Observational Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. May 6, 2022; 10(13): 4084-4096
Published online May 6, 2022. doi: 10.12998/wjcc.v10.i13.4084
High plasma CD40 ligand level is associated with more advanced stages and worse prognosis in colorectal cancer
Zoltan Herold, Magdolna Herold, Gyorgy Herczeg, Agnes Fodor, Attila Marcell Szasz, Magdolna Dank, Aniko Somogyi
Zoltan Herold, Attila Marcell Szasz, Magdolna Dank, Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
Zoltan Herold, Magdolna Herold, Aniko Somogyi, Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
Gyorgy Herczeg, Agnes Fodor, Department of General Surgery, Szent Imre University Teaching Hospital, Budapest H-1115, Hungary
Author contributions: Herold Z, Herold M, and Somogyi A built the study design; Herold M, Herczeg G, Fodor A, and Herold Z were involved in the collection of samples; Herold Z analyzed the data; Herold Z, Herold M, Herczeg G, Szasz AM, and Dank M interpreted data; Herold Z prepared the draft of the manuscript; all authors were involved in editing and reviewing; Somogyi A and Herold Z received funding; Somogyi A supervised the study; all authors have read and agreed to the published version of the manuscript.
Supported by the National Research, Development and Innovation Office, No. K-116128; and the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund, No. UNKP-20-4-I.
Institutional review board statement: The study was reviewed and approved by the Regional and Institutional Committee of Science and Research Ethics, Semmelweis University (SE TUKEB 21-12/1994, approval date of latest modification: February 10, 2017), the Institutional Review Board of Szent Imre University Teaching Hospital (SZIK IKEB 5/2017), and the Committee of Science and Research Ethics, Hungarian Medical Research Council (ETT TUKEB 8951-3/2015/EKU).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent before study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: Zoltan Herold, MSc, PhD, Research Scientist, Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, 25-29 Tomo u, Budapest H-1083, Hungary. herold.zoltan@med.semmelweis-univ.hu
Received: April 24, 2021
Peer-review started: April 24, 2021
First decision: June 13, 2021
Revised: June 25, 2021
Accepted: April 2, 2022
Article in press: April 2, 2022
Published online: May 6, 2022
Processing time: 370 Days and 19.2 Hours
Abstract
BACKGROUND

Colorectal cancer (CRC) is often associated with elevated platelet count (> 400 × 109/L), known as thrombocytosis. The role of CD40 ligand (CD40L), a member of the tumor necrosis factor family, is controversial in CRC. Circulating CD40L is higher in CRC, but its relationship with disease staging and local and distant metastasis is not clear. Although most of the circulating CD40L is produced by platelets, no previous study investigated its relationship with CRC-related thrombocytosis.

AIM

To investigate the role of CD40L to predict the outcome of CRC and its relation to thrombocytosis.

METHODS

A total of 106 CRC patients and 50 age and sex-matched control subjects were enrolled for the study. Anamnestic data including comorbidities and histopathological data were collected. Laboratory measurements were performed at the time of CRC diagnosis and 1.5 mo and at least 6 mo after the surgical removal of the tumor. Plasma CD40L and thrombopoietin were measured via enzyme-linked immunosorbent assay, while plasma interleukin-6 was measured via electrochemiluminescence immunoassay. Patient follow-ups were terminated on January 31, 2021.

RESULTS

Plasma CD40L of CRC patients was tendentiously higher, while platelet count (P = 0.0479), interleukin-6 (P = 0.0002), and thrombopoietin (P = 0.0024) levels were significantly higher as opposed to the control subjects. Twelve of the 106 CRC patients (11.3%) had thrombocytosis. Significantly higher CD40L was found in the presence of distant metastases (P = 0.0055) and/or thrombocytosis (P = 0.0294). A connection was found between CD40L and platelet count (P = 0.0045), interleukin-6 (P = 0.0130), and thrombocytosis (P = 0.0155). CD40L was constant with the course of CRC, and all baseline differences persisted throughout the whole study. Both pre- and postoperative elevated platelet count, CD40L, and interleukin-6 level were associated with poor overall and disease-specific survival of patients. The negative effect of CD40L and interleukin-6 on patient survival remained even after the stratification by thrombocytosis.

CONCLUSION

CD40L levels of CRC patients do not change with the course of the disease. The CD40L level is strongly correlated with platelet count, interleukin-6, thrombocytosis, and the presence of distant metastases.

Keywords: CD40 ligand; Colorectal neoplasms; Interleukin-6; Thrombocytosis; Thrombopoietin

Core Tip: This observational study investigated whether plasma CD40 ligand (CD40L) is related to colorectal cancer (CRC)-associated thrombocytosis and disease severity. Baseline CD40L was significantly higher in patients with distant metastasis and thrombocytosis. An association between CD40L, platelet count, and the interleukin-6 level was found. CD40L was constant with the course of the disease, and all its baseline differences persisted throughout the study. Both pre- and postoperative high CD40L levels negatively affected overall, disease-specific, and thrombocytosis-eliminated survival. A possible connection between elevated CD40L levels and increased general inflammation caused by CRC was also suggested.