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1.
J Clin Oncol ; 18(22): 3809-18, 2000 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11078494

RESUMO

PURPOSE: To evaluate carboplatin, etoposide, and bleomycin (JEB) in children with malignant extracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Malignant GCTs in children aged 0 to 16 years were excised without major morbidity or otherwise biopsied. Stage I testicular and some ovarian GCTs were resected and monitored with alpha-fetoprotein (AFP) ("watch-and-wait" approach). Patients with recurrent stage I disease and all other patients received JEB (etoposide 120 mg/m(2) on days 1 through 3, carboplatin 600 mg/m(2) on day 2, and bleomycin 15 mg/m(2) on day 3). Courses were administered every 3 to 4 weeks until remission, and then two more courses were given. Chemotherapy toxicities were assessed using World Health Organization or Brock grading. RESULTS: Between January 1989 and December 1997, 192 patients were registered. Eight were excluded because either there was no histologic diagnosis (n = 3) or chemotherapy was given off-study (n = 5). The remaining 184 patients had germinoma (n = 20), malignant teratoma (n = 55), embryonal carcinoma (n = 1), yolk sac tumor (n = 107), or choriocarcinoma (n = 1). Forty-seven patients were treated with surgery alone, and 137 patients received JEB. The 5-year survival rate in March 1999 for all 184 patients was 93.2% (95% confidence interval [CI], 87.9% to 96.3%); for the 137 JEB-treated patients, it was 90.9% (95% CI, 83.9% to 95.0%), with an event-free survival rate of 87.8% (95% CI, 81.1% to 92.4%). The median follow-up after JEB treatment was 53 months (range, 0 to 109 months); the median number of courses was five (range, three to eight). Site, stage, and AFP level had prognostic significance. Nonfatal hematologic toxicity was common, but deafness and pulmonary and renal toxicities were rare. One child died of a thoracic tumor and bronchopulmonary dysplasia, and another died of acute myeloid leukemia. CONCLUSION: Conservative surgery, a watch-and-wait approach after complete excision, and JEB for those requiring chemotherapy produced high cure rates and few serious complications.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Germinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Criança , Pré-Escolar , Gonadotropina Coriônica/sangue , Terapia Combinada , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Germinoma/patologia , Germinoma/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Análise de Sobrevida , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , alfa-Fetoproteínas/metabolismo
2.
J Clin Oncol ; 16(3): 931-6, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9508175

RESUMO

PURPOSE: Few patients with Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) have been cured by chemotherapy alone. Registry figures show that 38% of patients who have a matched-sibling bone marrow transplant (BMT) are disease-free 2 years after transplant, but the majority of patients lack a sibling donor. Most modern ALL protocols recommend unrelated donor (UD) BMT for patients with Ph-positive ALL in first complete remission (CR1), but the outcome of this is unknown. PATIENTS AND METHODS: We report the results of 15 children and adolescents who had a T-cell depleted UD-BMT for Ph-positive ALL. Thirteen of 15 had been previously treated on United Kingdom ALL protocols. Nine were in CR1 and six had more advanced disease. Eleven donor recipient pairs were matched at HLA-A, HLA-B, HLA-DR, and HLA-DQ, and four were mismatched at one or two HLA loci. RESULTS: The incidence of greater than grade I acute and chronic graft-versus-host disease (GVHD) was low (13% and 8%, respectively). Six patients have relapsed and seven patients survive at a median of 21 months post-BMT; six of seven are disease free. All seven survivors are in full-time education or work. The 2-year overall and disease-free survivals are 44% +/- 13% and 37% +/- 13% (+/- SE). None of four patients who had mismatched donors survived, but seven of 11 matched recipients survive (P < .05). CONCLUSION: UD-BMT can produce prolonged disease-free survival in young patients with Ph-positive ALL who otherwise would have an extremely poor outlook.


Assuntos
Transplante de Medula Óssea , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Imunologia de Transplantes , Adolescente , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro , Antígenos HLA , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Neoplasia Residual , Indução de Remissão , Análise de Sobrevida
3.
Bone Marrow Transplant ; 35(11): 1041-7, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15806120

RESUMO

Between July 1990 and March 2002, 35 consecutive children with ALL in third complete remission (CR3) underwent stem cell transplantation (SCT) from unrelated donors (UD). All patients received CAMPATH-1M 5-20 mg daily for 5 days. Grafts were T-cell depleted in 30 patients, 29 by CAMPATH antibodies and one by CD34 selection. Median follow-up was 3.8 years (0.3-9.3). Event-free survival (EFS) at 3 years was 35% (SE 8%); relapse rate and transplant-related mortality (TRM) at 3 years was 42 and 23%. Short first complete remission (CR1) <2.5 years was associated with lower EFS (P=0.001), higher TRM (P=0.019) and higher relapse rate (P=0.023). Short second complete remission (CR2) <2.5 years was associated with lower EFS (P=0.003) and higher TRM (0.009). Higher relapse rate and lower EFS were associated with isolated first extramedullary relapse (P=0.019, 0.012). There was no significant difference in outcome between mismatched unrelated donor stem cell transplantation (MMUD-SCT) and matched unrelated donor stem cell transplantation (UD-SCT). We conclude that UD-SCT is an effective treatment of ALL in CR3. The outcome remains limited by TRM and a high relapse rate. Short duration of CR1 and of CR2 and extramedullary site at first relapse are particularly adverse. MMUD should also be considered in high-risk patients, since the outcome of MMUD appears similar to MUD.


Assuntos
Transplante de Medula Óssea/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco/métodos , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos , Antígenos CD34/biossíntese , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunofenotipagem , Masculino , Complicações Pós-Operatórias , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Linfócitos T/citologia , Fatores de Tempo , Resultado do Tratamento
4.
Bone Marrow Transplant ; 36(3): 237-44, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15968291

RESUMO

CAMPATH-1H (C-1H) is widely used in vivo and / or in vitro for T cell depletion in hematopoietic SCT. This humanised monoclonal antibody is specific for CD52, a marker coexpressed on the majority of human lymphocytes with CD48 and other glycosylphosphatidyl-inositol (GPI) anchored proteins. We detected CD52 / CD48 dual expression on >99% of CD3(+) lymphocytes from normal individuals and all 15 post-SCT patients whose transplants did not utilise C-1H. By contrast, 23 / 26 patients with transplants involving C-1H (in vivo, in vitro or both) exhibited populations lacking CD52 expression that accounted for 49.7% (4.2-86.2%) of the CD3+ lymphocytes (median and range) in samples evaluated at a median of 2 months post-SCT. Most CD52- cells also lacked CD48 expression. These GPI- T cells were of either donor or mixed donor / recipient origin. They were predominant in the early months after SCT at times of profound lymphopenia and inversely correlated with the recovery of the absolute lymphocyte count (r= - 0.663, P<0.0001). The presence of CD52- cells has been correlated previously with clinical outcome after CAMPATH therapy for both malignant and nonmalignant diseases.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Antineoplásicos/química , Antineoplásicos/farmacologia , Hemoglobinúria Paroxística/metabolismo , Linfócitos T/citologia , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígenos CD/biossíntese , Antígenos CD/química , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/química , Complexo CD3/biossíntese , Antígeno CD48 , Antígeno CD52 , Separação Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Glicoproteínas/biossíntese , Glicoproteínas/química , Glicosilfosfatidilinositóis/metabolismo , Humanos , Separação Imunomagnética , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco , Linfócitos T/metabolismo , Fatores de Tempo , Quimeras de Transplante , Transplante Homólogo/métodos , Resultado do Tratamento
5.
Leukemia ; 6(11): 1213-9, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1434806

RESUMO

The genetic sequence of the third complementarity determining region (CDR III) of the immunoglobulin heavy chain (IgH) gene was analysed in 55 rearranged alleles from 36 children presenting with B-lineage acute lymphoblastic leukaemia (ALL). This confirmed the unique nature of these rearrangements. However, contrary to the hypothesis that the CDR III is produced by a random process of rearrangement, biased utilisation of diversity (D) segments and of joining (J) regions 4, 5 and 6 was demonstrated. Moreover, preferred sequence boundaries were seen in J regions 1 to 5 and were suggested at the 3'-end of certain D regions, notably D21/9 and DK1. Similar patterns of rearrangement have been noted in normal B-lymphocyte clones. Together with relatively limited N nucleotide addition, these factors may restrict the potential sequence variability at the D-N-J junction. The occurrence of clonal progression by secondary gene rearrangements, such as V-V replacement, favours the use of this site when designing clone-specific oligonucleotide probes for use in monitoring minimal residual disease (MRD). In cases where biased features of D-J rearrangement are shared by both the leukaemic and normal B-lymphocyte clones this could reduce the sensitivity of these probes in detecting low levels of residual disease.


Assuntos
Linfoma de Burkitt/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Sequência de Bases , DNA de Neoplasias/genética , Humanos , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , Reação em Cadeia da Polimerase
6.
Leukemia ; 6(4): 289-94, 1992 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1588791

RESUMO

The polymerase chain reaction (PCR) was used to study clonality in a group of children with B-lineage acute lymphoblastic leukaemia (ALL). Rearrangement of the immunoglobulin heavy chain gene (IgH) results in a hypervariable sequence known as the complementarity determining region III. This can be amplified by the PCR using one pair of consensus primers. The PCR product is highly clone-specific in both size and sequence. Successful amplification was achieved in 50 of 62 cases of B-lineage ALL studied (81%). Both DNA and RNA gave almost identical results. In contrast amplification was only achieved in 2 of 42 control cases (non-B-lineage leukaemias, normal and reactive marrows); these were both cases of T-ALL with IgH rearrangement on Southern blotting. The main advantages of this technique over Southern blot assessment of clonality are the short time to result and requirement for much less DNA allowing study of small samples eg cerebrospinal fluid and testicular biopsies. It is also generally more sensitive for the detection of a malignant clone in a polyclonal marrow cell population and forms the basis of techniques to study minimal residual disease (MRD).


Assuntos
Linfoma de Burkitt/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Sequência de Bases , Southern Blotting , Linfoma de Burkitt/genética , Criança , Pré-Escolar , DNA de Neoplasias/análise , Feminino , Amplificação de Genes , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Região Variável de Imunoglobulina/genética , Lactente , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA Neoplásico/análise
7.
Leukemia ; 15(10): 1596-603, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11587218

RESUMO

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL.


Assuntos
Células Dendríticas/citologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Apresentação de Antígeno/imunologia , Antígenos CD34 , Antígenos Virais/imunologia , Técnicas de Cultura de Células/métodos , Divisão Celular/efeitos dos fármacos , Criança , Pré-Escolar , Citocinas/farmacologia , Citomegalovirus/imunologia , Células Dendríticas/imunologia , Humanos , Imunofenotipagem , Leucócitos Mononucleares/citologia , Indução de Remissão
8.
Leukemia ; 7(8): 1302-14, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8350633

RESUMO

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.


Assuntos
Leucemia/diagnóstico , Linfoma/diagnóstico , Humanos , Leucemia/genética , Linfoma/genética , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Sensibilidade e Especificidade
9.
Leukemia ; 16(9): 1668-72, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12200679

RESUMO

We have retrospectively investigated the relationship between the level of minimal residual disease (MRD) detected in bone marrow taken prior to conditioning therapy and outcome following stem cell transplantation for high risk childhood ALL. Forty-one patients, in whom both a molecular marker of MRD and sufficient archival material was available, were included in the study. All were in remission at BMT: eight in CR1, 32 in CR2 and five in greater than CR2. MRD was measured by PCR amplification of antigen receptor gene rearrangements and clone-specific oligoprobing, the median sensitivity of detection being one leukaemic cell in 10000 normals. Results were classified as high-level positive (if a clonal band was evident after electrophoresis), low-level positive (if MRD was detected only after oligoprobing) and negative. MRD was detected at high levels in 17 patients, at low levels in 10 patients and 14 patients were MRD negative at the time of transplant. The 5-year event-free survival for these groups was 23%, 48% and 78%, respectively (P = 0.022). Limited multivariate analysis confirmed the significance of MRD (P = 0.0095) vs CR status, donor type, sex, immunophenotype and acute GvHD. This study confirms the strong relationship between MRD level and outcome following allogeneic transplantation. In contrast to a previous study we observed that a minority of children with high-level pre-BMT MRD can enter long lasting remission. The possible role for acute GVHD coupled with a graft-versus-leukaemia effect in the clearance of high level MRD in patients with ALL is discussed.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide/terapia , Doença Aguda , Adolescente , Ligação Competitiva , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Rearranjo Gênico do Linfócito T/genética , Genes de Imunoglobulinas/genética , Humanos , Lactente , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Masculino , Neoplasia Residual , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Receptores de Antígenos de Linfócitos T/genética , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento
10.
Am J Med Genet ; 57(2): 369-73, 1995 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-7668365

RESUMO

Lymphocytes from a patient with preclinical late infantile Batten disease were cultured alone and with lymphocytes from donors, and the fate of the curvilinear inclusions characteristic of the disease was monitored by electron microscopy. There was no evidence of transfer of deficient enzyme or factor that might have caused removal of the stored material, and the curvilinear profiles remained in the cultured cells without signs of degradation. Cells stimulated to divide with phytohaemaglutinin did not exhibit storage in culture suggesting that storage is a function of the age of the cell. The patient received a bone marrow transplant at 2 7/12 years while still clinically unaffected, and the effect on lymphocytes and cells in skin and rectal biopsies was monitored by electron microscopy over a period of 9 months until the donor marrow became displaced by the host cells. He has had one seizure and now has neurophysiological evidence of late infantile Batten's disease. Bone marrow transplant may have no effect on material already stored but might prevent further build-up and halt the onset of the clinical symptoms although very recent studies on early (fetal) transplants in sheep with a form of Batten disease have shown no benefit.


Assuntos
Transplante de Medula Óssea , Linfócitos/patologia , Lipofuscinoses Ceroides Neuronais/terapia , Células Cultivadas , Pré-Escolar , Feminino , Humanos , Corpos de Inclusão/patologia , Corpos de Inclusão/ultraestrutura , Lactente , Mucosa Intestinal/patologia , Mucosa Intestinal/ultraestrutura , Ativação Linfocitária , Linfócitos/imunologia , Linfócitos/ultraestrutura , Masculino , Microscopia Eletrônica , Mitógenos , Músculo Liso/patologia , Músculo Liso/ultraestrutura , Lipofuscinoses Ceroides Neuronais/imunologia , Lipofuscinoses Ceroides Neuronais/patologia , Reto/patologia , Reto/ultraestrutura , Pele/patologia , Pele/ultraestrutura
11.
Bone Marrow Transplant ; 7(6): 431-3, 1991 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1831395

RESUMO

Preparation for bone marrow transplantation (BMT) uses the extremely emetogenic combination of chemotherapy and total body irradiation (TBI). Ondansetron is a selective 5-HT3 antagonist and has clear anti-emetic capabilities. The efficacy of the drug was assessed in 15 children (aged 2-17 years) who received high dose cyclophosphamide (on days -6 and -5) and TBI (days -3 to 0 inclusive). During days -6 to -4 when the emetic effect of cyclophosphamide would be most pronounced, 12 of the 15 patients (80%) had fewer than five emetic episodes during their worst 24-h period, 11 (73%) had fewer than three vomits whilst nine (60%) experienced no vomiting or retching. Eleven patients progressed to TBI and 10 (91%) had fewer than five emetic events in the worst 24-h period (days -3 to +2), six (55%) had no vomiting at all. Of 100 evaluable 'patient-days' 83 (83%) were without any vomiting or retching and a further 10 'patient-days' had only one or two emetic episodes. There were no significant side-effects noted and in particular no extrapyramidal reactions. Headaches and constipation, which have been seen in adult studies, were not reported by patient or parent on any of the study days and transient elevation of liver enzymes were noted in only two patients. Ondansetron has a major role in preparing patients for BMT.


Assuntos
Transplante de Medula Óssea , Imidazóis/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Vômito/prevenção & controle , Adolescente , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/normas , Masculino , Ondansetron , Antagonistas da Serotonina/normas , Vômito/etiologia , Irradiação Corporal Total/efeitos adversos
12.
Bone Marrow Transplant ; 8(5): 357-61, 1991 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1768970

RESUMO

Fourteen children with high risk leukaemia received allogeneic bone marrow transplants from HLA-identical MLC-compatible sibling donors. All bone marrows were T cell depleted and a T cell addback was prepared from the donor's peripheral blood so that the mean total number of CD3+ cells given was 2.6 (1.0-4.1) x 10(5)/kg recipient body weight. This was administered as a short infusion prior to the bone marrow. The children were conditioned with 1440 cGy fractionated total body irradiation and cyclophosphamide 120 mg/kg and were not given cyclosporin A or methotrexate. All patients engrafted and none showed late graft rejection. Acute graft-versus-host disease (GVHD) developed in nine of 14 children and required treatment with steroids. Two children with grade IV GVHD and one with grade I acute GVHD who subsequently developed severe chronic GVHD died. There have been two relapses (both fatal) and one death from cytomegalovirus pneumonitis. Survival is currently 57% (8/14) with a mean follow-up of 548 days (range 384-810). A high incidence of GVHD which was fatal in three patients can occur despite infusion of low T cell numbers in the absence of post-graft immunosuppression.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Leucemia/cirurgia , Linfócitos T/imunologia , Adolescente , Transplante de Medula Óssea/imunologia , Transplante de Medula Óssea/patologia , Contagem de Células , Criança , Pré-Escolar , Feminino , Antígenos HLA , Humanos , Depleção Linfocítica , Masculino , Linfócitos T/patologia , Transplante Homólogo
13.
Bone Marrow Transplant ; 33(3): 303-10, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14647252

RESUMO

Gram-negative infection is an important cause of morbidity and mortality after unrelated donor-bone marrow transplantation (UD-BMT). We performed a retrospective case-control study to examine the risk factors, prophylaxis, therapy and outcome of Gram-negative bacteraemia (GNB) in 428 patients undergoing UD-BMT. The incidence of GNB was 3.6% in children and 19% in adults. Of the adults, 11% developed GNB >60 days post UD-BMT. Predisposing risk factors for GNB included 'high-risk' disease status, chronic graft-versus-host disease and use of systemic steroids. Fever, a raised C-reactive protein (CRP) and hypotension were common findings at presentation. Patients were routinely given prophylactic ciprofloxacin: resistance to this antibiotic was seen in 33% of isolates. We identified an age-matched control group undergoing UD-BMT over the same time period as the study group. Gram-positive bacteraemia was significantly more common in cases than controls. Mortality from GNB was 17% in children and 24% in adults. We conclude that GNB is a common complication of UD-BMT with a high associated mortality. Patients should be educated further to present rapidly with symptoms suggestive of infection.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Bactérias Gram-Negativas/etiologia , Adolescente , Adulto , Antibioticoprofilaxia , Bacteriemia/etiologia , Transplante de Medula Óssea/métodos , Estudos de Casos e Controles , Criança , Pré-Escolar , Ciprofloxacina/uso terapêutico , Farmacorresistência Bacteriana , Feminino , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/mortalidade , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
14.
Bone Marrow Transplant ; 20(7): 599-605, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9337063

RESUMO

Donor leukocyte infusions (DLI) have been used effectively to induce remission in patients who relapse after BMT. Using CD34+ cell immunoaffinity enrichment, donor T cells may be captured in the unadsorbed (residual) fraction and we assessed this as a potential source of functional T cells for post-BMT immunotherapy. We extended our study to compare CD34+ cell selection and antibody-mediated cell lysis using Campath-1M and measured T cell-depletion, CD34+ cell recovery and relative progenitor proliferative potential. The recovery of CD3+ cells (responsive to IL-2 or PHA) in the unadsorbed fraction was 84+/-12% (mean+/-s.d.) using a laboratory scale CD34+ cell selection process (CEPRATE LC). The immunoselected (CD34+ cell enriched) product contained 55+/-12% of the starting CD34+ cells (purity, 75+/-6%) with recoveries of 44+/-12% and 42+/-13% for CFU-GM and BFU-E respectively. T cell depletion was 99.8+/-0.2% (FACS) and the frequency of clonable T cells estimated at 1:640 (limiting dilution assay). In comparison, Campath-1M-treated marrow samples gave recoveries of CD34+ cells, CFU-GM and BFU-E of 50+/-7%, 78+/-20% and 79+/-18%, respectively. The frequency of clonable T cells was 1:2700 despite an estimated T cell depletion of 98.4+/-1.9%. Data obtained from four BM harvests processed on the clinical grade CEPRATE SC system was comparable in every respect to the laboratory scale system. The yield of 1259 +/- 222 x 10(6) CD3+ cells in the unadsorbed fraction would allow for multiple graded incremental T cell aliquots for DLI for patients with acute leukaemia.


Assuntos
Anticorpos Monoclonais/análise , Antígenos CD34/análise , Antígenos CD/análise , Antígenos de Neoplasias , Transplante de Medula Óssea , Glicoproteínas , Imunoterapia Adotiva , Depleção Linfocítica/métodos , Alemtuzumab , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos , Antígenos CD/imunologia , Antígenos CD34/imunologia , Antígeno CD52 , Humanos , Técnicas de Imunoadsorção , Transfusão de Leucócitos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
15.
Bone Marrow Transplant ; 25(4): 395-9, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10723582

RESUMO

A retrospective, case-matched analysis of the short-term toxicity, risk of GVHD and relapse as well as outcome in pediatric unrelated marrow transplantation was conducted by comparing recipients of T-replete and -depleted grafts in a two-center setting. Both groups contained 30 patients with acute leukemia matched by age at transplant, gender, primary diagnosis and disease status. Acute (90% vs 53%) and chronic (48% vs 0%) GVHD were more common among recipients of T-replete grafts. No significant differences in graft rejection/failure or viral infections were encountered between the two groups. Relapses were more prevalent (37% vs 15%) among recipients of T-depleted grafts. Outcome (EFS) was similar in the two groups. Consequently, in the analysis of transplant outcome, the higher risk of procedure-related, toxic complications among pediatric recipients of T-replete marrow grafts appears to be balanced by an increased risk of relapse among the recipients of T-depleted grafts.


Assuntos
Transplante de Medula Óssea , Leucemia/terapia , Doença Aguda , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Leucemia/imunologia , Depleção Linfocítica , Masculino , Estudos Retrospectivos , Imunologia de Transplantes , Transplante Homólogo , Resultado do Tratamento
16.
Bone Marrow Transplant ; 29(2): 113-5, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11850704

RESUMO

The use of zanamivir in seven patients with influenza (three A and four B) post allograft is described. Inhaled zanamivir (10 mg twice daily) was continued from the diagnosis of influenza until excretion of virus ceased (median duration 15 days, range 5 to 44 days). There was no toxicity attributable to zanamivir and rapid resolution of influenza symptoms was seen. There was no mortality due to influenza in the seven patients. The good outcome of 30 previous patients with influenza post transplant is described. A randomised multicentre study would be required to demonstrate efficacy.


Assuntos
Antivirais/uso terapêutico , Vírus da Influenza A , Vírus da Influenza B , Influenza Humana/tratamento farmacológico , Ácidos Siálicos/uso terapêutico , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Antivirais/efeitos adversos , Feminino , Guanidinas , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Influenza Humana/etiologia , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/terapia , Piranos , Ácidos Siálicos/efeitos adversos , Transplante Homólogo , Resultado do Tratamento , Zanamivir
17.
Bone Marrow Transplant ; 21(7): 687-90, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9578308

RESUMO

Graft failure is a common and severe complication of unrelated donor bone marrow transplantation (UD-BMT). However, there are few reports of a second UD-BMT in this setting. We describe 12 patients with graft failure (five primary, seven secondary) who had a second transplant, five from their original donor and seven from a different donor. Their median age was 9 years. Two patients died before day 10 of regimen-related toxicity. Nine of 10 evaluable patients engrafted in a median of 17 days. Secondary graft failure was seen in one patient. Transplant-related morbidity was significant. Six of nine developed acute GHVD, there were five severe infections and five patients developed Bearman grade 3 or 4 extramedullary toxicity. Overall, five patients survive at a median of 38 months after the second BMT and two are in continuous complete remission. Second transplants from unrelated donors for graft failure can result in prolonged survival.


Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto , Leucemia/terapia , Doadores de Tecidos , Adolescente , Criança , Pré-Escolar , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Transplante Homólogo , Resultado do Tratamento
18.
Bone Marrow Transplant ; 22(2): 117-24, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9707017

RESUMO

An advantage of CD34+ cell selection over antibody purging is that a component allograft is produced comprising a stem cell enriched and an unadsorbed fraction, the latter containing T cells which may be used for post-transplant immunotherapy. Initial reports with PBSC allografts suggested that T cell depletion (TCD) by CD34+ cell selection and post-graft cyclosporin A +/- methotrexate was insufficient prophylaxis against acute GVHD. We compared sequential TCD (of a CD34+ cell-selected fraction) using a second (CD2) immunoaffinity step or Campath-1M monoclonal antibody and complement. Since a high stem cell 'dose' enhances engraftment across HLA barriers and improves overall post-transplant outcome, the recovery of CD34+ cells and progenitors were assessed. Sequential positive (CD34+) and negative (CD2+) immunoaffinity selection resulted in a 3.4 log depletion of T cells as compared to a 4.05 log depletion when CD34+ cell selection was followed by Campath-1M treatment. Recoveries of CD34+ cells, CFU-GM and BFU-E following double depletion using CD34+ cell selection plus CD2+ cell depletion were 28, 25 and 17% as compared to 20, 18 and 16% when CD34+ cells were treated with Campath-1M. The unadsorbed fraction contained 85% of the original T cells, from which donor leukocyte infusions in the range of 10(5) to 10(7) CD3+ cells per kg body weight of the recipient were harvested. Despite the advantages of component allografts, the loss of stem/progenitor cells may restrict sequential TCD steps unless single BM harvests are supplemented and/or replaced with mobilised PBSCs.


Assuntos
Anticorpos Monoclonais/farmacologia , Purging da Medula Óssea , Transplante de Medula Óssea , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Depleção Linfocítica/métodos , Alemtuzumab , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos , Antígenos CD34 , Humanos , Técnicas de Imunoadsorção , Linfócitos T/imunologia , Transplante Autólogo , Transplante Homólogo
19.
Bone Marrow Transplant ; 17 Suppl 2: S62-4, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8722340

RESUMO

Six patients with high risk haematological malignancies received peripheral blood progenitor cells (PBPC) from unrelated donors. Four patients received PBPC as primary treatment and 2 following graft failure. Five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-6 days. The patients received a range of 3.4 to 11.4 x 10(8) mononuclear cells/kg and 1.0 to 15.0 x 10(6) CD34 positive cells/kg. Four patients were given Campath 1G and 2 ATG prior to transplantation. The patient with one antigen mismatch received in vitro T-cell depleted PBPC using Campath 1M. All received cyclosporin and 5 in addition methotrexate. All recipients were given G-CSF and all engrafted. The patients developed no or mild acute GVHD. Two patients had limited chronic GVHD of the skin. The recipient of the mismatched graft died from extensive chronic GVHD. Three patients have had a relapse and two are alive and free of leukaemia.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Antígenos CD4 , Criança , Feminino , Doença Enxerto-Hospedeiro/etiologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/citologia , Transplante Homólogo
20.
Bone Marrow Transplant ; 11(1): 7-13, 1993 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8431713

RESUMO

Serial assessment of peripheral blood T and B cell recovery and serum immunoglobulins was performed in 19 children for the first year following BMT and compared with normal values established from healthy children. Immunophenotypic analysis on bone marrow was performed in selected cases by Southern blotting of the immunoglobulin heavy chain (IgH) gene. We found no significant differences between T cell-replete or depleted allogeneic bone marrow transplants. Lymphocyte numbers were low until 9 months post-BMT. T cell numbers (CD2, CD3, CD5) were also low until 12 months but B cell numbers (CD19) became normal at 3 months. Both CD4+ and CD8+ T cell subsets were low post-BMT with depression of CD4+ greater and more prolonged than that of CD8+. No overshoot of CD8+ was seen. The principal effect of GVHD or its treatment was further depression of CD4+ cells but with no increase in CD8+; recovery of B cells was also delayed. Recovery of IgG was slow with only six of 11 children reaching an age-adjusted normal level by 1 year, whereas there was more rapid recovery of IgM and IgA. Several children had an increase in lymphocytes of immature appearance in their bone marrow at varying times post-BMT with increased cells of phenotype CD19+, CD10+, HLA-DR+ and TdT+. In each case Southern blotting showed a germline pattern of the IgH indicating a polyclonal early B cell regenerative population.


Assuntos
Transplante de Medula Óssea/imunologia , Adolescente , Linfócitos B/patologia , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Sistema Imunitário/fisiologia , Imunoglobulinas/sangue , Contagem de Leucócitos , Masculino , Regeneração , Linfócitos T/patologia , Fatores de Tempo
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