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1.
Lancet ; 402(10396): 129-140, 2023 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-37352885

RESUMEN

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Recién Nacido , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Longitudinales , Tamizaje Neonatal , Modelos de Riesgos Proporcionales , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/genética
2.
J Allergy Clin Immunol ; 151(2): 547-555.e5, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36456360

RESUMEN

BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.


Asunto(s)
Inmunodeficiencia Combinada Grave , Recién Nacido , Humanos , Lactante , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Estudios Retrospectivos , Estudios Prospectivos , Proteínas de Homeodominio/genética
3.
J Allergy Clin Immunol ; 149(3): 1097-1104.e2, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34375618

RESUMEN

BACKGROUND: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. OBJECTIVE: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders. METHODS: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models. RESULTS: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001). CONCLUSIONS: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfohistiocitosis Hemofagocítica , Busulfano/uso terapéutico , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Linfohistiocitosis Hemofagocítica/terapia , Melfalán/uso terapéutico , Tiotepa , Acondicionamiento Pretrasplante/efectos adversos , Vidarabina/uso terapéutico
4.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30660643

RESUMEN

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.


Asunto(s)
Ligando de CD40/deficiencia , Trasplante de Células Madre Hematopoyéticas , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapia , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Resultado del Tratamiento , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/mortalidad
5.
N Engl J Med ; 371(5): 434-46, 2014 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-25075835

RESUMEN

BACKGROUND: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave/terapia , Complejo CD3/sangre , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Inmunoglobulina A/sangre , Incidencia , Lactante , Recuento de Linfocitos , Masculino , Retratamiento , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/mortalidad , Hermanos , Tasa de Supervivencia , Linfocitos T/inmunología , Acondicionamiento Pretrasplante , Resultado del Tratamiento
6.
Indian J Crit Care Med ; 20(10): 617-619, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27829721

RESUMEN

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency due to mutations in the WAS gene expressed in hematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice when an appropriate human leukocyte antigen-matched donor is available. The use of the extracorporeal membrane oxygenation (ECMO) circuit to infuse donor cells for HSCT has not been previously published in the literature. We describe a case of a child who had successful engraftment after HSCT with infusion of the donor stem cells through the ECMO circuit.

7.
Nat Commun ; 15(1): 3258, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38637498

RESUMEN

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Virosis , Humanos , Niño , Herpesvirus Humano 4 , Factores de Riesgo , Trasplante de Células Madre Hematopoyéticas/efectos adversos
8.
N Engl J Med ; 362(7): 600-13, 2010 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-20164484

RESUMEN

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Hemorragia/prevención & control , Transfusión de Plaquetas , Trombocitopenia/terapia , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/etiología , Hemostasis , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Recuento de Plaquetas , Transfusión de Plaquetas/efectos adversos , Transfusión de Plaquetas/métodos , Trombocitopenia/etiología
9.
J Pediatr Hematol Oncol ; 34(6): e241-5, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22584776

RESUMEN

A variety of clinical and laboratory parameters have been used to predict bacteremia. We hypothesize that the generation of a cytokine profile could be used to identify patients at higher risk of bacteremia at the time of presentation with febrile neutropenia. We prospectively evaluated children with cancer who presented with an episode of febrile neutropenia. A multiplexed flow cytometric assay was performed which measured 15 cytokines and chemokines obtained before the initiation of antibiotics. Fifty-eight episodes of chemotherapy-induced febrile neutropenia were included in this study during which 4 patients (7%) had bacteremia. An interleukin-5 level of >8 pg/dL had a sensitivity of 67% and a specificity of 96% to predict bacteremia. An monocyte chemotactic protein-1 level >1650 pg/dL had a sensitivity of 80% and a specificity of 82% to predict bacteremia. Erythrocyte sedimentation rate, C-reactive protein, protein C, and other cytokines/chemokines were not predictive of bacteremia. Elevations of interleukin-5 and monocyte chemotactic protein-1 are predictive of bacteremia in children with cancer who have febrile neutropenia. Prospective studies should be undertaken to determine whether these parameters retain predictive value in a larger series of patients and can select children for outpatient management or early discharge.


Asunto(s)
Bacteriemia/diagnóstico , Biomarcadores/sangre , Quimiocina CCL2/sangre , Interleucina-5/sangre , Neoplasias/tratamiento farmacológico , Neutropenia/diagnóstico , Antineoplásicos/efectos adversos , Bacteriemia/sangre , Bacteriemia/inducido químicamente , Niño , Femenino , Humanos , Masculino , Neutropenia/sangre , Neutropenia/inducido químicamente , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Sensibilidad y Especificidad
10.
Pediatr Blood Cancer ; 57(4): 666-8, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21826781

RESUMEN

BACKGROUND: A routine chest radiograph is often performed to evaluate initial fever in patients undergoing hematopoietic stem cell transplantation (HSCT) given the signs and symptoms of infectious pulmonary pathology may be subtle or absent. Studies in patients receiving conventional chemotherapy have shown that chest radiographs do not appear to be helpful in the evaluation of asymptomatic patients with febrile neutropenia. We performed a retrospective review of pediatric stem cell transplant recipients to determine if chest radiographs are useful in the evaluation of initial fever. PROCEDURE: We retrospectively identified 81 consecutive pediatric hematopoietic stem transplant recipients who had a chest radiograph performed as a routine part of the evaluation of initial fever during stem cell transplantation. RESULTS: Seventy-six (94%) of the chest radiographs performed had no evidence of pulmonary infiltrate. Of the five children with positive radiographs, three had symptomatic respiratory infection and two (40%) were asymptomatic. One asymptomatic patient had a history of pulmonary infection with persistent stable infiltrates prior to transplantation. This patient did not have any evidence of pneumonia during the transplant. The second asymptomatic patient had subsequent resolution of the infiltrate with antibiotic administration. None of the patients had a change made in the empiric antibiotic regimen based upon the results of the chest film. CONCLUSIONS: Routine radiographs are not useful in the evaluation of asymptomatic children at the time of an initial febrile event while undergoing HSCT.


Asunto(s)
Fiebre/diagnóstico por imagen , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Adolescente , Niño , Preescolar , Femenino , Fiebre/etiología , Humanos , Lactante , Masculino , Radiografía Torácica , Infecciones del Sistema Respiratorio/diagnóstico , Estudios Retrospectivos , Adulto Joven
11.
Open Forum Infect Dis ; 8(11): ofab481, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34805427

RESUMEN

BACKGROUND: Patients with hematological malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at risk of developing invasive fungal infections, but the quantitative risk posed by exposure to airborne mold spores in the community has not been well characterized. METHODS: A single-institution, retrospective cohort study was conducted of pediatric patients treated for hematological malignancies and HSCT recipients between 2014 and 2018. Patients with invasive fungal disease (IFD) due to molds or endemic fungi were identified using published case definitions. Daily airborne mold spore counts were obtained from a local National Allergy Bureau monitoring station and tested for association with IFD cases by 0-inflated Poisson regression. Patients residing outside the region or with symptom onset more than 2 weeks after admission were excluded from the primary analysis. RESULTS: Sixty cases of proven or probable IFD were identified, of whom 47 cases had symptom onset within 2 weeks of admission and were therefore classified as possible ambulatory onset. The incidence of ambulatory-onset IFD was 1.2 cases per 10000 patient-days (95% CI, 0.9-1.7). A small excess of ambulatory-onset IFD was seen from July through September, during which period spore counts were highest, but this seasonal pattern did not reach statistical significance (P = .09). No significant association was found between IFD cases and community mold spore counts over intervals from 1 to 6 weeks before symptom onset. CONCLUSIONS: There was no significant association between IFD cases and community airborne mold spore counts among pediatric hematological malignancy and HSCT patients in this region.

13.
J Clin Oncol ; 22(8): 1413-9, 2004 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-15084615

RESUMEN

PURPOSE: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. PATIENTS AND METHODS: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m(2) cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m(2) and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. RESULTS: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m(2) in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m(2). Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m(2). This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curve(last) was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. CONCLUSION: The recommended dose of tirapazamine given with 1,500 mg/m(2) of cyclophosphamide once every 3 weeks is 325 mg/m(2). Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Neoplasias/tratamiento farmacológico , Triazinas/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Ciclofosfamida/efectos adversos , Ciclofosfamida/metabolismo , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Tirapazamina , Triazinas/efectos adversos , Triazinas/metabolismo
14.
Leuk Lymphoma ; 44(2): 343-8, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12688355

RESUMEN

The role of the thymus in immune reconstitution in adults receiving chemotherapy is controversial. Detection of T-cell-receptor gene rearrangement excisional circles (TREC) in peripheral blood T cells has been shown to estimate thymic output. Therefore, we measured TREC levels to assess the contribution of the thymus to immune recovery following treatment with fludarabine. Patients who had received fludarabine alone or a fludarabine containing regimen were identified. Cryopreserved peripheral-blood mononuclear cells were obtained and analyzed by four-color flow cytometry utilizing fluorochrome-conjugated antibodies against CD4, CD8, CD45RO and CD27. Proportions of naïve T cells in each CD4+ and CD8+ subset were measured by gating on CD45RO-negative, CD27+ cells. Quantification of TREC in sorted naïve CD4+ and CD8+ T cells was performed by real-time PCR. Thirteen patients received a mean of 3.8 +/- 0.4 courses of fludarabine and samples were obtained at a average of 18.8 (range 3.6-40.3) months after completing chemotherapy. Ten (77%) had detectable TREC levels. There was a positive correlation (Spearman's rank correlation) between the degree of TREC expression and the percentage of naïve T cells (r = 0.6, p = 0.03), naïve CD4+ (r = 0.6, p = 0.03) and naïve CD8+ (r = 0.66, p = 0.01) cells. We conclude that increased thymic output as demonstrated by an increase in TREC levels correlated with, and was predictive ofincreased numbers of naive T cell following fludarabine administration. The thymus appears to play a role in immune recovery in adults after receiving chemotherapy.


Asunto(s)
Reordenamiento Génico de Linfocito T , Timo/fisiología , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto , Anciano , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Sistema Inmunológico/efectos de los fármacos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Timo/inmunología , Vidarabina/farmacología
15.
Pediatr Infect Dis J ; 32(9): 933-6, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23538522

RESUMEN

BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy. METHODS: We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected. RESULTS: One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit. CONCLUSIONS: Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.


Asunto(s)
Antifúngicos/administración & dosificación , Quimioprevención/métodos , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Pentamidina/administración & dosificación , Neumonía por Pneumocystis/prevención & control , Administración Intravenosa/efectos adversos , Adolescente , Antifúngicos/efectos adversos , Quimioprevención/efectos adversos , Niño , Preescolar , Femenino , Humanos , Masculino , Pentamidina/efectos adversos , Pneumocystis carinii/efectos de los fármacos , Estudios Retrospectivos , Resultado del Tratamiento
16.
Crit Care Nurs Clin North Am ; 23(2): 349-76, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21624696

RESUMEN

Medical and nursing care of the hematopoietic stem cell transplantation (HSCT) recipient are complex because of the pathophysiology, HSCT process, pre-HSCT conditioning regimens, numerous medications and therapies, acute and chronic complications, adverse effects, resources involved, and environmental considerations. The HSCT process and therapies may affect any body system, requiring proficient and prioritized nursing care, possibly in an intensive care setting. Understanding the timing of potential adverse effects and complications based on engraftment will help provide competent, high-acuity care. Although autogenic and allogeneic HSCT are curative treatment options, there are numerous morbidity and/or mortality risks throughout the HSCT journey.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/enfermería , Enfermería Pediátrica/métodos , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Atención de Enfermería , Estados Unidos
18.
Pediatr Blood Cancer ; 49(5): 751-4, 2007 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16421913

RESUMEN

We report the cases of two children presenting with severe airway compromise secondary to a mediastinal malignancy managed with extracorporeal membrane oxygenation without intubation. Results are presented on the use of ECMO as a primary means of stabilizing a pediatric patient with a critical mediastinal mass, thus providing another management strategy for this difficult situation.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Neoplasias del Mediastino/terapia , Antineoplásicos/uso terapéutico , Niño , Preescolar , Humanos , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Radiografía , Inducción de Remisión , Insuficiencia Respiratoria/etiología
19.
J Pediatr Hematol Oncol ; 24(8): 662-5, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12439040

RESUMEN

The authors report a fatal case of acute bacterial myocarditis in a nonneutropenic child with acute lymphoblastic leukemia. She was admitted to the hospital with a urinary tract infection resulting from and remained persistently febrile despite resolution of the infection. On hospital day 4 signs of acute cardiac failure developed. Despite aggressive resuscitation measures, she died. Pathologic examination revealed the cause of death to be bacterial myocarditis. In addition, she was found to have a generalized decrease in her serum immunoglobulin levels. Acute bacterial myocarditis in patients with malignancy has been rarely reported. The rapid clinical deterioration and death in the patient in this report is particularly interesting.


Asunto(s)
Infecciones por Klebsiella/etiología , Klebsiella pneumoniae , Miocarditis/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Enfermedad Aguda , Agammaglobulinemia/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cefotaxima/uso terapéutico , Niño , Quimioterapia Combinada/uso terapéutico , Resultado Fatal , Femenino , Humanos , Huésped Inmunocomprometido , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/aislamiento & purificación , Miocarditis/microbiología , Oxacilina/uso terapéutico , Pericarditis/etiología , Pericarditis/microbiología , Pleuresia/etiología , Pleuresia/microbiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inducción de Remisión , Dolor de Hombro/etiología , Tobramicina/uso terapéutico , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Infecciones Urinarias/complicaciones , Infecciones Urinarias/microbiología
20.
J Pediatr Hematol Oncol ; 24(9): 710-3, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12468909

RESUMEN

PURPOSE: This study was undertaken to determine if central venous catheter (CVC)-related infection in children with cancer could be prevented by monthly flushing of the catheter with urokinase. PATIENTS AND METHODS: Between August 1994 and July 1998, 103 patients with cancer were randomized at the time of subcutaneous CVC placement to receive monthly flushing of their catheters with either 5000 IU of urokinase-heparin or heparin alone. Patients subsequently had blood cultures taken from their CVCs during an episode of fever. RESULTS: Seventy-four of the 103 patients (72%) enrolled in the study received at least 6 catheter flushes: 40 with urokinase-heparin and 34 with heparin. The median number of flushes was 9.5 in the urokinase-heparin group and 10.2 in the heparin-only group (P = 0.62). There were 5 positive blood cultures in the urokinase-heparin group and seven in patients receiving heparin alone (P = 0.27). Staphylococcus epidermidis was isolated from the blood of 3 patients receiving urokinase-heparin and 6 in those receiving heparin alone (P = 0.17). CONCLUSION: Prophylactic monthly catheter flushes with 5000 IU urokinase did not significantly decrease the number of documented bacteremic events in children with cancer who have CVCs.


Asunto(s)
Bacteriemia/prevención & control , Cateterismo Venoso Central/efectos adversos , Heparina/uso terapéutico , Activadores Plasminogénicos/uso terapéutico , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéutico , Adolescente , Adulto , Anticoagulantes/uso terapéutico , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Lactante , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Masculino , Neoplasias/tratamiento farmacológico
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