln(tumor size), microvascular invasion, Edmondson-Steiner grade and tumour capsular were the independent risk factors associated with mortality. 5 preoperative variables were incorporated to construct IROS-pre model; All eight available variables were used to draw IROS-post model. The C-index, K-index, time-dependent AUC and DCA of the two models showed significantly better predictive performances than other models. The models could stratify patients into three different risk groups. The web-based tools are convenient for clinical practice. CONCLUSIONS: These two nomograms were developed to estimate survival probability and stratify three strata with significantly different outcomes, outperforming other models in training and validation cohorts, as well as different subgroups. Both IROS models will help guide individualized follow-up.

Clinical Significance of Alpha-Fetoprotein in Alpha-Fetoprotein Negative Hepatocellular Carcinoma Underwent Curative Resection.

BACKGROUND: The clinical value of alpha-fetoprotein (AFP) in patients with AFP-negative (< 20 ng/ml) hepatocellular carcinoma (HCC) who underwent curative resection remained controversial. AIMS: To investigate clinical relevance and prognostic effect of preoperative serum AFP level in this subgroup. METHODS: A total of 1879 patients with AFP-negative HCC who underwent curative resection were included in the study. Overall survival (OS) and disease-free survival (DFS) rate were displayed by Kaplan-Meier method and compared by log-rank test. Multivariate cox proportional hazard regression analysis was used to identify the independent prognostic factors. The prognostic predictive performance was analyzed by time-dependent areas under receiver operating characteristic curve (AUC). RESULTS: Even in AFP-negative HCC, patients with high preoperative serum AFP level tended to have multiple tumor (P < 0.001), poorer differentiation of tumor cell (P < 0.001), presence of satellite nodules (P < 0.001), and MVI (P = 0.002). Kaplan-Meier analysis showed the adverse impact of AFP level on prognosis, especially for DFS. Multivariate analysis identified AFP as the independent unfavorable factor for OS and DFS (P < 0.001 for both). Time-dependent AUC analysis showed that the combination with AFP could improve the prognostic predictive performance of 8th AJCC and BCLC staging system. CONCLUSIONS: AFP was still the surrogate of aggressive behavior of HCC and independent prognostic factor for patients with AFP-negative HCC underwent curative resection. Even combining with such a low level of AFP could significantly improve the predictive performance of conventional staging system.

Reclassification of tumor size for solitary HBV-related hepatocellular carcinoma by minimum p value method: a large retrospective study.

BACKGROUND AND OBJECTIVES: Tumor size is one of the most important issues for hepatocellular carcinoma (HCC) treatment and prognosis, but the classification of it is still controversial. The aim of this study was to screen appropriate cutoffs for size of solitary hepatitis B virus (HBV)-related HCC. METHODS: A cohort of 1760 patients with solitary HBV-related HCC undergoing curative liver resection was divided into 11 groups based on tumor size in 1-cm interval. The minimum p value method was used to screen the appropriate size cutoff according to overall survival (OS). If multiple cutoffs meet the above standard, a univariate analysis will be performed by using the Cox proportional hazards regression model, and hazard ratio (HR) will be considered as a criterion to assess the difference in survival. RESULTS: There are 8 dichotomy, 8 trichotomy, and no inquartation cutoffs that were screened when classifying tumor sizes in accordance with OS. The HR values of tumor size at these trichotomy cutoffs for OS were compared, and the highest HR value is 2.79 when size cutoff is 3/9 cm. Then, we reclassified patients into three new classifications: ≤ 3 cm (n = 422), > 3 and ≤ 9 cm (n = 1072), and > 9 cm (n = 266). The comparison of clinicopathologic characteristics among these three classifications showed that the increase of tumor size was associated with the increase of α-fetoprotein (AFP), microvascular invasion (MVI), tumor differentiation, and liver cirrhosis. And the comparison of the OS among three classifications showed statistical differences. CONCLUSIONS: This study suggested that size criteria of 3 cm and 9 cm in solitary HBV-related HCC patients were appropriate based on biological characteristics and prognostic significance.

Adjuvant transarterial chemoembolization for patients with hepatocellular carcinoma after radical hepatectomy: a real world study.

Objective: To investigate the clinical value of the adjuvant transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) after radical resection, and identify the potential beneficiaries.Methods: Patients were identified through the primary liver cancer big data (PLCBD) between 2012 and 2015. Overall survival (OS) between adjuvant TACE group and non-TACE was evaluated by Kaplan-Meier before and after propensity scoring match (PSM). Subgroup analysis was conducted stratified by risk factors.Results: A total of 2066 HCC patients receiving radical resection were identified. Patients with multiple tumors, tumor diameter >5 cm, satellite, and advanced stage were more likely to accept adjuvant TACE. Before PSM, the 1-, 3-, and 5-year OS rates in the TACE group and non-TACE group were 89%, 58%, 17%, and 88%, 53%, 13% (p = .43), respectively. While, the corresponding rates were 89%, 58%, 17%, and 86%, 49%, 11%, (p = .038), respectively after 1:1 PSM. In addition, patients were found to significantly benefit from adjuvant TACE if they had age ≥50 years, no cirrhosis, AFP ≤ 200 ng/ml, surgical margin <1 cm, tumor diameter >5 cm, no capsule, no satellite, or CN stage Ib/IIa (all p < .05), but patients with age < 50 years, tumor size ≤5 cm, or CN stage Ia were found to significantly benefit from radical resection in DFS (all p < .05).Conclusion: Currently, we concluded that not all of patients with HCC would benefit from adjuvant TACE. Patients with age ≥50 years, tumor size >5 cm, or CN stage Ib/IIa were strongly recommended to receive adjuvant TACE.

Huaier granule improves liver inflammation and fibrosis and prevents recurrence in hepatitis B virus related hepatocellular carcinoma.

Background: There is basic research suggesting that Huaier granule can inhibit liver cirrhosis and hepatocellular carcinoma (HCC), but this conclusion has not been clinically verified. We analyzed the distant cancer tissue of two groups of hepatitis B virus (HBV) related HCC with/without Huaier granule, to clarify the effect of Huaier granule on liver inflammation, liver fibrosis, and postoperative recurrence. Methods: We collected clinicopathological data of HCC patients who received two surgery procedures at Mengchao Hepatobiliary Hospital of Fujian Medical University in China from January 2014 to December 2020. Patients according to taking/not taking Huaier granule after the first hepatectomy were divided into two groups, 51 patients with Huaier granule for more than 6 months after operation (Group A); 56 patients without Huaier granule (Group B). The effects on liver inflammation, fibrosis grade, and postoperative recurrence were compared between two groups. Results: The results showed that liver inflammation improved significantly in the Group A [19 (37.3%) cases improved, 31 (60.8%) cases remained unchanged, and 1 (2.0%) case deteriorated] was significantly more than that in the Group B [7 (12.5%) cases improved, 32 (57.1%) cases remained unchanged, and 17 (30.4%) cases deteriorated] (P<0.001). The liver fibrosis in the Group A [17 (33.3%) cases improved, 32 (62.7%) cases remained unchanged, and 2 (3.9%) cases deteriorated] was significantly improved in the Group B [5 (8.9%) cases improved, 45 (80.4%) cases remained unchanged, and 6 (10.7%) cases deteriorated] (P=0.005). The recurrence interval (27.0±21.2 months) in the Group A was significantly longer than that in the Group B (19.0±14.2 months) (P=0.026). Conclusions: Huaier granule can improve liver inflammation, fibrosis, and liver function and prolong the time to recurrence in HBV-related HCC. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear. METHODS: Bioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays. RESULTS: Our study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells. CONCLUSION: Our findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

Inflammation-Related Marker NrLR Predicts Prognosis in AFP-Negative HCC Patients After Curative Resection.

Background: The role of inflammation-related markers in alpha-fetoprotein (AFP) negative hepatocellular carcinoma (HCC) is not well known. This study aimed to investigate the clinical significance of inflammation-related markers in AFP-negative HCC patients after curative resection. Methods: One thousand one hundred and seventy-nine AFP-negative HCC patients after curative resection were included. Survival rate and prognostic analysis were performed using Kaplan-Meier and Cox regression analysis. Propensity score matching (PSM) was used for patient selection. Results: Multivariate Cox regression showed that neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio (NrLR) was the independent risk factor associated with OS (p = 0.002) and RFS (p = 0.017). Low NrLR groups (n = 628) had lower rates of albumin-bilirubin (ALBI) grade 2 (p < 0.001), lower rates of bleeding and blood transfusion (p < 0.001) than high NrLR groups. Considering tumor features, low NrLR groups had lower AFP levels (p < 0.001), smaller tumor size (p < 0.001), and lower rates of Edmondson grade III-IV (p = 0.024) than high NrLR groups. After PSM, the 1-year, 3 year-, and 5-year OS rates in the low NrLR and high NrLR groups were 96.3%, 86.9%, 64.9%, and 91.4%, 76.7%, 59.5% (p < 0.001), respectively. The 1-year, 3-year, and 5-year RFS rates in the low NrLR and high NrLR groups were 80.0%, 62.9%, 47.5%, and 71.7%, 52.6%, 39.5% (p < 0.001), respectively. Conclusion: NrLR was a poor prognostic factor for mortality and tumor recurrence in AFP-negative HCC patients after curative resection. The simple and low-cost marker could help physician to determine patients at high risk of tumor recurrence for frequent clinical surveillance.

Prognostic significance of three-tiered pathological classification for microvascular invasion in patients with combined hepatocellular-cholangiocarcinoma following hepatic resection.

BACKGROUND AND OBJECTIVES: Previous studies have reported that the microvascular invasion three-tiered grading (MiVI-TTG) scheme is a better prognostic predictor than the two-tiered microvascular invasion (MiVI) grading scheme in hepatocellular carcinoma. This study aims to explore the prognostic significance of MiVI-TTG in patients undergoing liver resection for combined hepatocellular-cholangiocarcinoma (cHCC) and to explore the risk factors for MiVI in cHCC. METHODS: This research included 208 patients graded as M0, M1, or M2 using the MiVI-TTG scheme. Predictive performance was assessed by Cox regression analysis, Kaplan-Meier curve with Log rank test, Harrell's c-index, and time-dependent areas under the receiver operating characteristic curve (tdAUC). The clinical utility of the two schemes was evaluated by decision cure analysis (DCA). The risk factors for MiVI were evaluated using logistic regression analysis. RESULTS: Among 208 cHCC patients, the proportions of M0, M1 and M2 were 38.9%, 36.5%, and 24.5%, respectively. Patients with severe MiVI status had worse recurrence-free survival and overall survival (OS) based on Kaplan-Meier analysis. M1, M2, and MiVI-positive were independent risk factors for early recurrence, while M2 and MiVI-positive were associated with overall survival (OS). MiVI-TTG had a larger c-index, tdAUC, and net benefit rate than the two-tiered MiVI grading scheme for predicting recurrence free survival and OS. AFP≥400 ng/ml was the independent risk factor for MiVI, and satellite nodules were independent risk factors for M2. CONCLUSIONS: MiVI-TTG has a greater prognostic value than the two-tiered MiVI grading scheme in patients undergoing hepatic resection for cHCC.

Efficacy of Adjuvant Transarterial Chemoembolization Combined Antiviral Therapy for HBV-Related HCC with MVI after Hepatic Resection: A Multicenter Study.

BACKGROUND: Efficacy of transarterial chemoembolization (TACE) combined antiviral therapy (AVT) on long-term outcome in hepatitis B virus-related HCC with microvascular invasion (MVI) after hepatic resection is unclear. METHODS: A multicenter retrospective study was conducted. All patients were divided into four groups according to postoperative adjuvant therapy (control group, AVT group, TACE group, and combined group). The overall survival (OS) and recurrence-free survival (RFS) were analyzed. RESULTS: A total of 1090 patients were enrolled in this study, including control group (n=319), TACE group (n=152), AVT group (n=335) and combined group (n=284). Multivariate Cox analysis showed that postoperative adjuvant AVT and TACE were the independent protective factors for OS and RFS. The median OS among the control group, TACE group, AVT group, and the combined group were 16.44, 18.36 months, 38.88 months, and 48.24 months respectively(p<0.01). The median RFS among 4 group were 4.68, 5.40 months, 8.64 months and 10.32 months respectively(p<0.01). CONCLUSIONS: Postoperative adjuvant TACE and AVT were the independent protective factors associated with mortality and tumor recurrence in HBV-related HCC with MVI after resection. This combined treatment strategy may provide useful clinical significance in the prevention of tumor recurrence in these patients.

Development of a machine learning model to predict early recurrence for hepatocellular carcinoma after curative resection.

Background: Early recurrence is common for hepatocellular carcinoma (HCC) after surgical resection, being the leading cause of death. Traditionally, the COX proportional hazard (CPH) models based on linearity assumption have been used to predict early recurrence, but predictive performance is limited. Machine learning models offer a novel methodology and have several advantages over CPH models. Hence, the purpose of this study was to compare random survival forests (RSF) model with CPH models in prediction of early recurrence for HCC patients after curative resection. Methods: A total of 4,758 patients undergoing curative resection from two medical centers were included. Fifteen features including age, gender, etiology, platelet count, albumin, total bilirubin, AFP, tumor size, tumor number, microvascular invasion, macrovascular invasion, Edmondson-Steiner grade, tumor capsular, satellite nodules and liver cirrhosis were used to construct the RSF model in training cohort. Discrimination, calibration, clinical usefulness and overall performance were assessed and compared with other models. Results: Five hundred survival trees were used to generate the RFS model. The five highest Variable Importance (VIMP) were tumor size, macrovascular invasion, microvascular invasion, tumor number and AFP. In training, internal and external validation cohort, the C-index of RSF model were 0.725 [standard errors (SE) =0.005], 0.762 (SE =0.011) and 0.747 (SE =0.016), respectively; the Gönen & Heller's K of RSF model were 0.684 (SE =0.005), 0.711 (SE =0.008) and 0.697 (SE =0.014), respectively; the time-dependent AUC (2 years) of RSF model were 0.818 (SE =0.008), 0.823 (SE =0.014) and 0.785 (SE =0.025), respectively. The RSF model outperformed early recurrence after surgery for liver tumor (ERASL) model, Korean model, American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) stage, Barcelona Clinic Liver Cancer (BCLC) stage and Chinese stage. The RSF model is capable of stratifying patients into three different risk groups (low-risk, intermediate-risk, high-risk groups) in the training and two validation cohorts (all P<0.0001). A web-based prediction tool was built to facilitate clinical application (https://recurrenceprediction.shinyapps.io/surgery_predict/). Conclusions: The RSF model is a reliable tool to predict early recurrence for patients with HCC after curative resection because it exhibited superior performance compared with other models. This novel model will be helpful to guide postoperative follow-up and adjuvant therapy.

Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells.

As an important global medical problem, hepatocellular carcinoma (HCC) has been recognized as the most frequent primary liver cancer and a leading cause of death among patients with cirrhosis. Surveillance of HCC using serum markers aims to reduce the disease-related mortality of HCC. MUC16 (mucin 16, also known as carbohydrate antigen 125, CA125) has been predicted as a tumor biomarker for many cancer types. Based on the high frequency mutation rate in a database from the Cancer Genome Atlas (TCGA), we investigated the effects of MUC16 knockdown and the regulatory profile of MUC16 in HepG2 and Huh7 cell lines. Knockdown of MUC16 was conducted via siRNA transfection, and the proliferation of cells was not affected by CCK8 assay results. Moreover, decreasing the expression of MUC16 enhanced the migration and invasion of cells, as shown by wound healing and transwell assays. Furthermore, RNA-seq was used to investigate the effect of MUC16 knockdown on the gene expression profile of HepG2 and Huh7 cells. Our study demonstrated the significant role of MUC16 in the inhibition of the migration and invasion of HepG2 and Huh7 cells.

Prognostic Significance of Platelet-to-Lymphocyte Ratio (PLR) in Extrahepatic Metastasis of Hepatocellular Carcinoma After Curative Resection.

BACKGROUND: The prognosis for patients diagnosed of hepatocellular carcinoma (HCC) who have extrahepatic metastasis after liver resection is unsatisfactory. This study aimed to find out the relationship between the inflammation-related indexes and metastasis. METHODS: One thousand three hundred and sixty-six patients diagnosed of HCC who underwent curative resection were included in this study and divided into metastasis group (n=180) and non-metastasis group (n=1186). A receiver operating characteristic (ROC) curve was constructed to estimate the optimal cut-off value for inflammation-related indexes. Independent risk factors were identified by Cox regression analysis. The metastasis rate was analyzed by the Kaplan-Meier method, then the subgroup analyses were taken. RESULTS: The cut-off values of NLR, PLR, LMR, NγLR, PNLR, and PNI were 2.65, 107.67, 5.47, 134.52, 335.03, and 51.23, respectively. Multivariate Cox analysis revealed that elevated serum AFP level (P=0.004), tumor size more than 5cm (P<0.001), multiple tumors (P=0.040), and higher PLR (P=0.042) were independent risk factors associated with extrahepatic metastasis. The Kaplan-Meier method showed that the high PLR group has a higher extrahepatic metastasis rate than the low PLR group. Meanwhile, the results of subgroup analyses were consistent with the conclusion. CONCLUSION: The PLR is an independent risk factor of extrahepatic metastasis after radical hepatectomy for HCC patients. The high PLR indicates a higher rate of extrahepatic metastasis.

Autophagy Is Required for Hepatic Differentiation of Hepatic Progenitor Cells via Wnt Signaling Pathway.

The molecular mechanisms regulating differentiation of hepatic progenitor cells (HPCs), which play pivotal roles in liver regeneration and development, remain obscure. Autophagy and Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. However, the roles of autophagy and Wnt signaling pathways in hepatic differentiation of HPCs are not well understood. Here, we describe the effects of autophagy and Wnt signaling pathways during hepatic differentiation of HPCs. We used a well-established rat hepatic progenitor cell line called WB-F344, which was treated with differentiation medium to promote differentiation of WB-F344 cells along the hepatic phenotype. Firstly, autophagy was highly activated in HPCs and gradually decreased during hepatic differentiation of HPCs. Induction of autophagy by rapamycin or starvation suppressed hepatic differentiation of HPCs. Secondly, Wnt3a signaling pathway was downregulated, and Wnt5a signaling pathway was upregulated in hepatic differentiation of HPCs. At last, Wnt3a signaling pathway was enhanced, and Wnt5a signaling pathway was inhibited by activation of autophagy during hepatic differentiation of HPCs. In summary, these results demonstrate that autophagy regulates hepatic differentiation of hepatic progenitor cells through Wnt signaling pathway.

Identification of Methicillin-Resistant Staphylococcus Aureus From Methicillin-Sensitive Staphylococcus Aureus and Molecular Characterization in Quanzhou, China.

To distinguish Methicillin-Resistant Staphylococcus aureus (MRSA) from Methicillin-Sensitive Staphylococcus aureus (MSSA) in the protein sequences level, test the susceptibility to antibiotic of all Staphylococcus aureus isolates from Quanzhou hospitals, define the virulence factor and molecular characteristics of the MRSA isolates. MRSA and MSSA Pfam protein sequences were used to extract feature vectors of 188D, n-gram and 400D. Weka software was applied to classify the two Staphylococcus aureus and performance effect was evaluated. Antibiotic susceptibility testing of the 81 Staphylococcus aureus was performed by the Mérieux Microbial Analysis Instrument. The 65 MRSA isolates were characterized by Panton-Valentine leukocidin (PVL), X polymorphic region of Protein A (spa), multilocus sequence typing test (MLST), staphylococcus chromosomal cassette mec (SCCmec) typing. After comparing the results of Weka six classifiers, the highest correctly classified rates were 91.94, 70.16, and 62.90% from 188D, n-gram and 400D, respectively. Antimicrobial susceptibility test of the 81 Staphylococcus aureus: Penicillin-resistant rate was 100%. No resistance to teicoplanin, linezolid, and vancomycin. The resistance rate of the MRSA isolates to clindamycin, erythromycin and tetracycline was higher than that of the MSSAs. Among the 65 MRSA isolates, the positive rate of PVL gene was 47.7% (31/65). Seventeen sequence types (STs) were identified among the 65 isolates, and ST59 was the most prevalent. SCCmec type III and IV were observed at 24.6 and 72.3%, respectively. Two isolates did not be typed. Twenty-one spa types were identified, spa t437 (34/65, 52.3%) was the most predominant type. MRSA major clone type of molecular typing was CC59-ST59-spa t437-IV (28/65, 43.1%). Overall, 188D feature vectors can be applied to successfully distinguish MRSA from MSSA. In Quanzhou, the detection rate of PVL virulence factor was high, suggesting a high pathogenic risk of MRSA infection. The cross-infection of CA-MRSA and HA-MRSA was presented, the molecular characteristics were increasingly blurred, HA-MRSA with typical CA-MRSA molecular characteristics has become an important cause of healthcare-related infections. CC59-ST59-spa t437-IV was the main clone type in Quanzhou, which was rare in other parts of mainland China.

[Genetic Testing for Alpha and Beta Thalassemia in Children in Quanzhou Region of Fujian Province in China].

OBJECTIVE: To analyze the genotypes and distribution of thalassemia in children in Quanzhou Region so as to provide reference for the prevention and control of thalassemia. METHODS: A total of 1 302 children with suspected thalassemia were collected from January 2014 to April 2020 in Quanzhou Region. The deletional α-thalassemia was detected by Gap-PCR, and DNA reverse dot blot (RDB) hybridization was used to detect α- and ß-thalassemia mutations. RESULTS: In the 1 302 cases, 667 cases were identified as thalassemia carriers, and the positive detection rate was about 51.23%. Among them, 380 cases of α-thalassemia gene were detected, and --SEA/αα was the most common genotype with the composition rate about 69.21%. Forty-two cases were identified as HbH disease, and -α3.7/--SEA was the most common genotype. While, 274 cases were identified as ß-thalassemia, and ßIVS-Ⅱ-654/ßN (35.40%) and ßCD41-42/ßN (33.94%) were the most common genotypes. Seventeen cases of ß-thalassemia major/intermedia were identified, and the most common genotypes were ßIVS-Ⅱ-654/ßIVS-Ⅱ-654 and ßIVS-Ⅱ-654/ßCD17. Meanwhile, 13 cases of α- complex ß- thalassemia were detected. Among them, 1 case of ß-thalassemia gene rare mutation Term CD+32 was firstly detected in Fujian Province, and 1 case of CD14-15 mutation was firstly detected in Quanzhou Region. In addition, 3 cases of abnormal hemoglobin disease were identified, in which 2 cases were Hb Q-Thailand and 1 case was Hb G-Honolulu. CONCLUSION: There are various genotypes of thalassemia in children in Quanzhou Region, and many children with thalassemia major or intermedia. Therefore, further prevention and control of thalassemia need to be strengthened for reducing the birth of thalassemia major or intermedia.