Oxidative Stress Is Associated with Poor Prognosis in Patients with Malignant Lymphoma
Authors: Nakazato Tomonori , Ito Chisako , Aisa Yoshinobu 
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. However, the prognostic role of oxidative stress in hematologic malignancies (HM) is still unknown. The objective of this study is to evaluate the role of oxidative stress in patients with HM.
[Methods] 8-hydroxy-2-deoxyguanosine (8-OHdG), which originates from damaged DNA repaired by non-specific endonucleases and specific glycosylates and is eliminated into urine, is widely used as a sensitive biomarker of oxidative stress. Urinary 8-OHdG levels have been reported to be elevated in patients with various malignancies. In the present study, urinary 8-OHdG levels were examined in 196 patients with HM (112 malignant lymphoma, 34 multiple myeloma, 28 myelodysplastic syndrome, 15 acute myeloid leukemia, 3 acute lymphoblastic leukemia, 4 chronic myeloid leukemia) by using a novel automatic oxidative stress analyzer, ICR-001. The study protocol and sampling were approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital.
[Results] The urinary 8-OHdG levels in patients with HM were elevated compared with normal controls (23.2+/-18.3 vs. 13.7+/-3.4ng/mg/Cr, P=0.02). In particular, urinary 8-OHdG levels were significantly elevated in patients with malignant lymphoma (25.9+/-31.4ng/mg/Cr, P=0.02). In 112 lymphoma patients, patients with high urinary 8-OHdG levels (over 25.0ng/mg/Cr) had significantly shorter overall survival (OS) than those with low urinary 8-OHdG levels (under 25.0ng/mg/Cr) (2-year OS, 44.0% versus 83.4%, respectively; P&lt;0.001) (Figure. 1). Among lymphoma patients, urinary 8-OHdG levels were significantly higher in patients with diffuse large B-cell lymphoma (DLBCL) (31.04+/-36.54ng/mg/Cr, P=0.01). In 55 DLBCL patients, high urinary 8-OHdG levels were also associated with shorter OS (2-year OS, 31.1% versus 88.9%, respectively; P&lt;0.001) (Figure. 2). In univariate analysis, a high 8-OHdG level, high PS, a high LDH level, advanced stage, a high sIL2R level, and R-IPI poor risk were associated with poor OS in patients with DLBCL. In multivariate analysis, parameters having independent adverse significance for OS were: a high urinary 8-OHdG level (over 25.0ng/mg/Cr) (p=0.01, HR 4.97), high PS (2-4) (p=0.01, HR 6.61).
[Conclusion] In the present study we demonstrated that many patients with HM have elevated urinary 8-OHdG levels, and these elevated levels are associated with a poor prognosis in patients with ML. In particular, our data proved that a high urinary 8-OHdG level is an independent prognostic factor for survival in patients with DLBCL. These results suggest that oxidative stress may have an important role in ML and also may be 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.