Case Control Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2019; 11(12): 1126-1140
Published online Dec 15, 2019. doi: 10.4251/wjgo.v11.i12.1126
Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma
Livia Petrusel, Ioana Rusu, Daniel Corneliu Leucuta, Radu Seicean, Ramona Suharoschi, Paula Zamfir, Andrada Seicean
Livia Petrusel, Andrada Seicean, Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
Ioana Rusu, Paula Zamfir, Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
Daniel Corneliu Leucuta, Medical Informatics and Biostatistics Department, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400012, Romania
Radu Seicean, First Surgery Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
Ramona Suharoschi, Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca 400372, Romania
Author contributions: Petrusel L and Seicean A conceived and designed the study; Petrusel L, Rusu I, Seicean R, Suharoschi R and Zamfir P performed the research; Leucuta DC analysed data; Petrusel L and Seicean A wrote the paper.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Regional Institute of Gastroenterology and Hepatology in Cluj-Napoca.
Conflict-of-interest statement: The authors report no relevant conflicts of interest.
Data sharing statement: Participants gave written informed consent for data sharing.
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Livia Petrusel, MD, PhD, Doctor, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, 19-21 Croitorilor Street, Cluj-Napoca 400162, Romania. livia.cutas@umfcluj.ro
Telephone: +40-72-4402389
Received: May 5, 2019
Peer-review started: May 8, 2019
First decision: July 31, 2019
Revised: September 9, 2019
Accepted: October 14, 2019
Article in press: October 14, 2019
Published online: December 15, 2019
Abstract
BACKGROUND

Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known.

AIM

To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value.

METHODS

This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease.

RESULTS

The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008).

CONCLUSION

The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.

Keywords: Pancreatic adenocarcinoma, Cachexia, Perineural invasion, Activin, Midkine, Biomarker, Survival, Metastases, Endosonography, Surgery

Core tip: Midkine (MK) is a neurotrophic factor that promotes perineural invasion in pancreatic cancer, neuronal differentiation and cell migration. Our results confirmed that high MK expression is closely correlated with perineural invasion and with advanced tumor stage, diabetes. No relationship with cachexia was found. Activin plays a dominant role in the development and progression of cachexia and in tumor cell growth in pancreatic adenocarcinoma, but this was not confirmed in this study, despite the association with poor survival.