BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with 85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m 2 , alemtuzumab 54 mg/m 2 (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.Bone Marrow Transplantation (2014) 49, 913-920;
Background No prior reports documenting the safety and diagnostic yield of cardiac catheterization and endomyocardial biopsy (EMB) in heart transplant recipients include multicenter data. Methods Data on the safety and diagnostic yield of EMB procedures performed in heart transplant recipients were recorded in the Congenital Cardiac Catheterization Outcomes Project database at 8 pediatric centers over a 3 year period. Adverse events (AE) were classified according to a 5 level severity scale. Generalized estimating equation models identified risk factors for high severity adverse events (HSAE) (Levels 3-5) and non-diagnostic biopsy samples. Results A total of 2665 EMB cases were performed in 744 pediatric heart transplant recipients (median age 12 years [IQR: 4.8,16.7] and 54% male). AE occurred in 88 cases (3.3%), of which 28 (1.1%) were HSAE. AE attributable to EMB included tricuspid valve injury, transient complete heart block, and RBBB. Amongst 822 cases involving coronary angiography, 10 (1.2%) resulted in a coronary related AE. There were no myocardial perforations or deaths. Multivariable risk factors for HSAE included fewer prior catheterizations (p=0.006) and longer case length (p=<0.001). EMB yielded sufficient tissue for diagnosis in 99% of cases. Longer time since heart transplant was the most significant predictor of a non-diagnostic biopsy sample (p<0.001). Conclusions In the current era, cardiac catheterizations involving EMB can be performed in pediatric heart transplant recipients with a low AE rate and high diagnostic yield. Risk of HSAE is increased in early post-transplant biopsies and with longer case length. Longer time since heart transplant is associated with non-diagnostic EMB sample.
Obesity is a multigenic trait that is a major risk factor for a number of common diseases, particularly Type II (non-insulin-dependent) diabetes mellitus, cardiovascular disease and hypertension. A recent review reported a total of 44 genomic locations with possible linkage to one or more obesity-related phenotypes [1]. Because false positive findings are common in genome scans for complex traits, replication is essential before undertaking gene identification studies. Previously, linkages for obesity traits have been replicated in three regions, 2p21, 7q31, and 20q13 [1].To date one of the strongest findings of linkage was reported by French investigators, linking obesity (BMI ³ 27 kg/m 2 ) to markers in chromosome 10p12 [2]. Recently [3], these results were replicated in a cohort of German families. In our previous genome scan [4], we did not find significant linkage to this region, although we did find secondary linkages for centromeric and distal 10 q markers, corresponding to secondary peaks found in the French study for a leptin phenotype. Our genome scan had a relatively small sample size of only 92 families and we examined more extreme levels of obesity (BMI ³ 30 kg/m 2 and BMI ³ 40 kg/m 2 ) and we did not have dense marker coverage in the region of the French linkage finding.In the current analysis, we examined linkage in this region in cohorts of 170 European-American and 43 African-American families (including the 92 families from the original genome scan). AbstractAims/hypothesis. Obesity is a complex trait influenced by multiple genes. We evaluated linkage in three regions of human chromosome 10 previously linked to obesity-related phenotypes. Methods. We conducted non-parametric linkage analysis of obesity-related phenotypes in cohorts of 170 European-American and 43 African-American families having extremely obese and normal weight subjects.
Summary Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.
Pediatric donor hearts are regularly refused for donor quality with limited evidence as to which donor parameters are predictive of poor outcomes. We compare outcomes of recipients receiving hearts previously refused by other institutions for quality with the outcomes of recipients of primarily-offered hearts. Data for recipients aged ≤ 18 and their donors were obtained. Specific UNOS refusal codes were used to place recipients into refusal and non-refusal groups; demographics, morbidity, and mortality were compared. Kaplan-Meier analysis with log-rank test was used to determine differences in graft survival. A multivariable Cox proportional hazards model was constructed to determine independent risk factors for post-operative mortality. From 7/1/2000-4/30/2011, 182 recipients were transplanted and included for analysis. 130 received a primarily-offered heart; 52 received a refused heart. No difference in post-operative complications or graft survival between the two groups (p=0.355) was found. Prior refusal was not an independent risk factor for recipient mortality. Analysis of this large pediatric cohort examining outcomes with quality-refused hearts shows that in-hospital morbidity and long-term mortality for recipients of quality-refused hearts is no different than recipients of primarily-offered hearts, suggesting that donor hearts previously refused for quality are not necessarily unsuitable for transplant and often show excellent outcomes.
Organ transplantation from ABO blood groupincompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/ graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.
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