RESUMO
Adverse drug reactions (ADRs) reduce patients' quality of life, increase mortality and morbidity, and have a negative economic impact on healthcare systems. Nevertheless, the importance of ADR reporting is often underestimated. The project "FarmaREL" has been developed to monitor and evaluate ADRs in haematological patients and to increase pharmacovigilance culture among haematology specialists. In 13 haematology units, based in Lombardy, Italy, a dedicated specialist with the task of encouraging ADRs reporting and sensitizing healthcare professionals to pharmacovigilance has been assigned. The ADRs occurring in haematological patients were collected electronically and then analysed with multiple logistic regression. Between January 2009 and December 2011, 887 reports were collected. The number of ADRs was higher in older adults (528; 59%), in male (490; 55%), and in non-Hodgkin lymphoma patients (343; 39%). Most reactions were severe (45% required or prolonged hospitalization), but in most cases, they were fully resolved at the time of reporting. According to Schumock and Thornton criteria, a percentage of ADRs as high as 7% was found to be preventable versus 2% according to reporter opinion. Patients' haematological diagnosis, not age or gender, resulted to be the variable that most influenced ADR, in particular severity and outcome. The employment of personnel specifically dedicated to pharmacovigilance is a successful strategy to improve the number and quality of ADR reports. "FarmaREL", the first programme of active pharmacovigilance in oncohaematologic patients, significantly contributed to reach the WHO "Gold Standard" for pharmacovigilance in Lombardy, Italy.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias Hematológicas/complicações , Farmacovigilância , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
Post-transplant lymphoproliferative disorders (PTLDs) represent a frequent complication of solid organ transplantation. Although most PTLDs arise from recipient lymphoid cells, a considerable fraction of cases may arise from donor B-cells. In an attempt to clarify the histogenesis and pathogenesis of PTLDs derived from donor B-cells, monoclonal PTLDs occurring in liver transplant recipients were chosen as a model to compare donor (D-PTLDs) versus recipient PTLDs (R-PTLDs). The tumour panel included nine D-PTLDs and six R-PTLDs. D-PTLDs were early-onset, EBV-infected lymphoproliferations classified as polymorphic PTLD (P-PTLD; n = 7) or diffuse large B-cell lymphoma (DLBCL; n = 2) with tumour localization confined to the hepatic hilum. All R-PTLDs were late-onset DLBCLs and showed extrahepatic localization. A BCL-6(-)/MUM1(+)/CD138(+/-) phenotype, consistent with a post-germinal centre (GC) stage of pre-terminal B-cell differentiation, was observed in all D-PTLDs and in 2/6 R-PTLDs, whereas a BCL6(+)/MUM1(-)/CD138(-) profile, reminiscent of GC B-cells, was detected in 4/6 R-PTLDs. The presence of somatic IGHV hypermutation was observed in 6/9 D-PTLDs and in 4/6 R-PTLDs, suggesting derivation from antigen-experienced B-cells. IGHV4-39 was the IGHV gene most frequently encountered, being rearranged in 3/9 D-PTLDs. Among IGHV-mutated PTLDs, a mutational profile suggesting antigen stimulation and/or selection was observed in 4/6 D-s and in 2/4 R-PTLDs. The presence of ongoing IGHV mutations was detected in 2/4 D-PTLDs. Aberrant SHM was detected in 10/15 (66.7%) PTLDs, including 6/9 D-PTLDs and 4/6 R-PTLDs. Our findings suggest that (i) D-PTLDs show a clinical presentation distinct from R-PTLDs; (ii) immunophenotypic and genetic features of D-PTLDs are consistent with mature, GC-experienced B-cells; (iii) transformed donor-derived B-cells may experience antigen-driven stimulation and selection, and may acquire genetic lesions during neoplastic expansion in the recipient environment; and (iv) EBV infection and expression of viral oncoproteins may be relevant in the pathogenesis of D-PTLDs.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/virologia , Complicações Pós-Operatórias/virologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/virologia , Feminino , Rearranjo Gênico , Centro Germinativo , Humanos , Região Variável de Imunoglobulina/genética , Imunofenotipagem , Linfoma de Células B/imunologia , Linfoma de Células B/virologia , Transtornos Linfoproliferativos/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Complicações Pós-Operatórias/imunologia , Doadores de Tecidos , Transplante HomólogoRESUMO
Eight patients with ocular adnexal mucosal-associated lymphpid tissue (MALT) lymphoma were treated with rituximab, at diagnosis (n=5) or relapse (n=3). All untreated patients achieved lymphoma regression, while relapsing patients had no benefit. Four responding patients experienced early relapse. The median time to progression was 5 months. The efficacy of rituximab in ocular adnexal lymphoma is lower than that reported for gastric MALT lymphomas.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Oculares/terapia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos , Neoplasias Oculares/patologia , Neoplasias Oculares/prevenção & controle , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/prevenção & controle , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , RituximabRESUMO
BACKGROUND AND OBJECTIVES: The incidence of invasive filamentous fungal infections in hematologic patients is increasing as a consequence of high dose chemotherapy and bone marrow transplant procedures. Mortality is usually very high. The diagnosis is often difficult and yet a fast, accurate diagnosis is of fundamental importance for treating the infection and planning subsequent management of the hematologic disease. We evaluated the sensitivity of computed tomography (CT)-guided percutaneous biopsy in diagnosing pulmonary fungal infections. DESIGN AND METHODS: Between 1997 and 2002 we performed 17 CT-guided percutaneous transthoracic lung biopsies in 17 hematologic patients with suspected filamentous fungi infection with negative BAL, to obtain a certain diagnosis and to know what species of fungi was responsible for infection. In all cases suspected mycosis began during the post-chemotherapy aplastic period. Patients were receiving antifungal therapy at the time of all biopsies. When the platelet count rose above 50 x 10(9)/L, CT-guided percutaneous lung biopsy with fine-needle aspiration for cytology was performed. RESULTS: Twelve of 17 patients had histologic confirmation of the fungal infection (70.5%), 8 with Aspergillus spp. 4 with Mucorales spp. Biopsies provided non-specific results in 4 cases; in 2 of these cases, clinical course and response to therapy confirmed the diagnosis of mycosis; in the last case bronchoalveolar carcinoma was found as a new diagnosis. Cultures were positive in only 6 cases, all for Aspergillus spp. The sensitivity of CT-guided percutaneous lung biopsy was 70.6% and its positive predictive value (PPV) was 100%. This procedure provided an immediate diagnosis and only one side-effect (1 pneumothorax, without complications). INTERPRETATION AND CONCLUSIONS: Histologic discrimination between aspergillosis and mucormycosis is very important for deciding secondary prophylaxis during transplant procedures, because Mucor is usually resistant to azoles.
Assuntos
Aspergilose/diagnóstico , Biópsia por Agulha/métodos , Neoplasias Hematológicas/complicações , Pneumopatias Fúngicas/diagnóstico , Pulmão/patologia , Mucormicose/diagnóstico , Radiografia Intervencionista , Adenocarcinoma Bronquioloalveolar/diagnóstico , Adenocarcinoma Bronquioloalveolar/patologia , Adulto , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/etiologia , Aspergilose/microbiologia , Aspergilose/patologia , Aspergillus/isolamento & purificação , Líquido da Lavagem Broncoalveolar/microbiologia , Suscetibilidade a Doenças , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/etiologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mucorales/isolamento & purificação , Mucormicose/tratamento farmacológico , Mucormicose/etiologia , Mucormicose/microbiologia , Mucormicose/patologia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
Plasma exchange (PEX) with fresh frozen plasma, usually in association with steroid therapy, has been shown to be the first-line treatment of thrombotic thrombocytopenic purpura. It works by removing ultralarge von Willebrand factor (vWF) multimers and inhibitory antibody and by supplying normal protease. For patients with disease refractory to PEX, there is no standardized treatment. Limited and sporadic success with different therapies (vincristine sulfate, prostacyclin, intravenous immunoglobulins, splenectomy) has been described. We report the case of a woman who developed refractory disease after an initial response to PEX and despite a very high number of PEX procedures performed. Low activity (< 5%) of serum vWF-cleaving protease and a low level of protease inhibitor were documented. The patient had a slow but sustained response when oral cyclosporine was administered concomitantly with PEX, which was slowly tapered. The activity of serum vWF-cleaving protease normalized. At relapse, treatment with cyclosporine, added after the failure of steroids and PEX, led to a lasting response. It is possible that in some cases cyclosporine therapy must be of particularly long duration before being considered ineffective.
Assuntos
Ciclosporina/farmacologia , Imunossupressores/farmacologia , Troca Plasmática , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Adulto , Ciclosporina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Trombótica/patologia , Recidiva , Esteroides/uso terapêutico , Resultado do TratamentoRESUMO
Tacrolimus (FK506)-induced hematological toxicity, which has rarely been reported in transplant recipients, may result in anemia episodes, reported mainly in kidney and heart transplant recipients, sporadic cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, red cell aplasia (4 reported cases), and generalized bone marrow suppression (only 1 reported case). We describe a case of a liver transplant recipient with pancytopenia that appeared during immunosuppressive therapy with tacrolimus. This patient suffered from progressive anemia, leukopenia with severe neutropenia, and mild thrombocytopenia; bone marrow biopsy showed hypoplasia (20% of cellularity) without dysplasia. Bone marrow recovery was made possible by suspending tacrolimus and changing to immunosuppression with cyclosporine A, despite the two drugs being very similar in their mechanism of immunosuppression. Contrary to previously reported cases (pure red cell aplasia and bone marrow hypoplasia), the recovery of hemoglobin and neutrophil values was slow after tacrolimus suspension, even though in the first month transfusions were no longer necessary.
Assuntos
Doenças da Medula Óssea/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/cirurgia , Imunossupressores/efeitos adversos , Transplante de Fígado , Tacrolimo/efeitos adversos , Adolescente , Ciclosporina/administração & dosagem , Feminino , Humanos , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversosRESUMO
Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations.
Assuntos
Linfoma de Burkitt/genética , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Segunda Neoplasia Primária/genética , Transplante de Órgãos , Apoptose/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Feminino , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Rearranjo Gênico de Cadeia Leve de Linfócito B/genética , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/genética , Cadeias Leves de Imunoglobulina/biossíntese , Região Variável de Imunoglobulina/biossíntese , Imuno-Histoquímica , Masculino , Mutação , Proteínas Proto-Oncogênicas c-bcr/biossíntese , Proteínas Proto-Oncogênicas c-bcr/genética , Hipermutação Somática de Imunoglobulina/genéticaRESUMO
BACKGROUND: An association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infection has been proposed, and recent reports suggest that doxycycline treatment causes tumor regression in patients with Cp-related OAL. The effectiveness of doxycycline treatment in Cp-negative OAL has not been tested. METHODS: In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were two-sided. RESULTS: Eleven patients were Cp DNA-positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in six patients, and a partial response (> or = 50% reduction of all measurable lesions) was observed in seven patients (overall response rate [complete and partial responses] = 48%). Lymphoma regression was observed in both Cp DNA-positive patients (seven of 11 experienced regression) and Cp DNA-negative patients (six of 16 experienced regression) (64% versus 38%; P = .25, Fisher's exact test). The three patients with regional lymphadenopathies and three of the five patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline-treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. CONCLUSIONS: Doxycycline is a fast, safe, and active therapy for Cp DNA-positive OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR-negative OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria.
Assuntos
Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Chlamydophila psittaci/efeitos dos fármacos , Doxiciclina/uso terapêutico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Neoplasias Orbitárias/tratamento farmacológico , Psitacose/tratamento farmacológico , Adulto , Idoso , Chlamydophila psittaci/isolamento & purificação , DNA Bacteriano/isolamento & purificação , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Orbitárias/microbiologia , Neoplasias Orbitárias/patologia , Reação em Cadeia da Polimerase , Estudos Prospectivos , Psitacose/complicações , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Clinical and pathologic variability of post-transplant lymphoproliferative disorders (PTLDs), their aggressive behavior and the recognized therapy-related toxicity make management of patients with these disorders difficult. Assessment of first-line treatment and identification of prognostic factors need to be better defined. DESIGN AND METHODS: Data on 40 PTLDs which developed in adult solid organ recipients were analyzed in order to evaluate clinical and pathologic features, response to treatment and prognostic factors. Data were collected retrospectively between 1989 and 1996; since 1997 a prospective study has been activated. RESULTS: The median time from transplant to PTLD was 56 months. Regarding histologic features, plasmacytic hyperplasia was diagnosed in 5 patients (12.5%), polymorphic lymphoproliferative disorders in 3 (7.5%), malignant lymphoma in 32 (80%). The diagnosis was made at autopsy in eight patients (20%). Late-onset PTLDs (>12 months from transplant) occurred in 33 patients (83%), EBV-negative forms in 12 (31%). Relevant differences have been observed between EBV-positive and EBV-negative forms. Twenty-nine patients completed their scheduled treatment and are evaluable for outcome. The cumulative probability of survival at 1 year is 57% (CI 37.6-73.4) and the median survival time of the entire group has not been reached at 54 months. Clinical stage, performance status, lactate dehydrogenase and number of sites are predictive factors for survival. The International Prognostic Index and the PTLD index are able to identify different risk groups. INTERPRETATION AND CONCLUSIONS: Although rare, PTLDs are a significant cause of mortality in allograft recipients. Therapy tailored on histologic and clinical features of PTLD is feasible and is able to give long-lasting complete responses.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Terapia de Imunossupressão/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Complicações Pós-Operatórias/etiologia , Transplante/efeitos adversos , Adulto , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Transplante de Coração/efeitos adversos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Herpesvirus Humano 4/isolamento & purificação , Humanos , Hospedeiro Imunocomprometido , Interleucina-10/sangue , Transplante de Rim/efeitos adversos , Tábuas de Vida , Transplante de Fígado/efeitos adversos , Transplante de Pulmão/efeitos adversos , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/microbiologia , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Complicações Pós-Operatórias/virologia , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Rituximab , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
Post-transplant lymphoproliferative disorders (PTLDs) are heterogeneous severe complications occurring in 1-10% of transplanted patients. In most cases, PTLDs are associated with Epstein-Barr virus (EBV) infection but, recently, some clinical studies have reported an increasing number of EBV-negative PTLDs. Several studies have emphasized the critical role of the early identification of patients at risk for PTLD, in prompting the adoption of either pre-emptive strategies or timely treatment. To this purpose, monitoring of EBV DNA load in peripheral blood mononuclear cells is considered to be a useful test. Moreover, recently, the role of interleukin (IL)-10 in EBV-related diseases has been remarked, and high levels of IL-10 have been detected in PTLD patients. In this study, both EBV load and IL-10 were monitored in 38 PTLD patients at diagnosis and during follow-up, as well as in a control group, in order to establish the diagnostic role of the two tests, their relationship with the different PTLD subsets (EBV-positive and EBV-negative) and their behaviour during treatment. Results of our study suggest that the usefulness of IL-10 assay for early diagnosis of PTLD is similar to that of EBV load quantification, and its clinical diagnostic value is lower in EBV-negative than in EBV-positive PTLDs.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/isolamento & purificação , Interleucina-10/sangue , Transtornos Linfoproliferativos/diagnóstico , Transplante de Órgãos , Adulto , Biomarcadores/sangue , DNA Viral/sangue , Seguimentos , Humanos , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Sensibilidade e Especificidade , Carga ViralRESUMO
Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogeneity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells (P = 0.15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development.
Assuntos
Rearranjo Gênico do Linfócito B/genética , Genes de Imunoglobulinas/genética , Transtornos Linfoproliferativos/genética , Receptores de Antígenos de Linfócitos B/genética , Glicosilação , Humanos , Linfoma Relacionado a AIDS/genética , Linfoma de Células B/genética , Imunologia de Transplantes/genéticaRESUMO
Aberrant promoter hypermethylation is a mechanism of tumour suppressor gene inactivation. We explored aberrant promoter hypermethylation of multiple genes in 88 human immunodeficiency virus (HIV)-non Hodgkin lymphomas (NHL), 25 post-transplant lymphoproliferative disorders (PTLD) and five common variable immunodeficiency (CVI)-related NHL. Twenty-six of 79 (32.9%) HIV-NHL, eight of 14 (57.1%) PTLD and two of five (40.0%) CVI-NHL showed aberrant hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT). Aberrant hypermethylation of death-associated protein-kinase (DAP-K) occurred in 70 of 84 (83.3%) HIV-NHL, 19 of 25 (72.0%) PTLD and three of five (60.0%) CVI-NHL. These data implicate MGMT and DAP-K hypermethylation in lymphomagenesis of immunodeficient hosts. In particular, promoter hypermethylation of DAP-K represents the most frequent molecular alteration yet identified in immunodeficiency-related lymphomas.
Assuntos
Imunodeficiência de Variável Comum/genética , Metilação de DNA , Linfoma Relacionado a AIDS/genética , Linfoma não Hodgkin/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas , Proteínas Reguladoras de Apoptose , Linfoma de Burkitt/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Caspase 8 , Caspase 9 , Caspases/genética , Neoplasias do Sistema Nervoso Central/genética , Imunodeficiência de Variável Comum/complicações , Proteínas de Ligação a DNA/genética , Proteínas Quinases Associadas com Morte Celular , Genes Supressores de Tumor , Humanos , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/imunologia , Linfoma de Células T/genética , Mieloma Múltiplo/genética , Proteínas Nucleares/genética , Proteína Tumoral p73 , Proteínas Supressoras de TumorRESUMO
Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.