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Find video protocols related to scientific articles indexed in Pubmed.
A Team-Based Approach to Reducing Cardiac Monitor Alarms.
Pediatrics
PUBLISHED: 11-12-2014
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Excessive cardiac monitor alarms lead to desensitization and alarm fatigue. We created and implemented a standardized cardiac monitor care process (CMCP) on a 24-bed pediatric bone marrow transplant unit. The aim of this project was to decrease monitor alarms through the use of team-based standardized care and processes.
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Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531.
J. Clin. Oncol.
PUBLISHED: 08-06-2014
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To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.
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High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells.
J. Virol.
PUBLISHED: 07-16-2014
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DNA repair plays a crucial role in embryonic and somatic stem cell biology and cell reprogramming. The Fanconi anemia (FA) pathway, which promotes error-free repair of DNA double-strand breaks, is required for somatic cell reprogramming to induced pluripotent stem cells (iPSC). Thus, cells from Fanconi anemia patients, which lack this critical pathway, fail to be reprogrammed to iPSC under standard conditions unless the defective FA gene is complemented. In this study, we utilized the oncogenes of high-risk human papillomavirus 16 (HPV16) to overcome the resistance of FA patient cells to reprogramming. We found that E6, but not E7, recovers FA iPSC colony formation and, furthermore, that p53 inhibition is necessary and sufficient for this activity. The iPSC colonies resulting from each of these approaches stained positive for alkaline phosphatase, NANOG, and Tra-1-60, indicating that they were fully reprogrammed into pluripotent cells. However, FA iPSC were incapable of outgrowth into stable iPSC lines regardless of p53 suppression, whereas their FA-complemented counterparts grew efficiently. Thus, we conclude that the FA pathway is required for the growth of iPSC beyond reprogramming and that p53-independent mechanisms are involved.
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[Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation].
Rinsho Ketsueki
PUBLISHED: 07-01-2014
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Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplantation exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.
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Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults.
Blood
PUBLISHED: 05-29-2014
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Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions.
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Abnormal echocardiography seven days after stem cell transplant may be an early indicator of thrombotic microangiopathy.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-20-2014
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Cardiac complications after hematopoietic stem cell transplant (HSCT) can lead to significant morbidity and mortality. Cardiac evaluation during the first 100 days after HSCT is usually performed only if clinically indicated and there are no studies examining if routine screening would be of benefit in this patient population at high risk for tissue injury. We conducted a single center prospective clinical study to screen for cardiac complications in pediatric and young adult patients. One hundred consecutive HSCT patients underwent scheduled echocardiographic screening on day +7 after transplantation, independent of their clinical condition. At least one abnormality was identified in 30% of cases. Seventeen children had a pericardial effusion, 13 elevated right ventricular pressure and 3 reduced left ventricular function. Survival was reduced in children with any echocardiographic abnormality at day 7 (67% vs. 80% in those with and without abnormality, p= 0.073). Moreover, raised right ventricular pressure at day +7 was significantly associated with transplant-associated thrombotic microangiopathy (TA-TMA) (p=0.004), and may indicate early vascular injury in the lungs. These data suggest that echocardiography 7 days after HSCT can detect early cardiac complications of HSCT and may identify early vascular injury associated with TA-TMA.
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Veno-occlusive Disease of the Liver in the Absence of Elevation in Bilirubin in Pediatric Patients after Hematopoietic Stem Cell Transplant.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-13-2014
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Veno-occlusive disease (VOD) of the liver is a well-described and significant complication of hematopoietic stem cell transplantation (HSCT), with limited successful therapeutic options in severe cases. Prompt diagnosis and initiation of treatment is crucial to restrict the extent of disease. However, a subset of patients may not meet all current diagnostic criteria at presentation, and waiting for these to be met may delay therapy. We retrospectively reviewed 794 HSCT patients treated at our institution between 2003 and 2013, identifying 17 (2.1%) who developed VOD. Of these, 5 (29%) were noted to have an absence of elevated bilirubin at the time of VOD diagnosis and reversal of portal venous flow on ultrasound. Median total and conjugated bilirubin at VOD diagnosis were 1.0 and 0.2 mg/dL respectively. All five of these patients were subsequently diagnosed with multi-organ failure associated with VOD, including one with encephalopathy. Four were treated with intravenous high dose methylprednisolone (500 mg/m(2) per dose every 12 hours for six doses). One patient received defibrotide therapy in addition to steroids and another supportive care alone. VOD resolved in 4 of the 5 patients, with median time to resolution of VOD, defined as recovery of all organ function and normalization of bilirubin and portal venous flow, of 8 days. Two patients died later from progressive primary disease and chronic GVHD respectively. We conclude that a high index of suspicion for VOD should be maintained in patients despite lack of bilirubin elevation in the presence of other diagnostic criteria such as hepatomegaly, abdominal pain, ascites or weight gain. Early ultrasound evaluation in these patients may lead to more timely diagnosis and therapeutic interventions.
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Comprehensive analysis of pathogenic deletion variants in fanconi anemia genes.
Hum. Mutat.
PUBLISHED: 05-02-2014
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Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution comparative genome hybridization arrays, single-nucleotide polymorphism arrays, and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by nonallelic homologous recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants.
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Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency/X-linked lymphoproliferative disease type 1.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-31-2014
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X-linked lymphoproliferative disease type 1 (XLP1) is a rare immune deficiency caused by mutations in SH2D1A. Allogeneic hematopoietic cell transplantation (HCT) is often performed because of the morbidity and mortality associated with XLP1. There is limited experience using reduced-intensity conditioning (RIC) regimens for these patients. Here we report our 8-year single-center experience. Sixteen consecutive patients diagnosed with XLP1 underwent allogeneic HCT between 2006 and 2013 after a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan. Patient phenotypes included hemophagocytic lymphohistiocytosis (HLH) after Epstein-Barr virus (n = 5) or human herpesvirus 6 (n = 1), macrophage activation syndrome (n = 1), interstitial pneumonitis and encephalitis (n = 1), B cell lymphoma (n = 8), and hypogammaglobulinemia (n = 2). One patient was asymptomatic. Fourteen of 16 patients received 8/8 HLA-matched unrelated or related bone marrow grafts, whereas 2 patients received mismatched unrelated grafts. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methylprednisolone and cyclosporine in all but 1 patient, who additionally received methotrexate. All patients had hematopoietic recovery. There were no cases of hepatic veno-occlusive disease or pulmonary hemorrhage. One patient (6%) developed acute GVHD and later also developed chronic GVHD (6%). Five patients (31%) developed mixed chimerism. Only 1 patient with mixed chimerism (6%) experienced a decline of donor chimerism to less than 50% but returned to full donor chimerism after infusion of donor lymphocytes and a CD34(+) selected stem cell boost. Infectious complications were frequent, particularly viral reactivation. One-year survival estimated by Kaplan-Meier analysis was 80%, with long-term survival estimated at 71%. Survival was similar for patients with or without a history of HLH (86% versus 75%, respectively, P = .70). There were no occurrences of lymphoma or HLH after HCT. RIC HCT with alemtuzumab, fludarabine, and melphalan is an effective treatment for patients with XLP1, offering good survival rates regardless of prior disease manifestations, including HLH.
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Estimated versus Measured Glomerular Filtration Rate in Children before Hematopoietic Cell Transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-19-2014
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An accurate assessment of kidney function before hematopoietic cell transplantation (HCT) can help to properly dose conditioning chemotherapy and follow patients for the development of chronic kidney disease. We cross-sectionally examined 94 children and young adults before HCT to compare formal nuclear glomerular filtration rate (GFR) testing with estimated GFR using creatinine and cystatin C-based equations, including the original Schwartz formula and the more recent formulas developed in the Chronic Kidney Disease in Children (CKiD) cohort. The median age of the cohort was 5.9 years (range, .26 to 30.5 years). The mean cohort nuclear GFR was 107.4 ± 24.7 mL/min/1.73 m(2), with 18 of 94 subjects (19.1%) having abnormal kidney function (GFR < 90 mL/min/1.73 m(2)) before HCT. The creatinine-based original Schwartz and bedside CKiD formulas showed significant bias, overestimating the nuclear GFR by 57.4 (95% confidence interval [CI], 49.0 to 65.8) and 14.1 (95% CI, 7.1 to 21.1) mL/min/1.73 m(2), respectively. Cystatin C formulas had less mean bias and improved accuracy but also had decreased sensitivity to detect abnormal kidney function before HCT. The Full CKiD equation showed the best performance, with a mean bias of -3.6 mL/min/1.73 m(2) (95% CI, -8.4 to 1.2) that was not significantly different from the measured value and 87.7% of estimates within ±30% of the nuclear GFR. Although the more recent bedside CKiD formula performed better than the original Schwartz formula, both formulas had poor sensitivity for detecting a low GFR. An abnormal pretransplant nuclear GFR was not associated with post-HCT acute kidney injury, the need for dialysis, or death in the first 100 days. In conclusion, we observed cystatin C-based equations outperformed creatinine-based equations in estimating GFR in children before HCT. However, all formulas had decreased sensitivity to detect impaired GFR. Formal measurement of kidney function should be considered in children and young adults who need an accurate assessment of kidney function before HCT.
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Concomitant inactivation of foxo3a and fancc or fancd2 reveals a two-tier protection from oxidative stress-induced hydrocephalus.
Antioxid. Redox Signal.
PUBLISHED: 03-12-2014
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This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus.
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Identifying religious and/or spiritual perspectives of adolescents and young adults receiving blood and marrow transplants: a prospective qualitative study.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-05-2014
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The potential benefits (or detriments) of religious beliefs in adolescent and young adults (AYA) are poorly understood. Moreover, the literature gives little guidance to health care teams or to chaplains about assessing and addressing the spiritual needs of AYA receiving hematopoietic stem cell transplants (HSCT). We used an institutional review board-approved, prospective, longitudinal study to explore the use of religion and/or spirituality (R/S) in AYA HSCT recipients and to assess changes in belief during the transplantation experience. We used the qualitative methodology, grounded theory, to gather and analyze data. Twelve AYA recipients were interviewed within 100 days of receiving HSCT and 6 participants were interviewed 1 year after HSCT; the other 6 participants died. Results from the first set of interviews identified 5 major themes: using R/S to address questions of "why me?" and "what will happen to me;" believing God has a reason; using faith practices; and benefitting from spiritual support people. The second set of interviews resulted in 4 major themes: believing God chose me; affirming that my life has a purpose; receiving spiritual encouragement; and experiencing strengthened faith. We learned that AYA patients were utilizing R/S far more than we suspected and that rather than losing faith in the process of HSCT, they reported using R/S to cope with illness and HSCT and to understand their lives as having special purpose. Our data, supported by findings of adult R/S studies, suggest that professionally prepared chaplains should be proactive in asking AYA patients about their understanding and use of faith, and the data can actively help members of the treatment team understand how AYA are using R/S to make meaning, address fear, and inform medical decisions.
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Deletion of Fanca or Fancd2 dysregulates Treg in mice.
Blood
PUBLISHED: 02-05-2014
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Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-?B activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.
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Bortezomib for refractory autoimmunity in pediatrics.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-17-2014
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Therapy of refractory autoimmunity remains challenging. In this study, we evaluated the therapeutic effect of bortezomib, a proteasome inhibitor, by targeting plasma cells in 7 patients (median age, 9.9 years). Four doses of bortezomib were administered at a dose of 1.3 mg/m(2) intravenously (n = 6) or subcutaneously (n = 1) every 72 hours. Bortezomib was administered at a median of 120 days from laboratory confirmation of autoantibodies. All patients had failed 2 or more standard therapies. Rituximab was administered on the first day if B cells were present, and all patients received plasmapheresis 2 hours before bortezomib administration. Six patients experienced resolution of cytopenias. Two of 6 patients experienced recurrence of cytopenias after initial response. Adverse effects include nausea (n = 1), thrombocytopenia (n = 2), Clostridium difficile colitis (n = 1)), febrile neutropenia (n = 1), and cellulitis at the subcutaneous injection site (n = 1). Our experience suggests that bortezomib may be beneficial in the treatment of refractory autoimmunity in children.
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Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens.
Blood
PUBLISHED: 01-16-2014
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The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population.
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Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry.
J. Pediatr.
PUBLISHED: 01-07-2014
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To investigate the range of clinical presentations for Shwachman-Diamond syndrome (SDS) with the long-term goal of improving diagnosis.
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Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
Biol. Blood Marrow Transplant.
PUBLISHED: 11-19-2013
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We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated six children with severe HSCT-TMA using eculizumab and adjusted the dose to achieve a therapeutic level of >99 ?g/ml. HSCT-TMA resolved over time in four of six children after achieving therapeutic eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that eculizumab may be a therapeutic option for HSCT-TMA but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ?4 complement activity enzyme (CAE) units correlated with therapeutic eculizumab levels and clinical response, and therefore CH50 may be useful to guide eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
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The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients.
Pediatr Transplant
PUBLISHED: 09-24-2013
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SR-aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR-aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5-28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR-aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3-2 mg/kg) divided over 2-6 days. Eighty-nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR-aGVHD in pediatric patients with a tolerable spectrum of complications.
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Adherence to outpatient oral medication regimens in adolescent hematopoietic stem cell transplant recipients.
Eur J Oncol Nurs
PUBLISHED: 08-05-2013
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Hematopoietic stem cell transplantation (HSCT) is an increasingly utilized treatment option for adolescents with many life-threatening diagnoses. Suboptimal adherence may result in compromised treatment effectiveness and increased risk of adverse medical outcomes.
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Pulmonary hypertension after hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-03-2013
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Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its nonspecific clinical presentation, it is likely that this clinical entity is underdiagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients are minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication because timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis, and management of PH in HSCT recipients.
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Prevalence of hematopoietic cell transplant survivors in the United States.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-01-2013
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Advances in hematopoietic cell transplantation (HCT) have led to an increasing number of transplant survivors. To adequately support their healthcare needs, there is a need to know the prevalence of HCT survivors. We used data on 170,628 recipients of autologous and allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research from 1968 to 2009 to estimate the current and future number of HCT survivors in the United States. Stacked cohort simulation models were used to estimate the number of HCT survivors in the United States in 2009 and to make projections for HCT survivors by the year 2030. There were 108,900 (range, 100,500 to 115,200) HCT survivors in the United States in 2009. This included 67,000 autologous HCT and 41,900 allogeneic HCT survivors. The number of HCT survivors is estimated to increase by 2.5 times by the year 2020 (242,000 survivors) and 5 times by the year 2030 (502,000 survivors). By 2030, the age at transplant will be < 18 years for 14% of all survivors (n = 64,000), 18 to 59 years for 61% survivors (n = 276,000), and 60 years and older for 25% of survivors (n = 113,000). In coming decades, a large number of individuals will be HCT survivors. Transplant center providers, hematologists, oncologists, primary care physicians, and other specialty providers will need to be familiar with the unique and complex health issues faced by this population.
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Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy.
Blood
PUBLISHED: 06-27-2013
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Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorphologic similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and tissue damage. Although significant advances have been made in understanding the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-TMA and may therefore guide the development of targeted treatment interventions.
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An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-14-2013
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Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P < .01), and 75% in the distal group patients who received ?2 mg/kg alemtuzumab (P = .03). The CI of acute GVHD grades II-IV before the development of mixed chimerism was 4% in the intermediate group, 0% in the proximal group, and 13% in the distal group (P = .04, proximal versus distal). The 1-year CI of administration of additional hematopoietic cell products for mixed chimerism (donor lymphocyte infusion ± hematopoietic stem cell boost ± repeat HCT) was 14% in the intermediate group, 53% in the proximal group (P = .01), and 38% in the distal ?2 mg/kg alemtuzumab group (P = .02). Our findings indicate that intermediate RIC reduces the incidence of mixed chimerism, is associated with a low incidence of upfront acute GVHD, and decreases the need for additional hematopoietic cell products after HCT.
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Renal arteriolar C4d deposition: a novel characteristic of hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
Transplantation
PUBLISHED: 05-24-2013
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The mechanism of kidney injury in hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is not completely understood. Renal C4d staining is a marker of classic complement activation and endothelial injury and has been described in preliminary reports of HSCT recipients with TA-TMA. Our objective was to evaluate complement in the pathogenesis of small vessel injury in children receiving HSCT. We hypothesized that kidney tissue from children with TA-TMA would more frequently show C4d deposition compared with HSCT recipients without histologic TA-TMA.
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ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Childrens Oncology Group.
Leuk. Res.
PUBLISHED: 03-05-2013
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Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ?1.33, Ptrend?0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction?0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction?0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.
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Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-28-2013
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We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.
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BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-04-2013
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BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses.
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Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults.
Br. J. Haematol.
PUBLISHED: 01-10-2013
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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2.5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.
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Factors associated with parental activation in pediatric hematopoietic stem cell transplant.
Med Care Res Rev
PUBLISHED: 12-26-2011
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Patient activation, the extension of self-efficacy into self-management, is an essential component of effective chronic care. In pediatric populations, caregiver activation is also needed for proper disease management. This study investigates the relationships between parental activation and other characteristics of parent-child dyads (N = 198) presenting for pediatric hematopoietic stem cell transplant. Parental activation concerning their childs health was assessed using the Parent Patient Activation Measure (Parent-PAM), a modified version of the well-validated Patient Activation Measure (PAM). Using hierarchical linear regression and following the Belsky process model for determining parenting behaviors, a multivariate model was created for parental activation on behalf of their child that showed that the parents age, rating of their own general health, self-activation, and duration of the childs illness were significantly related to Parent-PAM score. Our findings characterize a potentially distinct form of activation in a parent-child cohort preparing for a demanding clinical course.
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Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 10-21-2011
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Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplantation exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.
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NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-06-2011
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Hematopoietic cell transplantation (HCT) is now a curative option for certain categories of patients with hematologic malignancies and other life-threatening illnesses. Technical and supportive care has resulted in survival rates that exceed 70% for those who survive the first 2 years after HCT. However, long-term survivors carry a high burden of morbidity, including endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies. Understanding the etiologic pathways that lead to specific post-HCT morbidities is critical to developing targeted prevention and intervention strategies. Understanding the molecular underpinnings associated with graft-versus-host disease (GVHD), organ toxicity, relapse, opportunistic infection, and other long-term complications now recognized as health care concerns will have significant impact on translational research aimed at developing novel targeted therapies for controlling chronic GVHD, facilitating tolerance and immune reconstitution, reducing risk of relapse and secondary malignancies, minimizing chronic metabolic disorders, and improving quality of life. However, several methodological challenges exist in achieving these goals; these issues are discussed in detail in this paper.
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Severe allergic reactions to thiol-based cytoprotective agents mesna and amifostine in a child with a supratentorial primitive neuroectodermal tumor.
J. Pediatr. Hematol. Oncol.
PUBLISHED: 06-08-2011
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Both 2-mercaptoethane sulfonate sodium (mesna) and amifostines active metabolite WR-1065 are thiol-based cytoprotective agents that are critical components of high-dose chemotherapy regimens used to treat various cancers in both adults and children. This case report describes a patient with a supratentorial primitive neuroectodermal tumor who developed severe drug reactions to both mesna and amifostine/WR-1065, suggesting that the thiol component of these agents triggered the adverse reactions. This report highlights the clinical presentation of drug-induced hypersensitivity syndrome in the context of pediatric oncology and the supportive care measures that, if implemented rapidly, may diminish the reaction severity and allow successful completion of chemotherapy.
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Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
Blood
PUBLISHED: 05-19-2011
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Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMAs overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease.
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Impaired immune function in children with Fanconi anaemia.
Br. J. Haematol.
PUBLISHED: 05-04-2011
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Fanconi anaemia is an autosomal recessive or X-linked disease characterized by progressive bone marrow failure, variable congenital abnormalities and a predisposition to malignancy. Reports of immune function in this population are limited, and include only specific areas of immune performance, showing variable defects. We report a cross-sectional immunological assessment in 10 children with FA. Absolute numbers of B cells and natural killer (NK) cells were reduced compared to controls (P = 0·048 and P = 0·0002, respectively), while absolute number of T cells were within normal range. Perforin and granzyme content of NK cells was reduced (P < 0·00001 and P = 0·0057, respectively) along with the NK cell cytotoxicity (P < 0·001). Antigen proliferation in response to tetanus was decreased (P = 0·008) while responses to candida and phytohaemagglutinin were not. Cytotoxic T cell function was also reduced (P < 0·0001). Immunoglobulin G levels were normal in those evaluated. Our series represents the first attempt at a comprehensive quantitative and functional evaluation of immune function in this rare group of patients and demonstrates a significant deficit in the NK cell compartment, a novel quantitative B cell defect, along with abnormal cytotoxic function. These findings may be especially relevant in this patient population with known predisposition to DNA damage and malignancy.
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Outcome of myeloablative conditioning and unrelated donor hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-25-2011
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We conducted a retrospective study of 155 children who underwent unrelated donor hematopoietic cell transplantation (HCT) between 1990 and 2005 for acute lymphoblastic leukemia in third remission. The median patient age was 11 years, the median time from diagnosis to first relapse was 36 months, and the median time from first relapse to second relapse was 26 months. Stem cell sources were bone marrow (n = 115), peripheral blood (n = 11), and cord blood (n = 29). All patients received a myeloablative pretransplantation conditioning regimen. The 5-year estimates of leukemia-free survival, relapse, and nonrelapse mortality were 30%, 25%, and 45%, respectively. In multivariate analysis, the only risk factor associated with relapse was the interval between the first relapse and the second relapse. Second relapses occurring >26 months from the first relapse were associated with lower risk for post-HCT relapse compared with second relapses occurring at ?26 months (relative risk, 0.4; P = .01). Relapse risk was lowest when late second relapse was preceded by late first relapse (>36 months from diagnosis), as demonstrated by a 3-year relapse rate of 9% (P = .0009). Our data indicate that long-term leukemia-free survival can be achieved in children with acute lymphoblastic leukemia in third remission using unrelated donor HCT, especially when the second relapse occurs late.
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The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations.
Pediatr Blood Cancer
PUBLISHED: 01-29-2011
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Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group.
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Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-18-2011
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BK virus is a significant cause of hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT). However, its role in nephropathy post-HSCT is less studied. We retrospectively evaluated clinical outcomes in pediatric HSCT patients with hemorrhagic cystitis. Although most of these patients had very high urine BK viral loads (viruria), patients with higher BK plasma loads (viremia) had significant renal dysfunction, a worse clinical course, and decreased survival. Patients with a peak plasma BK viral load of >10,000 copies/mL (high viremia) were more likely to need dialysis and aggressive treatment for hemorrhagic cystitis compared to patients with ? 10,000 copies/mL (low viremia). Conversely, most patients with low viremia had only transient elevations in creatinine, and less severe hemorrhagic cystitis that resolved with supportive therapy. Overall survival (OS) at 1 year post-HSCT was 89% in the low viremia group and 48% in the high viremia group. We conclude that the degree of BK viremia, and not viruria, may predict renal, urologic, and overall outcome in the post-HSCT population.
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Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients.
Blood
PUBLISHED: 01-12-2011
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Quantifying the risk of hematopoietic cell transplantation (HCT)-related mortality for pediatric patients is challenging. The HCT-specific comorbidity index (HCT-CI) has been confirmed as a useful tool in adults, but has not yet been validated in children. We conducted a retrospective cohort study of 252 pediatric patients undergoing their first allogeneic HCT between January 2008 and May 2009. Pretransplantation comorbidities were scored prospectively using the HCT-CI. Median age at transplantation was 6 years (range, 0.1-20) and median follow-up was 343 days (range, 110-624). HCT-CI scores were distributed as follows: 0, n=139; 1-2, n=52; and 3+, n=61. The 1-year cumulative incidence of nonrelapse mortality (NRM) increased (10%, 14%, and 28%, respectively; P<.01) and overall survival (OS) decreased (88%, 67%, and 62%, respectively; P<.01) with increasing HCT-CI score. Multivariate analysis showed that compared with score 0, those with scores of 1-2 and 3+ had relative risks of NRM of 1.5 (95% confidence interval, 0.5-4.3, P=.48) and 4.5 (95% confidence interval, 1.7-12.1, P<.01), respectively. These results indicate that the HCT-CI score predicts NRM and OS in pediatric patients undergoing HCT and is a useful tool to assess risk, guide counseling in the pretransplantation setting, and devise innovative therapies for the highest risk groups.
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Incidence of acute and chronic graft-versus-host disease and donor T-cell chimerism after small bowel or combined organ transplantation.
J. Pediatr. Surg.
PUBLISHED: 01-10-2011
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Graft-versus-host disease (GVHD) after organ transplantation is a rare but life-threatening complication with very high mortality.
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From trees to the forest: genes to genomics.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-04-2011
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Crick, Watson, and colleagues revealed the genetic code in 1953, and since that time, remarkable progress has been made in understanding what makes each of us who we are. Identification of single genes important in disease, and the development of a mechanistic understanding of genetic elements that regulate gene function, have cast light on the pathophysiology of many heritable and acquired disorders. In 1990, the human genome project commenced, with the goal of sequencing the entire human genome, and a "first draft" was published with astonishing speed in 2001. The first draft, although an extraordinary achievement, reported essentially an imaginary haploid mix of alleles rather than a true diploid genome. In the years since 2001, technology has further improved, and efforts have been focused on filling in the gaps in the initial genome and starting the huge task of looking at normal variation in the human genome. This work is the beginning of understanding human genetics in the context of the structure of the genome as a complete entity, and as more than simply the sum of a series of genes. We present 3 studies in this review that apply genomic approaches to leukemia and to transplantation to improve and extend therapies.
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Successful early intervention for hyperacute transplant-associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation.
Pediatr Transplant
PUBLISHED: 11-05-2010
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TA-TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA-TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA-TMA after allogeneic HSCT.
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Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation.
Blood
PUBLISHED: 09-20-2010
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Recent experience suggests that reduced-intensity conditioning (RIC) regimens can improve the outcomes of patients with hemophagocytic lymphohistiocytosis (HLH) undergoing allogeneic hematopoietic cell transplantation (HCT). However, studies directly comparing RIC to myeloablative conditioning (MAC) regimens are lacking. Forty patients with HLH underwent allogeneic HCT between 2003-2009 at Cincinnati Childrens Hospital. Fourteen patients received MAC consisting of busulfan, cyclophosphamide, and antithymocyte globulin plus or minus etoposide. Twenty-six patients received RIC consisting of fludarabine, melphalan, and alemtuzumab. All patients engrafted. Acute graft-versus-host disease grades II to III occurred in 14% of MAC patients and 8% of RIC patients (P = .3171). Posttransplantation mixed donor/recipient chimerism developed in 18% of MAC patients and 65% of RIC patients (P = .0110). The majority of patients with mixed chimerism received intervention with reduction of immune suppression plus or minus donor lymphocyte infusion or stem cell boost, which stabilized or increased donor contribution to hematopoiesis and prevented relapse of HLH in all but 1 patient. Grade II to III graft-versus-host disease occurred in 5 of 14 RIC patients after donor lymphocyte infusion. The overall estimated 3-year survival after HCT was 43% (confidence interval = ± 26%) for MAC patients and 92% (confidence interval = ± 11%) for RIC patients (P = .0001). We conclude that RIC significantly improves the outcome of patients with HLH undergoing allogeneic HCT.
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Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors.
Blood
PUBLISHED: 07-29-2010
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Although some trials have allowed matched or single human leukocyte antigen (HLA)-mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.
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Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-16-2010
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We describe long-term disease-free survival (DFS) after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ?18 years. Forty-six patients had refractory cytopenia (RC), 55 refractory anemia with excess blasts (RAEB), and 17 refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, P = .002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, P = .01) or RAEB-t (RR 11.00, P = .004). Treatment failure (recurrent disease or death from any cause; inverse of DFS) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, P = .001) and in those with RAEB-t (RR 2.38, P = .02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy, and children with RC can be expected to have the best outcome.
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Pediatric acute lymphoblastic leukemia: is there still a role for transplant?
Hematology Am Soc Hematol Educ Program
PUBLISHED: 07-09-2010
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Constant questioning of the applicability of transplant for any diagnosis is appropriate. This is particularly necessary in fields such as pediatric leukemia, in which significant progress in therapy and risk classification is being made. Outcomes with chemotherapy are constantly improving, and donor availability and transplant outcomes are also better. It is important to be aware of likely outcomes when counseling families and recommending therapy, and to consider issues of likely late side effects. Biological studies that predict prognosis, for example, array-based studies, hold hope of identifying the children destined to relapse at the outset of disease. However, a rigorous approach must be taken in determining whether transplant does improve outcome whenever this strategy is applied.
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MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Childrens Oncology Group.
Pediatr Blood Cancer
PUBLISHED: 06-29-2010
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The variant polymorphism in the gene MDM2, SNP309, leads to increased level of mdm2 protein and subsequent downregulation of p53 tumor suppressor pathway. Presence of this single nucleotide polymorphism (SNP) has been associated with earlier tumorigenesis in patients with Li-Fraumeni syndrome, as well as decreased survival in patients with CLL. In addition, cells homozygous (G/G) for SNP 309 were found to have 10-fold increase resistance to topoisomerase II inhibitors in vitro.
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Characteristics of responders to a request for a buccal cell specimen among survivors of childhood cancer and their siblings.
Pediatr Blood Cancer
PUBLISHED: 05-21-2010
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Analysis of biological samples in large cohort studies may provide insight into the mechanism of, and risk factors for, disease onset and progression.
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Infant leukemia and congenital abnormalities: a Childrens Oncology Group study.
Pediatr Blood Cancer
PUBLISHED: 05-21-2010
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Leukemia in infants is rare and has not been well studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants versus older children suggest a distinct etiology, likely involving prenatal factors.
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Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-02-2010
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Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged < or =10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation.
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Patient-derived granulocyte/macrophage colony-stimulating factor autoantibodies reproduce pulmonary alveolar proteinosis in nonhuman primates.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 03-11-2010
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Granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals.
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Numerical chromosomal changes and risk of development of myelodysplastic syndrome--acute myeloid leukemia in patients with Fanconi anemia.
Cancer Genet. Cytogenet.
PUBLISHED: 01-14-2010
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Fanconi Anemia (FA) is an inherited bone marrow failure syndrome characterized by congenital abnormalities, progressive marrow failure and predisposition to myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. The most common acquired chromosomal aberrations in FA patients are trisomy of 1q and monosomy of chromosome 7; the latter is known to be associated with poor prognosis. A few reports also suggest that gains of 3q are associated with progression to MDS-AML and overall poor prognosis. It is not uncommon for patients with Fanconi anemia to have easily detectable (oligoclonal) chromosomal alterations in their still normal (nonmalignant) marrow, which makes it even more challenging to determine the import of such alterations. We conducted a retrospective longitudinal analysis of fluorescent in situ hybridization (FISH) analysis for gains in 1q and 3q and for monosomy 7 and 7q deletions on 212 bone marrow samples from 77 children with FA treated at our institution between 1987 and 2007. Given the baseline increased chromosomal instability and defective DNA repair in patients with FA, which leads to unbalanced chromosomal aberrations such as deletions, insertions, and translocations, for the purpose of this analysis an abnormal clone was defined as ?10% abnormal cells. Chromosome 3 and 7 aberrations were associated with increased risk of developing MDS-AML (P = 0.019 and P < 0.001 respectively), although the significance of chromosome 3 aberrations disappeared when different observation times were accounted for. Gain of 1q alone did not predict development of MDS-AML. In conclusion, children with FA should be followed closely with FISH analyses, because some of the clonal chromosomal abnormalities may be early indicators of progression toward MDS-AML and thus also of the need for hematopoietic stem cell transplantation.
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Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-13-2010
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Reduced-intensity conditioning regimens have been used extensively in adults with hematologic malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia, we evaluated transplant outcomes in 38 recipients transplanted from 1995-2005 for whom this was their first transplant. The median age at transplant was 12 years, and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, > or =CR2 in 60% of patients, and 22% had active disease at transplantation. Matched related donors were available for a third of patients, about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells. Sixty percent of unrelated donor transplant recipients received peripheral blood progenitor cells. The day-100 probability of grade II-IV acute graft-versus-host disease was 37% and the 3-year probability of chronic graft-versus-host disease, 26%. At 3 years, the probability of treatment-related mortality was 40%, relapse 37%, and disease-free survival 30%. These data indicate long-term DFS can be achieved using reduced-intensity conditioning regimens in children with acute lymphoblastic leukemia. Given the relatively small cohort, these findings must be validated in a larger population.
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Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-10-2009
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Restricting transgene expression to maturing erythroid cells can reduce the risk for activating oncogenes in hematopoietic stem cells (HSCs) and their progeny, yet take advantage of their robust protein synthesis machinery for high-level protein production. This study sought to evaluate the feasibility and efficacy of reprogramming erythroid cells for production of a lysosomal enzyme, alpha-L-iduronidase (IDUA). An erythroid-specific hybrid promoter provided inducible IDUA expression and release during in vitro erythroid differentiation in murine erythroleukemia cells, resulting in phenotypical cross-correction in an enzyme-deficient lymphoblastoid cell line derived from patients with mucopolysaccharidosis type I (MPS I). Stable and higher than normal plasma IDUA levels were achieved in vivo in primary and secondary MPS I chimeras for at least 9 months after transplantation of HSCs transduced with the erythroid-specific IDUA-containing lentiviral vector (LV). Moreover, long-term metabolic correction was demonstrated by normalized urinary glycosaminoglycan accumulation in all treated MPS I mice. Complete normalization of tissue pathology was observed in heart, liver, and spleen. Notably, neurological function and brain pathology were significantly improved in MPS I mice by erythroid-derived, higher than normal peripheral IDUA protein. These data demonstrate that late-stage erythroid cells, transduced with a tissue-specific LV, can deliver a lysosomal enzyme continuously at supraphysiological levels to the bloodstream and can correct the disease phenotype in both viscera and CNS of MPS I mice. This approach provides a paradigm for the utilization of RBC precursors as a depot for efficient and potentially safer systemic delivery of nonsecreted proteins by ex vivo HSC gene transfer.
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Congenital disorders of ribosome biogenesis and bone marrow failure.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-19-2009
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Diamond Blackfan anemia (DBA) is a congenital bone marrow (BM) failure syndrome that typically results in macrocytic anemia within the first year of life. DBA is also associated with birth defects, increased incidence of cancer, and other cytopenias. Shwachman-Diamond syndrome (SDS) is a multisystem disease characterized by exocrine pancreatic dysfunction, impaired hematopoiesis, and leukemia predisposition. Other clinical features include skeletal, immunologic, hepatic, and cardiac disorders. Treatment for these BM failure syndromes, including stem cell transplantation (SCT), will be discussed in this review.
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Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-27-2009
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We examined the role of hematopoietic stem cell transplantation (HSCT) for patients aged< or =18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (DLBCL; n=52), and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92; 43 matched sibling and 49 unrelated donor) HSCT in 1990-2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, bone marrow (BM) stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs 4%; P < .01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histological subtypes.
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Race and socioeconomic status influence outcomes of unrelated donor hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-20-2009
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Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 141), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT. Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [CI] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% CI 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% CI 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.
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The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research.
J. Clin. Oncol.
PUBLISHED: 04-13-2009
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Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.
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Private cord blood banking: experiences and views of pediatric hematopoietic cell transplantation physicians.
Pediatrics
PUBLISHED: 03-04-2009
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Private cord blood banks are for-profit companies that facilitate storage of umbilical cord blood for personal or family use. Pediatric hematopoietic cell transplantation physicians are currently best situated to use cord blood therapeutically. We sought to describe the experiences and views of these physicians regarding private cord blood banking.
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Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia.
Br. J. Haematol.
PUBLISHED: 02-21-2009
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Cytosine arabinoside (ara-C) is irreversibly deaminated to a non-toxic metabolite by cytidine deaminase (CDA). A common polymorphism, A79C, in the gene encoding cytidine deaminase (CDA) changes a lysine residue to glutamine resulting in decreased enzyme activity. CDA A79C genotypes were determined in 457 children with acute myeloid leukaemia (AML) treated on the Childrens Cancer Group (CCG) 2941 and 2961 protocols and analyzed the impact of CDA genotype on therapy outcomes. Postinduction treatment-related mortality (TRM) was significantly elevated in children with the CC genotype (5-year TRM 17 +/- 13% CC vs. 7 +/- 4% AA, 5 +/- 4% AC, P = 0.05). This was more notable in children who received idarubicin, fludarabine, ara-C, and granulocyte colony-stimulating factor (IDA-FLAG; ara-C = 7590 mg/m2) (5-year TRM 24 +/- 21% CC vs. 6 +/- 6% AA, 6 +/- 7% AC, P = 0.07) as consolidation therapy compared to idarubicin, dexamethasone, cytarabine, thioguanine, etoposide and daunomycin (IDA-DCTER; ara-C = 800 mg/m2) (5-year TRM 15 +/- 20% CC vs. 8 +/- 6% AA, 4 +/- 6% AC; P = 0.29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 +/- 20% CC vs. 59 +/- 12% AA and 55 +/- 14% AC; P = 0.40). These data indicate that children with a low activity CDA genotype are at increased risk of TRM with ara-C based therapy for AML.
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Recent decrease in acute graft-versus-host disease in children with leukemia receiving unrelated donor bone marrow transplants.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-11-2009
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Unrelated donor (URD) bone marrow transplantation (BMT) is an effective treatment for leukemia in children, but its success is threatened by graft-versus-host disease (GVHD) and relapse. In this report, we describe the incidence of and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMTs performed between 1990 and 2003 to treat acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, or myelodysplastic syndrome MDS, using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. All recipients were under age 18 years and had available high-resolution HLA typing for HLA-A, -B, -C, and -DRB1. Overall, 27% of the recipients developed acute GVHD (aGVHD) grade III-IV; the risk was significantly higher in children receiving T cell-replete grafts compared with those receiving T cell-depleted grafts (odds ratio [OR] = 3.12; 95% confidence interval [CI] = 2.02 to 4.83; P < .0001). Acute GVHD significantly reduced the risk of relapse in children with ALL (OR = 0.34; 95% CI = 0.13 to 0.86; P = .0052), but not in those with AML (OR = 0.58; 95% CI = 0.22 to 2.98; P = .26). The risk of aGVHD was higher in children undergoing transplantation in 1990-1998 (n = 365) compared with those doing so in 1999-2003 (OR = 1.93; 95% CI = 1.27 to 2.91; P = .002). We conclude that outcomes have changed significantly over time, with a reduced risk of aGVHD associated with the more recent transplantations.
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Hematopoietic stem cell transplantation for bone marrow failure syndromes in children.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-11-2009
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Bone marrow failure (BMF) syndromes include a broad group of diseases of varying etiologies, in which hematopoeisis is abnormal or completely arrested in one or more cell lines. BMF can be an acquired aplastic anemia (AA) or can be congenital, as part of such syndromes as Fanconi anemia (FA), Diamond Blackfan anemia, and Schwachman Diamond syndrome (SDS). In this review, we first address the evolution and current status of bone marrow transplantation (BMT) in the pediatric population in the most common form of BMF, acquired AA. We then discuss pediatric BMT in some of the more common inherited BMF syndromes, with emphasis on FA, in which experience is greatest. It is important to consider the possibility of a congenital etiology in every child (and adult) with marrow failure, because identification of an associated syndrome provides insight into the likely natural history of the disease, as well as prognosis, treatment options for the patient and family, and long-term sequelae both of the disease itself and its treatment.
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Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: an update.
Hematol. Oncol. Clin. North Am.
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Shwachman-Diamond syndrome (SDS) is an inherited neutropenia syndrome associated with a significant risk of aplastic anemia and malignant transformation. Multiple additional organ systems, including the pancreas, liver, and skeletal and central nervous systems, are affected. Mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene are present in most patients. There is growing evidence that SBDS functions in ribosomal biogenesis and other cellular processes. This article summarizes the clinical phenotype of SDS, diagnostic and treatment approaches, and novel advances in our understanding of the molecular pathophysiology of this disease.
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High-dose methylprednisolone for veno-occlusive disease of the liver in pediatric hematopoietic stem cell transplantation recipients.
Biol. Blood Marrow Transplant.
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Veno-occlusive disease (VOD) of the liver is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT), with few successful treatment modalities available for severe disease. Some reports have demonstrated success in adults with the use of high-dose steroid therapy, but experience in the pediatric population is lacking. We retrospectively reviewed HSCT patients treated at our institution since 2003 and identified 15 (2.4%) who developed VOD. Of these, nine (60%) were treated with intravenous high-dose methylprednisolone (500 mg/m(2) per dose every 12 hours for six doses). Steroid therapy was initiated at or before first ultrasound evidence of reversal of portal venous flow and before meeting criteria for initiation of defibrotide therapy. Four patients were also treated with defibrotide starting 2 to 5 days after initiation of steroids. Eight of nine patients (88%) with VOD were diagnosed with multiorgan failure. Response to high-dose steroid therapy as defined by decrease in bilirubin by 50% in 10 days from therapy initiation was noted in six of nine patients (67%), occurring within 3 to 6 days of steroid therapy. Two patients died from multiorgan failure due to VOD. Seven survivors of VOD recovered at the median 6 days (range, 5 to 38) from VOD diagnosis. Overall, VOD survival as a group was 78%; however, survival among responders was 100%. No serious toxicities related to high-dose steroid therapy were observed. We conclude that high-dose steroid therapy if initiated early may reverse VOD of the liver in pediatric HSCT patients, abrogating the need for defibrotide therapy with its associated toxicities and regulatory difficulties.
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Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.
Rev Bras Hematol Hemoter
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Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (e.g. umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, periand post-transplant exposures and risk-factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.
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Pulmonary arterial hypertension in pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy.
Biol. Blood Marrow Transplant.
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Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH, and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed, demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA and PAH, accordingly.
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