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      Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma

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          Abstract

          MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell-free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA that reflect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally-invasive disease response biomarkers in DLBCL.

          Quantification of 99 DLBCL tissues, to select miRNA implicated in immunosuppressive monocytes/macrophage biology, found miR-494 differentially elevated. In a discovery cohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raised relative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced post immuno-chemotherapy. The validation cohort (56 patients) was from a prospective clinical trial. Interestingly, in sequential samples both miRNAs decreased in patients becoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve, but not in those remaining interim-PET/CT+. Patient monocytes were phenotypically and functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cell proliferation in patient but not healthy samples. Pre-therapy monocytes showed an immunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present in all c-f nanoparticle fractions but was most readily detectable in unfractionated plasma.

          Circulating c-f miR-494 and miR-21 are disease response biomarkers with differential response stratified by interim-PET/CT in patients with DLBCL. Further studies are required to explore their manipulation as potential therapeutic targets.

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          Most cited references38

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          Diffuse large B-cell lymphoma.

          Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, representing approximately 30-40% of all cases in different geographic regions. Patients most often present with a rapidly growing tumour mass in single or multiple, nodal or extranodal sites. The most common type of DLBCL, designated as not otherwise specified, represents 80-85% of all cases and is the focus of this review. There are also rare types of lymphoma composed of large B-cells, in aggregate about 15-20% of all neoplasms that are sufficiently distinctive to recognise separately. DLBCL not otherwise specified (referred to henceforth as DLBCL) is a heterogeneous entity in terms of clinical presentation, genetic findings, response to therapy, and prognosis. A major advance was the application of gene expression profiling (GEP) to the study of DLBCL which further clarified this heterogeneity and provided a rationale for subdividing cases into groups. The most popular system divides cases of DLBCL according to cell-of-origin into germinal centre B-cell like (GCB) and activated B-cell like (ABC) subtypes, with about 10-15% of cases being unclassifiable. Patients with the GCB subtype usually have better prognosis than patients with the ABC subtype. Although cell-of-origin is useful for predicting outcome, the GCB and ABC subtypes remain heterogeneous, with better and worse prognostic subsets within each group. Next generation sequencing (NGS) analysis of DLBCL has facilitated global identification of numerous and diverse genetic abnormalities in these neoplasms and has shown that GCB and ABC tumours have different mutation profiles. Although the therapy of patients with DLBCL is an active area of research, the current 5-year overall survival rate is 60-70% using standard-of-care frontline therapy. A precision medicine approach for the design of new therapies based on molecular findings in DLBCL is likely the best path forward. As pathologists, our role has expanded beyond diagnosis. We must perform a complete work-up of DLBCL cases. In addition to our traditional role in establishing the diagnosis, we need to analyse markers that provide information regarding prognosis and potential therapeutic targets. We also must ensure that adequate tissue is triaged for molecular studies which are essential for designing therapy regimens, particularly in the setting of disease relapse.
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            Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity.

            Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), patients who fail R-CHOP have a dismal outcome. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have led to the discovery of key oncogenic pathways. In addition to the major molecular designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing technologies have unveiled the remarkable complexity of DLBCL and identified unique molecular targets that may be differentially exploited for therapeutic benefit. These findings have translated into a growing list of promising novel agents. Moving forward, it is of paramount importance to recognize the heterogeneity of DLBCL and to investigate these targeted agents within patient populations who are most likely to benefit. It will be necessary to prioritize drugs that affect key driver pathways and to combine them rationally to optimize their benefit. Improved prognostication and the availability of predictive biomarkers will be crucial to allow for the possibility of individualized risk-adapted therapy.
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              The tumour microenvironment in B cell lymphomas.

              B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                5 October 2018
                5 October 2018
                : 9
                : 78
                : 34644-34657
                Affiliations
                1 University of Queensland Diamantina Institute, Brisbane, QLD, Australia
                2 University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia
                3 University of Concepción, Concepción, Chile
                4 Canberra Hospital, Garran, ACT, Australia
                5 Australia National University Medical School, Garran, ACT, Australia
                6 Prince of Wales Hospital, Sydney, NSW, Australia
                7 Princess Alexandra Hospital, Brisbane, QLD, Australia
                Author notes
                Correspondence to: Qingyan Cui, Q.Cui@ 123456uq.edu.au
                Maher K. Gandhi, M.Gandhi@ 123456uq.edu.au
                Article
                26141
                10.18632/oncotarget.26141
                6205167
                92723c4f-7a9e-4d2c-86d5-4d88ea43ba8b
                Copyright: © 2018 Cui et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 27 July 2018
                : 8 September 2018
                Categories
                Research Paper

                Oncology & Radiotherapy
                mirna-494,mirna-21,positron emission tomography,diffuse large b-cell lymphoma,biomarker

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