Serum Reactive Oxygen Metabolite Levels Are Associated with Poor Prognosis in Patients with Diffuse Large B-Cell Lymphoma
Authors: Ogura Shinji , Kamiya Takahiro , Mizuno Kota , Ito Chisako , Fujita Yuriko , Aisa Yoshinobu , Nakazato Tomonori 
Published: October 2019

Abstract
[Introduction] Oxidative stress caused by the increased production of reactive oxygen species (ROS) or decreased efficacy of the antioxidant system is implicated in the pathogenesis of various disease entities, such as atherosclerosis, cardiovascular disease, renal failure, malignant tumors, and autoimmune diseases. Recent observations suggested that oxidative stress is closely related to all aspects of cancer. Oxidative stress markers are prognostically important in various cancers including diffuse large B-cell lymphoma (DLBCL). However, the prognostic role of serum reactive oxygen metabolites (ROMs) in DLBCL is still unknown. The objective of this study is to evaluate the role of serum ROMs in patients with DLBCL.
[Methods] We enrolled 52 patients with DLBCL who were treated at our institution between 2012 and 2014. To assess oxidative stress, instead of measuring serum ROS directly, we measured serum d-ROMs (the derivatives of Reactive Oxygen Metabolites) levels. In the present study, serum d-ROMs levels were prospectively examined in 52 patients with DLBCL and 12 healthy subjects by using the Free Radical Analytical System 4 (FRAS 4, Wismerll Co. Ltd., Tokyo, Japan). The d-ROMs test has been successfully used to evaluate oxidative stress in a very large number of studies on humans and animals. The d-ROMs test essentially determines the concentration of hydroperoxides in the blood, which are substances that belong to a broad class of reactive oxygen metabolites. The d-ROMs concentration is expressed in Carratelli Units (1 CARR U = 0.08mg hydrogen peroxide/dl). The study protocol and sampling were approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital, and it was carried out in accordance with the Declaration of Helsinki.
[Results] The median follow-up time was 52 months. Median age at diagnosis was 74 years (range, 39-91 years) and 60% were male. 34 patients (65%) were stage 3-4 and 33 patients (63%) were R-IPI poor risk. The serum d-ROMs levels in patients with DLBCL were significantly elevated compared with normal controls (578.9+/-194.3 vs. 286.8+/-24.2 CARR U, P<0.001). In 52 DLBCL patients, patients with high serum d-ROMs levels (≥513 CARR U) had significantly shorter overall survival (OS) than those with low serum d-ROMs levels (<513 CARR U) (5-year OS, 37.9% versus 77.7%, respectively; P<0.001) (Figure. 1). In multivariate analysis, parameters having independent adverse significance for OS were: high serum d-ROMs levels (≥513 CARR U) (p=0.002, HR 5.17), high LDH levels (p=0.008, HR 4.58), and extranodal involvement >1 (p=0.002, HR 4.57).
[Conclusion] In the present study we demonstrated that elevated serum d-ROMs levels are associated with poor prognosis in patients with DLBCL. In particular, our data proved that a high serum d-ROMs level is an independent prognostic factor for survival in patients with DLBCL. These results suggest that oxidative stress may have an important role in DLBCL and may be also a useful prognostic biomarker. Since our results are based on a small-sized analysis, further large prospective studies are warranted to verify this conclusion.

Disclosures
No relevant conflicts of interest to declare.