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      Correlation Between Baseline 18F-FDG PET/CT Findings and CD38- and CD138-Expressing Myeloma Cells in Bone Marrow and Clinical Parameters in Patients with Multiple Myeloma Translated title: Multipl Myelom Hastalarında Kemik İliği 18F-FDG PET/BT Bulguları ile Myelom Hücrelerinde CD38, CD138 Ekspresyonu ve Hematolojik Parametreler Arasındaki Korelasyon

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          Abstract

          Objective

          The aim of this study was to evaluate the relation between the rate of fluorine-18 (18F) fludeoxyglucose (FDG) uptake and CD38 and CD138 expression in myeloma cells in bone marrow and other clinical parameters in patients with multiple myeloma (MM).

          Materials and Methods

          Patients with the diagnosis of MM who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) for initial staging were evaluated retrospectively. We analyzed a total of 42 patients (43-83 years old, mean: 64.4±9.9). Hematological and biochemical tests including hemoglobin, hematocrit, C-reactive protein, β2-microglobulin, creatinine, albumin, calcium, lactate dehydrogenase, and erythrocyte sedimentation rate were recorded. In bone marrow samples, plasma cell ratio and CD38 and CD138 immunohistochemical staining were evaluated. On PET/CT images, mean standardized uptake values (SUV mean) of the right anterior and posterior iliac crest and right proximal femora were calculated. The correlations between the average SUV mean of bone marrow and CD38- and CD138-expressing myeloma cells and other parameters were analyzed by Spearman’s correlation test. Values of p<0.05 were considered statistically significant.

          Results

          Types of MM were IgG K (45%), IgG L (21%), IgA K (7%), IgA L (10%), and others (17%). Thirty-two (76%) patients were at stage III according to the Salmon-Durie staging system. There was a statistically significant positive correlation between bone marrow FDG uptake and percentage of plasma cells in bone marrow and CD38 and CD138 expression in plasma cells (r=0.403, r=0.339, and r=0.409) and β2-microglobulin and C-reactive protein levels (r=0.676, r=0.541). There was a negative correlation between bone marrow FDG uptake and hemoglobin and hematocrit values (r=-0.377 and r=-0.368). Other hematological parameters were not correlated with FDG uptake in bone marrow.

          Conclusion

          Increased FDG uptake is correlated with the percentage of CD38 and CD138 expression in plasma cells in bone marrow. In addition to initial staging, 18F-FDG PET/CT is useful in treatment planning and prognostic evaluation in MM patients.

          Translated abstract

          Amaç

          Bu çalışmanın amacı multipl myelom (MM) hastalarında kemik iliği florin-18 (18F) fluorodeoxyglucose (FDG) tutulumu ile plazma hücrelerinde CD38, CD138 ekspresyonu oranı ve diğer klinik parametreler arasındaki ilişkiyi değerlendirmektir.

          Gereç ve Yöntemler

          MM tanısı almış, ilk evreleme amacıyla 18F-FDG positron emisyon tomografi/bilgisayarlı tomografi (PT/BT) yapılan hastalar geriye dönük olarak değerlendirildi. Toplam 42 hasta analiz edildi (43-83 yaş, ortalaması: 64,4±9,9). Hematolojik ve biyokimyasal testlerden hemoglobin, hematokrit, C reaktif protein, beta 2-mikroglobulin, kreatinin, albumin, kalsiyum, laktat dehidrogenaz, sedimentasyon düzeyleri kayıt altına alındı. Kemik iliğinde plazma hücre düzeyi ve immünhistokimya ile CD38 ve CD138 boyanma oranına bakıldı. 18F-FDG PET/BT görüntülerinde sağ proksimal femur, sağ ön ve arka ilyak krest ortalama standart tutulum oranı (SUV ort.) kaydedildi. Kemik iliği SUV ort. ve myelom hücrelerinde CD38, CD138 ekspresyonu ve diğer klinik parametreler arasındaki korelasyon Spearman korelasyon testi ile analiz edildi. P değerleri <0,05 olduğunda anlamlı kabul edildi.

          Bulgular

          Hastaların %45’ini IgG K, %21’ini IgG L, %7’sini IgA K, %10’unu IgA L ve %17’sini diğer myeloma tipleri oluşturuyordu. Otuz iki hasta (%76) Salmon-Durie sınıflamasına göre evre 3 idi. Kemik iliği FDG tutulumu ile plazma hücre oranı ve CD38, CD138 ekspresyonu arasında (r=0,403, r=0,339 ve r=0,409) ve beta 2-mikroglobulin ve C reaktif protein düzeyi arasında (r=0,676, r=0,541) istatistiksel anlamlı pozitif korelasyon vardı. Kemik iliği FDG uptake ile hemoglobin ve hematokrit değerleri arasında negatif korelasyon bulundu (r=-0,377 ve r=-0,368). Diğer hematolojik paremetreler kemik iliği FDG tutulumu arasında bir korelasyon saptanmadı.

          Sonuç

          Kemik iliğinde artmış FDG tutulumu, plazma hücre oranı ve CD38, CD38 ekspresyonu ile ilişkilidir. MM hastalarında 18F-FDG PET/BT, ilk evreleme yanında tedavi planlaması ve prognostik değerlendirmede de yararlıdır.

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          Most cited references26

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          Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

          Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.
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            Role of (18)F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.

            The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of (18)fluorodeoxyglucose ((18)F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. (18)F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of (18)F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of (18)F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. (18)F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.
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              Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab.

              In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.
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                Author and article information

                Journal
                Turk J Haematol
                Turk J Haematol
                TJH
                Turkish Journal of Hematology
                Galenos Publishing
                1300-7777
                1308-5263
                September 2018
                5 August 2018
                : 35
                : 3
                : 175-180
                Affiliations
                [1 ]Adnan Menderes University Faculty of Medicine, Department of Nuclear Medicine, Aydın, Turkey
                [2 ]Adnan Menderes University Faculty of Medicine, Department of Internal Medicine, Aydın, Turkey
                [3 ]Adnan Menderes University Faculty of Medicine, Department of Pathology, Aydın, Turkey
                [4 ]Adnan Menderes University Faculty of Medicine, Department of Hematology, Aydın, Turkey
                Author notes
                * Address for Correspondence: Adnan Menderes University Faculty of Medicine, Department of Nuclear Medicine, Aydın, Turkey Phone: +90 505 264 58 57 E-mail: arzukincengiz@ 123456gmail.com
                Author information
                https://orcid.org/0000-0003-2110-4450
                https://orcid.org/0000-0001-6471-3112
                https://orcid.org/0000-0002-6687-2966
                https://orcid.org/0000-0003-1703-2175
                https://orcid.org/0000-0001-5823-0659
                https://orcid.org/0000-0003-0651-5462
                Article
                19475
                10.4274/tjh.2017.0372
                6110447
                29806594
                d62b8750-5861-4bdb-a7bd-b1b39f31e6db
                © Copyright 2018, Turkish Journal of Hematology, Published by Galenos Publishing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 October 2017
                : 28 May 2018
                Categories
                Research Article

                multiple myeloma, cd38/cd138 antigen, positron emission tomography/computed tomography, pet/ct

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