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      miR-371a-3p, miR-373-3p and miR-367-3p as Serum Biomarkers in Metastatic Testicular Germ Cell Cancers Before, During and After Chemotherapy

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          Abstract

          Background: LDH (lactate dehydrogenase), AFP (alpha-fetoprotein) and β-HCG (human chorionic gonadotropin) are used in diagnosis and follow-up of testicular germ cell cancer (TGCC) patients. Our aim was to investigate the association between levels of miR-371a-3p, miR-373-3p and miR-367-3p and clinical features in metastatic TGCC. Methods: relative levels of miR-371a-3p, miR-373-3p and miR-367-3p were evaluated in serum of metastatic TGCC patients. A prospectively included and a retrospectively selected cohort were studied (total patient number = 109). Blood samples were drawn at start of chemotherapy and during follow-up. Serum microRNA (miR) levels were determined using the ampTSmiR test. Results: at start of chemotherapy, miR-371a-3p, miR-373-3p and miR-367-3p levels were positively correlated to LDH. The median level of these miRs was higher in patients who developed a relapse after complete biochemical remission ( n = 34) than in those who had complete durable remission ( n = 60). Higher levels of miR-367-3p were found in patients with refractory disease ( n = 15) compared to those who had complete response. miR levels decreased during the first week of chemotherapy in patients with complete response and stayed below threshold after one year of treatment. Conclusion: high miR levels at start of chemotherapy are associated with worse clinical outcome and can assist in early diagnosing of relapses.

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          Most cited references21

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          International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.

          Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.
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            Guidelines on Testicular Cancer: 2015 Update.

            This is an update of the previous European Association of Urology testis cancer guidelines published in 2011, which included major changes in the diagnosis and treatment of germ cell tumours.
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              Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study

              PURPOSE Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                08 October 2019
                October 2019
                : 8
                : 10
                : 1221
                Affiliations
                [1 ]Department of Medical Oncology, University Medical Center Groningen, University of Groningen, NL-9713 GZ Groningen, The Netherlands; f.x.rosas.plaza@ 123456umcg.nl (X.R.P.); j.meijer01@ 123456umcg.nl (C.M.); m.vugt@ 123456umcg.nl (M.A.T.M.v.V.); s.de.jong@ 123456umcg.nl (S.d.J.)
                [2 ]Department of Pathology, Erasmus MC Cancer Institute, NL-3015 GD Rotterdam, The Netherlands; a.vanagthoven@ 123456erasmusmc.nl
                [3 ]Princess Maxima Center for Pediatric Oncology, NL-3584 CS Utrecht, The Netherlands
                Author notes
                [†]

                These authors contributed equally to this work.

                [‡]

                These senior authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-5831-6997
                https://orcid.org/0000-0002-8146-1911
                Article
                cells-08-01221
                10.3390/cells8101221
                6830325
                31597402
                c0812fdc-73df-4341-88c2-17f7927bd010
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 August 2019
                : 02 October 2019
                Categories
                Article

                testicular germ cell cancer,microrna,serum biomarkers,β-hcg,afp,ldh

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