Cancer Res Treat.  2018 Apr;50(2):538-550. 10.4143/crt.2017.106.

Declined Preoperative Aspartate Aminotransferase to Neutrophil Ratio Index Predicts Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma after Hepatectomy

• Liu L
• Wang W
• Zhang Y
• Long J
• Zhang Z
• Li Q
• Chen B
• Li S
• Hua Y
• Shen S
• Peng B

• KMID: 2411142
• DOI: http://doi.org/10.4143/crt.2017.106

Abstract

PURPOSE
Various inflammation-based prognostic biomarkers such as the platelet to lymphocyte ratio and neutrophil to lymphocyte ratio, are related to poor survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aims to investigate the prognostic value of the aspartate aminotransferase to neutrophil ratio index (ANRI) in ICC after hepatic resection.
MATERIALS AND METHODS
Data of 184 patients with ICC after hepatectomy were retrospectively reviewed. The cut-off value of ANRI was determined by a receiver operating characteristic curve. Preoperative ANRI and clinicopathological variables were analyzed. The predictive value of preoperative ANRI for prognosis of ICC was identified by univariate and multivariate analyses.
RESULTS
The optimal cut-off value of ANRI was 6.7. ANRI was associated with tumor size, tumor recurrence, white blood cell, neutrophil count, aspartate aminotransferase, and alanine transaminase. Univariate analysis showed that ANRI, sex, tumor number, tumor size, tumor differentiation, lymph node metastasis, resection margin, clinical TNM stage, neutrophil count, and carcinoembryonic antigen were markedly correlated with overall survival (OS) and disease-free survival (DFS) in patients with ICC. Multivariable analyses revealed that ANRI, a tumor size > 6 cm, poor tumor differentiation, and an R1 resection margin were independent prognostic factors for both OS and DFS. Additionally, preoperative ANRI also had a significant value to predict prognosis in various subgroups of ICC, including serum hepatitis B surface antigen"’negative and preoperative elevated carbohydrate antigen 19-9 patients.
CONCLUSION
Preoperative declined ANRI is a noninvasive, simple, and effective predictor of poor prognosis in patients with ICC after hepatectomy.

Keyword

Aspartate aminotransferase; Neutrophil; Cholangiocarcinoma; Prognosis; Biomarkers

MeSH Terms

Alanine Transaminase
Aspartate Aminotransferases*
Aspartic Acid*
Biomarkers
Blood Platelets
Carcinoembryonic Antigen
Cholangiocarcinoma*
Disease-Free Survival
Hepatectomy*
Hepatitis B
Humans
Leukocytes
Lymph Nodes
Lymphocytes
Multivariate Analysis
Neoplasm Metastasis
Neutrophils*
Prognosis*
Recurrence
Retrospective Studies
ROC Curve
Alanine Transaminase
Aspartate Aminotransferases
Aspartic Acid
Biomarkers
Carcinoembryonic Antigen

Figure

• 

  Fig. 1. Receiver operating characteristic (ROC) curve and distribution of preoperative aspartate aminotransferase/neutrophil count ratio index (ANRI) in different intrahepatic cholangiocarcinoma (ICC) subgroups. (A) ROC analysis was performed to determine the optimal cut-off value of ANRI in patients with ICC after hepatectomy (cut-off value=6.7). The area under the ROC curve for survival status was 0.703 (95% confidence interval, 0.604 to 0.802; p < 0.001), with a sensitivity of 81.3% and a specificity of 57.9%. (B) Comparison of preoperative ANRI in ICC subgroups, stratified by tumor size, recurrence, and lymph node metastasis (LNM). The proportions of ICC patients with declined preoperative ANRI along with tumor size > 6 cm, recurrence, and with LNM are much higher than those with tumor size ≤ 6 cm, without recurrence, and without LNM, respectively (all p < 0.05, Mann-Whitney U test). AUC, area under the curve.

• 

  Fig. 2. Kaplan-Meier survival curves of overall survival (A) and disease-free survival (B) for intrahepatic cholangiocarcinoma patients with aspartate aminotransferase/neutrophil count ratio index (ANRI) > 6.7 and ANRI ≤ 6.7 in the entire cohort. p-values were obtained by log-rank tests.

• 

  Fig. 3. Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by TNM stage I+II (A, B), single tumor status (C, D), and without lymph node metastasis (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/neutrophil count ratio index.

• 

  Fig. 4. Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by R0 resection margin (A, B), without biliary-intestinal anastomosis (C, D), and Child-Pugh Class A (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/ neutrophil count ratio index.

• 

  Fig. 5. Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by serum hepatitis B surface antigen (HBsAg) negative (A, B), α-fetoprotein (AFP) ≤ 200.0 μg/L (C, D), and carbohydrate antigen 19-9 (CA19-9) > 35.0 U/mL (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/neutrophil count ratio index.

Reference

References

1. Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016; 22:291–300.

2. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014; 60:1268–89.

3. Jutric Z, Johnston WC, Hoen HM, Newell PH, Cassera MA, Hammill CW, et al. Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database. HPB (Oxford). 2016; 18:79–87.

4. Spolverato G, Kim Y, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol. 2016; 23:235–43.

5. Poultsides GA, Zhu AX, Choti MA, Pawlik TM. Intrahepatic cholangiocarcinoma. Surg Clin North Am. 2010; 90:817–37.

6. Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004; 328:983.

7. Fu SJ, Shen SL, Li SQ, Hua YP, Hu WJ, Liang LJ, et al. Prognostic value of preoperative peripheral neutrophil-to-lymphocyte ratio in patients with HBV-associated hepatocellular carcinoma after radical hepatectomy. Med Oncol. 2013; 30:721.

8. Jin J, Zhu P, Liao Y, Li J, Liao W, He S. Elevated preoperative aspartate aminotransferase to lymphocyte ratio index as an independent prognostic factor for patients with hepatocellular carcinoma after hepatic resection. Oncotarget. 2015; 6:19217–27.

9. Ji F, Fu S, Guo Z, Pang H, Chen D, Wang X, et al. Prognostic significance of preoperative aspartate aminotransferase to neutrophil ratio index in patients with hepatocellular carcinoma after hepatic resection. Oncotarget. 2016; 7:72276–89.

10. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC Press;2010.

11. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454:436–44.

12. Nakashima H, Matsuoka Y, Yoshida R, Nagata M, Hirosue A, Kawahara K, et al. Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma: a retrospective study. BMC Cancer. 2016; 16:41.

13. Park HS, Lee HS, Park JS, Park JS, Lee DK, Lee SJ, et al. Prognostic scoring index for patients with metastatic pancreatic adenocarcinoma. Cancer Res Treat. 2016; 48:1253–63.

14. Zhang L, Cai JQ, Zhao JJ, Bi XY, Tan XG, Yan T, et al. Impact of hepatitis B virus infection on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol. 2010; 101:233–8.

15. Wislez M, Rabbe N, Marchal J, Milleron B, Crestani B, Mayaud C, et al. Hepatocyte growth factor production by neutrophils infiltrating bronchioloalveolar subtype pulmonary adenocarcinoma: role in tumor progression and death. Cancer Res. 2003; 63:1405–12.

16. Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 2010; 16:219–23.

17. Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta K, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer. 2009; 45:1950–8.

18. Zhou SL, Dai Z, Zhou ZJ, Chen Q, Wang Z, Xiao YS, et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis. 2014; 35:597–605.

19. Kusumanto YH, Dam WA, Hospers GA, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003; 6:283–7.

20. Peng H, Zhang Q, Li J, Zhang N, Hua Y, Xu L, et al. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma. Oncotarget. 2016; 7:17220–9.

21. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005; 366:1303–14.