Clinical Lymphoma and Myeloma最新文献

{"title":"Valproic Acid, a Histone Deacetylase Inhibitor, Induces Apoptosis, Inhibits Proliferation, and Synergizes With Chemotherapy: The Rationale to Combine it for the Treatment of B-Cell Chronic Lymphocytic Leukemia","authors":"Basile Stamatopoulos ,&nbsp;L. Lagneaux ,&nbsp;C. De Bruyn ,&nbsp;P. Mineur ,&nbsp;L. Willems","doi":"10.3816/CLM.2009.n.100","DOIUrl":"10.3816/CLM.2009.n.100","url":null,"abstract":"<div><p>In this work, we showed that valproic acid (VPA) induces apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA also inhibits proliferation by disturbing many cell cycle messenger RNAs and potentiates cytotoxic effects of chemotherapeutic agents, suggesting its introduction in B-CLL treatment.</p></div><div><h3>Full Abstract</h3><p></p></div><div><h3>Background</h3><p>Epigenetic code modifications by histone deacetylase (HDAC) inhibitors have recently been proposed as potential new therapies for hematologic malignancies. B-cell chronic lymphocytic leukemia (B-CLL) remains incurable despite the introduction of new treatments. B-CLL cells are characterized by an apoptosis defect rather than an excessive proliferation, but proliferation areas can be found in some organs such as bone marrow and lymph nodes.</p></div><div><h3>Patients and Methods</h3><p>In this study, we analyzed the gene expression modifications in B-CLL cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. B-CLL cells obtained from 14 patients were exposed in vitro to a concentration of 1 mM VPA during 4 h. VPA effects on gene expression were studied before and after exposure using Affymetrix technology, and some identified genes were validated by real-time polymerase chain reaction and Western blot.</p></div><div><h3>Results</h3><p>We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA inhibited the proliferation of CpG/IL2-stimulated B-CLL cells and modulated many cell cycle messenger RNAs. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide, and lenalidomide.</p></div><div><h3>Conclusion</h3><p>(1) Exposure of B-CLL cells to VPA induces apoptosis, inhibits proliferation, and potentiates cytotoxic effects of chemotherapeutic agents. (2) These data strongly suggest that VPA combined with cytotoxic chemotherapy is particularly appealing in B-CLL treatment. Based on our data and literature data (Bokelmann et al; Bouzar et al), we have planed to study, in a multicentric phase I/II Belgian clinical trial, the combination of VPA and 2CDA (cladribine).</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"113070274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bing-Neel Syndrome: A Case Report and Systematic Review of Clinical Manifestations, Diagnosis, and Treatment Options","authors":"Jaspreet S. Grewal ,&nbsp;Preetkanwal K. Brar ,&nbsp;Walter M. Sahijdak ,&nbsp;Joseph A. Tworek ,&nbsp;Elaine G. Chottiner","doi":"10.3816/CLM.2009.n.091","DOIUrl":"10.3816/CLM.2009.n.091","url":null,"abstract":"<div><h3>Background</h3><p>Bing-Neel syndrome is an extremely rare neurologic complication of Waldenström macroglobulinemia (WM) that was first described in 1936. It is associated with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells with or without cerebrospinal fluid (CSF) hyperglobulinemia.</p></div><div><h3>Case Report</h3><p>We report a case of a 69-year-old white man with a 10-year history of WM. He was diagnosed with Bing-Neel syndrome based on magnetic resonance imaging and pathology studies of CSF. In addition, a comprehensive review of the reported cases of Bing-Neel syndrome in the up-to-date English-language literature was performed.</p></div><div><h3>Results</h3><p>Our patient underwent successful treatment with cranial radiation and intrathecal chemotherapy. He has been in clinical and pathologic remission for 3 years following the completion of his treatment. Based on our literature review, we also summarize and discuss clinical manifestations, diagnosis, and treatment options for Bing-Neel syndrome.</p></div><div><h3>Conclusion</h3><p>Bing-Neel syndrome is a rare and potentially treatable complication of WM. Patients with a history of WM presenting with neurologic symptoms should be evaluated for possible Bing-Neel syndrome. Cranial radiation therapy alone or in combination with intrathecal chemotherapy is more likely to achieve sustainable remission than intrathecal chemotherapy alone.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10258718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CME Test","authors":"","doi":"10.1016/S1557-9190(11)70369-9","DOIUrl":"https://doi.org/10.1016/S1557-9190(11)70369-9","url":null,"abstract":"","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1557-9190(11)70369-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137224334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Diagnostic Approach in Acute Myeloid Leukemia in the Republic of Macedonia: A Proposal for Minimal Screening-Based Clinical Stratification","authors":"Liljana Hadzi-Pecova,&nbsp;Sanja Trajkova,&nbsp;Aleksandar Stojanovik,&nbsp;Lidija Cevreska","doi":"10.3816/CLM.2009.n.105","DOIUrl":"10.3816/CLM.2009.n.105","url":null,"abstract":"<div><h3>Introduction</h3><p>Acute myeloid leukemia (AML) represents a heterogeneous complex of disorders resulting from diverse mechanisms of leukemogenesis. Correct diagnosis of AML subtypes plays a central role for individual clinical risk stratification and therapeutic decisions. Motivated to improve and simplify the diagnosis and management of AML in the Republic of Macedonia, we conducted a prospective study at the University Clinic of Hematology.</p></div><div><h3>Patients and Methods</h3><p>A total of 76 adults (&gt; 15 years of age; from an initial 77 tested) with acute leukemia who were consecutively admitted at the clinic were enrolled in the study. The aim of our study was to establish and standardize diagnostic approaches based on minimal screening tests that will facilitate risk-adapted therapy for each single AML patient. The diagnosis of acute leukemia was made by standard criteria of the French-American-British (FAB) Cooperative Study Group and confirmed by immunophenotyping bone marrow aspirates and/or peripheral blood samples following the criteria of the European Group for the Immunological Classification of Leukemia's (EGIL) and the British Committee for Standards in Hematology (BCSH).</p></div><div><h3>Results</h3><p>Our results showed that morphology and cytochemistry established lineage in 68 (89.4%) of patients. Immunophenotyping further revealed the exact lineage assignment of the blast cells in 11.8% of patients and also changed the lineage assignment in 3 patients and guided to implementation of specific molecular analyses for the further definition of some AML cases. Using an RQ-PCR assay we detected the presence of the fusion transcript <em>PML/RAR</em>α in 5 patients and classified 10 more patients in the prognostic favorable genetic entity Core Binding Factor (CBF)-AML according to the presence of the abnormal fusion transcripts AML1—ETO, CBFβ—MYH11. Those results were essential for more appropriate single-patient therapeutic decisions.</p></div><div><h3>Conclusion</h3><p>Our multimodal diagnostic approach consisted of cytomorphology, cytochemistry, multiparameter flow cytometry, and molecular analyses improved the diagnosis and enabled individual clinical stratification in 38.2% of our AML patients.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"100162742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment","authors":"Jian Li,&nbsp;Dao-Bin Zhou,&nbsp;Li Jiao,&nbsp;Ming Hui Duan,&nbsp;Wei Zhang,&nbsp;Yong Qiang Zhao,&nbsp;Ti Shen","doi":"10.3816/CLM.2009.n.077","DOIUrl":"10.3816/CLM.2009.n.077","url":null,"abstract":"<div><h3>Background</h3><p>Renal impairment is a common complication of multiple myeloma (MM) and is related to shorter overall survival and increased rates of early death. Bortezomib is a new agent for the treatment of patients with myeloma, with high response rates and controllable side effects. In this study, we will evaluate the efficacy and safety of bortezomib and dexamethasone in patients with newly diagnosed MM complicated by renal impairment.</p></div><div><h3>Patients and Methods</h3><p>This is a prospective study of the general characteristics, reversibility of renal impairment, response of myeloma, and side effects of 18 consecutive newly diagnosed patients with MM and renal impairment who received ≥ 2 cycles of bortezomib and dexamethasone.</p></div><div><h3>Results</h3><p>Of 18 patients newly diagnosed with MM, the median age was 60 years, and the median serum creatinine was 5.3 mg/dL. Patients received a median of 4 cycles of bortezomib and dexamethasone. Reversal of renal impairment was documented in 38.9% of the patients, and the median time to reversal was 16 days. Moreover, 33.3% of the patients achieved renal response (a 50% decrease in serum creatinine). The overall response rate of MM was 83.3%, including a 33.3% complete response (CR) rate, a 16.7% near-CR rate, a 16.7% very good partial response (PR) rate, and a 16.7% PR rate. Grade 3/4 adverse events consisted of infection (n = 3), peripheral neuropathy (n = 3), and ileus (n = 1). After a median follow-up of 15.7 months, the median progression-free survival for all patients was 12.6 months.</p></div><div><h3>Conclusion</h3><p>Bortezomib plus dexamethasone is a safe and effective regimen for newly diagnosed patients with MM complicated by renal impairment.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28459615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of Chronic Myelogenous Leukemia From a Background of Myeloproliferative Disorder: JAK2V617F as a Potential Risk Factor for BCR-ABL Translocation","authors":"Sai Ravi Kiran Pingali ,&nbsp;Michelle A. Mathiason ,&nbsp;Steven D. Lovrich ,&nbsp;Ronald S. Go","doi":"10.3816/CLM.2009.n.080","DOIUrl":"10.3816/CLM.2009.n.080","url":null,"abstract":"<div><p>We report the emergence of chronic myelogenous leukemia (CML) in a patient with <em>JAK2V617F</em>-positive polycythemia vera after 15 years of phlebotomy. The polycythemia vera clinical and molecular findings were suppressed at the time of CML diagnosis, only to re-emerge after the leukemia was successfully treated with imatinib. We explored the potential association between myeloproliferative disorders and CML in the context of the current literature and found a higher-than-expected coincidence based on known epidemiologic data for each specific condition. We hypothesize that myeloproliferative disorder (<em>JAK2V617F</em> or molecular events that cause <em>JAK2V617F</em>) is a risk factor for CML (<em>BCR-ABL</em> translocation). Because of therapeutic implications, clinicians should be aware that the conditions co-occur more frequently than once thought.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28461967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selected Clinical Trials in Chronic Lymphocytic Leukemia","authors":"","doi":"10.1016/S1557-9190(11)70026-9","DOIUrl":"https://doi.org/10.1016/S1557-9190(11)70026-9","url":null,"abstract":"","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1557-9190(11)70026-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92172979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infectious Complications in Patients With Chronic Lymphocytic Leukemia: Pathogenesis, Spectrum of Infection, and Approaches to Prophylaxis","authors":"Vicki A. Morrison","doi":"10.3816/CLM.2009.n.071","DOIUrl":"10.3816/CLM.2009.n.071","url":null,"abstract":"<div><p>Infections continue to be a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), as therapeutic advances have occurred over the past several decades. The pathogenesis of infection in these patients is multifactorial, including inherent immune defects related to the primary disease process, such as hypogammaglobulinemia, as well as therapy-related immunosuppression. A characteristic spectrum of infectious complications has been described for specific treatment agents. With chlorambucil, most infections are bacterial in origin, caused by common Gram-positive and -negative organisms. Recurrent infections are a hallmark, with the respiratory tract being the most common site of infection. The pathogenesis of infection with the purine analogues is related to the quantitative and qualitative T-cell abnormalities induced by these agents. Risk factors for infection identified in patients treated with fludarabine include advanced-stage disease, prior CLL therapy, response to therapy, elevated serum creatinine, hemoglobin &lt; 12 g/dL, and decreased serum IgG. As compared with patients receiving chlorambucil, patients receiving fludarabine have more major infections and herpes virus infections. However, <em>Pneumocystis, Aspergillus</em>, and cytomegalovirus (CMV) infections are uncommon. The use of alemtuzumab is complicated by frequent opportunistic infections. CMV reactivation is especially problematic, occurring in 10%–25% of patients. For prevention of infection, the use of vaccinations and immunoglobulin replacement has been studied. Recommendations for prophylactic antimicrobial therapy have arisen from CLL treatment trials and anecdotal reports. As new treatment approaches are developed for CLL, one must consider not only the efficacy of these agents for disease response but also the effect on subsequent infectious complications. Infectious complications remain a significant cause of morbidity and mortality in patients with CLL. We will review the pathogenesis as well as the spectrum of infections in these patients. We will also discuss approaches to the prophylactic and therapeutic management of infections in these patients.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28461970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rituximab Combined With MACOP-B or VACOP-B and Radiation Therapy in Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study","authors":"Pier Luigi Zinzani ,&nbsp;Vittorio Stefoni ,&nbsp;Erica Finolezzi ,&nbsp;Ercole Brusamolino ,&nbsp;Maria Giuseppina Cabras ,&nbsp;Annalisa Chiappella ,&nbsp;Flavia Salvi ,&nbsp;Andrea Rossi ,&nbsp;Alessandro Broccoli ,&nbsp;Maurizio Martelli","doi":"10.3816/CLM.2009.n.074","DOIUrl":"10.3816/CLM.2009.n.074","url":null,"abstract":"<div><h3>Background</h3><p>Third-generation regimens (MACOP-B [methotrexate/leucovorin (LV)/doxorubicin/cyclophosphamide/vincristine/prednisone/bleomycin] or VACOP-B [etoposide/LV/doxorubicin/cyclophosphamide/vincristine/prednisone/bleomycin]) in combination with local radiation therapy seem to improve lymphoma-free survival of primary mediastinal large B-cell lymphoma (PMLBCL). Recently, the superiority of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone) over CHOP-like regimens has been demonstrated in elderly and younger patients with low-risk diffuse large B-cell lymphoma.</p></div><div><h3>Patients and Methods</h3><p>Retrospectively, between February 2002 and July 2006, 45 previously untreated patients with PMLBCL were treated with a combination of a third-generation chemotherapy regimen (MACOP-B or VACOP-B), concurrent rituximab, and mediastinal radiation therapy.</p></div><div><h3>Results</h3><p>Twenty-six (62%) patients achieved a complete response (CR), and 15 (36%) obtained a partial response after MACOP-B/VACOP-B plus rituximab. After radiation therapy, the CR rate was 80%. At a median follow-up of 28 months, among the 34 patients who obtained a CR, 3 relapsed after 16, 19, and 22 months, respectively. Projected overall survival was 80% at 5 years; the relapse-free survival (RFS) curve of the 34 patients who achieved CR was 88% at 5 years.</p></div><div><h3>Conclusion</h3><p>In this retrospective study, in patients with PMLBCL, combined-modality treatment using the MACOP-B/VACOP-B regimen plus rituximab induces a high remission rate, with patients having a &gt; 80% chance of surviving relapse free at 5 years. In comparison with historical data on MACOP-B/VACOP-B without rituximab, there are no statistically significant differences in terms of CR and RFS rates.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28461973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microsatellite Instability Is a Common Finding in Multiple Myeloma","authors":"Ayşen Timurağaoğlu ,&nbsp;Sema Demircin ,&nbsp;Seray Dizlek ,&nbsp;Guchan Alanoğlu ,&nbsp;Evren Kiriş","doi":"10.3816/CLM.2009.n.072","DOIUrl":"10.3816/CLM.2009.n.072","url":null,"abstract":"<div><h3>Purpose</h3><p>Microsatellite instability (MSI) occurs as a result of sliding in the DNA sequences from shortening or elongation of the repeat zones of DNA during replication. Such abnormalities can normally be corrected by the enzymes coded by the DNA mismatch repair (MMR) genes. Therefore, detection of MSI is considered to be a sign of disorder of the MMR genes and is interpreted as a replication error phenotype.</p></div><div><h3>Patients and Methods</h3><p>We evaluated the MSI in 5 different loci in the 14q32 region of immunoglobulin heavy chain IgH gene in 26 newly diagnosed patients with multiple myeloma (MM).</p></div><div><h3>Results</h3><p>Fifty-four percent of the patients disclosed MSI and at least 1 locus but no significant association of MSI was found between different clinical stages and the MM subtype. MSI was not found in 5 light-chain myeloma patients.</p></div><div><h3>Conclusion</h3><p>Although our case number is small, probably the genomic instability in heavy-chain MM may be a common finding and probably plays a critical role in the MM pathogenesis.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28461971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}