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2.
Blood ; 134(24): 2159-2170, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31562134

RESUMO

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.

3.
Clin Lymphoma Myeloma Leuk ; 19(7): e400-e405, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155409

RESUMO

BACKGROUND: Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown. PATIENTS AND METHODS: We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control). RESULTS: No statistical significance was detected in patient's overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model. CONCLUSION: Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.

4.
Scand J Work Environ Health ; 45(6): 600-609, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31246262

RESUMO

Objectives Some epidemiological studies have suggested positive associations between glyphosate use and non-Hodgkin lymphoma (NHL), but evidence is inconsistent and few studies could evaluate histological sub-types. Here, associations between glyphosate use and NHL incidence overall and by histological sub-type were evaluated in a pooled analysis of case-control studies. Methods The analysis included 1690 NHL cases [647 diffuse large B-cell lymphoma (DLBCL), 468 follicular lymphoma (FL), 171 small lymphocytic lymphoma (SLL), and 404 other sub-types] and 5131 controls. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for NHL overall and sub-types with self-reported ever/never, duration, frequency, and lifetime-days of glyphosate use. Results Subjects who ever used glyphosate had an excess of NHL overall (OR 1.43, 95% CI 1.11-1.83). After adjustment for other pesticides, the OR for NHL overall with "ever use" was 1.13 (95% CI 0.84-1.51), with a statistically significant association for handling glyphosate >2 days/year (OR 1.73, 95% CI 1.02-2.94, P-trend=0.2). In pesticide-adjusted sub-type analyses, the ordinal measure of lifetime-days was statistically significant (P=0.03) for SLL, and associations were elevated, but not statistically significant, for ever years or days/year of use. Handling glyphosate >2 days/year had an excess of DLBCL (OR 2.14, 95% CI 1.07-4.28; P-trend=0.2). However, as with the other sub-types, consistent patterns of association across different metrics were not observed. Conclusions There was some limited evidence of an association between glyphosate use and NHL in this pooled analysis. Suggestive associations, especially for SLL, deserve additional attention.

5.
Environ Int ; 127: 199-205, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928843

RESUMO

Organophosphates and carbamates have been among the most commonly used insecticides, with both agricultural and residential uses. Previous studies have suggested associations of non-Hodgkin lymphoma (NHL) with some of these chemicals; however, many studies have been limited in their ability to evaluate associations with lymphoma subtypes. We evaluated the use of eleven organophosphate and two carbamate insecticides in association with NHL in the North American Pooled Project, which includes data from case-control studies in the United States and Canada (1690 cases/5131 controls). We used unconditional logistic regression adjusting for potential confounders, including use of other pesticides, to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between these chemicals and NHL overall, and NHL subtypes, i.e., follicular (FL), diffuse large B-cell (DLBCL), small lymphocytic lymphoma (SLL) and others. Ever use of malathion was associated with increased risk of NHL overall (OR = 1.43; 95% CI: 1.14-1.81) compared with never users. Categories using tertiles of duration (<4 yrs., 4-12 yrs., and >12 yrs) also showed a significant exposure-response for increasing years of use of malathion and risk of NHL (OR<4vsUnex = 1.33 (0.88, 2.03), OR4-12vsUnex = 1.42 (1.02, 1.96), OR>12vsUnex = 1.55 (1.05, 2.28, p-trend < 0.01)). In addition, malathion use was statistically significantly associated with FL (OR = 1.58; 95% CI: 1.11-2.27) and DLBCL (OR = 1.61; 95% CI: 1.16-2.22) while there were no apparent associations with SLL or other subtypes, the p-value for heterogeneity across subtypes, however, was not significant. These results support previous studies suggesting an association between insecticide use and NHL overall, and provide new information on associations with NHL subtypes.


Assuntos
Carbamatos/toxicidade , Inseticidas/toxicidade , Linfoma não Hodgkin/induzido quimicamente , Organofosfatos/toxicidade , Idoso , Canadá , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Praguicidas , Fatores de Risco , Estados Unidos
7.
Blood ; 133(15): 1664-1676, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30782609

RESUMO

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.


Assuntos
Variações do Número de Cópias de DNA , Linfoma de Células T Periférico/genética , Oncogenes , Feminino , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/classificação , Masculino , Mutação , Proteínas com Domínio T/genética
8.
Cancer Treat Res ; 176: 1-29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30596211

RESUMO

PURPOSE: This review will describe and update readers on the recent changes in the 2017 WHO classification regarding peripheral T-cell lymphomas. RECENT FINDINGS: Signficant advances in molecular studies have resulted in revisions to the classification as well as introduction to provisional entities such as breast implant-associated ALCL and nodal PTCL with T-follicular helper phenotype. SUMMARY: Major advances in molecular and gene expression profiling has expanded our knowledge of these rare and aggressive diseases.


Assuntos
Células Matadoras Naturais , Linfoma de Células T Periférico , Perfilação da Expressão Gênica , Humanos , Linfoma de Células T Periférico/epidemiologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologia
9.
Blood ; 133(4): 306-318, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30530749

RESUMO

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.


Assuntos
Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Fatores de Transcrição SOXC/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Células HEK293 , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Interleucinas/farmacologia , Fosfotirosina/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima/genética
10.
Blood ; 132(22): 2401-2405, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30257882

RESUMO

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.


Assuntos
Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neoplasias do Mediastino/diagnóstico , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/genética , Neoplasias do Mediastino/classificação , Neoplasias do Mediastino/genética , Mediastino/patologia , Inclusão em Parafina
11.
Hum Pathol ; 72: 180-190, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29170017

RESUMO

The World Health Organization classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into 3 grades (FL1-3) based on the average number of centroblasts per high-power field in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the World Health Organization criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity. The features of FLC include a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1µ, approximately twice that of small lymphocytes and similar to centroblasts. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high Ki67 proliferation (81%). The clinical features of patients with FLC were similar to those with other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. FLC is a variant of follicular lymphoma which should be recognized in future lymphoma classifications because the diagnosis of FLC may be important for the selection of therapy.


Assuntos
Linfócitos B/patologia , Linfócitos/patologia , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/efeitos dos fármacos , Diagnóstico Diferencial , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Translocação Genética/genética
12.
Biol Blood Marrow Transplant ; 24(3): 514-520, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29196080

RESUMO

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Neoplasias do Mediastino , Transplante de Células-Tronco , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Linfoma de Células B/terapia , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
13.
Clin Lymphoma Myeloma Leuk ; 17(8): 488-497.e2, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28842137

RESUMO

BACKGROUND: The combination of rituximab with chemotherapy has improved the outcome of patients with follicular lymphoma (FL). However, data on Grade 3 FL (FL3) and its subtypes are lacking. The aims of the study were to determine: (1) the clinical features and outcome of patients with FL3 treated with rituximab and anthracycline-based chemotherapy; and (2) the clinical significance of the 3 subtypes of FL3. PATIENTS AND METHODS: Eighty-seven patients with Grade 1/2 FL, 84 with FL3 including 46 FL3A, 17 FL3B, and 21 follicular large cleaved cell (FL3C), and 411 patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab and anthracycline-based chemotherapy, and a historical cohort of 167 patients with FL3 who received only anthracycline-based chemotherapy (FL3*) were included in this retrospective study. RESULTS: The FL3 group had a significantly better overall survival (OS) and event-free survival (EFS) compared with those with FL3* or DLBCL. No significant differences in OS were found among the 3 subtypes of FL3. However, patients with FL3B had a shorter EFS than those with FL3A and FL3C. Moreover, patients with FL3B had an outcome similar to those with DLBCL, whereas patients with FL3A and 3C had significantly better outcomes than those with DLBCL. Less than 50% of the patients with FL3B and less than 20% of the patients with FL3A and 3C have relapsed, and relapses were uncommon after 5 years. CONCLUSION: The use of rituximab with anthracycline-based chemotherapy significantly improved the survival of patients with FL3 and should be considered the benchmark by which other therapies for FL3 are evaluated in the future.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Rituximab/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento
14.
Blood ; 130(16): 1819-1831, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-28801451

RESUMO

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.


Assuntos
Linfoma de Burkitt/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Adulto Jovem
15.
J Clin Oncol ; 35(15): 1668-1677, 2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28291392

RESUMO

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.


Assuntos
Biópsia/métodos , Linfoma de Célula do Manto/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/fisiologia , Feminino , Formaldeído , Perfilação da Expressão Gênica , Humanos , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reprodutibilidade dos Testes , Fixação de Tecidos
16.
Int J Surg Pathol ; 25(3): 276-280, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27688525

RESUMO

Composite lymphomas consist of 2 or more distinct lymphomas occurring in a single anatomical site or simultaneously in different sites and can be composed of any combination of B-cell non-Hodgkin lymphoma (NHL), T-cell NHL, or Hodgkin lymphoma (HL). Cases of composite lymphomas with more than 2 lymphomas are extremely rare, with only 4 reports in the literature. We report the case of a 49-year-old man with a triple composite lymphoma in a single lymph node, consisting of small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma in situ. The patient received multiple courses of chemotherapy and an autologous stem cell transplant, which resulted in complete remission. Then, 6 years after the stem cell transplant, he developed classical HL. This unique case is, to our knowledge, the first report of a patient with triple composite lymphoma consisting of 3 small mature B-cell NHLs, who subsequently developed a fourth lymphoma.


Assuntos
Linfoma Composto/patologia , Doença de Hodgkin/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Folicular/patologia , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/patologia , Segunda Neoplasia Primária/patologia , Linfoma Composto/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , Linfonodos/patologia , Linfoma Folicular/terapia , Linfoma de Célula do Manto/terapia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade
17.
Leuk Lymphoma ; 58(3): 676-688, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27338091

RESUMO

Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.


Assuntos
Ciclina D1/metabolismo , Dano ao DNA , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Animais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Replicação do DNA , Modelos Animais de Doenças , Xenoenxertos , Humanos , Linfoma de Célula do Manto/patologia , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética
18.
Hematol Oncol ; 35(2): 198-205, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26482423

RESUMO

Epidemiologic studies of non-Hodgkin lymphoma (NHL) in Eastern Europe are scarce in the literature. We report the experience of the "Ion Chiricuta" Institute of Oncology in Cluj-Napoca (IOCN), Romania, in the diagnosis and outcome of patients with NHL. We studied 184 consecutive NHL patients diagnosed in the Pathology Department of IOCN during the years 2004-2006. We also obtained epidemiological data from the Northwestern (NW) Cancer Registry. In the IOCN series, the most common lymphoma subtype was diffuse large B-cell lymphoma (43.5%), followed by the chronic lymphocytic leukaemia/small lymphocytic lymphoma (21.2%). T-cell lymphomas represented a small proportion (8.2%). The median age of the patients was 57 years, with a male-to-female ratio of 0.94. Patients with indolent B-cell lymphomas had the best overall survival, whereas those with mantle cell lymphoma had the worst survival. The NW Cancer Registry data showed that the occurrence of NHL in the NW region of Romania was higher in men [world age-standardized incidence rate/100 000 (ASR)-5.9; 95% CI 5.1-6.6] than in women (ASR-4.1; 95% CI 3.5-4.7) with age-standardized male-to-female ratio of 1.44 (p = 0.038). Chronic lymphocytic leukaemia/small lymphocytic lymphoma was the most common NHL in the NW region of Romania, accounting for 43% of all cases, followed by diffuse large B-cell lymphoma (36%). The 5-year, age-standardized cumulative relative survival for NHL in the County of Cluj in NW Romania, for the period of 2006-2010, was 51.4%, with 58.4% survival for men and 43.2% for women. Additional studies of NHL in Eastern Europe are needed. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Linfoma não Hodgkin/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Romênia/epidemiologia
20.
J Clin Oncol ; 35(1): 24-31, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28034071

RESUMO

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/química , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-6/análise , Proteínas Proto-Oncogênicas c-myc/análise , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
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