RESUMEN
The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 (P = .028) and GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568.
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Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ácidos Hidroxámicos/uso terapéutico , Metotrexato/uso terapéutico , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante/efectos adversos , Donante no Emparentado , Acetilación , Enfermedad Aguda , Adolescente , Adulto , Anciano , Demografía , Estudios de Factibilidad , Femenino , Inhibidores de Histona Desacetilasas/uso terapéutico , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/efectos adversos , Incidencia , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Tacrolimus/efectos adversos , Vorinostat , Adulto JovenAsunto(s)
Leucemia Mieloide Aguda , Neoplasias del Mediastino , Neoplasias de Células Germinales y Embrionarias , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/terapia , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Inducción de Remisión , AdolescenteRESUMEN
Extracorporeal photopheresis (ECP) in young pediatric patients has a risk for procedural hypotension and anemia due to extracorporeal fluid shifts. A standard mitigation policy in these patients is to prime the device with packed red blood cells (RBC) or whole blood. We now report multiple episodes of hemolysis while attempting to prime the Therakos Cellex in a pediatric transplant patient undergoing a course of ECP for severe graft-vs-host-disease. Over the course of 40 ECP treatments, hemolysis was observed on five occasions. An extensive investigation found an association between hemolysis and apheresis RBC (A-RBC). Of 46 RBC units dispensed for blood priming, hemolysis occurred with 22% (4 of 18) of A-RBC and accounted for 80% (4 of 5) of all hemolysis episodes. Hemolysis was significantly higher with A-RBC when compared with RBC collected by whole blood donations (WB-RBC: 3.5% [1 of 28]; P = .049). A comparison of RBC attributes, including unit age, showed that hemolyzed A-RBC units tended to be younger than both nonhemolyzed RBC (6.5 vs 10.3 days, P = .018) and WB-RBC (8.5 days, P = .10). We hypothesize that A-RBC may exhibit "sublethal" RBC damage following prior exposure to centrifugal shear and negative forces at the time of collection, leading to a decrease in RBC deformability and increased susceptibility to hemolysis. This is the first report showing an increased susceptibility to hemolysis with A-RBC during priming of the Cellex.
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Eliminación de Componentes Sanguíneos/métodos , Eritrocitos , Hemólisis , Fotoféresis/métodos , Eliminación de Componentes Sanguíneos/efectos adversos , Eliminación de Componentes Sanguíneos/normas , Niño , Deformación Eritrocítica , Femenino , Enfermedad Injerto contra Huésped/terapia , Humanos , Masculino , Pediatría , Fotoféresis/efectos adversos , Fotoféresis/instrumentación , Factores de RiesgoRESUMEN
Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy.
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Proteínas Sanguíneas/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Modelos Biológicos , Neumonía/sangre , Proteínas de Fase Aguda/aislamiento & purificación , Proteínas de Fase Aguda/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Biomarcadores/sangre , Proteínas Sanguíneas/aislamiento & purificación , Electrocromatografía Capilar , Estudios de Casos y Controles , Progresión de la Enfermedad , Etanercept , Humanos , Inmunoglobulina G/uso terapéutico , Neumonía/tratamiento farmacológico , Neumonía/etiología , Neumonía/patología , Análisis de Componente Principal , Proteómica , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Reproducibilidad de los Resultados , Trasplante Homólogo/efectos adversosRESUMEN
Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children's hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.
Asunto(s)
Líquido del Lavado Bronquioalveolar , Disbiosis , Trasplante de Células Madre Hematopoyéticas , Lesión Pulmonar , Humanos , Niño , Femenino , Lesión Pulmonar/patología , Lesión Pulmonar/microbiología , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Preescolar , Adolescente , Líquido del Lavado Bronquioalveolar/microbiología , Disbiosis/microbiología , Disbiosis/inmunología , Microbiota , Lactante , Pulmón/patología , Pulmón/microbiología , Pulmón/inmunologíaRESUMEN
Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.
RESUMEN
Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.
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Enfermedad Injerto contra Huésped , Enfermedad Crónica , Consenso , Diagnóstico Precoz , Enfermedad Injerto contra Huésped/diagnóstico , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMEN
BACKGROUND: Positron-emission tomography (PET) imaging using [(18)F]fluorodeoxyglucose (FDG) is useful for detection, staging, and monitoring a variety of malignancies, including lymphoma, in adults, but its utility in sarcomas, especially soft tissue sarcomas (STS), in children and young adults is not clear. PROCEDURE: To evaluate the potential utility of FDG PET in the care of STS in children and young adults, we analyzed 46 PET scans in 25 patients acquired over 12 years. Scans were interpreted by two imaging physicians blinded to findings from other imaging studies and clinical information. Results were compared with computed tomography and magnetic resonance imaging, biopsy results, where available, and clinical follow-up of at least 12 months. RESULTS: For a total of 46 scans in 25 patients, there were 25 true-positive scans, 3 false-positive scans, 12 true-negative scans, and 6 false-negative scans. The sensitivity of the PET scan was 86%, specificity was 80%, positive predictive value was 89%, and negative predictive value was 67%. CONCLUSION: FDG PET may be a useful imaging modality in the management of children and young adults with STS, although prospective studies are needed to establish its true utility.
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Fluorodesoxiglucosa F18 , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Rabdomiosarcoma/diagnóstico por imagen , Sarcoma de Ewing/diagnóstico por imagen , Adolescente , Biopsia , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Estadificación de Neoplasias , Tumores Neuroectodérmicos Primitivos/patología , Estudios Retrospectivos , Rabdomiosarcoma/patología , Sarcoma de Ewing/patología , Sensibilidad y Especificidad , Método Simple Ciego , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
PURPOSE: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. PATIENTS AND METHODS: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. RESULTS: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. CONCLUSIONS: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azepinas/administración & dosificación , Azepinas/farmacocinética , Niño , Preescolar , Estudios de Cohortes , Monitoreo de Drogas , Resistencia a Antineoplásicos , Femenino , Humanos , Lactante , Irinotecán/administración & dosificación , Irinotecán/farmacocinética , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/mortalidad , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Retratamiento , Temozolomida/administración & dosificación , Temozolomida/farmacocinética , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.
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3-Yodobencilguanidina/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias Primarias Secundarias/inducido químicamente , Neuroblastoma/tratamiento farmacológico , Radiofármacos/efectos adversos , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Terapia Combinada , Femenino , Neoplasias Hematológicas/inducido químicamente , Humanos , Lactante , Masculino , Síndromes Mielodisplásicos/inducido químicamente , Estudios Retrospectivos , Medición de Riesgo , Adulto JovenRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing. FLT3-mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs 37%, P<0.001) and with a shorter median time to relapse (100 vs 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (hazard ratio (HR) 3.63, 95% confidence interval (CI): 2.13, 6.19, P<0.001) and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3-mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Mutación , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
PURPOSE: (131)I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan. EXPERIMENTAL DESIGN: Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBG-avid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m(2)/dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m(2) IV) on days 0 and 7. MIBG was given on day 1 following a 3 + 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more. RESULTS: Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9-26.8 years) received 1 (n = 17), 2 (n = 5), or 3 (n = 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients. CONCLUSIONS: MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Neuroblastoma/tratamiento farmacológico , 3-Yodobencilguanidina/administración & dosificación , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Radioisótopos de Yodo/farmacocinética , Irinotecán , Masculino , Dosis Máxima Tolerada , Pronóstico , Distribución Tisular , Vincristina/administración & dosificación , Adulto JovenRESUMEN
Purpose. (123)I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6-73.7%) versus 5.9% (range 0.6-110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0-100%) in MIBG avid patients compared to 10% (range 0-80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.