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BACKGROUND: Thrombotic microangiopathies (TMA) are a group of disorders with overlapping clinical features that require urgent intervention. Treatment is based on the recognition of the TMA type, which is often challenging. The aim of this study was to identify specific HLA associations with different TMA types to aid rapid diagnosis and appropriate treatment, since the HLA assay can be completed within five hours. METHODS: All 86 consecutive patients who presented to the University of Arkansas for Medical Sciences between May 2013 and January 2021 with a presumptive diagnosis of TMA were included in this study. HLA typing was performed and correlated with other clinical and laboratory studies. RESULTS: In comparison with other types of TMA, patients with acquired thrombotic thrombocytopenic purpura (aTTP) showed increased frequencies of HLA-DRB1*11, HLA-DQB1*03:01/19, HLA-DRB1*08 and HLA-DRB3. Combining the presence of these HLA associations with a PLASMIC score of 6 or more achieved a higher positive predictive value (90%) for identifying aTTP than the PLASMIC score alone (69%). In comparison with other TMA types, patients with aTTP showed decreased frequencies of HLA-DRB4, HLA-DRB1*07, HLA-DQB1*02. The HLA-DRB1*07/DQB1*02 was not observed in any aTTP patients (negative predictive value: 100%), and thus the presence of this haplotype essentially rules out aTTP. Further, HLA-DRB1*11/DQB1*03:01/19 was absent in atypical hemolytic uremic syndrome patients. CONCLUSION: HLA alleles can be used as an adjunct for the rapid assessment of TMA and can help to differentiate it from other primary and secondary forms of TMA, allowing for earlier definitive therapy.
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ABSTRACT: The total therapy (TT) IIIB phase 2 study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in International Staging System stage 1 patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM. The study was registered on www.clinicaltrials.gov as #NCT00572169.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/diagnóstico , Bortezomib/uso terapêutico , Seguimentos , Dexametasona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Uncovering the cellular and molecular mechanisms by which hematopoietic stem cell (HSC) self-renewal is regulated can lead to the development of new strategies for promoting ex vivo HSC expansion. Here, we report the discovery that alternative (M2)-polarized macrophages (M2-MΦs) promote, but classical (M1)-polarized macrophages (M1-MΦs) inhibit, the self-renewal and expansion of HSCs from mouse bone marrow (BM) in vitro. The opposite effects of M1-MΦs and M2-MΦs on mouse BM HSCs were attributed to their differential expression of nitric oxide synthase 2 (NOS2) and arginase 1 (Arg1), because genetic knockout of Nos2 and Arg1 or inhibition of these enzymes with a specific inhibitor abrogated the differential effects of M1-MΦs and M2-MΦs. The opposite effects of M1-MΦs and M2-MΦs on HSCs from human umbilical cord blood (hUCB) were also observed when hUCB CD34+ cells were cocultured with M1-MΦs and M2-MΦs generated from hUCB CD34- cells. Importantly, coculture of hUCB CD34+ cells with human M2-MΦs for 8 days resulted in 28.7- and 6.6-fold increases in the number of CD34+ cells and long-term SCID mice-repopulating cells, respectively, compared with uncultured hUCB CD34+ cells. Our findings could lead to the development of new strategies to promote ex vivo hUCB HSC expansion to improve the clinical utility and outcome of hUCB HSC transplantation and may provide new insights into the pathogenesis of hematological dysfunctions associated with infection and inflammation that can lead to differential macrophage polarization.