Radical resection has been the only thempeutic method that can improve the long-term survival for patients with gallbladder cancer (GBC) so far.However,for advanced GBC,patients generally have poor prognosis due to late awareness of the disease and poor surgical resection rate.Sometimes,the neoadjuvant chemotherapy can downstage tumors for potential surgery thus increases the R0 resection rate,as confirmed in esophageal carcinoma,gastric carcinoma,colorectal carcinoma,and so on.Currently,the neoadjuvant chemotherapy in GBC has not been extensively performed.In this article,we will review the recent progression,current status,and effectiveness of associated regimens of chemotherapy treatment of GBC,as well as discussing the feasibility of delivering neoadjuvant chemotherapy to the patients with advanced GBC and solutions to major issues.

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.