Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia de Consolidação/métodos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Adulto , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , História Antiga , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Taxa de SobrevidaRESUMO
PURPOSE: Updated results are presented after a median follow-up of 7.3 years from the phase III First-Line Indolent Trial of yttrium-90 ((90)Y) -ibritumomab tiuxetan in advanced-stage follicular lymphoma (FL) in first remission. PATIENTS AND METHODS: Patients with CD20(+) stage III or IV FL with complete response (CR), unconfirmed CR (CRu), or partial response (PR) after first-line induction treatment were randomly assigned to (90)Y-ibritumomab consolidation therapy (rituximab 250 mg/m(2) days -7 and 0, then (90)Y-ibritumomab 14.8 MBq/kg day 0; maximum 1,184 MBq) or no further treatment (control). Primary end point was progression-free survival (PFS) from date of random assignment. RESULTS: For 409 patients available for analysis ((90)Y-ibritumomab, n = 207; control, n = 202), estimated 8-year overall PFS was 41% with (90)Y-ibritumomab versus 22% for control (hazard ratio [HR], 0.47; P < .001). For patients in CR/CRu after induction, 8-year PFS with (90)Y-ibritumomab was 48% versus 32% for control (HR, 0.61; P = .008), and for PR patients, it was 33% versus 10% (HR, 0.38; P < .001). For (90)Y-ibritumomab consolidation, median PFS was 4.1 years (v 1.1 years for control; P < .001). Median time to next treatment (TTNT) was 8.1 years for (90)Y-ibritumomab versus 3.0 years for control (P < .001) with approximately 80% response rates to second-line therapy in either arm, including autologous stem-cell transplantation. No unexpected toxicities emerged during long-term follow-up. Estimated between-group 8-year overall survival rates were similar. Annualized incidence rate of myelodysplastic syndrome/acute myeloblastic leukemia was 0.50% versus 0.07% in (90)Y-ibritumomab and control groups, respectively (P = .042). CONCLUSION: (90)Y-ibritumomab consolidation after achieving PR or CR/CRu to induction confers 3-year benefit in median PFS with durable 19% PFS advantage at 8 years and improves TTNT by 5.1 years for patients with advanced FL.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Folicular/terapia , Radioimunoterapia/métodos , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cooperação Internacional , Estimativa de Kaplan-Meier , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Linfoma Folicular/radioterapia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Fatores de Tempo , Resultado do Tratamento , Radioisótopos de Ítrio/uso terapêuticoRESUMO
PURPOSE: We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. PATIENTS AND METHODS: We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001--of whom 3,432 also received radiotherapy--to assess second primary malignancy risks compared with general population-based expectations. RESULTS: Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. CONCLUSION: Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia/diagnóstico , Leucemia/epidemiologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The impact of active surveillance, comprising annual computed tomography scanning and bone marrow biopsies, in the follow-up of patients after high-dose therapy with autologous stem cell rescue for recurrent follicular lymphoma was analyzed. DESIGN AND METHODS: Seventy-one of 99 patients who received high-dose therapy commenced the surveillance program. Response duration, time to next treatment and overall survival were compared according to whether disease progression had been diagnosed on the basis of surveillance investigations or on clinical grounds. RESULTS: After a median follow-up of 16 years, progression was documented by surveillance in 16 patients and clinically in 18, the median response duration being 2.4 and 2.3 years, respectively (P=NS). Ten patients with a relapse detected clinically started treatment immediately, contrasting with one patient whose relapse was detected by surveillance investigations. Five patients with relapses detected by surveillance investigations have not required treatment after a median follow-up of 18 years, whereas all but two patients with a relapse detected clinically have been treated. The median time to next treatment was 7 years for patients with a relapse identified by surveillance investigations and 4 years for those whose relapse was manifested clinically (P=0.03). Overall survival was not significantly different between the two groups. CONCLUSIONS: Surveillance investigations, consisting of annual computed tomography scanning and bone marrow biopsies, have no impact on the management of patients with recurrent follicular lymphoma and do not improve the outcome of these patients.
Assuntos
Linfoma Folicular/diagnóstico , Linfoma Folicular/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Exame de Medula Óssea , Gerenciamento Clínico , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia , Transplante AutólogoRESUMO
Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 x 10(9)/l before treatment had the longest relapse-free survival (P < 0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Cladribina/administração & dosagem , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia de Células Pilosas/mortalidade , Masculino , Pessoa de Meia-Idade , Pentostatina/administração & dosagem , Recidiva , Indução de Remissão , Rituximab , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Primary testicular lymphomas typically occur in patients over 60 years of age. Most are diffuse large B-cell lymphomas with frequent dissemination and a poor prognosis. Primary follicular lymphoma of the adult testis has not been well characterized. However, a small number of primary testicular follicular lymphomas have recently been described in children. These showed stage 1E disease, a lack of BCL2 gene rearrangement and Bcl-2 protein expression, and a good clinical outcome. Here, we describe 5 cases of primary follicular lymphoma of the testis and epididymis in adults. These presented as unilateral testicular masses 12 to 40 mm in diameter and were characterized histologically by small neoplastic follicles in a sclerotic background. The neoplastic cells expressed CD10 and Bcl-6, but not Bcl-2 and lacked t(14;18)(q32;q21)/IGH-BCL2 and BCL6 gene rearrangements. Four of the five patients were 35 years old or younger, and 4 presented with stage 1EA disease. Although follow-up is 12 months or less in 2 of the 5 patients, to date each has followed an indolent clinical course. These features are different from those of most adult nodal follicular lymphomas but are very similar to those of the pediatric primary testicular follicular lymphomas. Together, the pediatric and adult cases represent a discrete clinicopathologic entity of t(14;18)(q32;q21)/IGH-BCL2-negative primary follicular lymphoma of the testis and epididymis, which typically present as clinically indolent localized disease in young males and should be distinguished from the diffuse large B-cell lymphoma more frequently seen in the testes of older adults.
Assuntos
Epididimo/patologia , Linfoma Folicular/patologia , Neoplasias Testiculares/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Terapia Combinada , Epididimo/química , Humanos , Linfoma Folicular/química , Linfoma Folicular/terapia , Masculino , Neoplasias Testiculares/química , Neoplasias Testiculares/terapia , Resultado do TratamentoRESUMO
PURPOSE: To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL). PATIENTS AND METHODS: From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew's Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. RESULTS: The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed. CONCLUSION: Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.
Assuntos
Linfoma de Células B/patologia , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Células B/terapia , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: The aim of this retrospective analysis was to determine the outcome of patients with follicular lymphoma who received myeloablative therapy supported by autologous bone marrow transplantation as consolidation of second or subsequent remission, with a minimum follow-up of 12 years. PATIENTS AND METHODS: One hundred twenty-one adults received cyclophosphamide (CY) and total-body irradiation (TBI) supported by autologous bone marrow transplantation, with the marrow mononuclear cell fraction having been treated with monoclonal antibodies and complement. Data from St Bartholomew's Hospital and Dana-Farber Cancer Institute were combined for the purpose of this analysis because the patients were treated in an identical manner. RESULTS: Fifty-seven patients are alive, 41 without progression between 9 and 19 years; 64 patients have died, 20 without progression. With a median follow-up of 13.5 years, 60 patients have developed recurrent lymphoma. There is an apparent plateau on the remission duration curve at 48% at 12 years. Survival of patients treated in second remission was significantly longer than the survival of patients treated later in the course of the illness. Both remission duration and overall survival were also significantly longer for patients treated in second remission compared with an age-matched, remission-matched group of patients treated at St Bartholomew's Hospital before the introduction of this treatment. However, use of CY+TBI was associated with a significant risk of secondary myelodysplasia and secondary acute myeloblastic leukemia, resulting in 15 patient deaths. CONCLUSION: These mature data confirm that prolonged freedom from recurrence may be achieved with myeloablative therapy and that a plateau on the curve seems to emerge with long follow-up.
Assuntos
Transplante de Medula Óssea , Linfoma Folicular/terapia , Adulto , Terapia Combinada , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
BACKGROUND: Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction. METHODS: We followed a cohort of 7033 Hodgkin disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided. RESULTS: A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5). CONCLUSIONS: The risk of death from myocardial infarction after treatment for Hodgkin disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Coração/efeitos dos fármacos , Coração/efeitos da radiação , Doença de Hodgkin/terapia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Lesões por Radiação/complicações , Adulto , Fatores Etários , Idoso , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Lesões por Radiação/etiologia , Lesões por Radiação/mortalidade , Radioterapia Adjuvante , Sistema de Registros , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia , Vincristina/efeitos adversosRESUMO
The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and nonengrafters. FLT3 internal tandem duplication (ITD) and nucleophosmin mutations occurred at a similar frequency in engrafters and nonengrafters. The only variable that was related to engraftment ability was the karyotypically defined risk stratification of individual AML cases. Of interest, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID engrafting and nonengrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning, or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and nonengrafting AML cases that correlates with treatment response.
Assuntos
Bioensaio , Sobrevivência de Enxerto , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Transplante de Células-Tronco , Fatores Etários , Animais , Duplicação Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Proteínas Nucleares/genética , Nucleofosmina , Valor Preditivo dos Testes , Prognóstico , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Human hematopoietic stem cells (HSCs) are generally regarded as being devoid of the markers expressed by differentiated blood cells, the lineage-specific antigens. However, recent work suggests that genes associated with the myeloid lineage are transcribed in mouse HSCs. Here, we explore whether myeloid genes are actually translated in human HSCs. We show that CD33, CD13, and CD123, well-established myeloid markers, are expressed on human long-term repopulating cells from cord blood and bone marrow. In addition, we demonstrate that nonobese diabetic/severe combined immunodeficiency (NOD/SCID) leukemia-initiating cells (SL-ICs) are restricted to the CD33+ fraction in 11 of 12 acute myeloid leukemia (AML) samples studied, indicating that leukemic stem cells (LSCs) express this antigen. This study changes our view of HSCs and the process of differentiation. Furthermore, based on the phenotypic similarity of HSCs and LSCs, our data provide support for the hypothesis that AML derives from an HSC. Our findings also provide a challenge to contemporary attempts to improve the outcome of AML using myeloid antigen-targeted therapies, given the potential for HSC killing.
Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Animais , Sangue Fetal/metabolismo , Humanos , Camundongos , Camundongos SCID , Fenótipo , Sensibilidade e EspecificidadeRESUMO
Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme that is responsible for the oxidation of intracellular aldehydes. Elevated levels of ALDH have been demonstrated in murine and human progenitor cells compared with other hematopoietic cells, and this is thought to be important in chemoresistance. A method for the assessment of ALDH activity in viable cells recently has been developed and made commercially available in a kit format. In this study, we confirmed the use of the ALDH substrate kit to identify cord blood stem/progenitor cells. Via multicolor flow cytometry of cord blood ALDH+ cells, we have expanded on their phenotypic analysis. We then assessed the incidence, morphology, phenotype, and nonobese diabetic/ severe combined immunodeficiency engraftment ability of ALDH+ cells from acute myeloid leukemia (AML) samples. AML samples had no ALDH+ cells at all, an extremely rare nonmalignant stem/progenitor cell population, or a less rare, leukemic stem cell population. Hence, in addition to identifying nonmalignant stem cells within some AML samples, a high ALDH activity also identifies some patients' CD34+/ CD38- leukemic stem cells. The incidence of normal or leukemic stem cells with an extremely high ALDH activity may have important implications for resistance to chemotherapy. Identification and isolation of leukemic cells on the basis of ALDH activity provides a tool for their isolation and further analysis.
Assuntos
Aldeído Desidrogenase/metabolismo , Sangue Fetal/enzimologia , Leucemia Mieloide Aguda/sangue , ADP-Ribosil Ciclase/biossíntese , ADP-Ribosil Ciclase 1 , Animais , Antígenos CD/biossíntese , Antígenos CD34/biossíntese , Linhagem Celular Tumoral , Linhagem da Célula , Células Cultivadas , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Glicoproteínas de Membrana , Camundongos , Camundongos SCID , Fenótipo , Células-Tronco/citologiaRESUMO
Follicular lymphoma serves as a paradigm for the other subtypes of non-Hodgkin's lymphoma previously collectively known as 'indolent' or 'low-grade'. As such, its clinical course (that is, the natural history as influenced by conventional therapy) can act as a useful baseline against which the efficacy of new approaches may be assessed. The illness is characterised by repeated responsiveness to treatment but typically this is transient and incomplete. Death occurs at a median of 9-10 years after diagnosis, generally as a consequence of resistant disease, transformation to diffuse large B cell pathology or as a result of side effects of therapy. It has been demonstrated that there is no survival advantage associated with starting treatment prior to there being a clinical need to do so. It is hoped that the advent of new treatment modalities will alter the inexorable pattern of recurrence.
Assuntos
Linfoma Folicular/patologia , Transformação Celular Neoplásica , Progressão da Doença , Humanos , Linfoma Folicular/mortalidade , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , PrognósticoRESUMO
The prognostic significance of IgH/Bcl2 rearrangement in follicular lymphoma (FL) remains contentious; polymerase chain reaction (PCR) methodology and tissue source variability may account for some inconsistencies. As IgH/Bcl2 major breakpoint region (MBR) sequences may be found in normal blood, an MBR+ result by conventional PCR in blood/bone marrow may not indicate FL. To establish tumour MBR status, 190 lymphoid tissue samples with histologically evident FL (and therefore >1% tumour cells) were examined by real-time quantifiable PCR; 50% (95/190) had clonal MBR IgH/Bcl2 (MBR was considered clonal when >1%). Overall survival (median = 11.5 years) of MBR+ and MBR- patients was not significantly different.
Assuntos
Rearranjo Gênico , Genes de Imunoglobulinas , Genes bcl-2 , Linfoma Folicular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quebra Cromossômica , Feminino , Marcadores Genéticos , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Taxa de SobrevidaRESUMO
PURPOSE: This study was undertaken to test the hypothesis that serum selenium concentration at presentation correlates with dose delivery, first treatment response, and overall survival in patients with aggressive B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: The patients presented between July 1986 and March 1999 and received anthracycline-based chemotherapy, radiotherapy, or both. The total selenium content was retrospectively analyzed in 100 sera, frozen at presentation, using inductively coupled plasma mass spectrometry. RESULTS: The serum selenium concentration ranged from 0.33 to 1.51 micromol/L (mean, 0.92 micromol/L; United Kingdom adult reference range, 1.07 to 1.88 micromol/L). Serum selenium concentration correlated closely with performance status but with no other clinical variable. Multivariate analysis revealed that increased dose delivery, summarized by an area under the curve, correlated positively with younger age (P <.001), advanced stage (P =.001), and higher serum selenium concentration (P =.032). Selenium level also correlated positively with response (odds ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.90; P =.011) and achievement of long-term remission after first treatment (log-rank test, 4.38; P =.036). On multivariate analysis, selenium concentration was positively predictive of overall survival (hazard ratio [HR], 0.76 for 0.2 micromol/L increase; 95% CI, 0.60 to 0.95; P =.018), whereas age indicated negative borderline significance (HR, 1.09; 95% CI, 0.99 to 1.18; P =.066). CONCLUSION: Serum selenium concentration at presentation is a prognostic factor, predicting positively for dose delivery, treatment response, and long-term survival in aggressive non-Hodgkin's lymphoma. Unlike most existing prognostic factors in aggressive non-Hodgkin's lymphoma, selenium supplementation may offer a novel therapeutic strategy in this frequently curable malignancy.
Assuntos
Biomarcadores Tumorais/sangue , Linfoma não Hodgkin/sangue , Selênio/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Área Sob a Curva , Bleomicina , Terapia Combinada , Ciclofosfamida , Doxorrubicina , Etoposídeo , Feminino , Humanos , Leucovorina , Modelos Lineares , Linfoma não Hodgkin/terapia , Masculino , Metotrexato , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prednisona , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , VincristinaRESUMO
CEBPA encodes the transcription factor C/EBPalpha and is specifically up-regulated during granulocytic differentiation. The gene is mutated in approximately 20% of patients with acute myeloid leukemia (AML) FAB type M2 and occurs in the absence of the t(8;21). In much the same way as specific translocations are associated with a particular AML FAB type, the identification of non-random associations of gene mutation with karyotype or FAB type may be helpful in elucidating the molecular basis of certain forms of leukemia. To confirm these initial findings, 99 patients with AML FAB type M1 or M2 were screened for CEBPA mutations by use of a PCR-single-strand conformational polymorphism and sequencing approach. Nine CEBPA mutations were identified in eight patients. The mutations were clustered toward the COOH terminal of the protein and occurred exclusively in the intermediate cytogenetic risk group (8/64, 12.5%). Two patients with biallelic mutation, one homozygous for 1137Ins (57 bp) and another with two CEBPA mutations, 1096Ins (27 bp) and 363Ins (GGCC), were observed. There was no evidence for deletion of this region in the other six mutated samples analyzed by fluorescence in situ hybridization with a BAC clone spanning the CEBPA locus. CEBPA mutation status was not demonstrated to be of prognostic importance in this patient group, although this may reflect the selection and size of the AML population studied. In conclusion, mutation of CEBPA is a recurrent finding in AML and appears specific to the intermediate cytogenetic risk group patients.
Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Humanos , Zíper de Leucina/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fatores de RiscoRESUMO
The purpose of this chapter is to review the available information on the use of high-dose treatment (HDT) in large B-cell, follicular and mantle-cell lymphoma. The last 10 years have seen a dramatic increase in the number of patients receiving high-dose treatment with autologous haemopoietic progenitor cell support for non-Hodgkin's lymphoma. In patients with recurrent large B-cell lymphoma, HDT is now accepted as the 'standard of care', provided responsiveness to conventional chemotherapy at the time of recurrence has been demonstrated. In contrast, the situation in newly diagnosed patients is far from clear. Several phase III studies have been conducted, comparing conventional chemotherapy with either: the same treatment followed by HDT or an abbreviated number of cycles of conventional therapy followed by HDT. The results hitherto have not conclusively shown an advantage for HDT. In mantle-cell and follicular lymphoma, HDT should still be regarded as experimental. Current studies are evaluating the use of anti-CD20, given either as part of the treatment prior to HDT or as maintenance therapy. In view of the propensity for both of these illnesses to involve the bone marrow, a number of studies have addressed the question of in vitro treatment of the stem cell product. The advent of PCR analysis has made it possible to evaluate the significance of 'molecular remission'. In follicular lymphoma, there is a correlation between freedom from recurrence and persistent PCR negativity for bcl-2 rearrangement-containing cells in follow-up bone marrow samples.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma de Células B/mortalidade , Linfoma de Células B/terapia , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Linfoma não Hodgkin/mortalidade , Transplante Autólogo , Resultado do TratamentoRESUMO
Elderly patients (age >60 years) with AML who are selected for curative treatment frequently receive anthracycline/cytarabine containing regimens. The anthracendione mitoxantrone (MTN) in combination with cytarabine (Ara-C) produces comparable complete remission rates to other regimens and may be less toxic. Over a 12 year period, 75 patients (median age 67 years, range 60-83 years) referred with newly diagnosed AML were treated with MTN and ara-C. MTN was administered at 12 mg/m(2)/day intravenously for three days in the first 26 patients, and 10 mg/m(2)/day intravenously for five days in a subsequent 49 patients. Ara-C was administered at a dose of 100 mg/m(2) twice daily intravenously for seven days. Complete remission (CR) was achieved in 34 out of 75 patients (45%). The median disease-free survival overall was 7.5 months (one month to nine and a half years). The median survival was one year for patients in whom CR was achieved, compared to four months in patients whom treatment failed (P=0.001). Age alone was predictive of achievement of CR, whilst presentation karyotype, serum LDH and patient age correlated with overall survival. These results confirm that although elderly patients have a poor outcome, prognostic factors can be identified that influence treatment outcome in this important group of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Biomarcadores/sangue , Aberrações Cromossômicas , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Ploidias , Prognóstico , Indução de Remissão/métodos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Peripheral blood (PB) and bone marrow (BM) are used interchangeably for t(14;18) (IgH/BCL-2) molecular monitoring in follicular lymphoma (FL) and detection of rearrangement after treatment has been correlated to increased risk of relapse. To determine the relative value of each tissue, MBR t(14;18) was quantified by real-time polymerase chain reaction in 52 simultaneous paired PB and BM samples from 38 FL patients. In total, 79% of sample pairs taken in remission (n = 19) or when no morphological disease was evident in the BM (n = 29) had t(14;18) copy number within one log difference and the median difference was small. These findings suggest that, in remission, PB may be adequately monitored. In general, however, higher copy number was detected in BM than in the corresponding PB sample.