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Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Development of cancer has been linked to inflammatory cytokines such as interleukin (IL)-6 and IL-17. In this study, we assessed the expression of these cytokines in intrahepatic cholangiocarcinoma (ICC) and determined their correlation to the survival probability.

Methods

A total of 72 consecutive patients who underwent curative resection of ICC at Osaka University Hospital from March 1998 to November 2014 were enrolled. Immunohistochemical analysis was performed for IL-17 and its receptor A (IL-17RA), as well as IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed for preoperative plasma levels of IL-6 and IL-17 in 32 patients with ICC.

Results

Immunohistochemical analysis showed that the IL-6high (n = 34) and IL-17RAhigh (n = 29) groups had significantly worse disease-free survival (DFS) than IL-6low (n = 38) and IL-17RAlow (n = 43) groups, respectively. Although IL-17+ cells were abundant in the intratumoral area, patients with high peritumoral, but not intratumoral, IL-17+ cells (n = 28) corresponded with a significantly lower overall survival (OS) and DFS (OS, p = 0.023; DFS, p = 0.026) than those with low group. Moreover, multivariate Cox proportional hazards analysis revealed that IL-6, peritumoral IL-17+, and IL-17RA are independent prognostic factors for DFS (p = 0.023, p = 0.0088, p = 0.039, respectively). In addition, high preoperative plasma levels of IL-6 in patients with ICC corresponded with significantly lower DFS (p = 0.002).

Conclusions

Our data suggested that IL-6, peritumoral IL-17+ cells, and IL-17RA expression are postoperative useful markers for predicting recurrence in patients with ICC.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; a Grant-in-Aid, P-DIRECT; a Grant-in-Aid from the Ministry of Health, Labor and Welfare; a grant from the National Institute of Biomedical Innovation; and a grant from the Osaka University Drug Discovery Funds. Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd., Evidence Based Medical (EBM) Research Center, Chugai Co., Ltd., Yakult Honsha Co., Ltd., and Merck Co., Ltd. Those funders had no role in main experimental equipments, supplies expenses, study design, data collection and analysis, decision to publish, or preparation of the manuscript, in this work.

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Author notes

  1. Hiroaki Nagano MD, PhD

    Present address: Department of Surgery, Graduate School of Medicine, Yamaguchi University, Ube City, Yamaguchi, Japan

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Kei Asukai MD, Koichi Kawamoto MD, PhD, Hidetoshi Eguchi MD, PhD, Kozo Noguchi MD, Shinichiro Hasegawa MD, PhD, Hisataka Ogawa MD, Daisaku Yamada MD, PhD, Yoshito Tomimaru MD, PhD, Akira Tomokuni MD, PhD, Tadafumi Asaoka MD, PhD, Takehiro Noda MD, PhD, Hiroshi Wada MD, PhD, Kunihito Gotoh MD, PhD, Shigeru Marubashi MD, PhD, Hiroaki Nagano MD, PhD, Yuichiro Doki MD, PhD & Masaki Mori MD, PhD, FACS

  2. Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Koichi Kawamoto MD, PhD, Masamitsu Konno PhD, Naohiro Nishida MD, PhD & Hideshi Ishii MD, PhD

  3. Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Jun Koseki PhD & Hideshi Ishii MD, PhD

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Corresponding author

Correspondence to Hideshi Ishii MD, PhD.

Electronic supplementary material

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Supplementary material 1 (DOCX 16 kb)

10434_2015_4782_MOESM2_ESM.tif

IL-17+ cells in intratumoral tissue were significantly higher in number than in peritumoral tissue (intratumoral vs peritumoral, 117.3 ± 116.2 vs 30.5 ± 17.9, p < 0.01). Analysis was performed by the χ2 test. Supplementary material 2 (TIFF 61 kb)

10434_2015_4782_MOESM3_ESM.tif

Enzyme-linked immunosorbent assay (ELISA) was used to assess the preoperative plasma level of IL-6 (left side) and IL-17 (right side) in ICC patients (n = 32). Supplementary material 3 (TIFF 123 kb)

10434_2015_4782_MOESM4_ESM.tif

The correlation between the preoperative plasma IL-6 level and IL-6 IHC score (left side)/IL-17RA IHC score (right side). P values were calculated using the Mann–Whitney test. Supplementary material 4 (TIFF 150 kb)

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Asukai, K., Kawamoto, K., Eguchi, H. et al. Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 22 (Suppl 3), 1524–1531 (2015). https://doi.org/10.1245/s10434-015-4782-y

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