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1.
Cancer ; 129(10): 1591-1601, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-36828805

RESUMEN

BACKGROUND: The optimal management of febrile stem cell transplant (SCT) patients presenting without severe neutropenia (absolute neutrophil count [ANC] ≥ 500/µL) is unclear. The authors have developed iterative risk prediction models (Esbenshade Vanderbilt [EsVan] models) that reliably predict bloodstream infections (BSIs) in the febrile general pediatric oncology population without severe neutropenia, but SCT-specific data are limited. METHODS: All SCTs occurring from May 2005 to November 2019 at a single institution were identified. Episodes of fever with a central venous catheter and ANC values ≥ 500/µL were abstracted. All previous versions of the EsVan model were applied to the SCT data, and c-statistics were generated. The models were additionally applied to each type of transplant (autologous/allogeneic), and a new allogeneic model that further adjusted for metrics of immunosuppression, Esbenshade Vanderbilt Allogeneic SCT Model (EsVanAlloSCT), was developed and internally validated. RESULTS: For 429 SCT episodes (221 autologous and 208 allogeneic), the BSI incidence was 19.6% (84 of 429), and it was higher in allogeneic transplant patients (25.5%) than autologous transplant patients (14.0%; p < .01). All versions of the EsVan model performed well for the overall SCT cohort (c-statistics, 0.759-0.795). The EsVan models performed better for the autologous episodes (c-statistics, 0.869-0.881) than the allogeneic SCT episodes (c-statistics, 0.678-0.717). The new allogeneic transplant-specific model, EsVanAlloSCT, which added an adjustment for the extent of immunosuppression, yielded a c-statistic of 0.792 (bootstrap-corrected, 0.750). CONCLUSIONS: The EsVan models work exceptionally well when they are applied to autologous SCT, but they work less well for allogeneic SCT. EsVanAlloSCT appears to improve the predictive ability in allogeneic SCT, but it will need additional external validation.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neutropenia , Sepsis , Humanos , Niño , Trasplante de Células Madre/efectos adversos , Trasplante Autólogo , Trasplante de Células Madre Hematopoyéticas/efectos adversos
2.
Pharmacogenomics J ; 20(2): 306-319, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31673144

RESUMEN

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.


Asunto(s)
Anticoagulantes/administración & dosificación , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Polimorfismo de Nucleótido Simple/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Niño , Estudios Transversales/métodos , Humanos , Quimioterapia de Mantención/métodos , Estudios Observacionales como Asunto/métodos
3.
J Pediatr Hematol Oncol ; 42(7): e637-e640, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-31634238

RESUMEN

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Vincristine is a core chemotherapeutic agent for patients with ALL; unfortunately, ∼78% will develop vincristine-induced peripheral neuropathy (VIPN). VIPN can result in vincristine dose reductions that decrease therapeutic efficacy: making it important to understand which children are at highest risk for VIPN. We hypothesized that pediatric ALL patients who were obese at diagnosis would develop worse VIPN than healthy weight children with ALL within the first year. Our results confirmed that obese pediatric patients have significantly (P=0.03) worse VIPN than patients of healthy weight.


Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Obesidad/complicaciones , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Vincristina/efectos adversos , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Factores de Riesgo
4.
Mol Pharmacol ; 95(5): 490-506, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30782852

RESUMEN

The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Humanos , Neoplasias/genética , Farmacogenética/métodos
5.
Mol Pharmacol ; 91(1): 14-24, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27777271

RESUMEN

The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b-/- versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2-/- mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.


Asunto(s)
Doxorrubicina/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico , Membrana Celular/metabolismo , Perros , Células HeLa , Humanos , Cinética , Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado , Células de Riñón Canino Madin Darby , Masculino , Ratones , Modelos Biológicos , Proteínas Mutantes/metabolismo , Ratas , Transfección
6.
Mol Pharm ; 14(1): 310-318, 2017 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-27977217

RESUMEN

Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.


Asunto(s)
Proteínas de Transporte de Membrana/metabolismo , Metilaminas/metabolismo , Óxidos/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico , Carnitina/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Proteínas de Transporte de Catión Orgánico/metabolismo , Oxigenasas/metabolismo
7.
Br J Clin Pharmacol ; 83(6): 1176-1184, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27936281

RESUMEN

OATP1B1 (SLCO1B1) is predominantly expressed at the basolateral membrane of hepatocytes and is critically important for the hepatic uptake and clearance of numerous drug substrates and endogenous compounds. In general, the organic anion transporting polypeptides (OATP; SLCO) represent a superfamily of uptake transporters that mediate the sodium-independent transport of a diverse range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic peptides, numerous drugs and other xenobiotic substances. OATP1B1 is highly polymorphic and a number of relevant and ethnically dependent polymorphisms have been identified and functionally characterized. In particular, the SLCO1B1 521T>C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG-CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin-induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity.


Asunto(s)
Transportador 1 de Anión Orgánico Específico del Hígado/genética , Preparaciones Farmacéuticas/metabolismo , Polimorfismo Genético , Distribución Tisular/genética , Etnicidad , Genotipo , Humanos , Polimorfismo Genético/genética
8.
Pediatr Blood Cancer ; 62(2): 208-213, 2015 02.
Artículo en Inglés | MEDLINE | ID: mdl-25345874

RESUMEN

BACKGROUND: Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109 /L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109 /L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP. PROCEDURE: Patients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109 /L, maximum dose 10 µg/kg). Bone marrow examinations were not required. RESULTS: At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109 /L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109 /L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities. CONCLUSIONS: Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208-213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.


Asunto(s)
Plaquetas/efectos de los fármacos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/uso terapéutico , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Adolescente , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Recuento de Plaquetas , Proteínas Recombinantes de Fusión/efectos adversos , Trombopoyetina/efectos adversos , Resultado del Tratamiento
9.
J Peripher Nerv Syst ; 20(1): 37-46, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25977177

RESUMEN

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.


Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Vincristina/efectos adversos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Dimensión del Dolor , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Índice de Severidad de la Enfermedad
10.
Br J Haematol ; 165(6): 832-5, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24601977

RESUMEN

The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P < 0·0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (P = 0·001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.


Asunto(s)
Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Variación Genética , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Adolescente , Factores de Edad , Alelos , Niño , Preescolar , Estudios Transversales , Citocromo P-450 CYP2C9 , Genotipo , Humanos , Lactante , Farmacogenética , Estudios Retrospectivos
11.
Pediatr Blood Cancer ; 60(9): 1402-7, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23682017

RESUMEN

Warfarin is the most commonly used oral anticoagulant worldwide. Warfarin has a narrow therapeutic index, requiring frequent monitoring of the INR to achieve therapeutic anticoagulation. The role of pharmacogenomics in warfarin disposition and response has been well established in adults, but remains unclear for pediatric patients. In this review, we focus on the important CYP2C9 and VKORC1 variants involved in warfarin response, our current understanding of warfarin disposition and pharmacogenomics, and recent warfarin pharmacogenetic studies in pediatric patients. Finally, we discuss the need for future pediatric studies and the clinical implications of developing pharmacogenetic-based dosing algorithms in children.


Asunto(s)
Algoritmos , Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas , Oxigenasas de Función Mixta , Farmacogenética/métodos , Warfarina/farmacocinética , Adolescente , Adulto , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Niño , Preescolar , Citocromo P-450 CYP2C9 , Femenino , Humanos , Relación Normalizada Internacional , Masculino , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Farmacogenética/tendencias , Vitamina K Epóxido Reductasas , Warfarina/uso terapéutico
12.
JCI Insight ; 8(14)2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37347545

RESUMEN

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.


Asunto(s)
Enfermedades del Sistema Nervioso Periférico , Xenobióticos , Ratones , Animales , Vincristina/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Hiperalgesia/inducido químicamente , Ganglios Espinales , Proteínas de Transporte de Membrana
13.
Mol Pharm ; 9(4): 986-95, 2012 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-22352740

RESUMEN

The human organic anion-transporting polypeptides OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-enriched membrane transporters of major importance to hepatic uptake of numerous endogenous compounds, including bile acids, steroid conjugates, hormones, and drugs, including the 3-hydroxy-3-methylglutaryl Co-A reductase inhibitor (statin) family of cholesterol-lowering compounds. Despite their remarkable substrate overlap, there are notable exceptions: in particular, the gastrointestinal peptide hormone cholecystokinin-8 (CCK-8) is a high affinity substrate for OATP1B3 but not OATP1B1. We utilized homologous recombination of linear DNA by E. coli to generate a library of cDNA containing monomer size chimeric OATP1B1-1B3 and OATP1B3-1B1 transporters with randomly distributed chimeric junctions to identify three discrete regions of the transporter involved in conferring CCK-8 transport activity. Site-directed mutagenesis of three key residues in OATP1B1 transmembrane helices 1 and 10, and extracellular loop 6, to the corresponding residues in OATP1B3, resulted in a gain of CCK-8 transport by OATP1B1. The residues appear specific to CCK-8, as the mutations did not affect transport of the shared OATP1B substrate atorvastatin or the OATP1B1-specific substrate estrone sulfate. Regions involved in gain of CCK-8 transport by OATP1B1, when mapped to the crystal structures of bacterial transporters from the major facilitator superfamily, are positioned to suggest these regions could readily interact with drug substrates. Accordingly, our data provide new insight into the molecular determinants of the substrate specificity of these hepatic uptake transporters with relevance to targeted drug design and prediction of drug-drug interactions.


Asunto(s)
Aminoácidos/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/química , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Transportadores de Anión Orgánico/química , Transportadores de Anión Orgánico/metabolismo , Aminoácidos/química , Aminoácidos/genética , Colecistoquinina/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado , Mutagénesis Sitio-Dirigida , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Fragmentos de Péptidos/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Especificidad por Sustrato
14.
Pediatr Blood Cancer ; 58(4): 616-20, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21721114

RESUMEN

BACKGROUND: Pneumatosis Intestinalis (PI) is a rare complication following hematopoietic stem cell transplant (HSCT). We sought to assess the incidence, risk factors, and outcome associated with PI. PROCEDURE: We retrospectively reviewed the incidence of PI among 178 patients who underwent allogeneic HSCT between September 1999 and February 2010. RESULTS: Eighteen of 178 children (10.1%) who received allogeneic HSCT developed PI at a median of 94 days (range, 11-1169) after transplant. All patients presented with either abdominal pain or distention, and half of the patients had free air on radiographs. Patients who developed PI had a significantly higher proportion of acute (83% vs. 44%, P = 0.002) and chronic graft versus host disease (GVHD; 56% vs. 18%, P < 0.001). Only 39% of patients with PI had GVHD involving the gasterointestinal track. All patients were managed conservatively without surgery. Transplant related mortality (TRM) was significantly higher in patients who developed PI compared to those who did not (OR 4.3, 95% CI: 1.3-13.1; P = 0.007), but no deaths were attributable to PI. CONCLUSIONS: We conclude that PI is a common complication associated with treatment of GVHD after HSCT, and patients who develop PI experience higher TRM. Patients who develop PI should be managed medically.


Asunto(s)
Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Neumatosis Cistoide Intestinal , Trasplante de Células Madre , Enfermedad Aguda , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Incidencia , Masculino , Neumatosis Cistoide Intestinal/etiología , Neumatosis Cistoide Intestinal/mortalidad , Neumatosis Cistoide Intestinal/terapia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Trasplante Homólogo
15.
Pediatr Transplant ; 16(5): 438-42, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22533817

RESUMEN

Engraftment and OS after umbilical CBT is highly dependent on the TNC. The contribution of the wash step to cell loss and ultimately the dose of cells available for transplant is not well described. To investigate the amount of cell loss after washing and its impact on major outcomes compared to pre-cryopreserved TNC, we analyzed data from patients prospectively enrolled on a National Heart, Lung and Blood Institute sponsored cord blood transplant study between 1999 and 2003. There were 310 patients ≤18 yr of age with malignant (N = 218) or non-malignant (N = 92) disease enrolled on this trial. Only single CBU were used. All CBU were thawed and washed using an identical process. The median TNC after thawing and washing (PTW) was 5.43 × 10(7) /kg (79% recovery of cells). The cumulative incidence of neutrophil engraftment was significantly higher in patients receiving a PTW TNC ≥2.5 × 10(7) /kg (p = 0.01). The cumulative incidence of TRM was higher among patients receiving post-thaw-and-wash TNC <2.5 × 10(7) /kg (p = 0.039). In conclusion, receiving a PTW TNC of <2.5 × 10(7) /kg resulted in worse neutrophil engraftment and increased transplant-related mortality compared to a PTW TNC of ≥2.5 × 10(7) /kg.


Asunto(s)
Recolección de Muestras de Sangre/métodos , Trasplante de Células Madre de Sangre del Cordón Umbilical , Criopreservación , Sangre Fetal/citología , Leucemia Mieloide Aguda/cirugía , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adolescente , Recuento de Células , Niño , Preescolar , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Masculino , Análisis Multivariante , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resultado del Tratamiento
16.
Cancer ; 117(15): 3485-92, 2011 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-21246536

RESUMEN

BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis.


Asunto(s)
Anemia Aplásica/terapia , Antiinfecciosos/efectos adversos , Dapsona/efectos adversos , Neoplasias Hematológicas/terapia , Metahemoglobinemia/inducido químicamente , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Análisis Multivariante , Neumonía por Pneumocystis/prevención & control , Modelos de Riesgos Proporcionales
17.
Pharmacogenet Genomics ; 21(3): 103-14, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21278621

RESUMEN

OBJECTIVE: The uptake carrier organic anion-transporting polypeptide 1B3 (OATP1B3, gene SLCO1B3) is involved in the hepatic clearance of xenobiotics including statins, taxanes, and mycophenolic acid. We thought to assess the SLCO1B3 coding region for yet unidentified polymorphisms and to analyze their functional relevance. METHODS: We used DNA of ethnically diverse individuals for polymerase chain reaction, and determined polymorphisms by sequencing or temperature-dependent capillary electrophoresis. We then created variant OATP1B3 expression plasmids by site-directed mutagenesis, which were transiently expressed and functionally characterized in human cervical carcinoma (HeLa) cells using radiolabeled substrates. RESULTS: We identified six nonsynonymous polymorphisms including novel variants such as 439A>G (Thr147Ala), 767G>C (Gly256Ala), 1559A>C (His520Pro), and 1679T>C (Val560Ala). Allelic frequencies occurred to be ethnicity-dependent, with the latter observed only in African-Americans (3.6%). After expression in HeLa cells, His520Pro, Val560Ala, and Met233Ile or Met233Ile_Ser112Ala haplotype variants showed decreased uptake activity compared with wild type for cholecystokinin-8 and rosuvastatin, but not for atorvastatin. Kinetic cholecystokinin-8 analysis showed reduced Vmax without altering Km. His520Pro and Val560Ala exhibited decreased total and plasma membrane protein expressions. Val560 mapped onto a structural model of OATP1B3 showed that this is a key region for substrate-transporter interaction. His520 resides in a predicted extracellular region thought to be critical to the pH-dependent component of OATP1B3 activity. Loss of activity at pH 7.4 and 8.0 relative to pH 6.5 was significantly greater for the Pro520 variant. CONCLUSION: OATP1B3 polymorphisms that result in altered expression, substrate specificity, and pH-dependent activity may be of potential relevance to hepatic clearance of substrate drugs in vivo.


Asunto(s)
Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Atorvastatina , Fluorobencenos/metabolismo , Expresión Génica , Células HeLa , Ácidos Heptanoicos/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Hígado/metabolismo , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Transportadores de Anión Orgánico Sodio-Independiente/química , Polimorfismo Genético , Conformación Proteica , Pirimidinas/metabolismo , Pirroles/metabolismo , Rosuvastatina Cálcica , Sincalida/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Relación Estructura-Actividad , Especificidad por Sustrato/genética , Sulfonamidas/metabolismo
18.
J Gastroenterol Hepatol ; 26(12): 1740-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21649730

RESUMEN

BACKGROUND AND AIM: The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity. METHODS: Single nucleotide polymorphisms in SLC10A2 from genomic DNA of ethnically-defined healthy individuals were identified using a polymerase chain reaction (PCR)-based temperature gradient capillary electrophoresis (TGCE) system. A heterologous gene expression system was used to assess transport activity of SLC10A2 nonsynonymous variants and missense mutations. Total and cell surface protein expression of wild-type and variant ASBT was assessed by Western blot analysis and immunofluorescence confocal microscopy. Expression of ASBT mRNA and protein was also measured in human intestinal samples. RESULTS: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. A novel variant, 790A>G, was also shown to exhibit near complete loss of taurocholate transport, similar to the previously identified ASBT missense mutations. Examination of ASBT protein expression revealed no significant differences in expression or trafficking to the cell surface among variants versus wild-type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples revealed modest intersubject variability. CONCLUSIONS: Genome sequencing and in vitro studies reveal the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Variación Genética/genética , Homeostasis/genética , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Simportadores/genética , Membrana Celular/metabolismo , Frecuencia de los Genes , Humanos , Mucosa Intestinal/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Polimorfismo de Nucleótido Simple/genética , Simportadores/metabolismo
19.
Clin Transl Sci ; 14(1): 343-353, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32961024

RESUMEN

High-dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function-altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (P < 0.001). The addition of the SLCO1B1 variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Leucemia Linfoide/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Antimetabolitos Antineoplásicos/administración & dosificación , Peso Corporal , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Leucemia Linfoide/sangre , Masculino , Metotrexato/administración & dosificación , Modelos Biológicos , Pruebas de Farmacogenómica/estadística & datos numéricos , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Adulto Joven
20.
Head Neck Pathol ; 15(1): 236-243, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32077054

RESUMEN

NUT (midline) carcinoma is a rare, highly aggressive, poorly differentiated carcinoma that characteristically harbors a rearrangement of the NUTM1 gene. Most of these tumors occur in adolescents and young adults, arise from the midline structures of the thorax, head, and neck, and are associated with extremely poor outcomes. Rare cases originating from salivary glands have been reported with clinicopathologic features comparable to NUT carcinoma of other sites. Outcome studies regarding this subgroup are currently lacking. We report a case of NUT carcinoma arising in a submandibular gland of a 12-year-old boy. Diagnosis was confirmed by fluorescence in situ hybridization demonstrating fusion of the BRD4 (19p13.12) and NUTM1 (15q14) gene loci. A systematic review of all previously reported salivary gland NUT carcinomas (n = 15) showed exclusive occurrence of pediatric cases (n = 6) in males compared to adult patients (n = 9, male: female = 1:2; p < 0.05). The median survival was 24 and 4 months for pediatric and adult patients, respectively (95% confidence interval was 8-24 and 1-7 months, respectively; p < 0.01). The 1-year overall survival was 67% for pediatric and 11% for adult patients. Among all NUT carcinomas, pediatric salivary gland tumors may represent a distinct clinical subset associated with male predilection and comparatively prolonged survival.


Asunto(s)
Carcinoma/patología , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Neoplasias de las Glándulas Salivales/patología , Carcinoma/genética , Carcinoma/mortalidad , Proteínas de Ciclo Celular/genética , Niño , Resultado Fatal , Humanos , Masculino , Mutación , Proteínas de Fusión Oncogénica/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/mortalidad , Factores de Transcripción/genética
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