Perioperative remedial antiviral therapy in hepatitis B virus-related hepatocellular carcinoma resection: How to achieve a better outcome.

BACKGROUND: Although the benefits of antiviral therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) have been proven, researchers have not confirmed the differences in patient outcomes between patients who received preoperative antiviral therapy for a period of time (at least 24 wk) and patients who received remedial antiviral therapy just before radical resection for HBV-related HCC. AIM: To investigate the efficacy of perioperative remedial antiviral therapy in patients with HBV-related HCC. METHODS: A retrospective study of patients who underwent radical resection for HBV-related HCC at the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to June 2019 was conducted. Considering the history of antiviral therapy, patients were assigned to remedial antiviral therapy and preoperative antiviral therapy groups. RESULTS: Kaplan-Meier analysis revealed significant differences in overall survival (P < 0.0001) and disease-free survival (P = 0.035) between the two groups. Multivariate analysis demonstrated that a history of preoperative antiviral treatment was independently related to improved survival (hazard ratio = 0.27; 95% confidence interval: 0.08-0.88; P = 0.030). CONCLUSION: In patients with HBV-related HCC, it is ideal to receive preoperative long-term antiviral therapy, which helps patients tolerate more extensive hepatectomy; however, remedial antiviral therapy, which reduces preoperative HBV-DNA levels to less than 4 Log10 copies DNA/mL, can also result in improved outcomes.

The effect of aging on VEGF/VEGFR2 signal pathway genes expression in rat liver sinusoidal endothelial cell.

Liver sinusoidal endothelial cells (LSECs) play a key role in the initiation and neoangiogenesis of liver regeneration. We presume that the abnormity of the VEGF/VEGFR2 and its pathway gene Id1, Wnt2 and HGF expression in aged LSECs may be an important mechanism to affect liver regeneration of the elderly. LSECs from two different groups (adult and old) were isolated in a rodent model, and observed by SEM and TEM. The adult and old rats were underwent 70% partial hepatectomy. The proliferation of hepatocytes and LSECs were analyzed by Immunofluorescence staining. The expression of VEGF/VEGFR2 and its pathway gene in isolated LSECs and liver tissue after hepatectomy were detected by qRT-PCR and Western blot. There is a decreased number of endothelial fenestrae in the LSECs of the old group, compared to the adult group. The old group had a lower expression of VEGF/VEGFR2 and its pathway gene than the adult groups (p < 0.01). The results of western blot were consistent with those of qRT-PCR. The hepatocytes had a high proliferation rate at first 4 days after hepatectomy, and a significantly higher proliferation rate in the adult group. The LSECs began to proliferate after 4 days of hepatectomy, and showed a quantity advantage in the adult group. The adult group had a significantly higher expression of VEGF/VEGFR2 and its pathway gene after hepatectomy than the old group (p < 0.01). LSCEs turn to be defenestration in structure and have a low expression of VEGF/VEGFR2 and its pathway gene with aging.

Redefining Conditional Overall and Disease-Free Survival After Curative Resection for Intrahepatic Cholangiocarcinoma: a Multi-institutional, International Study of 1221 patients.

OBJECTIVES: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC). METHODS: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at "x" years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at "x" years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for "x" years postoperatively. RESULTS: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year; however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence. CONCLUSION: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence.

Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after curative resection is common. OBJECTIVE: The aim of this study was to investigate the patterns, timing and risk factors of disease recurrence after curative-intent resection for ICC. METHODS: Patients undergoing curative resection for ICC were identified from a multi-institutional database. Data on clinicopathological and initial operation information, timing and first sites of recurrence, recurrence management, and long-term outcomes were analyzed. RESULTS: A total of 920 patients were included. With a median follow-up of 38 months, 607 patients (66.0%) experienced ICC recurrence. In the cohort, 145 patients (23.9%) recurred at the surgical margin, 178 (29.3%) recurred within the liver away from the surgical margin, 90 (14.8%) recurred at extraheptatic sites, and 194 (32.0%) developed both intrahepatic and extrahepatic recurrence. Intrahepatic margin recurrence (median 6.0 m) and extrahepatic-only recurrence (median 8.0 m) tended to occur early, while intrahepatic recurrence at non-margin sites occurred later (median 14.0 m; p < 0.05). On multivariate analysis, surgical margin < 10 mm was associated with increased margin recurrence (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.11-2.60; p = 0.014), whereas female sex (HR 2.12, 95% CI 1.40-3.22; p < 0.001) and liver cirrhosis (HR 2.36, 95% CI 1.31-4.25; p = 0.004) were both associated with an increased risk of intrahepatic recurrence at other sites. Median survival after recurrence was better among patients who underwent repeat curative-intent surgery (48.7 months) versus other treatments (9.7 months) [p < 0.001]. CONCLUSIONS: Different recurrence patterns and timing of recurrence suggest biological heterogeneity of ICC tumor recurrence. Understanding timing and risk factors associated with different types of recurrence can hopefully inform discussions around adjuvant therapy, surveillance, and treatment of recurrent disease.

Impact of microvascular invasion on clinical outcomes after curative-intent resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. METHODS: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). RESULTS: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (±MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P < 0.01). On multivariable analysis, MiVI was an independent risk factor of DFS (hazard ratios [HR] 1.5; 95%confidence intervals [CI], 1.3-1.9; P < 0.001), but not OS (HR 1.1; 95%CI, 0.9-1.3; P = 0.379). While MiVI and MaVI patients had similar DFS (median, MiVI 14.0 vs MaVI 12.0 months, HR 0.9; 95%CI, 0.7-1.2; P = 0.377), OS was better among MiVI patients (median, MiVI 39.0 vs MaVI 21.0 months, HR 0.7; 95%CI, 0.5-0.8; P = 0.002). Whereas nodal metastasis, R1 margin, and postoperative morbidity were associated with early death (≤18 months) among patients with MiVI, only nodal metastasis was associated with late (>18 months) prognosis. CONCLUSIONS: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence.

Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model.

AIM: To compare the effect of University of Wisconsin (UW) solution with or without metformin, an AMP-activated protein kinase (AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion (HMP). METHODS: Eighteen young (4 mo old) and 18 aged (17 mo old) healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group (UWP), and UW solution with metformin perfusion group (MUWP). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase (eNOS) in liver sinusoidal endothelial cells were also examined. Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done. RESULTS: AST, ALT, LDH, IL-18 and TNF-α levels in the young and aged liver-perfused liquid were, respectively, significantly lower in the MUWP group than in the UWP group (P < 0.05), but no significant differences were found between the young and aged MUWP groups. Metformin increased the expression of AMPK and eNOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-eNOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group. CONCLUSION: The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats.

Impact of cigarette smoking on recurrence of hyperlipidemic acute pancreatitis.

AIM: To investigate the impact of cigarette smoking on the recurrence rate and recurrence-free survival in patients with hyperlipidemic acute pancreatitis (HLAP). METHODS: A total of 863 patients were admitted to our hospital for acute pancreatitis (AP) from January 2013 to March 2016, of whom 88 diagnosed with HLAP were enrolled in this retrospective study. Demographic data, medical history, previous episodes of pancreatitis, consumption of alcohol and cigarettes, as well as biochemical and hematological data were carefully recorded for univariate and multivariate analyses. During follow-up, the information on current smoking status and recurrent AP was gathered. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method, and the differences between groups were compared using the log-rank test. RESULTS: No significant differences were observed between the three groups in age or medical history of hyperlipidemia, fatty liver, diabetes mellitus, hypertension, or AP. The current smokers had a remarkably higher recurrence rate and a greater incidence of repeated episodes of AP (50.0% and 77.8%, respectively) than non-smokers (9.8% and 39.0%), and these two percentages were reduced to 9.1% and 36.4% for patients who gave up smoking. The median follow-up time was 13.5 mo and HLAP recurred after hospital discharge in 23 (26.1%) patients. Multivariate analysis identified current smoking (HR = 6.3, P = 0.020) as an independent risk factor contributing to HLAP recurrence. Current smokers had significantly worse RFS than non-smokers (23 mo vs 42 mo), but no significant difference was documented between ex-smokers (34 mo) and non-smokers. The RFS was not significantly different between light and heavy smokers. CONCLUSION: Smoking is associated with worse RFS and an increased rate of HLAP recurrence. Continued smoking correlates with a compromised survival and smoking cessation should be recommended.

[Screening and identification of CD13-binding peptides with phage display peptide library].

OBJECTIVE: To screen and identify the peptides that specifically bind to CD13 on monocytes. METHODS: The phages capable of specific binding to CD13 were screened in the phage-displayed 12-peptide library. The affinity of the selected phages with CD13 was verified with enzyme-linked immunosorbent assay (ELISA). The sequences of the peptides bound to the phages were deduced according to the phage DNA sequences, and the functional peptides aligned using the BLASTP on the Website NCBI were synthesized. To analyze the biological function of the screened peptides, the location of the peptides bound to THP-1 cells was detected using immunofluorescence assay. The blocking effect of WM15 on the peptide binding to THP-1 cells was assessed by immunofluorescence assay. RESULTS: The phages that specifically bound to CD13 were effectively enriched to approach saturation after 4 rounds of panning. The recovery rate in the fourth round was 30 times that in the first round. Twenty selected phages were verified by ELISA, and the signals of 10 phages were higher than the control. The sequences of the peptides P9 and P7 showed 83% and 100% identity with those of human cytomegalovirus (HCMV) UL38 and UL105, respectively. The peptides bound to the cell membrane of THP-1 cells as shown by immunofluorescence assay. The binding of the peptides P9 and P7 to THP-1 cells was blocked by CD13-specific monoclonal antibody WM15 at different levels. CONCLUSION: Two peptides (P7 and P9) that can specifically bind to CD13 have been screened successfully, and these two peptides show specific binding to CD13 on the membrane of THP-1 cells.