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1.
Leukemia ; 36(2): 591-595, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34365473

RESUMO

Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.


Assuntos
Biomarcadores Tumorais/metabolismo , Ciclo Celular , Evolução Molecular , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Complexo Repressor Polycomb 2/metabolismo , Mieloma Múltiplo Latente/patologia , Biomarcadores Tumorais/genética , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Plasmócitos/metabolismo , Complexo Repressor Polycomb 2/genética , Prognóstico , Transdução de Sinais , Mieloma Múltiplo Latente/genética , Mieloma Múltiplo Latente/metabolismo
3.
Best Pract Res Clin Haematol ; 33(1): 101148, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32139013

RESUMO

Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of elevated glucose metabolism in malignancies. There has been increasing interest in FDG PET/CT for plasma cell disorders since the International Myeloma Working Group outlined multiple applications of this imaging modality, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. The field of molecular imaging is now shifting focus from evaluation of metabolism to targeted evaluation of specific tumor markers. Targeted PET imaging targeted of CXCR4 and CD38 has advanced into translational clinical trials, bringing us closer to powerful imaging options for myeloma. In this review we discuss the current applications of FDG PET/CT in plasma cell disorders, as well as advances in targeted PET imaging.


Assuntos
Fluordesoxiglucose F18/metabolismo , Proteínas de Neoplasias/genética , Plasmocitoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Mieloma Múltiplo Latente/diagnóstico por imagem , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Antígeno de Maturação de Linfócitos B/genética , Antígeno de Maturação de Linfócitos B/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Medula Óssea/metabolismo , Medula Óssea/patologia , Progressão da Doença , Expressão Gênica , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasia Residual , Plasmócitos/metabolismo , Plasmócitos/patologia , Plasmocitoma/genética , Plasmocitoma/metabolismo , Plasmocitoma/patologia , Compostos Radiofarmacêuticos/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Mieloma Múltiplo Latente/genética , Mieloma Múltiplo Latente/metabolismo , Mieloma Múltiplo Latente/patologia
4.
J Cutan Pathol ; 46(11): 844-851, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31161673

RESUMO

Herein, we describe a patient with immunoglobulin G (IgG)-lambda smoldering multiple myeloma with translocation t(4:14) who developed widespread ulcerative horny-like spicules, heralding rapid progression to overt myeloma requiring aggressive chemotherapy and autologous stem cell transplantation. The serum abnormal immunoglobulin in the blood was cryoglobulin, which typically precipitates in the tissues at low temperatures causing inflammation and tissue damage. Histopathological changes, observed in lesions at different evolutionary stages, evidenced columns of horny-like eosinophilic homogeneous material, immunoreactive for IgG lambda, protruding from the dilated and/or distorted follicular openings or acrosyringia and small vessel thrombotic vasculopathy and vasculitis in concert with an inflammatory neutrophilic and lymphocytic reaction. Biochemical investigations on material from a spicule and ulcero-necrotic lesion revealed cryoprecipitates containing IgG-lambda with electrophoretic characteristics identical to those of the serum dysprotein. Our findings suggest that the formation of spicules and development of ulcerative lesions are a part of the same clinical spectrum where the cold-dependent precipitation of the immunogenic dysprotein, both in the skin vessels and hair follicle infundibula, play a major pathogenetic role. Whether this highly characteristic paraneoplastic dermatosis can identify patients with high-risk cytogenetic abnormalities and be incorporated into prognostic models, applicable early on in the course of myeloma, warrants further investigation.


Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 4/genética , Mieloma Múltiplo , Neoplasias Cutâneas , Mieloma Múltiplo Latente , Translocação Genética , Autoenxertos , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Mieloma Múltiplo Latente/genética , Mieloma Múltiplo Latente/metabolismo , Mieloma Múltiplo Latente/patologia , Mieloma Múltiplo Latente/terapia , Transplante Autólogo
5.
Ann Hematol ; 98(7): 1713-1720, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053880

RESUMO

Symptomatic multiple myeloma (MM) is a plasma cell neoplasm that represents the final stage of a continuum of clinical conditions that start from monoclonal gammopathy of unknown significance (MGUS), then transits in the more advance, but still asymptomatic, smoldering MM (SMM), with a final evolution in symptomatic MM. To investigate SMM microenvironment modifications, we studied 16 patients diagnosed at our hospital. Eight of them (group A) developed MM within 2 years from diagnosis while the others (group B) had stable SMM. Samples were bone marrow biopsies at diagnosis and after 2 years (± 4 months) and were analyzed by immunohistochemical analysis. Firstly, we found a significant increase in both CD4+ cells (11 vs 17%, p < 0.01) and CD8+ cells (15 vs 18%, p < 0.01) between diagnosis and at follow-up samples (whole cohort). This was associated to an increase in the CD4+/CD8+ ratio (0.74 vs 0.93, p < 0.01). Secondly, we discovered an increased expression of T cell inhibitory molecules during SMM evolution. In fact, plasma cell PD-L1 and microenvironment cell LAG3 expression increased from 1 to 12% (p = 0.03) and 4 to 10% (p = 0.04), respectively, from diagnosis to follow-up. Also, plasma cells and microenvironment cells HLA-DR expression augmented during SMM evolution from 7 to 10% (p = 0.04) and 29 to 39% (p = 0.01), respectively. When comparing group A vs group B, we found an increased CD68-KP1+ cell infiltration in favor of group B at diagnosis (23 vs 28%, p = 0.01) and a greater plasma cell infiltration at follow-up (50 vs 26%, p < 0.01). Our findings suggest how immune escape mechanisms appear earlier during multiple myeloma evolution, and that LAG3 could be a possible immunologic target in this setting.


Assuntos
Antígenos CD/biossíntese , Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Antígenos HLA-DR/biossíntese , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/biossíntese , Mieloma Múltiplo Latente , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Relação CD4-CD8 , Feminino , Humanos , Masculino , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Estudos Retrospectivos , Mieloma Múltiplo Latente/metabolismo , Mieloma Múltiplo Latente/patologia , Evasão Tumoral , Microambiente Tumoral , Proteína do Gene 3 de Ativação de Linfócitos
7.
Anticancer Res ; 38(9): 5087-5092, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194153

RESUMO

BACKGROUND/AIM: Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma often precede multiple myeloma (MM). The identification of biomarkers predicting progression to MM might facilitate an earlier diagnosis of MM. Our study assessed the diagnostic value of plasma levels of endocan, a 50-kDa soluble dermatan sulfate proteoglycan produced and secreted by endothelial cells, hitherto unknown in MM, in patients with plasma cell dyscrasia. MATERIALS AND METHODS: Endocan levels were determined in 96 peripheral blood plasma samples by sandwich enzyme-linked immunosorbent assay (ELISA) in healthy controls (n=12), in patients with MGUS (n=17), and in patients newly diagnosed with (n=42) or relapsed/refractory (n=25) MM. RESULTS: Median endocan concentration increased from MGUS (315.00 pg/ml) and healthy controls (316.19 pg/ml) to newly-diagnosed MM (371.82 pg/ml; p=0.027). The low endocan levels (median=246.20 pg/ml) in patients with relapsed/refractory MM were similar to those in healthy controls and patients with MGUS. A cut-off value of >220 pg/ml endocan in peripheral blood discriminated patients newly diagnosed with MM from those with MGUS (area under the curve(AUC)=0.66, 95% confidence interval(CI)=0.55-0.81). CONCLUSION: The plasma levels of endocan can non-invasively differentiate patients newly diagnosed with MM from those with MGUS and should therefore be evaluated prospectively as a potential diagnostic marker.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/sangue , Proteoglicanas/sangue , Mieloma Múltiplo Latente/metabolismo , Regulação para Cima , Idoso , Biomarcadores Tumorais/sangue , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo Latente/sangue , Mieloma Múltiplo Latente/diagnóstico
8.
Leuk Lymphoma ; 59(11): 2660-2669, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29616856

RESUMO

Oncogene-induced senescence (OIS) is a cellular tumor-suppressive mechanism present in several premalignant conditions. Here, we analyze the possible impact of OIS on malignant transformation in plasma cell disorders. Tumor samples from 125 patients with different disease stages were analyzed immunohistochemically for expression of senescence markers. Protein expression of cyclin-dependent kinase inhibitor p21Cip1/Waf1 was significantly higher in smoldering multiple myeloma (SMM) compared to monoclonal gammopathy of undetermined significance (MGUS) (p = .02) or symptomatic multiple myeloma (MM) (p = .005). SMM plasma cells expressing p21Cip1/Waf1 were negative for Ki67, consistent with senescence. While p27Kip1 was highly expressed in healthy controls, MGUS and SMM, expression decreased significantly in MM (p = .02). SMM plasma cells displayed a mutually exclusive expression of p21Cip1/Waf1/p27Kip1 suggesting compensatory mechanisms of senescence. In conclusion, we found markers of cellular senescence differentially expressed in SMM compared to MGUS and MM supporting the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders.


Assuntos
Transformação Celular Neoplásica/metabolismo , Senescência Celular , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Mieloma Múltiplo Latente/metabolismo , Mieloma Múltiplo Latente/patologia
9.
Cytometry B Clin Cytom ; 94(5): 611-620, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29577600

RESUMO

BACKGROUND: Recent approaches in multiple myeloma (MM) treatment have targeted CD38. As antigen expression levels on plasma cells (PCs) were demonstrated to affect response to monoclonal antibody (mAb) treatment, a precise characterization of PC phenotype is warranted. METHODS: Anti-CD38 mAb (isatuximab) was tested for antibody-dependent cellular cytotoxicity (ADCC) in MM cell lines. Quantification of the number of sites (NOS) of CD38 on bone marrow PCs and other immune cells obtained from light chain (AL) amyloidosis (n = 46) and smoldering multiple myeloma (SMM) patients (n = 19) was performed with two different quantitative flow cytometry (QFCM) applications. RESULTS: ADCC activity of isatuximab was observed in cell lines with >100 × 103 CD38-NOS only. The average PC CD38-NOS was 153 ± 53 × 103 in AL amyloidosis and 138.7 ± 53 × 103 in SMM patients. Eight (17%) AL amyloidosis and 4 (21%) SMM patients showed a PC CD38-NOS level <100 × 103 . In four AL amyloidosis and two SMM patients <10% of PCs had a CD38-NOS ≥100 × 103 . The CD38-NOS identified on bone marrow lymphocytes, monocytes, and granulocytes was two log units below the CD38-NOS on PCs (P < 0.001). No significant differences in CD38-NOS expression levels on any of the analyzed PC subpopulations in AL amyloidosis and SMM patients were identified. CONCLUSION: Levels of CD38 expression affect the isatuximab-mediated ADCC in vitro. As PCs of patients with AL amyloidosis and SMM do not homogenously express high CD38 our data provide a rationale for assessment of CD38-NOS in patients with PC disorders prior to anti-CD38 treatment. © 2018 International Clinical Cytometry Society.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Células da Medula Óssea/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo Latente/tratamento farmacológico , ADP-Ribosil Ciclase 1/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Células da Medula Óssea/química , Células da Medula Óssea/patologia , Feminino , Citometria de Fluxo , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Mieloma Múltiplo Latente/metabolismo
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