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1.
Ann Hematol ; 99(2): 381-383, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31768673
3.
Blood ; 134(25): 2261-2270, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856276

RESUMO

Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphomas (DLBCLs) express high levels of programmed death ligand 1 (PD-L1) and PD-L2. MicroRNA (miR) regulation is an important mechanism for the fine-tuning of gene expression via 3'-untranslated region (3'UTR) targeting, and we have previously demonstrated strong EBV miR expression in EBV+ DLBCL. Whereas the EBV latent membrane protein-1 (LMP1) is known to induce PD-L1/L2, a potential counterregulatory role of EBV miR in the fine-tuning of PD-L1/L2 expression remains to be established. To examine this, a novel in vitro model of EBV+ DLBCL was developed, using the viral strain EBV WIL, which unlike common laboratory strains retains intact noncoding regions where several EBV miRs reside. This enabled interrogation of the relationship among EBV latency genes, cell of origin (COO), PD-L1, PD-L2, and EBV miRs. The model successfully recapitulated the full spectrum of B-cell differentiation, with 4 discrete COO phases: early and late germinal center B cells (GCBs) and early and late activated B cells (ABCs). Interestingly, PD-L1/L2 levels increased markedly during transition from late GCB to early ABC phase, after LMP1 upregulation. EBV miR-BamHI fragment H rightward open reading frame 1 (BHRF1)-2-5p clustered apart from other EBV miRs, rising during late GCB phase. Bioinformatic prediction, together with functional validation, confirmed EBV miR-BHRF1-2-5p bound to PD-L1 and PD-L2 3'UTRs to reduce PD-L1/L2 surface protein expression. Results indicate a novel mechanism by which EBV miR-BHRF1-2-5p plays a context-dependent counterregulatory role to fine-tune the expression of the LMP1-driven amplification of these inhibitory checkpoint ligands. Further identification of immune checkpoint-targeting miRs may enable potential novel RNA-based therapies to emerge.


Assuntos
Antígeno B7-H1/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , RNA Viral/metabolismo , Antígeno B7-H1/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/genética , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , RNA Viral/genética
4.
Cancer Biomark ; 25(3): 259-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282408

RESUMO

BACKGROUND: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. METHODS: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. RESULTS: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). CONCLUSIONS: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.


Assuntos
Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/genética , Linfoma/genética , Neuropilina-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Imuno-Histoquímica , Linfoma/classificação , Linfoma/patologia , Linfoma/virologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
5.
Pathol Int ; 69(7): 407-413, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215109

RESUMO

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed-Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS-like cells and numerous macrophages. The HRS-like cells were infected with Epstein-Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B-cell markers other than PAX5 were negative, and the HRS-like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified and EBV-positive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV-positive large B-cell neoplasms with reactive inflammatory cells and sometimes contains HRS-like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV-positive large B-cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.


Assuntos
Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Idoso , Linfócitos B/patologia , Linfócitos B/virologia , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/patologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/virologia , Humanos , Imunofenotipagem/métodos , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Células de Reed-Sternberg/patologia , Células de Reed-Sternberg/virologia
6.
Int J Med Sci ; 16(4): 556-566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171907

RESUMO

Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígenos CD5/genética , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Rearranjo Gênico/genética , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Malásia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Serpinas/genética , Resultado do Tratamento , Adulto Jovem
7.
Int J Cancer ; 145(11): 3078-3088, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044434

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is up to 17-fold more likely to occur, follows a more aggressive clinical course and frequently presents at advanced stages in HIV infected (+) individuals compared to HIV negative (-) individuals. However, the molecular pathology underpinning the clinical features of DLBCL in HIV(+) patients relative to the general population is poorly understood. We performed a retrospective study examining the transcriptional, genomic and protein expression differences between HIV(+) and HIV(-) germinal center B-cell (GCB) DLBCL cases using digital gene expression analysis, array comparative genomic hybridization (CGH) and immunohistochemistry (IHC). Genes associated with cell cycle progression (CCNA2, CCNB1, CDC25A, E2F1), DNA replication (MCM2, MCM4, MCM7) and DNA damage repair, including eight Fanconi anemia genes (FANCA, FANCD1/BRCA2, FANCE, FANCG, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCV/MAD2L2), were significantly increased in HIV(+) GCB-DLBCL tumors compared to HIV(-) tumors. In contrast, genes associated with cell cycle inhibition (CDKN1A, CDKN1B) as well as apoptosis regulating BCL2 family members (BCL2, BAX, BIM, BMF, PUMA) were significantly decreased in the HIV(+) cohort. BCL2 IHC confirmed this expression. Array CGH data revealed that HIV(+) GCB-DLBCL tumors have fewer copy number variations than their HIV(-) counterparts, indicating enhanced genomic stability. Together, the results show that HIV(+) GCB-DLBCL is a distinct molecular malignancy from HIV(-) GCB-DLBCL; with an increased proliferative capacity, confirmed by Ki67 IHC staining, and enhanced genomic stability, the latter of which is likely related to the enhanced expression of DNA repair genes.


Assuntos
Reparo do DNA , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica , Infecções por HIV/genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Hibridização Genômica Comparativa , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
J Craniofac Surg ; 30(3): e259-e262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048622

RESUMO

Lymphomas of the oral cavity are rare and the most frequent type is diffuse large B-cell lymphoma (DLBCL). Epstein-Barr virus (EBV) is known to be associated with the development of different lymphomas. In 2008, the World Health Organization provisionally included the EBV-positive DLBCL of the elderly in the classification of hematopoietic and lymphoid tumors as a lymphoma occurring in older individuals without any known immunodeficiency. However, it has since been recognized that this entity may occur in younger individuals and present similar clinical parameters in both age groups. As a result, the 2017 revision has declined the term elderly and modified it to EBV-positive DLBCL, not otherwise specified (NOS). In this report, we describe a rare case of EBV-positive DLBCL, NOS, presenting as a painless swelling in the oral cavity. This entity shows a more aggressive clinical course than EBV-negative DLBCL, and other lymphoproliferative disorders should be considered in the differential diagnosis.


Assuntos
Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/virologia , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/virologia , Infecções por Vírus Epstein-Barr , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação
11.
Clin J Gastroenterol ; 12(4): 330-335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903514

RESUMO

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.


Assuntos
Doença de Crohn/tratamento farmacológico , Infecções por Vírus Epstein-Barr/complicações , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/virologia , Adulto , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Colonoscopia , Doença de Crohn/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Evolução Fatal , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Tomografia Computadorizada por Raios X , Úlcera/imunologia , Úlcera/virologia
12.
Cancer Res Treat ; 51(4): 1666-1670, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30913860

RESUMO

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), specifically arising in ileal neobladder, is a rare neoplasm. We present an unusual case of Epstein- Barr virus (EBV)-positive DLBCL-CI arising within neobladder with detailed clinical, histological, and immunophenotypical features in an immunocompetent patient. An 88-year-old male was admitted for gross hematuria. He had undergone radical cystectomy and ileal neobladder 17 years ago for invasive bladder cancer. Computed tomography showed enhancing lesions on dome and posterior wall of neobladder with mucosal thickening and multiple enlarged retroperitoneal lymphadenopathies. Transurethralresection of neobladder lesion revealed the diffuse infiltration of large lymphoid cells which were positive for CD20, CD30, and multiple myeloma oncogen-1 with EBV-encoded small RNAs co-localizing, and diagnosis of EBV-positive DLBCL-CI was made. After multi-agent chemotherapy, the lesion disappeared. We suggest that clinicians should consider the possibility of DLBCL-CI in patients presented with hematuria during follow-up after bladder reconstruction.


Assuntos
Infecções por Vírus Epstein-Barr/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Bexiga Urinária/diagnóstico por imagem , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Herpesvirus Humano 4 , Humanos , Linfoma Difuso de Grandes Células B/virologia , Masculino , Prednisona , Rituximab , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Vincristina
13.
Rinsho Ketsueki ; 60(2): 124-129, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30842379

RESUMO

A 63-year-old woman was admitted to our hospital to receive a fourth course of modified rituximab-ESHAP chemotherapy for relapsed primary breast diffuse large B-cell lymphoma. She developed hemophagocytic lymphohistiocytosis (HLH) 20 days after admission. Polymerase chain reaction (PCR) detected cytomegalovirus (CMV) DNA in her peripheral blood; therefore, she was diagnosed with CMV-associated HLH and consequently treated with foscarnet (FCN). Her general condition and pancytopenia soon improved, and the antiviral drug was stopped for 1 week. However, she suddenly became disoriented 10 days later, and this condition rapidly worsened. Cerebrospinal fluid (CSF) examination revealed an elevated white blood cell count with lymphocytic predominance and a high CMV DNA load, prompting a final diagnosis of CMV meningoencephalitis. We began intravenous combination therapy with FCN and ganciclovir (GCV), and her conscious state gradually improved. CMV DNA sequencing did not reveal drug resistance associated with mutations, and intravenous GCV was stopped for 1 week. FCN treatment was then continued until CMV DNA was no longer detected in her CSF samples via PCR. CMV meningoencephalitis is a rare neurological infection complicated with hematological malignancy in non-transplant patients and can be serious and life-threatening with a high mortality rate. This infection requires a differential diagnosis of consciousness impairment that develops in a patient with lymphoid malignancy during chemotherapy.


Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/diagnóstico , Linfoma Difuso de Grandes Células B/virologia , Meningoencefalite/virologia , Adulto , Criança , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , DNA Viral/sangue , Feminino , Foscarnet , Ganciclovir , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Terapia de Salvação
14.
Ann Hematol ; 98(5): 1197-1207, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30729289

RESUMO

The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.


Assuntos
Transformação Celular Viral , Hepacivirus/metabolismo , Hepatite C , Linfoma Difuso de Grandes Células B , RNA Viral/metabolismo , Neoplasias Esplênicas , Proteínas não Estruturais Virais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite C/metabolismo , Hepatite C/patologia , Humanos , Hibridização In Situ , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Esplênicas/metabolismo , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/virologia
15.
Blood ; 133(16): 1753-1761, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30782610

RESUMO

Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent, and ∼80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, virologic, and immunologic features vs 20 patients with HIV-associated diffuse large B-cell lymphoma and 19 patients with symptomatic interleukin (IL)-6 related KSHV-associated multicentric Castleman disease. Survival analyses of treated patients with PEL were then performed to identify prognostic factors and cancer-specific mortality. Compared with HIV-associated diffuse large B-cell lymphoma, PEL was associated with significant hypoalbuminemia (P < .0027), thrombocytopenia (P = .0045), and elevated IL-10 levels (P < .0001). There were no significant differences in these parameters between PEL and KSHV-associated multicentric Castleman disease. Median overall survival in treated patients with PEL was 22 months, with a plateau in survival noted after 2 years. Three-year cancer-specific survival was 47%. EBV-positive tumor status was associated with improved survival (hazard ratio, 0.27; P = .038), and elevated IL-6 level was associated with inferior survival (hazard ratio, 6.1; P = .024). Our analysis shows that IL-6 and IL-10 levels contribute to the natural history of PEL. Inflammatory cytokines and tumor EBV status are the strongest prognostic factors. Pathogenesis-directed first-line regimens are needed to improve overall survival in PEL.


Assuntos
Hiperplasia do Linfonodo Gigante/virologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Efusão Primária/patologia , Sarcoma de Kaposi/virologia , Adulto , Idoso , Citocinas/sangue , Citocinas/imunologia , Feminino , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Linfoma de Efusão Primária/complicações , Linfoma de Efusão Primária/imunologia , Linfoma de Efusão Primária/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma de Kaposi/patologia , Análise de Sobrevida , Adulto Jovem
16.
Leukemia ; 33(7): 1687-1699, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30683910

RESUMO

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/complicações , Variação Genética , Linfoma Extranodal de Células T-NK/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma de Células T Periférico/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/isolamento & purificação , Humanos , Ligantes , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/virologia
17.
Leukemia ; 33(1): 132-147, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29946193

RESUMO

Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/imunologia , Linfoma Difuso de Grandes Células B/imunologia , MicroRNAs/genética , Proteínas Virais/metabolismo , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/virologia , Prognóstico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Células Tumorais Cultivadas , Proteínas Virais/genética
18.
Int J Surg Pathol ; 27(1): 98-101, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29968492

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is characterized by medium- to large-sized neoplastic cells that express a wide range of B-cell markers including CD19, CD20, CD22, and CD79a. Also, as this is a hematopoietic malignancy, there is expression of the leukocyte common antigen CD45. Lack of CD20 expression occurs in a specific rare heterogeneous subgroup of DLBCL including primary effusion lymphoma, plasmablastic lymphoma, ALK-positive large B-cell lymphoma, and large B-cell lymphoma arising in HHV8+ multicentric Castleman disease. In this article, we report a rare case of CD20- and CD45-negative Epstein-Barr virus-positive DLBCL in which the entities listed above were ruled out, thereby posing a significant diagnostic challenge. Arriving at the correct diagnosis of Epstein-Barr virus-positive DLBCL was supported by immunoreactivity for the B-cell transcription factor Oct-2 and the pan-B cell marker CD79a.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Difuso de Grandes Células B/diagnóstico , Adulto , Antígenos CD20/análise , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Humanos , Antígenos Comuns de Leucócito/análise , Linfoma Difuso de Grandes Células B/virologia , Masculino
20.
Int J Hematol ; 109(1): 125-129, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30293217

RESUMO

Bone marrow necrosis (BMN) is a condition that can be difficult to diagnose, requiring a hematologist experienced in bone marrow morphology. This diagnostic challenge should alert the clinician of a severe disease or a possible underlying malignancy, either hematological or a solid tumor. We describe the concomitant presence of a primary bone marrow lymphoma (diffuse large B-cell lymphoma-DLBCL), along with an extensive BMN in an HIV patient for the first time in a living individual. HIV infection, BMN and DLBCL presented a multifactorial crossword of molecular events underlying the complex pathophysiology. The exact precipitating pathophysiological events resulting in BMN remain obscure and provide their clear impact for future research. The present report is instructive and also contains a critical review of the literature related to the case presented.


Assuntos
Doenças da Medula Óssea/patologia , Neoplasias da Medula Óssea/virologia , Medula Óssea/patologia , HIV , Necrose , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/virologia , Neoplasias da Medula Óssea/diagnóstico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/virologia , Prognóstico
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