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1.
Arch Pathol Lab Med ; 144(2): 160-167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990228

RESUMO

CONTEXT.­: Large B-cell lymphomas represent the most common non-Hodgkin lymphomas and often present as extranodal masses with advanced stage similar to metastatic tumors. Without proper intraoperative, microscopic, immunophenotypic, and cytogenetic evaluation they may be mistaken for other hematopoietic or even nonhematopoietic tumors. Also, diffuse large B-cell lymphomas often have clinical, morphologic, immunophenotypic, and cytogenetic clinical features that are similar to those of other less common B-cell lymphomas. Furthermore, classification of these neoplasms is continually becoming more refined. OBJECTIVE.­: To provide a rational, methodic approach to the evaluation of large B-cell lymphomas for community practice pathologists who provide general pathology services. DATA SOURCES.­: This review incorporates guidelines detailed in the 2017 update to the World Health Organization's Classification of Tumours of Haematopoietic and Lymphoid Tissues in addition to other recent peer-reviewed publications. CONCLUSIONS.­: Many large B-cell neoplasms respond favorably to current treatments, but these cases also require accurate and timely diagnoses. We propose a process following a brief checklist that focuses on diffuse large B-cell lymphoma, the most common entity, and rules out other similar lymphomas in a stepwise fashion.


Assuntos
Linfoma de Células B/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Patologia Clínica/métodos , Guias de Prática Clínica como Assunto , Antígenos CD20/metabolismo , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
2.
Medicine (Baltimore) ; 98(45): e17827, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702637

RESUMO

This study was designed to analyze the clinical characteristics and prognostic value of c-MYC and BCL-2 proteins expression in patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL).82 patients newly diagnosed with PCNS-DLBCL, from January 2008 to November 2018, were enrolled in this study. Clinical characteristics, immunohistochemical features, laboratory examinations, and treatment outcome were analyzed among these patients.Among these 82 cases, 45 were males (54.9%) and 37 were females (45.1%). Age ranged from 16 to 78 years old, and 29 patients (35.4%) were elder than 60 years old, with median age at 57 years old. According to Hans classification, 25 were accounted for origin of germinal center B-cell (GCB) subtype (30.5%) and 49 were accounted for non-GCB subtype (59.8%), respectively. Eight patients were unclassified due to lack of detailed pathological results. The median survival of these 82 patients was 30 months, and 1-year, 3-year, and 5-year overall survival (OS) rate was 59.7%, 44.6%, and 34.1%, respectively. Patients treated with sequential HD-MTX based chemotherapies showed a superior prognosis than those without. In combination with rituximab, the outcome was further improved. The median OS was 55 months in HD-MTX + R group, 27 months in HD-MTX group, and 9 months in other groups, respectively. Univariate analysis identified age ≥60, ECOG score ≥ 2 points, and overexpression of BCL-2 protein (≥85%) were adverse prognostic factors for OS. Co-expression of c-MYC (≥40%) and BCL-2 (≥50%) proteins was associated with poor ECOG score, high Ki-67 expression, and trended towards an inferior outcome. Gender, lesion location, number of lesions, lactic dehydrogenase (LDH), cell of origin, BCL-6 protein expression, expression of c-MYC protein alone and Ki-67 ≥85% had no significant impact on OS.In patients with PCNS-DLBCL, age ≥60 years old, ECOG score ≥2 points, and overexpression of BCL-2 protein (≥85%) were associated with a poor survival. HD-MTX based chemotherapies in combination with rituximab could improve the prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Tratamento Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
3.
BMC Cancer ; 19(1): 842, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31455250

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) is thought to have an oncogenic effect on the development of gastric malignancies. However, the effect of H. pylori status on the prognosis of gastric diffuse large B-cell lymphoma (DLBCL) remains unconfirmed. This study aimed to identify the prognostic importance of H. pylori infection in de novo gastric DLBCL. METHODS: One hundred and twenty-nine patients diagnosed with primary de novo gastric DLBCL at the West China Hospital of Sichuan University from 1st January 2009 to 31st May 2016 were included. The clinical features of the patients were documented. H. pylori status was assessed via urease breath tests and histologic examinations. The prognostic value of H. pylori was verified via univariate and multivariate analyses. RESULTS: Over a median follow-up of 52.2 months (range 4-116), the 5-year overall survival (OS) for all patients was 78.7%. Patients with H. pylori infections had significantly better 5-year PFS and OS than did the H. pylori-negative subgroup (5-year PFS, 89.3% vs. 74.1%, P = 0.040; 5-year OS, 89.7% vs. 71.8%, P = 0.033). Negative H. pylori status and poor ECOG performance were independent negative prognostic indicators for both PFS and OS (PFS, P = 0.045 and P = 0.001, respectively; OS, P = 0.021 and P < 0.001, respectively). CONCLUSIONS: H. pylori status in de novo gastric DLBCL can be a promising predictor of disease outcome, and patients with negative H. pylori status require careful follow-up since they tend to have a worse outlook.


Assuntos
Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/etiologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/epidemiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Vigilância em Saúde Pública , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Adulto Jovem
4.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408531

RESUMO

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes myc , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Translocação Genética , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Perfilação da Expressão Gênica , Genes bcl-2 , Centro Germinativo/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Estudos Retrospectivos
7.
Chin Med J (Engl) ; 132(15): 1807-1814, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31335477

RESUMO

BACKGROUND: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have a worse prognosis than younger patients, and the optimal treatment strategy for this group remains controversial. We conducted a retrospective analysis to investigate the clinical features and outcomes of elderly patients (>60 years) and to assess the impact of clinical and molecular factors on outcome in this age group. METHODS: From April 2006 to December 2012, a total of 349 elderly patients with DLBCL from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College were included in this analysis. Patients were further divided into two age groups (61-69 years and ≥70 years). We compared clinical characteristics and outcomes between groups. RESULTS: Of 349 total patients, 204 (58.5%) were aged 61 to 69 years, and 145 (41.5%) patients were aged 70 years or older. Except for the Eastern Cooperative Oncology Group performance status, clinical characteristics were comparable between the two groups. With a median follow-up of 82 (range, 1-129) months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 51.9% and 45.8%, respectively. The 5-year OS rates for patients aged 61 to 69 years and those over 70 years were 58.3% and 42.8% (P = 0.007), respectively, and the 5-year PFS rates were 51.0% and 38.6% (P = 0.034). Treatment regimens including rituximab provided a higher 5-year OS rate (63.1% vs. 37.1%, P < 0.001) and PFS rate (56.6% vs. 31.8%, P < 0.001) than chemotherapy alone. For patients aged 61 to 69 years, chemotherapy plus rituximab resulted in a higher 5-year OS rate (66.7% vs. 46.4%, P = 0.002) and PFS rate (60.0% vs. 38.1%, P = 0.002) than chemotherapy alone. For patients aged ≥70 years, there was a marked survival advantage in patients who received chemotherapy plus rituximab (5-year OS rate: 57.7% vs. 25.4%, P < 0.001; 5-year PFS rate: 51.3% vs. 23.9%, P < 0.001) compared with that seen in those who received chemotherapy alone. Multivariate analysis established that stage III/IV disease, elevated lactate dehydrogenase (LDH), initial treatment, and chemotherapy with rituximab were independent risk factors for 5-year OS, and stage III/IV disease, elevated LDH, and chemotherapy with rituximab were independent risk factors for 5-year PFS for elderly patients with DLBCL. CONCLUSIONS: In comparison to patients aged 61 to 69 years, those aged ≥70 years have poorer survival. Prolonged survival is obtainable with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-like in elderly Chinese patients in all age groups, indicating that the R-CHOP-like regimen should be considered for this population, even for those aged 70 years or older.


Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , L-Lactato Desidrogenase/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Estudos Retrospectivos , Rituximab/uso terapêutico , Vincristina/uso terapêutico
8.
Hematol Oncol ; 37(4): 360-367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359442

RESUMO

De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is increasingly recognized as a distinct pathologic phenomenon with a specific clinical picture. However, CD5+ DLBCL has not been studied on a large scale in China. In this study, we show that CD5+ DLBCL occurs at a low frequency (9.2%). Comparison of clinical characteristics of CD5+ vs CD5- DLBCL showed that CD5+ DLBCL was more frequently elderly (>60 years) and had B symptoms, high-performance status, stage III-IV, an IPI score >2 and bone marrow involvement. Patients with CD5+ DLBCL had tumours with a higher prevalence of BCL-2 and p53 overexpression than CD5- DLBCL. Patients with CD5+ DLBCL had inferior progression-free survival (PFS) and overall survival (OS) than did patients with CD5- DLBCL. For CD5+ DLBCL, the patients who were treated with rituximab showed significantly better PFS and OS than those treated without rituximab. However, patients treated with RCHOP showed similar PFS and OS when compared with the group treated with intensive therapy. In addition, patients with p53 and CD5 co-expression had the worst PFS and OS. In conclusion, CD5+ DLBCL was associated with unfavorable clinicopathologic variables and with inferior survival. CD5+ DLBCL has a high frequency of p53 overexpression, and CD5 augments the negative effect of p53 overexpression in DLBCL.


Assuntos
Antígenos CD5/análise , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Prednisona/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Fatores de Risco , Rituximab/administração & dosagem , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Vincristina/administração & dosagem , Adulto Jovem
9.
Int J Hematol ; 110(3): 340-346, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31187439

RESUMO

We analyzed the clinicopathologic characteristics of 136 intestinal diffuse large B-cell lymphomas (DLBCLs) among 126 patients. The DLBCL sites were categorized as: duodenum (n = 23), ileocecal region (n = 63), other small intestine (n = 29), rectum (n = 7), and other large intestine (n = 14). Patients with DLBCLs of the ileocecal region or other small intestine frequently underwent surgery for ileus or perforations (P < 0.001), were predominantly male (P = 0.042), and had a higher incidence of limited-stage disease (P = 0.001), lower International Prognostic Index (P = 0.015), and lower incidence of lactate dehydrogenase elevation (P = 0.007) than those with DLBCLs of other regions. Half of the intestinal DLBCLs exhibited the germinal center B-cell phenotype. A low-grade B-cell lymphoma background was found in 21% of the cases; the prevalence was significantly lower in the ileocecal region (13%, P = 0.025), suggesting a higher incidence of de novo DLBCLs. Intestinal follicular lymphoma (FL) and mucosa-associated lymphoid tissue (MALT) lymphoma backgrounds were observed in 10% and 0% of the cases, respectively. Five percent (5/107) of intestinal DLBCL cases were Epstein-Barr virus-encoded RNA-1 positive. The clinicopathologic characteristics of the DLBCLs differed by region. Histologic transformation of intestinal FL was observed in around 10% of the intestinal DLBCL cases.


Assuntos
Neoplasias Intestinais , Linfoma Difuso de Grandes Células B , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Intestinos/patologia , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade
10.
Eur J Med Chem ; 178: 767-781, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31234030

RESUMO

By the analysis of different binding modes with Bruton's tyrosine kinase (BTK), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC50 = 1.36-8.60 µM) and Raji cell (IC50 = 1.20-14.04 µM) as compared with ibrutinib (IC50 = 14.69 and 15.99 µM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant BTK with IC50 value of 0.061 µM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited BTK Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of BTK inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
11.
Diagn Pathol ; 14(1): 56, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189479

RESUMO

OBJECTIVES: Standard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL). METHODS: We conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017. RESULTS: There were 43 patients with a median age of 65 years (range 34-89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p = 0.036) or WBRT (75% versus 44%, p = 0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 (p = 0.001), multiple brain lesions (p = 0.010), multiple area of brain involvement (p = 0.023), MTD < 5 cm (p = 0.004), GCB subtype (p = 0.003) and positive CD10 staining (p = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients. DISCUSSION: The factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients' status and treatment regimen.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada/métodos , Feminino , Centro Germinativo/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Resultado do Tratamento
12.
Bull Exp Biol Med ; 167(1): 150-153, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31183651

RESUMO

In diffuse large B-cell lymphoma, bone marrow involvement is rarely diagnosed. We compared the properties of bone marrow stromal progenitor cells and the concentration of fibroblast CFU in patients with diffuse large B-cell lymphoma without bone marrow involvement and in healthy donors. It was found that the properties of multipotent mesenchymal stromal cells in patients in the debut of the disease differed considerably from those in healthy donors. In particular, the total cell production in patients was significantly higher than in donors. In multipotent mesenchymal stromal cells of patients, some cell parameters were changes; the mean fluorescence intensity of the adhesion molecule ICAM1 on the cell surface was increased. The mean fluorescence intensity of mesenchymal stromal cell markers (HLA-ABC, CD73 and CD90) was significantly elevated. The relative expression of BMP4, MMP2, FGFR1, and ICAM1 genes in mesenchymal stromal cell was reduced, while the expression of FGFR2 gene was enhanced. Despite the absence of proven involvement of the bone marrow, the properties of mesenchymal stromal cells, the components in the stromal microenvironment niche regulating hemopoiesis are altered in patients with diffuse large B-cell lymphoma.


Assuntos
Células da Medula Óssea/patologia , Linfoma Difuso de Grandes Células B/patologia , Células-Tronco Mesenquimais/patologia , Adulto , Idoso , Células da Medula Óssea/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
14.
PLoS One ; 14(5): e0216898, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141539

RESUMO

NKL homeobox genes encode developmental transcription factors regulating basic processes in cell differentiation. According to their physiological expression pattern in early hematopoiesis and lymphopoiesis, particular members of this homeobox gene subclass constitute an NKL-code. B-cell specific NKL-code genes generate a regulatory network and their deregulation is implicated in B-cell lymphomagenesis. Epstein-Barr virus (EBV) infects B-cells and influences the activity of signalling pathways including JAK/STAT and several genes encoding developmental regulators. Therefore, EBV-infection impacts the pathogenesis and the outcome of B-cell malignancies including Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Here, we isolated EBV-positive and EBV-negative subclones from the DLBCL derived cell line DOHH-2. These subclones served as models to investigate the role of EBV in deregulation of the B-cell specific NKL-code members HHEX, HLX, MSX1 and NKX6-3. We showed that the EBV-encoded factors LMP1 and LMP2A activated the expression of HLX via STAT3. HLX in turn repressed NKX6-3, SPIB and IL4R which normally mediate plasma cell differentiation. In addition, HLX repressed the pro-apoptotic factor BCL2L11/BIM and hence supported cell survival. Thus, EBV aberrantly activated HLX in DLBCL, thereby disturbing both B-cell differentiation and apoptosis. The results of our study appreciate the pathogenic role of EBV in NKL homeobox gene deregulation and B-cell malignancies.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/metabolismo , Proteínas de Homeodomínio/biossíntese , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , Fatores de Transcrição/biossíntese , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Infecções por Vírus Epstein-Barr/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologia , Proteínas da Matriz Viral/metabolismo
16.
Ann Diagn Pathol ; 40: 72-76, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31075666

RESUMO

Primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma (CHL) are the most common large cell lymphomas arising in the mediastinum and are thought to be closely related histogenetically. Although the distinction between PMBL and CHL is usually straightforward, in some cases it is challenging and rarely these neoplasms have intermediate features and qualify for the diagnosis of mediastinal gray zone lymphoma (GZL). CD83 and fascin are markers of CHL and CD23 is a marker of PMBL. In this study we assess the utility of this combination of these immunohistochemical markers to distinguish CHL from PMBL. We retrospectively collected cases of PMBL, CHL and GZL from three centers. Tissue sections were stained with CD83, fascin and CD23. CD83 was expressed in the neoplastic cells of 100% of CHL (22/22), 93% of GZL (16/18) and 41% of PMBL (9/22). Similarly, fascin was positive in the neoplastic cells of 100% of CHL (22/22), 86% of GZL (18/21) and 32% of PMBL (7/22). CD23 was positive in 95% of PMBL (21/22), 67% of GZL (12/18) and 9% of CHL (2/22). CD83 and fascin are sensitive markers for CHL but not specific whereas CD23 is sensitive for PMBL and uncommon in CHL. The GZL cases in this study had an intermediate immunophenotype, but the results were closer to CHL than PMBL. A large panel of immunohistochemical studies is recommended to distinguish CHL from PMBL entities and we suggest that CD83, fascin and CD23 add value to panels designed for this differential diagnosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/diagnóstico , Antígenos CD/metabolismo , Proteínas de Transporte/metabolismo , Diagnóstico Diferencial , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Imunoglobulinas/metabolismo , Imuno-Histoquímica , Imunofenotipagem , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Receptores de IgE/metabolismo , Estudos Retrospectivos
18.
Med Sci Monit ; 25: 3860-3868, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31124542

RESUMO

BACKGROUND Patients with type 2 diabetes mellitus have been reported to be at increased risk of developing non-Hodgkin's lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade NHL. This study aimed to investigate the effects of high glucose on cell migration, invasion and epithelial-mesenchymal transition (EMT), and the expression of high mobility group AT-hook 2 (HMGA2) in A20 murine DLBCL cells. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to analyze the expression of HMGA2 at the gene and protein level and EMT markers in the A20 murine DLBCL cell line. A transwell assay evaluated cell migration and invasion of A20 cells. Short-interfering RNA (siRNA) was used to knockdown HMGA2 expression. RESULTS High glucose levels upregulated the expression of HMGA2, induced phenotypic changes of EMT, and increased cell migration and invasion in A20 cells. Knockdown of HMGA2 by siRNA effectively inhibited EMT induced by high glucose in A20 cells by directly regulating the Wnt/ß-catenin signaling pathway. CONCLUSIONS In the A20 murine DLBCL cell line, high glucose upregulated the expression of HMGA2 to induce EMT and promote cell migration and invasion through the Wnt/ß-catenin signaling pathway.


Assuntos
Glucose/metabolismo , Proteína HMGA2/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Tipo 2/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Linfoma não Hodgkin/metabolismo , Camundongos , MicroRNAs/genética , Invasividade Neoplásica/genética , RNA Interferente Pequeno/genética , Via de Sinalização Wnt
19.
BMC Cancer ; 19(1): 514, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142285

RESUMO

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare lesion characterized by sheets of crystal-laden non-neoplastic histiocytes. CSH shows a prominent association with lymphoproliferative disorders that express monoclonal immunoglobulins, mainly multiple myeloma (MM), lymphoplasmacytic lymphoma (LPL) and monoclonal gammopathy of undetermined significance (MGUS). However, no aggressive B cell lymphoma has been reported to be associated with CSH. CASE PRESENTATION: A 74-year-old Chinese woman presented with multiple subcutaneous masses, abdominal pain, and fever. An IgM kappa type of monoclonal gammopathy (MG) was noted by immunofixation performed on the patient's serum. Computed tomographic (CT) scan revealed subcutaneous masses on the left upper arm and at the waist and multiple low-density lesions in the spleen. Microscopically, sections of subcutaneous masses revealed sheets of large polygonal and spindle cells with abundant eosinophilic cytoplasm, round to ovoid eccentric nuclei, reticulate chromatin, and median nucleoli. Massive needle-shaped crystals were confined to the cytoplasm. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1, CD163, IgM, and Igκ. Meanwhile, the splenic tumour was diagnosed as diffuse large B-cell lymphoma (DLBCL), non-germinal-centre B (non-GCB) subtype (Hans algorithm). Immunohistochemistry for IgM was positive in the cytoplasm of some neoplastic cells. Immunoglobulin heavy chain (IgH) gene rearrangement was detected by PCR analysis of the subcutaneous mass and the splenic tumour. CONCLUSION: To the best of our knowledge, this is the first case of generalized CSH with DLBCL and MG. Although the rarity of CSH and separate locations of CSH and lymphoma led to a diagnostic dilemma, the presence of MG was a clue to appreciate the relation between CSH and DLBCL. This case stressed a full investigation into the underlying lymphoproliferative disorder for integrated diagnosis and correct treatments.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Paraproteinemias/diagnóstico por imagem , Idoso , Feminino , Rearranjo Gênico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Paraproteinemias/genética , Paraproteinemias/metabolismo , Tomografia Computadorizada por Raios X
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