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1.
Br J Haematol ; 201(2): 256-266, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36740991

RESUMO

Low baseline NK-cell counts (NKCCs) in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab-chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/µl were associated with shorter PFS and OS (HRs = [2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p = 0.0025), but not of death without progression (p = 0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p  = 0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab-chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK-cell function could improve outcomes in DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Recidiva Local de Neoplasia , Idoso , Humanos , Contagem de Células , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Rituximab/uso terapêutico
2.
Blood ; 137(17): 2307-2320, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33211799

RESUMO

Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2-/PET4-) received immunochemotherapy. Responders after only cycle 4 (PET2+/4-) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2-/4- and PET2+/4- had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Humanizados , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
3.
Blood ; 135(16): 1396-1405, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-31978225

RESUMO

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell-like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Carga Tumoral/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
4.
Blood ; 126(14): 1695-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26239089

RESUMO

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas , Recidiva
5.
Blood ; 126(5): 604-11, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26022239

RESUMO

We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI-adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222.


Assuntos
Citarabina/administração & dosagem , Deleção de Genes , Genes p16 , Genes p53 , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Adulto , Idoso , Protocolos Antineoplásicos , Autoenxertos , Feminino , Dosagem de Genes , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Blood ; 126(22): 2466-74, 2015 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26373676

RESUMO

Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Rearranjo Gênico , Imunoglobulinas , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagem
7.
Blood ; 125(12): 1922-31, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25612624

RESUMO

Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.


Assuntos
Metilação de DNA , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Transformação Celular Neoplásica , Análise por Conglomerados , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Fator 4 Semelhante a Kruppel , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/mortalidade , Resultado do Tratamento
9.
Biol Blood Marrow Transplant ; 20(12): 1905-11, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25072780

RESUMO

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y(90)) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y(90) ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/µL and platelet count of >20,000/µL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y(90) ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y(90) ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia de Consolidação , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Autoenxertos , Carmustina/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Podofilotoxina/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Rituximab , Taxa de Sobrevida
10.
Eur J Immunol ; 43(5): 1383-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23400905

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in adults. It is generally treated by a combination of chemotherapy and CD20-specific mAbs, such as rituximab, which act, at least partially, by activating antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves NK cells, particularly the CD56(dim) NK-cell subset expressing CD16, the low affinity Fcγ receptor. Here, we show that CD16 expression levels are decreased in a cohort of 36 newly diagnosed DLBCL patients compared with those in 20 healthy controls (HCs). CD137, a co-stimulatory molecule expressed on activated NK cells, was also expressed at lower levels in patients compared with controls. Cells sampled from our cohort also showed severely reduced degranulation activity when challenged with rituximab-coated tumor cells, which could not be corrected by stimulation with high doses of IL-2. These results suggest that rituximab-induced NK-cell ADCC could be defective in some DLBCL patients at diagnosis. These patients should be closely monitored and attempts made to improve their NK-cell function.


Assuntos
Anticorpos Monoclonais Murinos/farmacologia , Antineoplásicos/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/patologia , Adulto , Estudos de Casos e Controles , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Células Cultivadas , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Expressão Gênica , Humanos , Imunidade Celular/efeitos dos fármacos , Imunofenotipagem , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Rituximab , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
11.
Blood ; 119(20): 4619-24, 2012 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-22408263

RESUMO

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC(+)). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC(+) rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC(-) DLBCL patients, the MYC(+) DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC(+) DLBCL patients than those in the MYC(-) DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC(+) DLBCL patients have a significant inferior prognosis than MYC(-) DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Genes myc/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Imunoterapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Rituximab , Terapia de Salvação , Transplante Autólogo , Falha de Tratamento , Adulto Jovem
12.
Blood ; 119(24): 5795-806, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22510872

RESUMO

The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αß) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/genética , Terapia de Alvo Molecular , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/genética , Adulto , Idoso , Sequência de Bases , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem da Célula/genética , Aberrações Cromossômicas , Análise por Conglomerados , Cristalinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isocromossomos/genética , Neoplasias Hepáticas/patologia , Linfoma de Células T/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Neoplasias Esplênicas/patologia , Quinase Syk , Adulto Jovem
13.
Eur J Nucl Med Mol Imaging ; 41(11): 2023-30, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24965842

RESUMO

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare Hodgkin lymphoma distinguished from classical Hodgkin lymphoma (cHL) by the nature of the neoplastic cells which express B-cell markers. We wanted to determine the diagnostic performance of FDG PET/CT in initial assessment and its therapeutic impact on staging. METHODS: We retrospectively studied a population of 35 patients with NLPHL (8 previously treated for NLHPL, 27 untreated). All patients underwent an initial staging by pretherapeutic FDG PET/CT. The impact on initial stage or relapse stage was assessed by an independent physician. RESULTS: In a per-patient analysis, the sensitivity of the pretherapeutic FDG PET/CT was 100%. In a per-site analysis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of pretherapeutic FDG PET/CT were 100%, 99%, 97%, 100% and 99%, respectively. Pretherapeutic FDG PET/CT led to a change in the initial stage/relapse stage in 12 of the 35 patients (34%). In contrast to previous results established without FDG PET/CT, 20% of patient had osteomedullary lesions. CONCLUSION: Pretherapeutic FDG PET/CT has excellent performance for initial staging or relapse staging of NLPHL.


Assuntos
Fluordesoxiglucose F18 , Doença de Hodgkin/diagnóstico por imagem , Linfócitos/patologia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Doença de Hodgkin/patologia , Humanos , Linfócitos/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Adulto Jovem
14.
Br J Haematol ; 161(6): 843-51, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23593987

RESUMO

Most cases of human immunodeficiency virus (HIV)-associated non-Hodgkin Lymphoma (NHL) are of B-cell origin; T-cell NHLs are rarely reported. Within a single centre prospective cohort of 370 HIV-NHL, 17 (5%) were of T-cell origin (82% male; median age, 39 years). Median CD4+ cell count was 0·194 × 10(9) /l and 41% had undetectable plasma HIV-RNA at lymphoma diagnosis. All patients received combination antiretroviral therapy during chemotherapy. All histological samples were centrally reviewed. The distribution of the histological subtypes differed from the general population with absence of angioimmunoblastic subtype. Lymphoma was disseminated in 14 patients, and seven patients had performance status >2. All patients received full-dose chemotherapy: eight standard and nine intensive regimens. Two patients who received intensive chemotherapy died during therapy. The complete remission rate was 53%; 62·5% with standard therapy and 44% with intensive therapy. After a median follow-up of 7·2 years, the median overall survival was 9·4 months. Most deaths (85%) occurred within the first year following diagnosis, as a consequence of lymphoma progression in 10/13 cases. In this rare but severe complication of HIV infection the use of intensive chemotherapy does not appear to be beneficial for response, with increased toxicity.


Assuntos
Infecções por HIV/complicações , Linfoma Relacionado a AIDS/diagnóstico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/etiologia , Adulto , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/mortalidade , Linfoma de Células B/diagnóstico , Linfoma de Células B/etiologia , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
15.
Blood ; 118(1): 37-43, 2011 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-21518924

RESUMO

The prognostic value of interim positron emission tomography (PET) interpreted according to visual criteria is a matter of debate in diffuse large B-cell lymphoma (DLBCL). Maximal standardized uptake value reduction (ΔSUVmax) may better predict outcome. To compare the prognostic value of both methods, we analyzed PET done at baseline (PET0) and after 2 (PET2) and 4 (PET4) cycles in 85 patients with high-risk DLBCL enrolled on a prospective multicenter trial. All images were centrally reviewed and interpreted visually according to the International Harmonization Project criteria and by computing ΔSUVmax between PET0 and PET2 (ΔSUVmaxPET0-2) or PET4 (ΔSUVmaxPET0-4). Optimal cutoff to predict progression or death was 66% for ΔSUVmaxPET0-2 and 70% for ΔSUVmaxPET0-4. Outcomes did not differ significantly whether PET2 and PET4 were visually positive or negative. Inversely, ΔSUVmaxPET0-2 analysis (> 66% vs ≤ 66%) identified patients with significantly different 2-year progression-free survival (77% vs 57%; P = .0282) and overall survival (93% vs 60%; P < .0001). ΔSUVmaxPET0-4 analysis (> 70% vs ≤ 70%) seemed even more predictive for 2-year progression-free survival (83 vs 40%; P < .0001) and overall survival (94% vs 50%; P < .0001). ΔSUVmax analysis of sequential interim PET is feasible for high-risk DLBCL and better predicts outcome than visual analysis. The trial was registered at http://clinicaltrials.gov as NCT00498043.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Bleomicina/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prednisona/uso terapêutico , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos , Rituximab , Vincristina/uso terapêutico , Vindesina/uso terapêutico
16.
Histopathology ; 62(6): 860-75, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23509938

RESUMO

AIMS: The aim of this study was to analyse the immunophenotypic and molecular features of a large series of follicular lymphomas, focusing in particular on atypical cases that fail to express CD10 and/or bcl-2. Such cases present diagnostic pitfalls, especially with regard to the differential diagnosis from follicular hyperplasia and marginal zone B-cell lymphoma. Therefore, we also included an immunohistochemical evaluation of stathmin, which is strongly expressed by germinal centre B cells, as a putative new marker for follicular lymphomas, particularly those with an atypical phenotype. METHODS AND RESULTS: Two hundred and five follicular lymphomas were investigated with immunohistochemistry and fluorescence in-situ hybridization (FISH). The use of three distinct anti-bcl-2 antibodies together with CD10 expression data and FISH analysis for bcl-2 and bcl-6 rearrangements allowed subclassification of follicular lymphoma into four distinct subgroups: (i) CD10-positive/bcl-2-positive, (ii) CD10-positive/bcl-2-negative, (iii) CD10-negative/bcl-2-positive, and (iv) CD10-negative/bcl-2-negative. All cases were bcl-6-positive. STMN1 (stathmin) was shown to be helpful in diagnosing bcl-2-negative and/or CD10-negative follicular lymphomas, and in their distinction from marginal zone B-cell lymphoma. CONCLUSIONS: Combined immunohistological and molecular analyses reveal that follicular lymphomas showing an atypical immunophenotypic and molecular profile exist, and we demonstrate that STMN1 represents a novel useful diagnostic marker for these.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Genes bcl-2 , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma Folicular/classificação , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-6 , Estatmina/metabolismo , Adulto Jovem
17.
Br J Haematol ; 158(5): 644-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22734472

RESUMO

The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Doença de Hodgkin/induzido quimicamente , Adulto , Idoso , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Resultado do Tratamento
18.
Mod Pathol ; 25(6): 805-14, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22322190

RESUMO

The angiogenic microenvironment has been known to be a component of angioimmunoblastic T-cell lymphoma since its initial characterization. We have shown that angioimmunoblastic T-cell lymphoma endothelial cells produce vascular endothelial growth factor-A (VEGFA), and participate in lymphoma progression. In squamous cell carcinoma, endothelial BCL2 expression induces a crosstalk with tumor cells through VEGFA, a major mediator of tumoral angiogenesis. In the present study, we analyzed BCL2 and VEGFA in 30 angioimmunoblastic T-cell lymphomas, using triple immunofluorescence to identify protein coexpression in well-characterized lymphoma cells and microenvironment neoangiogenic endothelial cells. Using quantitative real-time PCR, we assessed mRNA expression levels in laser-microdissected endothelial and lymphoma cells. In lymphoma cells, as in endothelial cells, BCL2 and VEGFA proteins were coexpressed. BCL2 was expressed only in neoangiogenic CD34(+)CD105(+) endothelial cells. In laser-microdissected cells, mRNA studies showed a significant relationship between BCL2 and VEGFA levels in CD34(+) endothelial cells, but not in CD3(+)CD10(+)lymphoma cells, or in CD34(+) endothelial cells from lymph node hyperplasia. Further study showed that, in AITL, BCL2 mRNA levels in CD34(+)CD105(+) neoangiogenic endothelial cells also correlated with microvessel density, International Prognostic Index, Ann Arbor stage, bone marrow involvement and elevated LDH. BCL2 expression by CD105(+) neoangiogenic endothelial cells is related to tumor progression in angioimmunoblastic T-cell lymphoma.


Assuntos
Antígenos CD/análise , Biomarcadores Tumorais/análise , Células Endoteliais/química , Linfadenopatia Imunoblástica/metabolismo , Linfonodos/química , Linfoma de Células T/química , Microvasos/química , Proteínas Proto-Oncogênicas c-bcl-2/análise , Receptores de Superfície Celular/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/análise , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Endoglina , Células Endoteliais/imunologia , Células Endoteliais/patologia , Feminino , Imunofluorescência , Humanos , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/imunologia , Linfadenopatia Imunoblástica/mortalidade , Linfadenopatia Imunoblástica/patologia , Linfadenopatia Imunoblástica/terapia , Estimativa de Kaplan-Meier , Microdissecção e Captura a Laser , Linfonodos/irrigação sanguínea , Linfonodos/imunologia , Linfonodos/patologia , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Linfoma de Células T/terapia , Masculino , Microvasos/imunologia , Microvasos/patologia , Pessoa de Meia-Idade , Análise Multivariada , Neovascularização Patológica , Paris , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética
19.
Blood ; 115(6): 1226-37, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19965620

RESUMO

Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Perfilação da Expressão Gênica , Células Matadoras Naturais/patologia , Linfoma Extranodal de Células T-NK/genética , Neoplasias Nasofaríngeas/genética , Oncogenes/fisiologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Proliferação de Células , Células Cultivadas , Hibridização Genômica Comparativa , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/fisiologia , Humanos , Técnicas Imunoenzimáticas , Células Matadoras Naturais/virologia , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/virologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Oncology (Williston Park) ; 26(2): 194-202, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22489356

RESUMO

Splenic marginal zone lymphoma (SMZL), along with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and nodal marginal zone lymphoma (NMZL), share a common origin from the "marginal zone." However, these three entities display different clinical characteristics, reflecting probable biological variations according to the organ and cellular origin. Within the past decade, new data have been reported regarding pathogenic mechanisms as well as therapeutic advances. Clinically, SMZL presents as an indolent and disseminated disease at diagnosis, with a specific clinical presentation that includes predominantly splenomegaly, and in half of patients, autoimmune manifestations. Establishing the diagnosis may be difficult, especially distinguishing SMZL from other low-grade lymphomas, such as small B-cell lymphomas; however, recent findings have contributed to a better characterization of the disease, and the criteria for diagnosis have been improved. Therapeutic approaches consist of splenectomy or immunochemotherapy, but there is no consensus regarding the best treatment, except when SMZL is associated with hepatitis C virus infection. In this article, we review the current knowledge on the biological findings, clinical features, and therapeutic approaches for SMZL.


Assuntos
Linfoma de Zona Marginal Tipo Células B/terapia , Neoplasias Esplênicas/terapia , Hepatite C/complicações , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/etiologia , Linfoma de Zona Marginal Tipo Células B/patologia , Mutação , Prognóstico , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/etiologia , Neoplasias Esplênicas/patologia
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