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1.
J Allergy Clin Immunol ; 148(6): 1559-1574.e13, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33872653

RESUMO

BACKGROUND: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood. OBJECTIVES: This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis. METHODS: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing. RESULTS: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization. CONCLUSIONS: Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.

3.
Pediatr Blood Cancer ; 67(9): e28568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32672896

RESUMO

BACKGROUND: Sickle cell disease (SCD) is associated with renal complications starting as early as infancy. Allogeneic hematopoietic stem cell transplant (HSCT) treatments using newer nonmyeloablative (NMA) conditioning regimens show promising results in treating SCD in the pediatric population, but renal outcome parameters after transplantation have not been described. AIM: To describe baseline renal parameters as well as short- and long-term renal outcomes in pediatric patients with SCD who underwent NMA-HSCT. METHODS: A retrospective chart review of pediatric patients who received NMA-HSCT in Alberta, Canada. Short-term renal outcomes evaluated were: (1) acute kidney injury (AKI), (2) fluid overload (FO), and (3) hypertension. Long-term outcomes evaluated were: (1) estimated glomerular filtration rate (eGFR) development and at last follow-up with hyperfiltration defined as eGFR ≥ 150 mL/min/1.73 m2 , (2) proteinuria, and (3) hypertension. RESULTS: The mean follow-up time was 128.6 weeks (standard deviations, 69.3). No posttransplant AKI events or FO were observed. eGFR remained > 90 mL/min/1.73 m2 at last follow-up in all patients, whereas hyperfiltration was present in eight (44.4%) and four (22.2%) patients pre- and post-HSCT, respectively, which are significantly different (P < 0.0001). Consequently, median GFR was significantly higher pre-HSCT compared with 24 months HSCT (P < 0.009). Long-term hypertension post-HSCT was present in six patients (33.3%). CONCLUSION: This study describes stable kidney function in children with SCD after NMA-HSCT without evidence of AKI or FO episodes. Rates of hyperfiltration decreased post-HSCT, which signifies that NMA-HSCT could potentially preserve long-term renal function in this population at risk of progressive chronic kidney disease. Further prospective studies are needed to confirm these novel findings.


Assuntos
Anemia Falciforme/terapia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertensão/patologia , Proteinúria/patologia , Insuficiência Renal Crônica/patologia , Adolescente , Anemia Falciforme/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Taxa de Filtração Glomerular , Doença Enxerto-Hospedeiro/etiologia , Humanos , Hipertensão/etiologia , Lactente , Recém-Nascido , Masculino , Prognóstico , Proteinúria/etiologia , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Homólogo
4.
J Clin Oncol ; 38(11): 1175-1185, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32105509

RESUMO

PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Radioterapia Conformacional/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Proteína SMARCB1/genética , Teratoma/genética , Teratoma/mortalidade , Adulto Jovem
5.
Blood ; 135(15): 1287-1298, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32047896

RESUMO

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Antígenos CD/análise , Antígenos CD/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores/sangue , Criança , Doença Crônica , Citocinas/sangue , Citocinas/imunologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
6.
J Clin Apher ; 34(5): 598-606, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390093

RESUMO

Factors affecting the success of peripheral blood stem cell collection (SCC) in children are not well characterized. We reviewed 218 stem cell collections among 199 pediatric donors, of which 35 were from healthy sibling donors and 164 were for autologous collections. Successful SCC, defined as a CD34+ cell count of ≥2 × 106 /kg of recipient weight per intended transplant, occurred in 188 of 199 donors (94%). Ideal SCC defined ≥5 × 106 CD34+ cells/kg of recipient per intended transplant, occurred in 147 (74%) patients. Failure of collection occurred in 11 (6%) patients and was significantly associated with an autologous collection for a brain tumor diagnosis (P = .003) and a pre-apheresis peripheral blood (PB) CD34+ count <20 × 106 cells/L (P = .002). Ideal SCC was significantly associated with age < 10 years (P = .01) and pre-apheresis PB-CD34+ count ≥20 × 106 cells/L (P < .0001). Factors associated with failure of SCC may be identified in advance of the collection procedure allowing appropriate counselling of patients as well as anticipatory guidance for multiple collections or justify the preemptive use of stem cell mobilizing agents.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco de Sangue Periférico/citologia , Medição de Risco , Adolescente , Antígenos CD34/análise , Criança , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Estudos Retrospectivos , Irmãos , Doadores de Tecidos , Transplante Autólogo , Falha de Tratamento
7.
Blood ; 134(3): 304-316, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31043425

RESUMO

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Aguda , Adolescente , Fatores Etários , Criança , Pré-Escolar , Doença Crônica , Consensus Development Conferences, NIH as Topic , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Guias de Prática Clínica como Assunto , Fatores de Risco , Índice de Gravidade de Doença , Avaliação de Sintomas , Fatores de Tempo , Transplante Homólogo , Estados Unidos , Fluxo de Trabalho
8.
Biol Blood Marrow Transplant ; 25(6): 1179-1186, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30772511

RESUMO

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.


Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Anemia Falciforme/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Retrospectivos , Irmãos , Doadores de Tecidos
9.
J Clin Endocrinol Metab ; 104(2): 213-222, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247635

RESUMO

Objective: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL). Methods: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status. Results: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m2 increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01). Conclusions: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.


Assuntos
Glucocorticoides/efeitos adversos , Transtornos do Crescimento/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fraturas da Coluna Vertebral/complicações , Adolescente , Antropometria/métodos , Estatura/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Transtornos do Crescimento/fisiopatologia , Humanos , Lactente , Masculino , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais
10.
Pediatr Hematol Oncol ; 35(4): 288-296, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-30592246

RESUMO

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC) is used in solid organ transplant. AUC potentially has an important relationship with the development of acute graft-versus-host-disease (aGVHD). We conducted a prospective study to describe the relationship between severe (grade III-IV) aGVHD and cyclosporine AUC in pediatric HSCT recipients. Pediatric patients who underwent allogeneic myeloablative HSCT and scheduled to receive cyclosporine for aGVHD prophylaxis participated in this multicenter study. Cyclosporine doses were adjusted based on C0 according to each center's standard of care. Cyclosporine AUC was determined weekly until neutrophil engraftment or Day +42, whichever was later. Associations between severe aGVHD and cyclosporine AUC and other patient and treatment-related factors were evaluated. Of the 110 children enrolled, 97 were evaluable. Thirty-seven (38%) children developed aGVHD; 13 (13.4%) had severe aGVHD. On univariate analysis, there was no association between severe aGVHD and cyclosporine AUC at any time point before engraftment. Future research should focus on refinement of C0 targets for cyclosporine therapeutic drug monitoring in HSCT.


Assuntos
Ciclosporina/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Condicionamento Pré-Transplante/métodos
11.
Biol Blood Marrow Transplant ; 24(10): 2040-2046, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29933069

RESUMO

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.


Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Condicionamento Pré-Transplante , Doadores não Relacionados , Proteínas WT1/sangue , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Neoplasia Residual , Transplante Homólogo
13.
Biol Blood Marrow Transplant ; 21(2): 266-74, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25445023

RESUMO

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Recém-Nascido , Cooperação Internacional , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Razão de Chances , Análise de Sobrevida , Transplante Homólogo
14.
Metallomics ; 6(11): 2034-41, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25255207

RESUMO

While cisplatin (CP) is still one of the world's bestselling anticancer drugs, its intravenous administration is inherently associated with severe, dose limiting toxic side-effects. Although the molecular basis of the latter are not well understood, biochemical transformations of CP in blood and the interaction of the generated platinum species with plasma proteins likely play a critical role since these processes will ultimately determine which platinum-species reach the intended tumor cells as well as non-target cells. Compared to healthy subjects, cancer patients often have decreased plasma human serum albumin (HSA) concentrations. Little, however, is known about how the plasma HSA concentration will affect the metabolism of CP. To gain insight, we obtained blood plasma from healthy adults (n = 20, 42 ± 4 g HSA per L) and pediatric cancer patients (n = 11, 26 ± 7 g HSA per L). After the incubation of plasma at 37 °C, a pharmacologically relevant dose of CP was added and the Pt-distribution therein was determined by size-exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer. At the 2 h time point, a 5.9% increase of toxic CP-derived hydrolysis products was detected in pediatric cancer patient plasma, while 9.8% less platinum was protein bound compared to plasma from healthy controls. These in vitro results suggest that the elevated concentration of highly reactive free CP-derived hydrolysis products in plasma may cause the toxic side-effects in cancer patients. More importantly, the deliberate increase of the plasma HSA concentration in cancer patients prior to CP treatment would represent a simple strategy to possibly alleviate the fraction of patients that suffer from drug induced toxic side-effects.


Assuntos
Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , Cisplatino/toxicidade , Cisplatino/uso terapêutico , Neoplasias , Albumina Sérica/metabolismo , Adulto , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Criança , Cisplatino/sangue , Cisplatino/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Albumina Sérica/uso terapêutico
15.
Biol Blood Marrow Transplant ; 20(11): 1847-51, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25016194

RESUMO

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mucolipidoses/terapia , Condicionamento Pré-Transplante/métodos , Pré-Escolar , Coleta de Dados , Humanos , Lactente , Inquéritos e Questionários , Resultado do Tratamento
16.
Br J Haematol ; 162(5): 648-56, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23829536

RESUMO

Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS(+) ) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS(-) ). There were significant baseline differences between the cohorts. CNS(+) patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS(+) group with a subset of CNS(-) patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS(+) patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Avaliação de Estado de Karnofsky , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adulto Jovem
17.
J Clin Oncol ; 31(13): 1669-76, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23547077

RESUMO

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. PATIENTS AND METHODS: We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. RESULTS: Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. CONCLUSION: Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.


Assuntos
Anemia de Fanconi/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/cirurgia , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Risco , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
18.
Leuk Lymphoma ; 54(7): 1505-16, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23176524

RESUMO

Acute lymphoblastic leukemia (ALL) is one of the most prevelant pediatric malignancies. Although cure rates have improved in recent decades, approximately one in five children relapse, and survival rates post-relapse remain low. Therefore, more effective and innovative therapeutic strategies are needed in order to improve the outcome in these children. Aurora kinases, a family of serine/threonine kinases essential for regulated mitosis, are overexpressed in many forms of cancer, and have been identified as potential targets for cancer therapeutics. Based on this premise, we evaluated the activity of the Aurora-A/B inhibitor AT9283 against pediatric leukemia cells. It was found that AT9283 significantly inhibited the growth and survival of cell lines derived from patients with pediatric leukemia. Specifically, AT9283 promoted Flt-3 dephosphorylation, inhibiting the activity of downstream effectors such as Erk and Mek. In addition, apoptotic markers were also identified, providing a panel of markers for biological correlative analysis for drug activity. Lastly, drug combination studies demonstrated the potential of several novel and conventional agents to synergize with AT9283, including apicidin, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and doxorubicin. These data provide a rationale for further studies and the formulation of a clinical trial of AT9283 for the treatment of refractory pediatric ALL.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Criança , Humanos , Concentração Inibidora 50 , Janus Quinase 2/antagonistas & inibidores , Poliploidia , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/toxicidade , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
19.
Blood ; 119(25): 6155-61, 2012 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-22573402

RESUMO

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation-based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell-replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell-replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation-based regimens.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunomodulação/fisiologia , Depleção Linfocítica , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irradiação Corporal Total , Adolescente , Criança , Pré-Escolar , Feminino , Células Precursoras de Granulócitos/patologia , Células Precursoras de Granulócitos/efeitos da radiação , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Contagem de Linfócitos , Depleção Linfocítica/métodos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Doadores não Relacionados , Irradiação Corporal Total/métodos
20.
Biol Blood Marrow Transplant ; 18(2): 280-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21810400

RESUMO

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.


Assuntos
Cariótipo Anormal/classificação , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Cariotipagem/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo
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