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1.
Pediatr Blood Cancer ; : e28337, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32391969

RESUMO

Hereditary hemolytic anemias (HHA) are a heterogeneous group of anemias associated with decreased red cell survival. While there can be clinical benefit of splenectomy in many cases, splenectomy is not appropriate for all types of HHA. Additionally, there are significant risks during and following splenectomy including surgical risks, postsplenectomy sepsis, and thrombotic complications. This review discusses the diagnostic approach to HHA as well as the role of splenectomy in the management. Surgical approaches and outcomes for total and partial splenectomy are discussed.

3.
Front Physiol ; 10: 815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333484

RESUMO

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or ß-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1-associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1-associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients' reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression αLEPRA allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis, either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1-associated HS and guide toward appropriate management.

4.
Am J Hematol ; 94(7): 741-750, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30945320

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.

5.
Haematologica ; 104(10): 1974-1983, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30948484

RESUMO

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

7.
Artigo em Inglês | MEDLINE | ID: mdl-29970384

RESUMO

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.


Assuntos
Doenças da Medula Óssea/genética , Insuficiência Pancreática Exócrina/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/fisiologia , Lipomatose/genética , Adolescente , Doenças da Medula Óssea/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Feminino , Variação Genética/genética , Humanos , Lipomatose/diagnóstico , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/fisiopatologia , Fatores de Alongamento de Peptídeos , Fenótipo , Proteínas/genética , Ribonucleoproteína Nuclear Pequena U5 , Sequenciamento Completo do Exoma
8.
Am J Hematol ; 93(7): 882-888, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29659042

RESUMO

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.


Assuntos
Tomada de Decisão Clínica , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Criança , Tomada de Decisões , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Médicos/psicologia , Rituximab/uso terapêutico , Esplenectomia
9.
Blood ; 131(20): 2183-2192, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29549173

RESUMO

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.


Assuntos
Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Estudos de Associação Genética , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/diagnóstico , Adolescente , Adulto , Anemia Hemolítica Congênita não Esferocítica/etiologia , Anemia Hemolítica Congênita não Esferocítica/metabolismo , Anemia Hemolítica Congênita não Esferocítica/terapia , Transfusão de Sangue , Criança , Pré-Escolar , Colecistectomia/efeitos adversos , Colecistectomia/métodos , Terapia Combinada , Ativação Enzimática , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Piruvato Quinase/metabolismo , Erros Inatos do Metabolismo dos Piruvatos/etiologia , Erros Inatos do Metabolismo dos Piruvatos/metabolismo , Erros Inatos do Metabolismo dos Piruvatos/terapia , Esplenectomia/efeitos adversos , Esplenectomia/métodos , Avaliação de Sintomas , Resultado do Tratamento , Adulto Jovem
10.
Pediatr Blood Cancer ; 65(5): e26955, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29350493

RESUMO

BACKGROUND: Pediatric patients undergoing liver transplant are at significant risk for bleeding and thrombotic complications due to the complex nature of rebalanced hemostasis in patients with liver disease. METHODS/OBJECTIVES: We reviewed records of 92 pediatric liver and multivisceral transplant cases at Duke University Medical Center between January 2009 and December 2015. The goal was to define the nature and incidence of bleeding and thrombotic complications in this cohort and define potential risk factors. RESULTS: There were 24 major bleeding events in 19 transplants (incidence 20.7%) and 30 thrombotic events in 23 transplants (incidence 25%). Five of the 10 retransplantations were for vascular thrombotic complications. Thirty-day mortality was 4.9%, and three of these four deaths were due to vascular thrombosis. No bleeding events led to retransplantation or mortality. Prophylactic aspirin was associated with decreased risk of thrombosis without increased bleeding. Prophylactic heparin did not increase bleeding risk. Laboratory assays predicted events poorly, apparently failing to capture the nuanced and dynamic interplay between pro- and anticoagulant factors in the posttransplant patient. CONCLUSIONS: Both bleeding and thrombosis are frequent in this population, but only thrombotic complications contributed to retransplantation and mortality. A standardized approach to coagulation testing and antithrombotic therapy may be useful in predicting and reducing adverse outcomes. Alternative approaches to monitoring hemostasis need to be prospectively investigated in this complex patient population.


Assuntos
Hemorragia/etiologia , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias , Trombose/etiologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Fatores de Risco
11.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28453928

RESUMO

Hemoglobin S/Black (A γδß)0 -thalassemia is a rare sickle cell disease (SCD) variant. On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course. We report the clinical and laboratory data of nine patients whose diagnoses were confirmed by DNA-based techniques. Despite having mild anemia and high fetal hemoglobin level postinfancy, these patients developed many of the classic complications of SCD, including vaso-occlusive crisis, acute chest syndrome, avascular necrosis, and cholelithiasis. On the basis of these findings, we recommend that patients with this rare disorder receive specialized hematology care according to SCD guidelines.


Assuntos
Afro-Americanos/genética , Anemia Falciforme/patologia , Hemoglobina Fetal/genética , Hemoglobina Falciforme/genética , Talassemia/patologia , Adolescente , Adulto , Anemia Falciforme/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Índice de Gravidade de Doença , Talassemia/genética , Adulto Jovem
12.
Child Neuropsychol ; 23(8): 889-906, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27439898

RESUMO

Research consistently indicates that children with sickle cell disease (SCD) face multiple risk factors for neurocognitive impairment. Despite this, no empirical research to date has examined the impact of neurocognitive functioning on quality of life for this pediatric group. Thus, the current study aims to examine the relationship between executive functioning and quality of life in a sample of children with SCD and further explore psychosocial and family/caregiver resources as moderators of this relationship. A total of 45 children with SCD aged 8 to 16 years and their caregivers completed measures of quality of life, behavioral ratings of executive functioning, and psychosocial functioning. Hierarchical linear regression models were utilized to determine the impact of executive functioning on quality of life and further test the interaction effects of proposed moderating variables. Controlling for age, pain, and socioeconomic status (SES), executive functioning was found to significantly predict child- and parent-reported quality of life among youth with SCD. Psychosocial resources of the primary caregiver or family was not found to moderate the relationship between executive functioning and quality of life. These results provide the first empirical evidence that lower executive skills negatively predict quality of life for children with SCD, supporting clinical and research efforts which aim to establish efficacious interventions that target cognitive decrements within this pediatric population.


Assuntos
Anemia Falciforme/psicologia , Função Executiva/ética , Qualidade de Vida/psicologia , Adolescente , Criança , Feminino , Humanos , Masculino
13.
J Clin Pharmacol ; 56(3): 298-306, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26201504

RESUMO

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSßspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.


Assuntos
Anemia Falciforme/sangue , Hidroxiureia/química , Hidroxiureia/farmacocinética , Adolescente , Antidrepanocíticos/sangue , Antidrepanocíticos/farmacocinética , Cápsulas , Criança , Pré-Escolar , Feminino , Humanos , Hidroxiureia/sangue , Masculino , Estudos Prospectivos , Soluções , Equivalência Terapêutica
14.
Lancet ; 387(10019): 661-70, 2016 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-26670617

RESUMO

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Transfusão de Sangue/métodos , Hidroxiureia/uso terapêutico , Adolescente , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular/fisiologia , Criança , Pré-Escolar , Terapia Combinada , Substituição de Medicamentos , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
15.
Urology ; 89: 118-22, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26674747

RESUMO

OBJECTIVE: To define rates of priapism diagnosis and inpatient admission among males with sickle cell disease (SCD). PATIENTS AND METHODS: We retrospectively reviewed the Pediatric Health Information System database for males aged <21 years treated 2004-2012. We identified patients with SCD and priapism based on the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Logistic regression and generalized estimating equation models were used to control for confounding and to adjust for within-hospital clustering of similar patients. RESULTS: We identified 17,186 males who were admitted 137,710 times during the study period. Of these, 362 (2.1%) were diagnosed with priapism on 748 admissions. There was a significant decrease in the number of priapism admissions among patients with SCD over time (0.81% in 2004 to 0.44% in 2012, P < .001). The number of patients diagnosed with SCD-related priapism varied over time without a statistically significant trend (2.3% in 2004, 2.69% in 2008, 1.01% in 2012, P = .34). Rates of priapism admissions (0-4.4%) varied widely between hospitals. Older patient age was associated with an increased likelihood of a priapism admission in the multivariate logistic regression model after adjusting for treatment year, hospital region, and for hospital-level clustering of similar patients. CONCLUSION: From 2004 to 2012, the number of admissions for SCD-related priapism declined whereas the number of individual patients diagnosed with SCD-related priapism did not. Rates of priapism-related admissions in males with SCD vary widely among PHIS hospitals.


Assuntos
Anemia Falciforme/complicações , Priapismo/etiologia , Adolescente , Criança , Pré-Escolar , Hospitais Pediátricos , Humanos , Lactente , Masculino , Admissão do Paciente/estatística & dados numéricos , Priapismo/diagnóstico , Priapismo/epidemiologia , Priapismo/terapia , Estudos Retrospectivos , Fatores de Tempo , Estados Unidos , Adulto Jovem
17.
Pediatr Blood Cancer ; 59(1): 100-4, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22238140

RESUMO

BACKGROUND: Clinical outcomes of children with sickle cell disease (SCD) who undergo total or partial splenectomy (PS) are poorly defined. The purpose of this retrospective study was to initiate an Internet-based registry to facilitate analysis of clinical outcomes for these children. We hypothesized that both surgical procedures would be well tolerated and would eliminate risk of splenic sequestration. METHODS: We developed a web-based registry using the Research Electronic Data Capture (REDCap) platform. Children were included if they had SCD and underwent total splenectomy (TS) or PS between 2003 and 2010. Clinical outcomes were compared between cohorts, with follow-up to 1 year. RESULTS: Twenty-four children were included, TS (n = 15) and PS (n = 9). There were no differences in surgical time or intraoperative blood loss. The length of stay was longer after PS (4.1 ± 1.7 days) compared to TS, (2.4 ± 1.2 days, P = 0.02). Within 30 days of surgery, 2 (20%) patients had acute chest syndrome (ACS) following TS and 2 (15%) patients had ACS after PS. During 1-year follow-up, no patient in either cohort had recurrent splenic sequestration, venous thrombosis or overwhelming postsplenectomy sepsis. All children who were transfused preoperatively to prevent recurrent splenic sequestration successfully discontinued transfusions. CONCLUSIONS: Both TS and PS result in favorable hematologic outcomes and low risk of adverse events for children with SCD. A REDCap-based registry may facilitate data entry and analysis of clinical outcomes to allow for comparison between different types of splenectomy.


Assuntos
Anemia Falciforme/cirurgia , Esplenectomia/métodos , Anemia Falciforme/mortalidade , Transfusão de Sangue , Criança , Pré-Escolar , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Humanos , Internet , Masculino , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/terapia , Sistema de Registros , Fatores de Risco , Sepse/mortalidade , Sepse/terapia , Esplenectomia/efeitos adversos , Trombose Venosa/mortalidade , Trombose Venosa/terapia
18.
Pediatr Blood Cancer ; 57(7): 1239-43, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21681935

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an immunodysregulatory disorder for which more effective treatments are needed. The macrolide rapamycin has immunosuppressive properties, making it an attractive candidate for controlling the aberrant T cell activation that occurs in HLH. To investigate its therapeutic potential, we used rapamycin to treat Lymphocytic Choriomeningitis Virus (LCMV)-infected perforin-deficient (Prf1(-/-)) mice according to a well-established model of HLH. At the regimens tested, rapamycin did not improve weight loss, splenomegaly, hemophagocytosis, cytopenias, or proinflammatory cytokine production in LCMV-infected Prf1(-/-) animals. Thus, single agent rapamycin appears ineffective in treating the clinical and laboratory manifestations of LCMV-induced HLH.


Assuntos
Imunossupressores/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Infecções por Arenaviridae/tratamento farmacológico , Infecções por Arenaviridae/imunologia , Separação Celular , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Vírus da Coriomeningite Linfocítica , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Perforina/deficiência
19.
J Rheumatol ; 36(10): 2264-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19755613

RESUMO

OBJECTIVE: Raynaud's phenomenon (RP) is an important clinical feature of systemic sclerosis (SSc) for which consistently effective therapies are lacking. The study was designed to assess the safety, tolerability, and efficacy of tadalafil, a selective, long acting type V cyclic GMP phosphodiesterase (PDE-5) inhibitor, in this clinical syndrome. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled, crossover study comparing oral tadalafil at a fixed dose of 20 mg daily for a period of 4 weeks versus placebo in women with RP secondary to SSc. RESULTS: Thirty-nine subjects completed the study and were evaluable. There were no statistically significant differences in Raynaud Condition Score (RCS), frequency of RP episodes, or duration of RP episodes between treatment groups. Placebo response was a confounding factor. Tadalafil was well tolerated. CONCLUSION: Tadalafil appears to be safe and well tolerated but lacks efficacy in comparison to placebo as a treatment for RP secondary to SSc.


Assuntos
Carbolinas/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Doença de Raynaud/tratamento farmacológico , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , Adulto , Carbolinas/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Tadalafila , Resultado do Tratamento
20.
Pediatr Blood Cancer ; 53(6): 1120-3, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19621458

RESUMO

X-linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally occur following Epstein-Barr virus (EBV) infection and include fulminant mononucleosis, hypogammaglobulinemia and lymphoma. In this report, we describe two unrelated patients with fatal T-cell-mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T-cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection.


Assuntos
Sistema Nervoso Central/imunologia , Vasos Linfáticos/patologia , Transtornos Linfoproliferativos/complicações , Vasculite/etiologia , Adolescente , Adulto , Infecções por Vírus Epstein-Barr , Evolução Fatal , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Linfócitos T/patologia
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