Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Br J Haematol ; 188(3): 413-423, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31468517

RESUMO

The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2+ vs. 88% for BCL2- , P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2+ vs. 88% for BCL2- , P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.

2.
EBioMedicine ; 48: 58-69, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31648986

RESUMO

BACKGROUND: Gene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes. METHODS: 223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed. FINDINGS: ICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes. INTERPRETATION: The results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups.

4.
Am J Surg Pathol ; 43(3): 341-351, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30540571

RESUMO

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease.


Assuntos
Linfoma/classificação , Linfoma/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Oncoimmunology ; 7(11): e1470735, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30377560

RESUMO

Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4- versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.

6.
Oncoimmunology ; 7(10): e1486950, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288350

RESUMO

Despite recent therapeutic progress, plasmablastic lymphoma (PBL), a distinct entity of high grade B cell lymphoma, is still an aggressive lymphoma with adverse prognosis. PBL commonly occurs in patients with HIV infection and PBL cells frequently express Epstein Barr virus (EBV) genome with type I latency. Occasionally however, PBL may develop in patients with an immunodepressed status without EBV and HIV infection. The aim of this study was to determine which PBL patients may benefit from the emerging strategies of immune checkpoint blockade. Here, we produced and analyzed the transcriptomic profiles of such tumors to address this question. Unsupervised hierarchical clustering analysis of PBL samples revealed they segregate according to their tumor EBV-status. Moreover, EBV+ PBL displays abundant leucocyte infiltrates and T-cell activation signatures, together with high expression levels of mRNA and protein markers of immune escape. This suggests that EBV infection induce an anti-viral cytotoxic immunity which progressively exhausts T lymphocytes and promotes the tolerogenic microenvironment of PBL. Hence, most EBV+ PBL patients presenting an early stage of cancer immune-editing process appear as the most eligible patients for immune checkpoint blockade therapies.

7.
Blood ; 132(14): 1486-1494, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30068505

RESUMO

Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade
8.
Br J Haematol ; 183(1): 68-75, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30043391

RESUMO

Lymphoma-associated haemophagocytic syndrome (LAHS) accounts for most cases of secondary haemophagocytic syndrome (HS) and has been extensively described in Asian populations. However, little is known about the epidemiology of LAHS in Western countries. We herein report a case series of 71 LAHS patients in which the lymphomas were mainly of the aggressive type. Diagnoses included non-Hodgkin B cell lymphoma (46·5%) including human herpes virus 8-associated non-Hodgkin lymphoma (12·7%), T cell lymphoma (28·2%) and Hodgkin lymphoma (23·9%). An underlying immunodeficiency was described in 30 patients (42·3%). Early mortality within the 30 days following HS diagnosis was observed in 26·8% of cases. The overall survival was estimated at 45·7% [95% confidence interval, CI (35·4-59·0)] at 6 months, and 34·3% [95% CI (24·8-47·4)] at 2 years. Concurrent infection, age over 50 years, ethnicity and etoposide treatment were independently associated with mortality. While it appears that certain types of lymphomas were more prone to trigger HS, LAHS were not restricted to a few types of lymphoma. The overall prognosis was poor, with a particularly high rate of early mortality, highlighting the importance of both early recognition and choice of initial therapeutic management.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Adulto , Idoso , Feminino , França , Doença de Hodgkin/diagnóstico , Humanos , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfoma de Células B/diagnóstico , Linfoma de Células T/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise de Sobrevida
10.
Dig Liver Dis ; 50(2): 124-131, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29301732

RESUMO

INTRODUCTION: This document is a summary of the French Intergroup guidelines on the management of gastro-intestinal lymphomas, available on the web-site of the French Society of Gastroenterology, SNFGE (www.tncd.org), updated in September 2017. METHODS: This collaborative work was realised under the auspices of several French medical societies and involved clinicians with specific expertise in the field of gastrointestinal lymphomas, including gastroenterologists, haematologists, pathologists, and radiation oncologist, representing the major French or European clinical trial groups. It summarises their consensus on the management of gastrointestinal lymphomas, based on the recent literature data, previous published guidelines and the expert opinions. RESULTS: The clinical management, and especially the therapeutic strategies of the gastro-intestinal lymphomas are specific to their histological subtypes and to their locations in the digestive tract, with the particularity of gastric MALT lymphomas which are the most frequent and usually related to gastritis induced by Helicobacter pylori. CONCLUSION: Lymphomas are much less common than epithelial tumours of gastro-intestinal digestive tract. Their different histological subtypes determine their management and prognosis. Each individual case should be discussed within the expert multidisciplinary team.


Assuntos
Linfoma de Células B/patologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Linfoma de Células T/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , França , Gastrite/complicações , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Humanos , Colaboração Intersetorial , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
J Clin Oncol ; 35(18): 2008-2017, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28459613

RESUMO

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.


Assuntos
Competência Clínica , Linfoma/diagnóstico , Linfoma/patologia , Patologia Clínica , França , Humanos , Linfoma/classificação , Linfoma/terapia , Gradação de Tumores , Estudos Prospectivos , Encaminhamento e Consulta
12.
Hum Pathol ; 64: 128-136, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28414090

RESUMO

Previous immunohistochemical (IHC) studies showed controversial data about the prognostic value of tumor-infiltrating lymphocytes (TILs) in follicular lymphoma (FL). To clarify this issue, a large series of FL samples from rituximab-treated patients enrolled in the randomized PRIMA trial was examined. IHC was quantified using automated image analysis in 417, 287, 418, 406, 379, and 369 patients for CD3, CD4, CD8, PD1, ICOS, and FOXP3, respectively. RNAseq analysis was used to quantify TIL-related mRNA transcripts from 148 patients. When each IHC marker was used as a continuous variable in the whole cohort, high CD3 counts were associated with better progression-free survival (PFS) (P = .025). When an optimal IHC cut point was applied to the whole patient population, high CD3 counts and high PD1 counts were associated with better PFS (P = .011 and P = .044, respectively), whereas none of the other TIL markers had any significant correlation with outcome. When a stringent analysis was performed by dividing the whole cohort into a training set and a validation set, none of the TIL markers showed a prognostic significance in both groups. RNAseq analysis showed a significant correlation between high levels of CD3 and CD8 transcripts and better PFS (P = .001 and P = .037, respectively). No prognostic correlation was found as to the level of other immune gene transcripts. These results suggest that the IHC prognostic value of TILs is circumvented by rituximab treatment, although there is a trend for high numbers of CD3+ TILs to correlate with better PFS.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Linfócitos T/efeitos dos fármacos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Complexo CD3/análise , Complexo CD3/genética , Intervalo Livre de Doença , Humanos , Interpretação de Imagem Assistida por Computador , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Valor Preditivo dos Testes , RNA Mensageiro/genética , Análise de Sequência de RNA , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Microambiente Tumoral
13.
Oncotarget ; 8(5): 8765-8774, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28060738

RESUMO

Recent advances in next-generation sequencing (NGS) have enabled the quantitation of circulating tumour DNA (ctDNA) encoding the clonal rearranged V(D)J immunoglobulin locus. We aimed to evaluate the clonal heterogeneity of follicular lymphoma (FL) in the tumour and the plasma at diagnosis and to assess the prognostic value of the ctDNA level. Plasma samples at diagnosis were available for 34 patients registered in the PRIMA trial (NCT00140582). One tumour clonotype or more could be detected for 29 (85%) and 25 (74%) patients, respectively, in the tumour or plasma samples. In 18 patients, several subclones were detected in the tumour (2 to 71 subclones/cases) and/or in the plasma (2 to 20 subclones/cases). In more than half of the cases, the distribution of subclones differed between the tumour and plasma samples, reflecting high clonal heterogeneity and diversity in lymphoma subclone dissemination. In multivariate analysis, a high level of ctDNA was the only independent factor associated with patients' progression-free survival (HR 4, IC 95 (1.1-37), p=.039). In conclusion, an NGS-based immunosequencing method reveals the marked clonal heterogeneity of follicular lymphoma in patients with FL, and quantification of ctDNA at diagnosis represents a potential powerful prognostic biomarker that needs to be investigated in larger cohorts.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Genes de Cadeia Pesada de Imunoglobulina/genética , Linfoma Folicular/genética , Recombinação V(D)J , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Distribuição de Qui-Quadrado , DNA Tumoral Circulante/sangue , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Folicular/sangue , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Haematologica ; 102(1): 150-159, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27758822

RESUMO

Mediastinal gray zone lymphoma, B-cell lymphomas with intermediate features between classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, have not been well described in the literature. We report the clinical characteristics and outcomes of a large retrospective series of 99 cases centrally reviewed by a panel of hematopathologists, with a consensus established for the diagnosis. Cases were defined as classical Hodgkin lymphoma-like morphology (64.6%) with primary mediastinal B-cell lymphoma immunophenotype, primary mediastinal B-cell lymphoma-like morphology (30.3%) with classical Hodgkin lymphoma or composite (5.1%) (synchronous occurrence of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma). The median age was 32 years (13-83 years); 55% were women. Thirteen of 81 evaluable cases (16%) were Epstein-Barr virus-positive. Twenty-eight percent of patients presented primary refractory disease (progression under first-line treatment or relapse within one year). The 3-year event-free and overall survival rates were 63% and 80%, respectively. Patients treated with a standard regimen (RCHOP/ABVD) had worse event-free survival (P=0.003) and overall survival (P=0.02) than those treated with a dose-intensive chemotherapy (high-dose RCHOP/escalated BEACOPP). Rituximab added to chemotherapy was not associated with better event-free survival (P=0.55) or overall survival (P=0.88). Radiotherapy for patients in complete remission had no impact on event-free survival. In multivariate prognostic analysis, ECOG-PS and anemia were the strongest factors associated with a shorter event-free survival and overall survival, respectively. In conclusion, this report describes the largest series of mediastinal gray zone lymphoma. Our data suggest that a dose-intensive treatment might improve the outcome of this rare and aggressive disease.


Assuntos
Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Medula Óssea/patologia , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Imunofenotipagem , Linfoma de Células B/terapia , Masculino , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
15.
Clin Cancer Res ; 23(9): 2232-2244, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27923841

RESUMO

Purpose:MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same MYD88 mutation. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort.Conclusions: This study highlights the relative heterogeneity of MYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. Clin Cancer Res; 23(9); 2232-44. ©2016 AACR.


Assuntos
Heterogeneidade Genética , Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA/genética , Feminino , Genoma Humano , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , NF-kappa B/genética , Transdução de Sinais/genética
16.
Clin Case Rep ; 4(12): 1088-1090, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27980738

RESUMO

In patients with atypical Crohn's disease features, including severe oral ulcerations and resistance to standard treatment, the possibility of a mature clonal CD8+ T-cell lymphoproliferative disorder should be investigated. Clinicians should be aware of this differential diagnosis because CD8+ T-cell lymphoma prognosis can be remarkably favorable upon oral treatment with cyclophosphamide.

17.
Blood ; 128(11): 1490-502, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27369867

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.


Assuntos
Genes Codificadores dos Receptores de Linfócitos T/genética , Linfadenopatia Imunoblástica/genética , Linfoma Folicular/genética , Linfoma de Células T Periférico/genética , Mutação/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Proteína rhoA de Ligação ao GTP/genética , Biomarcadores Tumorais/genética , Estudos de Coortes , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linfadenopatia Imunoblástica/imunologia , Linfadenopatia Imunoblástica/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologia , Estadiamento de Neoplasias , Prognóstico
18.
Haematologica ; 101(8): 976-84, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27175027

RESUMO

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease.


Assuntos
Biomarcadores Tumorais , Infecções por Vírus Epstein-Barr/complicações , Expressão Gênica , Herpesvirus Humano 4/genética , Imunomodulação/genética , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/etiologia , Adulto , Idoso , Biópsia , Terapia Combinada , Feminino , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfoma Plasmablástico/mortalidade , Linfoma Plasmablástico/terapia , Prognóstico , Translocação Genética , Resultado do Tratamento
19.
Clin Cancer Res ; 22(12): 2919-28, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-26819451

RESUMO

PURPOSE: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. EXPERIMENTAL DESIGN: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. RESULTS: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses. CONCLUSIONS: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/patologia , Proteínas de Ciclo Celular/genética , Ciclofosfamida/uso terapêutico , Proteínas de Ligação a DNA/genética , Doxorrubicina/uso terapêutico , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Carioferinas/genética , Proteínas Oncogênicas/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Prednisona/uso terapêutico , Estudos Prospectivos , Receptores Citoplasmáticos e Nucleares/genética , Rituximab , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Vincristina/uso terapêutico , Sequenciamento Completo do Exoma
20.
Radiother Oncol ; 117(1): 178-82, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26395311

RESUMO

BACKGROUND: In gastric MALT lymphomas persisting after Helicobacter pylori (H. pylori) eradication, a treatment by moderate-dose radiotherapy (RT) has been proposed but its efficacy has not been confirmed in large prospective series with long term endoscopic follow-up. METHOD: Patients with localised gastric MALT lymphoma persisting after H. pylori eradication were offered moderate-dose RT (30Gy, 2Gy/fraction) and followed with annual endoscopies. All biopsies before and after RT were reviewed by a committee of pathologists. RESULTS: From 1995 to 2011, out of the 232 patients followed prospectively, 53 received RT for persistence of lymphoma after H. pylori eradication: either macroscopic ulcer (n=31), or microscopic lymphomatous infiltrate (n=22), after a mean follow-up of 12 and 31months, respectively. All lymphomas were localised (45 stage IE and 8 stage IIE) and 38 (72%) were H. pylori-positive. The mean clinical and endoscopic follow-up from diagnosis was 7.6years (2.2-19.1). No acute or late toxicity occurred. A complete remission was achieved in all patients but one (98%) with no relapse after a median follow-up of 4.9years (1.3-16.6) after completion of RT. Overall survival and 5-year disease specific survival were 94% and 100%, respectively. One patient died of gastric adenocarcinoma. CONCLUSION: Moderate-dose RT (30Gy) is effective and safe for localised gastric MALT lymphoma persisting after H. pylori eradication.


Assuntos
Linfoma de Zona Marginal Tipo Células B/radioterapia , Neoplasias Gástricas/radioterapia , Adulto , Idoso , Biópsia , Feminino , Seguimentos , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Humanos , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Dosagem Radioterapêutica , Indução de Remissão , Neoplasias Gástricas/microbiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA