Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

BACKGROUND: Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. METHODS: In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). RESULTS: The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. CONCLUSIONS: Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

The Role of Purine Metabolism-Related Genes PPAT and IMPDH1 in the Carcinogenesis of Intrahepatic Cholangiocarcinoma Based on Metabonomic and Bioinformatic Analyses.

In this study, we investigated the role of tumor microenvironment and serum differential metabolites in intrahepatic cholangiocarcinoma (ICC) carcinogenesis, providing new evidence for ICC treatment. Serum samples from healthy individuals and ICC patients were collected for metabolomic analysis. The purine metabolites such as inosine, guanosine, hypoxanthine, and xanthine were increased in patient serum. TCGA database samples were collected, and the correlation between purine metabolism-related genes and ICC clinical features was analyzed using R language to obtain the differential genes including PPAT, PFAS, ATIC, and IMPDH2. High PPAT expression was associated with poor ICC prognosis. A PPAT silencing model in HCCC-9810 cells was constructed. The cell phenotype was examined by qRT-PCR, CCK-8, transwell, and flow cytometry, showing a decrease in IMPDH1 expression, colony and invasive cells numbers, and an increase in apoptosis. Guanosine reversed IMPDH1 expression in HCCC-9810 cells, promoting the secretion of inflammatory factors IL-6, IL-8, OPN, VEGF, and VCAM-1 and intensifying epithelial-mesenchymal transition (EMT) progression in the cells. In nude mice, the IMPDH1 inhibitory drug MMF inhibited tumor growth and reduced the expression of tumor stem cell characteristic markers CD133 and SOX2. Guanosine accelerated the malignant progression of ICC inhibition of purine metabolism-related genes, PPAT and IMPDH2, suppressed the malignant phenotype in HCCC-9810 cells, and inhibited tumor growth.

Efficacy of radiofrequency ablation following transarterial chemoembolisation combined with sorafenib for intermediate stage recurrent hepatocellular carcinoma: a retrospective, multicentre, cohort study.

Background: The evidence of radiofrequency ablation (RFA) following transarterial chemoembolisation (TACE) combined with sorafenib for intermediate-stage recurrent hepatocellular carcinoma (RHCC) is limited. Patient responses to this treatment vary because of the heterogeneous nature of RHCC, making it important to identify patients who are most likely to benefit from this combination therapy. The aim of this study was to evaluate the efficacy of RFA following TACE and sorafenib for the intermediate-stage RHCC. Methods: This retrospective, multicentre, cohort study included 363 patients with intermediate-stage RHCC underwent TACE combined with sorafenib (TACE-sorafenib group) or RFA following TACE and sorafenib (TACE-sorafenib + RFA group) between January 01, 2009 to December 31, 2015 from four institutions in China. Overall survival (OS), progression-free survival (PFS) and efficacy of patients were compared between the two groups by propensity score-matching (PSM). Findings: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% in TACE-sorafenib + RFA group, and 93.3%, 57.0%, 32.7% in TACE-sorafenib group. The 1-, 2-, and 3-year PFS rates were 85.3%, 58.0%, 26.9% in TACE-sorafenib + RFA group, and 55.3%, 30.7%, 15.3% in TACE-sorafenib group. Compared with the TACE-sorafenib group, the TACE-sorafenib + RFA group had significantly longer OS (HR, 0.54; 95%CI, 0.40-0.73; P < 0.001) and PFS (HR, 0.52; 95% CI, 0.41-0.66; P < 0.001). Subgroup analysis was conducted to precisely screen out the beneficial population from RFA treatment. Interpretation: Our findings suggest that addition of RFA following TACE and sorafenib combination was superior to TACE combined with sorafenib for intermediate-stage RHCC, resulting in longer OS and PFS. Patients who had good response to TACE and achieved downstaging successfully could not benefit from the RFA therapy. Funding: This research was funded by National Natural Science Foundation of China (No. 81627803), Chen Xiao-Ping Science and Technology Development Fund (CXPJJH1200009-06).

Development and validation of prognostic nomograms for single large and huge hepatocellular carcinoma after curative resection.

AIM: The prediction model of postoperative survival for single large and huge hepatocellular carcinoma (SLH-HCC, diameter > 5.0 cm) without portal vein tumour thrombus has not been well established. This study aimed to develop novel nomograms to predict postoperative recurrence and survival of these patients. METHODS: Data from 2469 patients with SLH-HCC who underwent curative resection from January 2005 to December 2015 in China were retrospectively collected. Specifically, nomograms of recurrence-free survival (RFS) and overall survival (OS) using data from a training cohort were developed with the Cox regression model (n = 1012). The modes were verified in an internal validation cohort (n = 338) and an external cohort comprising four tertiary institutions (n = 1119). RESULTS: The nomograms of RFS and OS based on tumour clinicopathologic features (diameter, differentiation, microvascular invasion, α-fetoprotein), operative factors (preoperative transcatheter arterial chemoembolisation therapy, scope of liver resection and intraoperative blood transfusion), underlying liver function (albumin-bilirubin grade) and systemic inflammatory or immune status (neutrophil-to-lymphocyte ratio) achieved high C-indexes of 0.85 (95% confidence interval [CI], 0.79-0.91) and 0.86 (95% CI, 0.79-0.93) in the training cohort, respectively, which were significantly higher than those of the five conventional HCC staging systems (0.62-0.73 for RFS, 0.63-0.75 for OS). The nomograms were validated in the internal cohort (0.83 for RFS, 0.84 for OS) and external cohort (0.87 for RFS, 0.88 for OS) and had well-fitted calibration curves. Our nomograms accurately stratified patients with SLH-HCC into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. CONCLUSIONS: The two nomograms achieved optimal prediction for postsurgical recurrence and OS for patients with SLH-HCC after curative resection.

Prediction of microvascular invasion in solitary hepatocellular carcinoma ≤ 5 cm based on computed tomography radiomics.

BACKGROUND: Liver cancer is one of the most common malignant tumors, and ranks as the fourth leading cause of cancer death worldwide. Microvascular invasion (MVI) is considered one of the most important factors for recurrence and poor prognosis of liver cancer. Thus, accurately identifying MVI before surgery is of great importance in making treatment strategies and predicting the prognosis of patients with hepatocellular carcinoma (HCC). Radiomics as an emerging field, aims to utilize artificial intelligence software to develop methods that may contribute to cancer diagnosis, treatment improvement and evaluation, and better prediction. AIM: To investigate the predictive value of computed tomography radiomics for MVI in solitary HCC ≤ 5 cm. METHODS: A total of 185 HCC patients, including 122 MVI negative and 63 MVI positive patients, were retrospectively analyzed. All patients were randomly assigned to the training group (n = 124) and validation group (n = 61). A total of 1351 radiomic features were extracted based on three-dimensional images. The diagnostic performance of the radiomics model was verified in the validation group, and the Delong test was applied to compare the radiomics and MVI-related imaging features (two-trait predictor of venous invasion and radiogenomic invasion). RESULTS: A total of ten radiomics features were finally obtained after screening 1531 features. According to the weighting coefficient that corresponded to the features, the radiomics score (RS) calculation formula was obtained, and the RS score of each patient was calculated. The radiomics model exhibited a better correction and identification ability in the training and validation groups [area under the curve: 0.72 (95% confidence interval: 0.58-0.86) and 0.74 (95% confidence interval: 0.66-0.83), respectively]. Its prediction performance was significantly higher than that of the image features (P < 0.05). CONCLUSION: Computed tomography radiomics has certain predictive value for MVI in solitary HCC ≤ 5 cm, and the predictive ability is higher than that of image features.

Multi-institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma.

The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.

Novel Models Predict Postsurgical Recurrence and Overall Survival for Patients with Hepatitis B Virus-Related Solitary Hepatocellular Carcinoma ≤10 cm and Without Portal Venous Tumor Thrombus.

BACKGROUND: The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm. PATIENTS AND METHODS: Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems. RESULTS: Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79-0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83-0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54-0.74 for RFS; 0.58-0.76 for OS) and those of HCC nomograms reported in literature. CONCLUSION: The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection. IMPLICATIONS FOR PRACTICE: This multicenter study proposed recurrence or mortality predictive nomograms for patients with hepatitis B virus-related solitary early hepatocellular carcinoma ≤10 cm after curative liver resection. A close postsurgical surveillance protocol and adjuvant therapy should be considered for patients at high risk of recurrence.

Association between body mass index and postoperative morbidity after liver resection of hepatocellular carcinoma: A multicenter study of 1,324 patients.

BACKGROUND: Morbidity remains a common problem following hepatic resection. The aim of this study was to investigate the association between preoperative body mass index (BMI) and morbidity in patients undergoing liver resection for hepatocellular carcinoma (HCC). METHODS: Patients were divided into three groups according to preoperative BMI: low-BMI (≤18.4 kg/m2), normal-BMI (18.5-24.9 kg/m2) and high-BMI (≥25.0 kg/m2). Baseline characteristics, operative variables, postoperative 30-day mortality and morbidity were compared. Univariable and multivariable analyses were performed to identify independent risk factors associated with postoperative morbidity. RESULTS: Among 1324 patients, 108 (8.2%), 733 (55.4%), and 483 (36.5%) were low-BMI, normal-BMI, and high-BMI, respectively. There were no differences in postoperative 30-day mortality among patients based on BMI (P = 0.199). Postoperative 30-day morbidity was, however, higher in low-BMI and high-BMI patients versus patients with a normal-BMI (33.3% and 32.1% vs. 22.9%, P = 0.018 and P < 0.001, respectively). Following multivariable analysis low-BMI and high-BMI remained independently associated with an increased risk of postoperative morbidity (OR: 1.701, 95%CI: 1.060-2.729, P = 0.028, and OR: 1.491, 95%CI: 1.131-1.966, P = 0.005, respectively). Similar results were noted in the incidence of postoperative 30-day surgical site infection (SSI). CONCLUSION: Compared with normal-BMI patients, low-BMI and high-BMI patients had higher postoperative morbidity, including a higher incidence of SSI after liver resection for HCC.

Identification of Actual 10-Year Survival After Hepatectomy of HBV-Related Hepatocellular Carcinoma: a Multicenter Study.

BACKGROUND: Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) worldwide. The aim of the study was to identify the incidence and predictive factors of actual 10-year survival following liver resection of HBV-related HCC. METHODS: A Chinese multicenter database of patients undergoing curative hepatectomy of HBV-related HCC was reviewed. Patients who survived ≥ 10 years and patients who died < 10 years after surgery were compared and analyzed. Univariable and multivariable regression analyses were performed to identify predictive factors associated with 10-year survival. RESULTS: Among all enrolled 1016 patients, the actuarial 10-year survival rate was 24.1%, while the actual 10-year survival rate was 16.6%. There were 169 patients who survived at least 10 years after surgery and 688 who died within 10 years from surgery. These patients constituted the study population of this study. Multivariable regression analysis revealed that cirrhosis, preoperative HBV viral load > 104 copies/mL, maximum tumor size > 5 cm, multiple tumors, macroscopic and microscopic vascular invasion, postoperative HBV reactivation, and early recurrence (< 2 years after surgery) were independent risk factors associated with actual 10-year survival, while postoperative antiviral therapy, regular recurrence surveillance, and curative treatments for initial recurrence were independent protective factors. CONCLUSIONS: The actual 10-year survival after curative resection of HBV-related HCC was calculated to be 16.6%. Postoperative antiviral therapy and regular recurrence surveillance were independent protective factors associated with actual 10-year survival after liver resection of HBV-related HCC.

Liver resection is justified for multinodular hepatocellular carcinoma in selected patients with cirrhosis: A multicenter analysis of 1,066 patients.

BACKGROUND: The role of liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) remains unclear, especially among patients with severe underlying liver disease. We sought to evaluate surgical outcomes among patients with cirrhosis and multinodular HCC undergoing liver resection. METHODS: Using a multicenter database, outcomes among cirrhotic patients who underwent curative-intent resection of HCC were examined stratified according to the presence or absence of multinodular disease. Perioperative mortality and morbidity, as well as overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. RESULTS: Among 1066 cirrhotic patients, 906 (85.0%) had single- or double-nodular HCC (the non-multinodular group), while 160 (15.0%) had multinodular HCC (the multinodular group). There were no differences in postoperative 30-day mortality and morbidity among non-multinodular versus multinodular patients (1.8% vs. 1.9%, P = 0.923, and 36.0% vs. 39.4%, P = 0.411, respectively). In contrast, 5-year OS and RFS of multinodular patients were worse compared with non-multinodular patients (34.6% vs. 58.2%, and 24.7% vs. 44.5%, both P < 0.001). On multivariable analyses, tumor numbers ≥5, total tumor diameter ≥8 cm and microvascular invasion were independent risk factors for decreased OS and RFS after resection of multinodular HCC in cirrhotic patients. CONCLUSIONS: Liver resection can be safely performed for multinodular HCC in the setting of cirrhosis with an overall 5-year survival of 34.6%. Tumor number ≥5, total tumor diameter ≥8 cm and microvascular invasion were independently associated with decreased OS and RFS after resection in cirrhotic patients with multinodular HCC.

Glutathione-s-transferase A 4 (GSTA4) suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting AKT pathway.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies of cancers and its prognosis remains dismal due to the paucity of effective therapeutic targets. Up-regulation of glutathione-s-transferase A 4 (GSTA4) is associated with poor prognosis of HCC, but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of GSTA4 in tumor growth and metastasis of HCC and found that GSTA4 was frequently up-regulated in HCC tissues. Through gain- and loss-of-function studies, GSTA4 was demonstrated to significantly regulate cell proliferation, migration, and invasion in vitro. Furthermore, GSTA4 overexpressing significantly promoted the tumorigenicity and metastasis of HCC cells in nude mice models bearing human HCC, whereas silencing endogenous GSTA4 caused an opposite outcome. Moreover, we demonstrated that GSTA4 enhanced HCC aggressiveness by activating protein kinase B (AKT) signaling. In multivariate analysis, our results GSTA4 overexpression promotes the progression of hepatocellular carcinoma and might represent a novel therapeutic target for its treatment.

Primary human hepatocyte transplantation in the therapy of hepatic failure: 2 cases report.

Liver failure is the end stage of hepatopathy with unfavorable prognosis. In two patients with liver failure, viable primary human hepatocytes, obtained from resected liver tissue of patients with hepatolithiasis, were transplanted into the spleen by interventional therapy through femoral arterial cannula. After transplantation, the patients' clinical symptoms and liver function were significantly improved. However, their bilirubin increased within six days following transplantation. One suffered from hepatic coma and give up treatment and the other patient died fourteen days after transplantation. It is technically safe to treat liver failure by intrasplenic transplantation of adult hepatocytes and the clinical efficacy has been confirmed. How to make transplanted hepatic cells proliferate and functionally survive is the key point to maintain continuous improvement of the recipient's hepatic function.

Down-regulation of c-Myc expression inhibits the invasion of bile duct carcinoma cells.

Cholangiocarcinoma is the second most common primary hepatic tumour originating from biliary tract epithelial cells with poor prognosis. Enhanced c-Myc protein expression contributes to many aspects of tumour cell biology. Although the ability of c-Myc to drive unrestricted cell proliferation and to inhibit cell differentiation had been well recognized, whether down-regulated c-Myc expression can inhibit tumour cell invasion still remains to be explored. The c-Myc ASODN (antisense oligodeoxyribonucleotide) and NSODN (nonsense oligodeoxyribonucleotide) were designed, synthesized and transfected into human QBC939 bile duct carcinoma cells using the Lipofectamine 2000 reagent. The protein expression of c-Myc was detected by Western blot. A transwell experiment was applied to evaluate the invasive capacity of the QBC939 cells. c-Myc ASODN could significantly suppress the c-Myc protein expression (P<0.05) and the invasion (P<0.01) of QBC939 cells transfected with c-Myc ASODN compared with that in the control and c-Myc NSODN-transfected group. Thus in the present study we show that down-regulation of c-Myc expression can inhibit the invasion of QBC939 cells in vitro.

Bile duct injuries associated with laparoscopic and open cholecystectomy: sixteen-year experience.

AIM: To summarize the experience in diagnosis, management and prevention of iatrogenic bile duct injury (IBDI). METHODS: A total of 210 patients with bile duct injury occurred during cholecystectomy admitted to Hunan Provincial People's Hospital from March 1990 to March 2006 were included in this study for retrospective analysis. RESULTS: There were 59.5% (103/173) of patients with IBDI resulting from the wrong identification of the anatomy of the Calot's triangle during cholecystectomy. The diagnosis of IBDI was made on the basis of clinical features, diagnostic abdominocentesis and imaging findings. Abdominal B ultrasonography (BUS) was the most popular way for IBDI with a diagnostic rate of 84.6% (126/149). Magnetic resonance cholangiography (MRC) could reveal the site of injury, the length of injured bile duct and variation of bile duct tree with a diagnostic rate 100% (45/45). According to the site of injury, IBDI could be divided into six types. The most common type (type 3) occurred in 76.7% (161/210) of the patients and was treated with partial resection of the common hepatic duct and common bile duct. One hundred and seventy-six patients were followed up. The mean follow-up time was 3.7 (range 0.25-10) years. Good results were achieved in 87.5% (154/176) of the patients. CONCLUSION: The key to prevention of IBDI is to follow the "identifying-cutting-identifying" principle during cholecystectomy. Re-operation time and surgical procedure are decided according to the type of IBDI.