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      High pretreatment plasma Epstein‐Barr virus (EBV) DNA level is a poor prognostic marker in HIV‐associated, EBV‐negative diffuse large B‐cell lymphoma in Malawi

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          Abstract

          Plasma Epstein‐Barr virus (EBV) DNA measurement has established prognostic utility in EBV‐driven lymphomas, where it serves as a circulating tumor DNA marker. The value of plasma EBV measurement may be amplified in sub‐Saharan Africa (SSA), where advanced imaging and molecular technologies for risk stratification are not typically available. However, its utility in diffuse large B‐cell lymphoma (DLBCL) is less certain, given that only a subset of DLBCLs are EBV‐positive. To explore this possibility, we measured plasma EBV DNA at diagnosis in a cohort of patients with DLBCL in Malawi. High plasma EBV DNA at diagnosis (≥3.0 log 10 copies/mL) was associated with decreased overall survival (OS) ( P = .048). When stratified by HIV status, the prognostic utility of baseline plasma EBV DNA level was restricted to HIV‐positive patients. Unexpectedly, most HIV‐positive patients with high plasma EBV DNA at diagnosis had EBV‐negative lymphomas, as confirmed by multiple methods. Even in these HIV‐positive patients with EBV‐negative DLBCL, high plasma EBV DNA remained associated with shorter OS ( P = .014). These results suggest that EBV reactivation in nontumor cells is a poor prognostic finding even in HIV‐positive patients with convincingly EBV‐negative DLBCL, extending the potential utility of EBV measurement as a valuable and implementable prognostic marker in SSA.

          Abstract

          In a cohort of HIV‐positive patients with diffuse large B‐cell lymphoma (DLBCL) in Malawi, we demonstrate that high plasma Epstein‐Barr virus (EBV) DNA level at diagnosis (≥3.0 log 10 copies/mL) is associated with decreased overall survival. Notably, even in those HIV‐positive patients with EBV‐negative tumors, high plasma EBV DNA remained associated with shorter survival. These results suggest that EBV reactivation in nontumor cells is a poor prognostic finding in HIV‐positive patients with EBV‐negative DLBCL.

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          Most cited references40

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          Epstein-Barr virus infection.

          J I Cohen (2000)
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            A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

            The recognition of several new types of non-Hodgkin's lymphoma (NHL) in recent years has led to proposals for changing lymphoma classifications, including a new proposal put forth by the International Lymphoma Study Group (ILSG). However, the clinical significance of the new entities and the practical utility of this new proposal have not been studied. Therefore, we performed a clinical evaluation of the ILSG classification. A cohort of 1,403 cases of NHL was organized at nine study sites around the world and consisted of consecutive patients seen between 1988 and 1990 who were previously untreated. A detailed protocol for histologic and clinical analysis was followed at each site, and immunologic characterization as to T- or B-cell phenotype was required. Five expert hematopathologists visited the sites and each classified each case using the ILSG classification. A consensus diagnosis was also reached in each case, and each expert rereviewed a 20% random sample of the cases. Clinical correlations and survival analyses were then performed. A diagnosis of NHL was confirmed in 1,378 (98.2%) of the cases. The most common lymphoma types were diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%), whereas the new entities comprised 21% of the cases. Diagnostic accuracy was at least 85% for most of the major lymphoma types, and reproducibility of the diagnosis was 85%. Immunophenotyping improved the diagnostic accuracy by 10% to 45% for a number of the major types. The clinical features of the new entities were distinctive. Both the histologic types and the patient characteristics as defined by the International Prognostic Index predicted for patient survival. In conclusion we found that the ILSG classification can be readily applied and identifies clinically distinctive types of NHL. However, for clinical application, prognostic factors as defined by the International Prognostic Index must be combined with the histologic diagnosis for appropriate clinical decisions.
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              Cytomegalovirus reactivation in critically ill immunocompetent patients.

              Cytomegalovirus (CMV) infection is associated with adverse clinical outcomes in immunosuppressed persons, but the incidence and association of CMV reactivation with adverse outcomes in critically ill persons lacking evidence of immunosuppression have not been well defined. To determine the association of CMV reactivation with intensive care unit (ICU) and hospital length of stay in critically ill immunocompetent persons. We prospectively assessed CMV plasma DNAemia by thrice-weekly real-time polymerase chain reaction (PCR) and clinical outcomes in a cohort of 120 CMV-seropositive, immunocompetent adults admitted to 1 of 6 ICUs at 2 separate hospitals at a large US tertiary care academic medical center between 2004 and 2006. Clinical measurements were assessed by personnel blinded to CMV PCR results. Risk factors for CMV reactivation and association with hospital and ICU length of stay were assessed by multivariable logistic regression and proportional odds models. Association of CMV reactivation with prolonged hospital length of stay or death. The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log(10) copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days. These preliminary findings suggest that reactivation of CMV occurs frequently in critically ill immunocompetent patients and is associated with prolonged hospitalization or death. A controlled trial of CMV prophylaxis in this setting is warranted.
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                Author and article information

                Contributors
                nathan.montgomery@unchealth.unc.edu
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                29 November 2019
                January 2020
                : 9
                : 2 ( doiID: 10.1002/cam4.v9.2 )
                : 552-561
                Affiliations
                [ 1 ] Department of Pathology & Laboratory Medicine University of North Carolina Chapel Hill NC USA
                [ 2 ] Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill NC USA
                [ 3 ] UNC Project‐Malawi Lilongwe Malawi
                [ 4 ] Department of Medicine Division of Hematology & Oncology University of North Carolina Chapel Hill NC USA
                [ 5 ] Department of Microbiology & Immunology University of North Carolina Chapel Hill NC USA
                [ 6 ] UNC Healthcare Chapel Hill NC USA
                Author notes
                [*] [* ] Correspondence

                Nathan D. Montgomery, Department of Pathology & Laboratory Medicine, The University of North Carolina at Chapel Hill, CB#7525, Chapel Hill, NC 27599-7525, USA.

                Email: nathan.montgomery@ 123456unchealth.unc.edu

                Author information
                https://orcid.org/0000-0003-1765-6623
                Article
                CAM42710
                10.1002/cam4.2710
                6970037
                31782984
                e69b8c35-d410-4e5a-a372-fe91f2081dec
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 May 2019
                : 24 October 2019
                : 30 October 2019
                Page count
                Figures: 2, Tables: 3, Pages: 10, Words: 6752
                Funding
                Funded by: AIDS Malignancy Consortium
                Funded by: Center for AIDS Research, University of North Carolina at Chapel Hill , open-funder-registry 10.13039/100011072;
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: CA019014
                Award ID: CA190152
                Award ID: CA210285
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:19.01.2020

                Oncology & Radiotherapy
                diffuse large b‐cell lymphoma,epstein‐barr virus,hiv,prognosis,sub‐saharan africa

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