ABSTRACT
Objective To analyze the surgical treatment and prognostic factors of patients with hepatolithiasis-associated intrahepatic cholangiocarcinoma (HICC).Methods The retrospective case-control study was conducted.The clinicopathological data of 109 patients with HICC who were admitted to the First Affiliated Hospital of Army Medical University between January 2011 and December 2015 were collected,including 40 males and 69 females,aged from 29 to 81 years,with an average age of 55 years.The patients underwent imaging and laboratory examinations before operation,and then the operation plan was worked out according to the results of examination and intraoperative conditions,including radical operation,palliative surgery and simple biopsy.Observation indicators:(1) surgical situations;(2) follow-up;(3) analysis of risk factors affecting postoperative survival of HICC patients.The follow-up using telephone interview and outpatient examination was performed to detect patients' survival up to January 2018.The normality test was done by ShapiroWilk.Measurement data with normal distribution were represented as Mean±SD and comparison between groups was analyzed using the t test.Measurement data with skewed distribution were described as M (range) and comparison between groups was analyzed using the Wilcoxon rank sum test.Categorical variables were analyzed using the chi-square test.The survival curve and cumulative survival rate were respectively drawn and calculated using the Kaplan-Meier method.The univariate analysis was done using the Log-rank test.The indexes with P＜ 0.05 were incorporated into COX regression model for multivariate analysis in the forward wald.Results (1) Surgical situations:109 patients with HICC underwent surgery.Distribution of hepatolithiasis and HICC in the 109 patients:the stones of 58,26 and 25 patients were located in the left liver,right liver and bilateral sides,respectively.The tumors of 65,31 and 13 patients were located in the left liver,right liver and bilateral sides,respectively.Operation methods:radical operation was performed in 51 cases (combined choledochojejunostomy in 38 cases,regional lymph node dissection in 33 cases,vascular reconstruction in 3 cases and pancreaticoduodenectomy in 2 cases),including 33 with hemihepatectomy and 18 with non-hemihepatectomy.Palliative surgery was performed in 46 cases (local resection of tumors in 13 cases,choledochojejunostomy in 19 cases,gastrointestinal anastomosis in 9 cases,jejunostomy in 13 cases,simple biliary drainage in 5 cases,other operations in 12 cases,some patients combined with a variety of surgical methods),and simple biopsy was performed in 12 cases.Invasion and metastasis in the 109 patients:intrahepatic metastasis occurred in 22 cases,vascular invasion in 52 cases,lymph node metastasis in 55 cases,extrahepatic invasion and metastasis in 58 cases (64 cases were complicated with multiple invasion and metastasis).The operation time and volume of intraoperative blood loss of 109 patients were respectively (359± 170)minutes and (556±382)mL,and 53 patients received intraoperative blood transfusion.Postoperative complications occurred in 35 patients,including pulmonary infection,pleural and peritoneal effusion,abdominal hemorrhage,abdominal infection,bile leakage and organ failure.Twenty-nine of the 35 patients were improved or recovered after treatment,and 6 died (3 died of severe pulmonary infection,1 died of liver failure,1 died of septic shock and 1 died of gastrointestinal hemorrhage).Histopathological characteristics of tumors in the 109 patients:mass type,peritubular infiltration type and intratubular growth type were detected respectively in 50,49 and 10 cases;according to the degree of tumor differentiation,high-differentiated,moderate-differentiated and low-differentiated tumors were detected in 22,50 and 37 cases,respectively.(2) Follow-up:107 patients were followed up for 1-84 months,with a median followup time of 51 months.The median survival time was 25.0 months (range,17.9-32.1 months).The 1-,3-and 5-year overall survival rates were 78.7％,39.4％ and 9.8％,respectively.The 1-,3-and 5-year survival rates were 86.3％,61.8％,20.6％ in patients with radical surgery and 88.4％,19.1％,0 in patients with palliative surgery and 34.6％,0,0 in patients with simple biopsy,respectively,showing a statistically significant difference (x2 =43.237,P＜0.05).(3) Analysis of risk factors affecting postoperative survival of HICC patients:① the results of univariate analysis showed that course of stone,cirrhosis,operation method,tumor diameter,tumor gross classification,degree of tumor differentiation,intrahepatic metastasis,vascular invasion,lymph node metastasis,extrahepatic invasion and metastasis,percentage of neutrophils,total bilirubin (TBiL),direct bilirubin (DBiL),albumin (Alb) and CA19-9 were the related factors affecting the prognosis of HICC patients after surgical treatment (x2 =5.764,8.768,43.273,4.086,11.995,21.910,15.436,6.469,17.181,35.307,24.676,10.691,11.367,5.808,3.907,P＜0.05).② The results of multivariate analysis showed that simple biopsy as operation method,course of stone ≥ 60 months,cirrhosis,low-differentiated tumor,vascular invasion,extrahepatic invasion and metastasis and Alb ＜ 35 g/L were independent factors affecting the prognosis of HICC patients after surgical treatment (hazard ratio =3.317,1.809,1.917,1.882,1.761,2.283,0.502,95％ confidence interval:1.263-8.712,1.132-2.892,1.061-3.463,1.291-2.744,1.087-2.852,1.220-4.271,0.304-0.827,P＜0.05).Conclusions Some patients with chronic hepatolithiasis can progress to HICC,and surgical resection is the first choice.However,due to the high malignancy,there is usually a combination of invasion and mnetastasis,resulting in poor prognosis.The simple biopsy as operation method,course of stone ≥ 60 months,cirrhosis,low-differentiated tumor,perihepatic vascular invasion,extrahepatic invasion and metastasis,Alb ＜ 35 g/L are independent risk factors affecting the prognosis of HICC patients after surgical treatment.
ABSTRACT
Objective To investigate the correlation of variations of ABCB11 gene and primary intrahepatic stone (PIS).Methods The retrospective case-control study was conducted.The clinical data of 319 patients with PIS and 344 healthy controls who were admitted to the Southwest Hospital of the Third Military Medical University between December 2012 and December 2015 were collected.Three hundred and ninteen patients with PIS and 344 healthy controls were respectively allocated into the PIS and control groups.Twenty-seven exons in ABCB11 gene were detected via polymerase chain reaction (PCR) and DNA sanger sequencing.Observation indicators included:(1) variations and genotype frequency distribution of ABCB11 gene in the 2 groups;(2) correlation analysis between variations of ABCB11 gene and clinical data of patients with PIS:preoperative indicators of liver function test,recurrent episodes of cholangitis,preoperative obstructive jaundice,type and recurrence of stones.Comparison between groups in variations and genotype frequency distribution of ABCB11 gene was analyzed by the Logistic regression.The Kruskal-Wallis H test was performed to explore the correlation between genotype of ABCB11 gene and clinical test results of patients with PIS.Correlation between genotype of ABCB11 gene and clinicopathological data of patients with PIS was analyzed by the chi-square test.Results (1) Variations and genotype frequency distribution of ABCB11 gene in the 2 groups:whole-exome sequencing results showed that synonymous mutations of rs3815675,rs2287616 and rs497692 and missense mutations of rs2287617,rs2287622 and rs118109635 in the PIS group were respectively detected in exon 4,9,24 and 9,13,21.CT genotype frequency of rs118109635 was 4.70％(15/319) in the PIS group and 1.45％ (5/344) in the control group,respectively,with a statistically significant difference [OR=3.49,95％ confidence interval (CI):1.17-10.40,P＜0.05].GG and AG+GG genotype frequency of rs497692 were 46.08％ (147/319),87.46％ (279/319) in the PIS group and 37.79％ (130/344),79.36％ (273/344) in the control group,respectively,with a statistically significant difference (OR=1.73,1.65,95％ CI:1.05-2.83,1.04-2.61,P＜0.05).(2) Correlation analysis between variations of ABCB11 gene and clinical data of patients with PIS:levels of glutamyl-transpeptidase (GGT),alkaline phosphatase (ALP) and direct bilirubin (DBil) in the PIS group were 167 U/L (range,7-1 968 U/L),166 U/L (range,36-1 527 U/L),4 μmol/L(range,1-272 μmol/L) in the CC genotype of rs118109635 and 433 U/L(range,17-864 U/L),232 U/L (range,85-613 U/L),6 μmol/L(range,2-173 μmol/L) in the CT genotype of rs118109635,respectively,with a statistically significant difference (H=6.025,5.879,8.056,P＜0.05).Globulin level of PIS group was respectively 32 g/L (range,20-40 g/L),34 g/L(range,17-50 g/L) and 33 g/L(range,14-49 g/L) in the AA,AG and GG genotype of rs497692,respectively,with a statistically significant difference (H=12.119,P＜0.05).Of 81 patients with recurrence of PIS,GG and GA genotypes of rs2287617 were detected in 78 and 3 patients,respectively,with a statistically significant difference (x2=5.367,P＜0.05);TT,TC and CC genotypes of rs2287622 were detected in 12,39 and 30 patients,respectively,with a statistically significant difference (x2=6.153,P＜0.05).Of 127 patients with obstructive jaundice,116 and 11 patients had CC and CT genotypes of rs118109635,respectively,with a statistically significant difference (x2=7.381,P＜0.05);11,43 and 73 patients had AA,AG and GG genotypes of rs497692,respectively,with a statistically significant difference (x2 =11.364,P＜0.05).Conclusion There is a correlation between rs118109635 and rs497692 of ABCB11 gene and PIS,meanwhile,the above variation loci are associated with obstruction of biliary tract and cholestasis.