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Article

The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma

1
Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany
2
NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6211 LK Maastricht, The Netherlands
3
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
4
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
5
Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
6
Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany
7
Department of Surgery, Maastricht University Medical Center (MUMC), 6229 HX Maastricht, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Luca Di Tommaso
Cancers 2021, 13(15), 3661; https://doi.org/10.3390/cancers13153661
Received: 10 June 2021 / Revised: 13 July 2021 / Accepted: 14 July 2021 / Published: 21 July 2021
Nerve fibers in the microenvironment of malignant tumors have been shown to be an important prognostic factor for long-term survival in various cancer types; however, their role in intrahepatic cholangiocarcinoma remains to be determined. Therefore, the impact of nerve fibers on long-term survival was investigated in a large European cohort of patients with intrahepatic cholangiocarcinoma who were treated by curative-intent surgical resection. By univariate and multivariate statistics, the absence of nerve fibers was determined to be an independent predictor of impaired long-term survival. A group comparison between patients with and without nerve fibers showed a statically significant difference with a cancer-specific 5-year-survival of 47% in patients with nerve fibers compared to 21% in patients without nerve fibers. Thus, the presence of nerve fibers in the microenvironment of intrahepatic cholangiocarcinoma is revealed as a novel and important prognostic biomarker in these patients.
The oncological role of the density of nerve fibers (NFs) in the tumor microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) remains to be determined. Therefore, data of 95 iCCA patients who underwent hepatectomy between 2010 and 2019 was analyzed regarding NFs and long-term outcome. Extensive group comparisons were carried out and the association of cancer-specific survival (CSS) and recurrence-free survival (RFS) with NFs were assessed using Cox regression models. Patients with iCCA and NFs showed a median CSS of 51 months (5-year-CSS = 47%) compared to 27 months (5-year-CSS = 21%) in patients without NFs (p = 0.043 log rank). Further, NFs (hazard ratio (HR) = 0.39, p = 0.002) and N-category (HR = 2.36, p = 0.010) were identified as independent predictors of CSS. Patients with NFs and without nodal metastases displayed a mean CSS of 89 months (5-year-CSS = 62%), while patients without NFs or with nodal metastases but not both showed a median CCS of 27 months (5-year-CSS = 25%) and patients with both positive lymph nodes and without NFs showed a median CCS of 10 months (5-year-CSS = 0%, p = 0.001 log rank). NFs in the TME are, therefore, a novel and important prognostic biomarker in iCCA patients. NFs alone and in combination with nodal status is suitable to identify iCCA patients at risk of poor oncological outcomes following curative-intent surgery. View Full-Text
Keywords: intrahepatic cholangiocarcinoma; nerve fibers; tumor microenvironment; oncological outcome; biomarker intrahepatic cholangiocarcinoma; nerve fibers; tumor microenvironment; oncological outcome; biomarker
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MDPI and ACS Style

Bednarsch, J.; Tan, X.; Czigany, Z.; Liu, D.; Lang, S.A.; Sivakumar, S.; Kather, J.N.; Appinger, S.; Rosin, M.; Boroojerdi, S.; Dahl, E.; Gaisa, N.T.; den Dulk, M.; Coolsen, M.; Ulmer, T.F.; Neumann, U.P.; Heij, L.R. The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma. Cancers 2021, 13, 3661. https://doi.org/10.3390/cancers13153661

AMA Style

Bednarsch J, Tan X, Czigany Z, Liu D, Lang SA, Sivakumar S, Kather JN, Appinger S, Rosin M, Boroojerdi S, Dahl E, Gaisa NT, den Dulk M, Coolsen M, Ulmer TF, Neumann UP, Heij LR. The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma. Cancers. 2021; 13(15):3661. https://doi.org/10.3390/cancers13153661

Chicago/Turabian Style

Bednarsch, Jan, Xiuxiang Tan, Zoltan Czigany, Dong Liu, Sven A. Lang, Shivan Sivakumar, Jakob N. Kather, Simone Appinger, Mika Rosin, Shiva Boroojerdi, Edgar Dahl, Nadine T. Gaisa, Marcel den Dulk, Mariëlle Coolsen, Tom F. Ulmer, Ulf P. Neumann, and Lara R. Heij. 2021. "The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma" Cancers 13, no. 15: 3661. https://doi.org/10.3390/cancers13153661

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