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1.
Br J Haematol ; 185(3): 480-491, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30793290

RESUMO

The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10-year period who needed therapy and were treated with rituximab-containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10-year overall survival (OS) of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex- and age-matched Spanish general population.

2.
Am J Hematol ; 93(7): 867-873, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29658143

RESUMO

The means of optimally managing very elderly patients with diffuse large B-cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80-100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression-free survival (PFS) and overall survival (OS). One hundred sixty-three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow-up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1-2) R-IPI, and treatment with R-CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R-CHOP-like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0-1 vs. 2-3 risk factors (age > 85 years, R-IPI 3-5 or CIRS > 5). In conclusion, treatment with R-CHOP-like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Gerenciamento Clínico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Rituximab , Espanha , Análise de Sobrevida , Vincristina/uso terapêutico
3.
Br J Haematol ; 178(5): 699-708, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28782811

RESUMO

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically-documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59 years), diagnosed with FL grades 1-3A, were, (i) the cumulative incidence of HT (CI-HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow-up of 6·2 years, 106 patients developed HT. Ten-year CI-HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5 years. High-risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5-4·5] and non-response to first-line therapy (HR 2·9, 95% CI: 1·3-6·8) were associated with HT. Seventy out of the 106 patients died (5-year SFT, 26%). Response to HT first-line therapy (HR 5·3, 95% CI: 2·4-12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5-10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1-4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.


Assuntos
Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/patologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Espanha/epidemiologia , Análise de Sobrevida , Adulto Jovem
4.
PLoS One ; 12(3): e0172978, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28249016

RESUMO

INTRODUCTION: Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL. AIMS: We evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107). RESULTS: No consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1*03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1*02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012). CONCLUSION: In conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn.


Assuntos
Genes de Cadeia Pesada de Imunoglobulina , Antígenos de Histocompatibilidade Classe I/genética , Linfocitose/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Contagem de Linfócitos , Linfocitose/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico
5.
Drug Des Devel Ther ; 11: 253-264, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28176904

RESUMO

Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Desenho de Drogas , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Depsipeptídeos/síntese química , Depsipeptídeos/química , Humanos
6.
Thromb Haemost ; 117(1): 66-74, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27734074

RESUMO

Currently, molecular diagnosis of haemophilia A and B (HA and HB) highlights the excess risk-inhibitor development associated with specific mutations, and enables carrier testing of female relatives and prenatal or preimplantation genetic diagnosis. Molecular testing for HA also helps distinguish it from von Willebrand disease (VWD). Next-generation sequencing (NGS) allows simultaneous investigation of several complete genes, even though they may span very extensive regions. This study aimed to evaluate the usefulness of a molecular algorithm employing an NGS approach for sequencing the complete F8, F9 and VWF genes. The proposed algorithm includes the detection of inversions of introns 1 and 22, an NGS custom panel (the entire F8, F9 and VWF genes), and multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 102 samples (97 FVIII- and FIX-deficient patients, and five female carriers) were studied. IVS-22 screening identified 11 out of 20 severe HA patients and one female carrier. IVS-1 analysis did not reveal any alterations. The NGS approach gave positive results in 88 cases, allowing the differential diagnosis of mild/moderate HA and VWD in eight cases. MLPA confirmed one large exon deletion. Only one case did have no pathogenic variants. The proposed algorithm had an overall success rate of 99 %. In conclusion, our evaluation demonstrates that this algorithm can reliably identify pathogenic variants and diagnose patients with HA, HB or VWD.


Assuntos
Algoritmos , Fator IX/genética , Fator VIII/genética , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia B/diagnóstico , Hemofilia B/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular , Mutação , Fator de von Willebrand/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hemofilia A/sangue , Hemofilia B/sangue , Heterozigoto , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
7.
Blood ; 127(24): 3035-9, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27069257

RESUMO

Immunoglobulin light-chain amyloidosis (AL) and multiple myeloma (MM) are 2 distinct monoclonal gammopathies that involve the same cellular compartment: clonal plasma cells (PCs). Despite the fact that knowledge about MM PC biology has significantly increased in the last decade, the same does not apply for AL. Here, we used an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 24 newly diagnosed patients with AL. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and both monoclonal gammopathy of undetermined significance and MM PCs. However, in contrast to MM, highly purified fluorescence-activated cell-sorted clonal PCs from AL (n = 9) showed almost normal transcriptome, with only 38 deregulated genes vs normal PCs; these included a few tumor-suppressor (CDH1, RCAN) and proapoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n = 11) were genomically unstable, with a median of 9 copy number alterations (CNAs) per case, many of such CNAs being similar to those found in MM. Whole-exome sequencing (WES) performed in 5 AL patients revealed a median of 15 nonrecurrent mutations per case. Altogether, our results show that in the absence of a unifying mutation by WES, clonal PCs in AL display phenotypic and CNA profiles similar to MM, but their transcriptome is remarkably similar to that of normal PCs.


Assuntos
Amiloidose/genética , Cadeias Leves de Imunoglobulina/genética , Paraproteinemias/genética , Plasmócitos/metabolismo , Transcriptoma , Amiloidose/metabolismo , Amiloidose/patologia , Células Clonais/metabolismo , Células Clonais/patologia , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Análise em Microsséries , Paraproteinemias/metabolismo , Paraproteinemias/patologia , Fenótipo , Plasmócitos/patologia
8.
Ann Hematol ; 95(2): 253-62, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26573278

RESUMO

Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.


Assuntos
Variações do Número de Cópias de DNA/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Hibridização Genômica Comparativa/métodos , Feminino , Seguimentos , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos
9.
Blood ; 125(15): 2370-80, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25655603

RESUMO

Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25(-)CD22(+) B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25(+)CD22(+low)) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone.


Assuntos
Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Gamopatia Monoclonal de Significância Indeterminada/genética , Macroglobulinemia de Waldenstrom/genética , Linfócitos B/metabolismo , Transformação Celular Neoplásica/patologia , Células Clonais , Citometria de Fluxo , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Imunoglobulina M/análise , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fenótipo , Macroglobulinemia de Waldenstrom/patologia
10.
Br J Haematol ; 167(3): 327-36, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25066542

RESUMO

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3-year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carmustina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Indução de Remissão , Rituximab , Transplante Autólogo , Resultado do Tratamento , Vincristina/administração & dosagem
12.
Leuk Lymphoma ; 55(5): 1007-12, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23885799

RESUMO

Abstract Purine analogs are highly effective in hairy cell leukemia (HCL) with response rates of 85%, but with many late relapses. We have retrospectively reviewed the clinical data from 107 patients treated with pentostatin (n = 27) or cladribine (n = 80), to investigate the long-term efficacy and to identify factors associated with the treatment-free interval (TFI). Complete remission and minimal residual disease (MRD) rates were similar in both groups. Median TFI was shorter (95 vs. 144 months) in the pentostatin group, although the difference was not significant (p = 0.476). MRD+ patients had shorter TFI than MRD- patients (97 months vs. not reached, p < 0.049). A hemoglobin level < 10 g/dL predicted for a shorter TFI only in the pentostatin group. Quality of response and number of hairy cells in the bone marrow are independent risk factors of treatment failure. The relationship between MRD+ and shorter TFI makes it of special interest to explore consolidation therapy with monoclonal antibodies to achieve durable responses.


Assuntos
Cladribina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Pentostatina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cladribina/administração & dosagem , Feminino , Humanos , Interferon-alfa/administração & dosagem , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/cirurgia , Masculino , Pessoa de Meia-Idade , Pentostatina/administração & dosagem , Rituximab , Esplenectomia , Resultado do Tratamento
13.
Blood ; 122(8): 1448-54, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23843497

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P = .019) and 5-year overall (71% vs 92%, P = .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.


Assuntos
Antígenos HLA/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Frequência do Gene , Cadeias HLA-DRB1/genética , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Prednisolona/uso terapêutico , Prognóstico , Fatores de Risco , Rituximab , Vincristina/uso terapêutico , Adulto Jovem
14.
Eur J Haematol ; 91(3): 236-41, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23679653

RESUMO

AIM: Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non-elderly ITP patients and to examine the effect of age on therapeutic response. MATERIAL AND METHODS: We carried out a retrospective analysis of a series of 218 patients who had undergone splenectomy for ITP. We compared the data from the elderly group (≥65 yrs, 57 patients) with the young group (<65 yrs, 162 patients). RESULTS: Surgical technique (laparoscopy or open laparotomy splenectomy) was comparable between the two age groups. The adjusted risk of major bleeding following splenectomy for elderly patients was three times that for young patients (OR 3.05, 95% CI: 1.44-6.52). The median duration of postoperative hospital stay was longer for elderly than for young patients (8 d vs. 4 d, P < 0.001). However, we identified a subgroup of elderly ITP patients, those aged between 65 and 70 yrs who had undergone laparoscopic splenectomy, with a low risk of postoperative complications. Of the 218 patients, 89% achieved a favorable response to splenectomy. A favorable response was significantly less common in elderly than in young people (79% vs. 92%, P = 0.005). However, we observed an acceptable long-term control of ITP in the elderly group, in which the probability of maintaining response for 14 yrs after splenectomy was 56%. CONCLUSIONS: Patients aged ≥65 yrs experienced negative effects on safety and efficacy outcomes of splenectomy for ITP, but further studies are needed to identify predictors of postsplenectomy outcomes in this group.


Assuntos
Púrpura Trombocitopênica Idiopática/cirurgia , Esplenectomia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/mortalidade , Estudos Retrospectivos , Fatores de Risco , Esplenectomia/efeitos adversos , Resultado do Tratamento
15.
Am J Pathol ; 181(5): 1879-88, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22982190

RESUMO

The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D-J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an overrepresentation of IGHV4-34 (15.5% overall). Interestingly, all IGHV4-34 rearrangements and all unmutated sequences belonged to the nongerminal center B-cell-like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL. The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.


Assuntos
Antígenos de Neoplasias/imunologia , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Centro Germinativo/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Aminoácidos/genética , Células Clonais , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , Recombinação V(D)J/genética , Recombinação V(D)J/imunologia , Adulto Jovem
16.
Blood ; 117(13): 3613-6, 2011 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-21266717

RESUMO

The clinical value of multiparameter flow cytometry (MFC) immunophenotyping in primary or light chain amyloidosis (AL) remains unknown. We studied 44 consecutive bone marrow samples from newly diagnosed patients with amyloidosis; 35 patients with AL and 9 with other forms of amyloidosis. Monoclonal plasma cells (PCs) were identifiable by MFC immunophenotyping in 34 of 35 (97%) patients with AL, whereas it was absent from all but 1 of the 9 (11%) patients with other forms of amyloidosis. Quantification of bone marrow plasma cells (BMPCs) by MFC immunophenotyping was a significant prognostic factor for overall survival (OS) (≤ 1% vs > 1% BMPC cutoff; 2-year OS rates of 90% vs 44%, P = .02). Moreover, detecting persistent normal PCs at diagnosis identifies a subgroup of patients with AL with prolonged OS (> 5% vs ≤ 5% normal PC within all BMPC cutoff, 2-year rates of 88% vs 37%, P = .01). MFC immunophenotyping could be clinically useful for the demonstration of PC clonality in AL and for the prognostication of patients with AL.


Assuntos
Amiloidose/diagnóstico , Citometria de Fluxo/métodos , Cadeias Leves de Imunoglobulina/metabolismo , Imunofenotipagem/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/metabolismo , Feminino , Cardiopatias/diagnóstico , Cardiopatias/metabolismo , Humanos , Nefropatias/diagnóstico , Nefropatias/metabolismo , Hepatopatias/diagnóstico , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
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