Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.

Application value of the different lymph node staging system predicting prognosis of advanced gallbladder carcinoma / 中华消化外科杂志

Objective To investigate the application value of the anatomical location of positive nodes (N staging) from TNM staging systems published by American Joint Committee on Cancer (AJCC) (7th edition),number of metastatic lymph nodes (NMLN),lymph node ratio (LNR) and log odds of metastatic lymph nodes (LODDS) as prognostic predictors in advanced gallbladder carcinoma(GBC).Methods The retrospective crosssectional study was conducted.The clinicopathological data of 176 patients who underwent radical resection of advanced GBC in the First Affiliated Hospital of Xi'an Jiaotong University between January 2008 and December 2014 were collected.According to preoperative assessment,intraoperative exploration and frozen section biopsy,staging and surgical procedure were confirmed.Observation indicators and evaluation criteria:(1) surgical and postoperative situations;(2) follow-up and survival situations;(3) N staging related indicators based on TNM staging systems of AJCC (7th edition):LNR =NMLN / total number of lymph node dissection,LODDS =Log (NMLN+0.5) / (total number of lymph node dissection-NMLN+0.5);(4) lymph node staging based on NMLN,LNR and LODDS:LODDS ＜-1.0 as LODDS 1 staging,-1.0 ≤ LODDS ＜ 0 as LODDS 2 staging,LODDS ≥0 as LODDS 3 staging;(5) prognostic comparisons of patients with different lymph node staging;(6) accuracy of 4 different types of lymph node staging predicting the prognosis of patients.Follow-up using outpatient examination and telephone interview was performed to detect postoperative survival up to December 31,2017.Measurement data with normal distribution were represented as x-±s.Measurement data with skewed distribution were described as M (range),and comparisons were done using the nonparametric test.The survival rate was calculated by the Kaplan-Meier method,and the Log-rank test was used for survival comparison.Correlation analysis was done using the Spearman correlation analysis,r ≥ 0.800 as a high correlation,0.500 ≤ r ＜ 0.800 as a moderate correlation and 0.300 ≤ r ＜ 0.500 as a low correlation.The receiver operating characteristic (ROC) curve and area under the curve (AUC) were respectively drawn and calculated based on 4 kinds of binary logistic regression model.Akaike information criterion (AIC) and Harrell concordance index (Harrell c-index) were respectively calculated based on 4 kinds of COX proportional hazard regression model.The larger values of AUC and Harrell c-index caused a smaller value of AIC,but a lymph node staging standard correlated with greater prognostic accuracy.Harrell c-index ＜ 0.50 was no prediction,and 0.50 ≤ Harrell c-index ≤ 1.00 was an obvious prediction.Results (1) Surgical and postoperative situations:176 patients underwent successful radical resection of GBC,including 161 in R0 resection and 15 in R1 resection,99 with D1 lymph node dissection and 77 with D2 lymph node dissection.Of 176 patients,9 with postoperative complications were improved by symptomatic treatment,including 6 with bile leakage,2 with hepatic dysfunction and 1 with intra-abdominal hemorrhage.Results of postoperative pathological examination:total number of lymph node dissection,NMLN and LNR were respectively 6.7±4.4,0 (range,0-12.0) and 0 (range,0-1.00);high-differentiated,moderate-differentiated and low-differentiated tumors were respectively detected in 16,81 and 79 patients;162 and 14 patients were in T3 and T4 stages;60 patients were combined with infiltration of the liver.(2) Follow-up and survival situations:176 patients were followed up for l-118 months,with a median time of 33 months.The 1-,3-and 5-year overall survival rates were respectively 63.1％,42.0％ and 32.0％.(3) N staging related indicators based on TNM staging systems ofAJCC (7th edition):95,45 and 36 patients were respectively detected in staging N0,N1 and N2.NMLN,LNR and LODDS were respectively 2.0 (range,1.0-7.0),0.40 (range,0.08-1.00),-0.15 (range,-0.99-1.04) in staging N1 and 4.0 (range,1.0-12.0),0.57 (range,0.13-1.00),0.11 (range,-0.70-1.04) in staging N2,with a statistically significant difference in NMLN (Z=-3.888,P＜0.05) and with no statistically significant difference in LNR and LODDS (Z=-1.492,-1.689,P＞0.05).(4) Lymph node staging based on NMLN,LNR and LODDS:NMLN and LNR as a cut-off point were respectively 4.0 and 0.70,NMLN 1 staging (NMLN=0) was detected in 95 patients,NMLN 2 staging (1.0 ≤ NMLN ≤ 4.0) in 61 patients and NMLN 3 staging (NMLN＞4.0) in 20 patients;LNR 1 staging (LNR=0) was detected in 95 patients,LNR 2 staging (0 ＜ LNR ≤ 0.70) in 58 patients and LNR 3 staging (LNR＞0.70) in 23 patients.LODDS 1,2 and 3 stagings was detected in 61,70 and 45 patients,respectively.The lymph node staging based on NMLN and LNR was significantly correlated with based on N staging of TNM staging systems of AJCC (7th edition) (r =0.949,0.922,P＜0.05);the lymph node staging based on LODDS was moderately correlated with based on N staging of TNM staging systems of AJCC (7th edition) (r =0.758,P＜ 0.05).(5) Prognostic comparisons of patients with different lymph node staging:1-,3-and 5-year overall survival rates were respectively 86.3％,65.3％,52.2％ in N0 staging patients and 44.4％,22.2％,13.3％ in N1 staging patients and 25.0％,5.6％,2.8％ in N2 staging patients,with a statistically significant difference (x2=88.895,P＜0.05).The 1-,3-and 5-year overall survival rates were respectively 86.3％,65.3％,52.2％ in NMLN 1 staging patients and 47.5％,19.7％,11.1％ in NMLN 2 staging patients and 0,0,0 in NMLN 3 staging patients,with a statistically significant difference (x2=121.086,P＜0.05).The 1-,3-and 5-year overall survival rates were respectively 86.3％,65.3％,52.2％ in LNR 1 staging patients and 41.4％,17.2％,11.8％ in LNR 2 staging patients and 17.4％,8.7％,0 in LNR 3 staging patients,with a statistically significant difference (x2 =86.503,P＜ 0.05).The 1-,3-and 5-year overall survival rates were respectively 85.2％,65.5％,51.8％ in LODDS 1 staging patients and 65.7％,40.0％,31.3％ in LODDS 2 staging patients and 28.9％,13.3％,5.9％ in LODDS 3 staging patients,with a statistically significant difference (x2=59.195,P＜0.05).(6) Accuracy of 4 different types of lymph node staging predicting the prognosis of patients:according to N staging of TNM staging systems of AJCC (7th edition),NMLN,LNR and LODDS,AUC,AIC and Harrell c-index of lymph node staging were respectively 0.878,0.881,0.870,0.864 and 1 047.5,1 026.4,1 044.2,1 063.6 and 0.77,0.78,0.77,0.76.AIC value was smaller with increased values of AUC and Harrell c-index based on NMLN,showing a greatest accuracy predicting the prognosis of patients.Conclusion Among N staging of TNM staging system of AJCC (7 edition),NMLN,LNR and LODDS as prognostic predictors,NMLN can more precisely predict radical resection of advanced GBC.

Research progress of intraductal papillary neoplasm of the bile duct / 中华消化外科杂志

Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct tumors characterized by papillary growth within the dilated bile duct lumen and secretion with a large amount of mucins.IPNB is an intraductal papillary cancer of the bile duct or a preinvasive lesion classified by the 2010 World Health Organization (WHO) classification.Although the specific etiology and pathogenesis are unclear,IPNB is known to two major risk factors:hepatoliathiasis and clonorchiasis.The clinical manifestations of IPNB include intermittent abdominal pain,acute cholangitis and obstructive jaundice.Results of laboratory test show abnormal liver function resulting from obstruction of bile duct,but it's not specific.The most common imaging findings for IPNB are bile duct dilatation and intraductal masses.Computed tomography,magnetic resonance image and cholangiography are usually performed to access tumor location and extension.According to morphology of the tumor epithelial cells,IPNB are classified into the pancreticbiliary,intestinal,gastric and oncocytic types.The surgical resection is a major treatment of IPNB.In principle,IPNB should be resected in a manner similar to that employed for other types of intrahepatic cholangiocarcinomas and extrabepatic bile duct carcinomas.The type of surgical procedure for IPNB depends upon tumor location and extension.Although several investigations have been conducted for illuminating molecular genetic changes during the development and progression of IPNB,the specific mechanism is still not clear,and further study is needed.