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1.
Pediatr Transplant ; 28(2): e14707, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38419558

RESUMEN

Epstein-Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post-transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV-directed T cells in rituximab-refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV-PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV-directed T-cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV-directed T-cell therapy for management and associated pitfalls.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Trasplante de Corazón , Trasplante de Células Madre Hematopoyéticas , Trastornos Linfoproliferativos , Humanos , Preescolar , Herpesvirus Humano 4 , Rituximab/uso terapéutico , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia , Tratamiento Basado en Trasplante de Células y Tejidos
2.
Pediatr Blood Cancer ; 68(4): e28811, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33381920

RESUMEN

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) survivors' increased risk for adverse health outcomes could be mitigated through consuming a balanced diet. Nonetheless, >70% of adult survivors do not meet survivorship dietary recommendations. ALL treatment may amplify risk for restricted dietary preferences (picky eating) and poor self-regulation of food intake that could contribute to suboptimal diets in survivorship. This study aims to: (a) characterize differences in picky eating and self-regulation of food intake between survivors and peer controls; and (b) examine the associations between these eating behaviors and dietary quality in ALL survivors relative to peer controls. METHODS: Participants were children (5-13 years) with (n = 32) and without (n = 32) a history of ALL and their caregivers. Children's dietary quality (Healthy Eating Index-2015) was calculated from 24-h dietary recalls. Caregivers completed the Child Eating Behavior Questionnaire-Food Fussiness subscale and the Child Self-Regulation in Eating Questionnaire. RESULTS: Independent samples t-tests revealed survivors exhibited greater picky eating than peer controls but comparable self-regulation of food intake. Bootstrapped grouped multivariate regression results showed that for ALL survivors, greater picky eating was associated with worse dietary quality (controlling for age and self-regulation of food intake). For peer controls, worse self-regulation of food intake was associated with poorer dietary quality (controlling for picky eating and age). CONCLUSIONS: Results provide preliminary support that different eating behaviors contribute to poor dietary quality in children with and without an ALL history. These findings suggest that interventions to improve ALL survivors' dietary quality may benefit targeting picky eating.


Asunto(s)
Supervivientes de Cáncer , Conducta Alimentaria , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Niño , Preescolar , Dieta , Ingestión de Alimentos , Femenino , Calidad de los Alimentos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
3.
Pediatr Blood Cancer ; 67(10): e28543, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32779849

RESUMEN

Treatment for children with Philadelphia chromosome-positive acute lymphoblastic leukemia has changed radically over the past 20 years. This type of leukemia used to have dismal prognosis, but today cure rates have improved with combination of cytotoxic chemotherapy and a tyrosine kinase inhibitor such as imatinib or dasatinib, with hematopoietic stem cell transplant reserved for patients who are at high risk based on slow response to therapy or who relapse. Treating these patients can be challenging particularly if they are not enrolled on a clinical trial. Here, we describe our approach to these patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Recurrencia Local de Neoplasia/terapia , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Terapia Combinada , Humanos , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico
4.
Pediatr Transplant ; 24(5): e13747, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32497335

RESUMEN

INTRODUCTION: PTLD is the most frequent malignancy following SOT in children and the second most common SOT complication in adults. However, factors determining outcomes in children are poorly understood due to its relative rarity. METHODS: This study was performed at the University of Florida. Univariate and multivariate analyses were used to identify prognostic factors in pediatric patients diagnosed with PTLD. RESULTS: We reviewed records of 54 pediatric (younger than 18 years old at diagnosis) patients diagnosed with PTLD from 1994 to 2017. The median follow-up was 28.8 months. The estimated 5-year survival rate was 87.6% (95% CI 74.3-94.2%). Univariate analysis showed that organ transplanted (specifically heart transplant), poor response to initial treatment, allograft rejection, and low Karnofsky score were statistically significant for negative prognostic factors in determining survival. Multivariate analysis determined progression in response to initial treatment and presence of allograft rejection as statistically significant prognostic factors affecting overall survival. We found no statistically significant impact of EBV serological status on PTLD prognosis. CONCLUSIONS: Disease progression and allograft rejection were strong negative prognostic indicators in our study cohort. Close attention to graft status and development of therapies that protect the graft from rejection while bolstering anti-EBV immunity will be essential to further improving PTLD outcomes in children.


Asunto(s)
Trastornos Linfoproliferativos/etiología , Trasplante de Órganos , Complicaciones Posoperatorias/etiología , Adolescente , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/mortalidad , Masculino , Análisis Multivariante , Trasplante de Órganos/mortalidad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia
5.
Mov Disord Clin Pract ; 11(6): 728-733, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38594844

RESUMEN

BACKGROUND: Most published reports on SAMD9L-related ataxia-pancytopenia syndrome (ATXPC) have emphasized the hematologic findings. Fewer details are known about the progression of neurologic manifestations and methods for monitoring them. CASES: We present six individuals from two families transmitting a heterozygous variant in SAMD9L, exhibiting clinical variations in their hematologic and neurologic findings. Serial motor function testing was used to monitor motor proficiency over a 2 to 3 year period in the proband and his father from Family 1. CONCLUSIONS: Our case series focuses on the neurologic progression in patients with heterozygous variants in SAMD9L. Patients with ATXPC should be followed to evaluate a wide range of neurologic manifestations. Serial motor function testing using a standardized method is helpful to track changes in balance and coordination in children and adults with ATXPC and could aid in a future extended natural history study.


Asunto(s)
Ataxia , Humanos , Masculino , Femenino , Adulto , Niño , Ataxia/genética , Ataxia/diagnóstico , Ataxia/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/genética , Adolescente , Progresión de la Enfermedad , Preescolar , Adulto Joven , Persona de Mediana Edad , Proteínas Supresoras de Tumor
6.
Cureus ; 15(2): e35061, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36938203

RESUMEN

Background The Florida Association of Pediatric Tumor Programs (FAPTP) has used the Statewide Patient Information Reporting System (SPIRS) since 1981 to track all new cases of pediatric cancer. We reviewed the last 40 years of data to see how pediatric cancer care has evolved. Methods We retrospectively analyzed SPIRS data from 1981 through 2020 in five-year increments, looking at numbers of new diagnoses, care delivery sites, and trial enrollment in Children's Oncology Group (COG) studies. Results From 1981-2020 Florida's population increased almost 88% while the pediatric population only grew 61%. New pediatric cancer diagnoses increased 326% to over 1,000 new cases/year. The percentage of patients treated at FAPTP centers grew from 30% to 57% with an annual percentage change (APC) of 10.3% (95% Confidence Interval [CI] of 0.6 to 20.9%). The rate of COG clinical trial enrollment decreased from 32% in 1981-1985 to 20% in 2016-2020, for an APC of 8.91% (95% CI of -13.3 to -4.3%). Conclusions The striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. More patients received care at FAPTP centers, but a lower percentage were enrolled on COG trials.

7.
Lancet Haematol ; 10(7): e510-e520, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37407142

RESUMEN

BACKGROUND: The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia. METHODS: CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged >1 year to <18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m2 orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed. FINDINGS: Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred. INTERPRETATION: Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission. FUNDING: Bristol Myers Squibb.


Asunto(s)
Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Masculino , Femenino , Mesilato de Imatinib/uso terapéutico , Dasatinib/efectos adversos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento
8.
Int J Radiat Oncol Biol Phys ; 112(1): 158-166, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34348176

RESUMEN

PURPOSE: For curative treatment of Hodgkin lymphoma, radiation therapy benefit must be weighed against toxicity. Although more costly, proton radiation therapy reduces dose to healthy tissue, potentially improving the therapeutic ratio compared with photons. We sought to determine the cost-effectiveness of proton versus photon therapy for mediastinal Hodgkin lymphoma (MHL) based on reduced heart disease. METHODS AND MATERIALS: Our model approach was 2-fold: (1) Use patient-level dosimetric information for a cost-effectiveness analysis using a Markov cohort model. (2) Use population-based data to develop guidelines for policymakers to determine thresholds of proton therapy favorability for a given photon dose. The HD14 trial informed relapse risk; coronary heart disease risk was informed by the Framingham risk calculator modified by the mean heart dose (MHD) from radiation. Sensitivity analyses assessed model robustness and identified the most influential model assumptions. A 30-year-old adult with MHL was the base case using 30.6-Gy proton therapy versus photon intensity modulated radiation therapy. RESULTS: Proton therapy was not cost-effective in the base case for male ($129,000/ quality-adjusted life years [QALYs]) or female patients ($196,000/QALY). A 5-Gy MHD decrease was associated with proton therapy incremental cost-effectiveness ratio <$100,000/QALY in 40% of scenarios. The hazard ratio associating MHD and heart disease was the most influential clinical parameter. CONCLUSIONS: Proton therapy may be cost-effective a select minority of patients with MHL based on age, sex, and MHD reduction. We present guidance for clinicians using MHD to aid decision-making for radiation therapy modality.


Asunto(s)
Enfermedad de Hodgkin , Terapia de Protones , Adulto , Análisis Costo-Beneficio , Femenino , Enfermedad de Hodgkin/radioterapia , Humanos , Masculino , Recurrencia Local de Neoplasia/etiología , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Años de Vida Ajustados por Calidad de Vida
9.
Circulation ; 120(19): 1910-8, 2009 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-19858415

RESUMEN

BACKGROUND: The bone marrow contains a variety of blood vessels that have different functions in bone marrow maintenance and hematopoiesis. Arterioles control the flow of blood into bone marrow compartments, and sinusoids serve as a conduit to the bloodstream and as niches for megakaryocyte development. Most studies of bone marrow vasculature, including studies quantifying changes in the marrow vascular by microvascular density, do not differentiate between different types of marrow vessels. Recognizing changes in different types of blood vessels after chemotherapy exposure or during leukemia development has important physiological implications. We hypothesized that the functional heterogeneity of marrow vasculature could be recognized through the use of functional markers such as tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) expression or 1,1-dioctadecyl -3,3,3,3-tetramethyl-indocarbocyanine perchlorate with acetylated low-density lipoprotein (DiI-Ac-LDL) uptake. METHODS AND RESULTS: When transgenic mice with green fluorescent protein (GFP) expressed downstream of the Tie2 promoter were injected with Ac-LDL, Ac-LDL was specifically endocytosed by sinusoids, and Tie2 expression was more pronounced in the arteries, arterioles, and transitional capillaries. Combining these 2 functional endothelial markers and using confocal microscopy to obtain 3-dimensional images, we identified transitional zones where arterioles emptied into the sinusoids. Alternatively, coinjection of lectin with DiI-Ac-LDL has a similar result in normal mice, as seen in Tie2/GFP mice, and can be used to differentiate vessel types in nontransgenic mice. CONCLUSIONS: These results demonstrate that bone marrow vasculature is functionally heterogeneous. Methods to study changes in the marrow vasculature using microvascular density or quantifying changes in the vascular niche need to take this heterogeneity into account.


Asunto(s)
Biomarcadores/metabolismo , Médula Ósea/irrigación sanguínea , Médula Ósea/fisiología , Lipoproteínas LDL/farmacocinética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Acetilación , Animales , Arteriolas/citología , Arteriolas/fisiología , Células de la Médula Ósea/fisiología , Carbocianinas , Endocitosis/fisiología , Células Endoteliales/fisiología , Factor de Crecimiento Epidérmico/química , Factor de Crecimiento Epidérmico/genética , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/genética , Inmunoglobulinas/química , Inmunoglobulinas/genética , Lectinas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal/métodos , Regiones Promotoras Genéticas/fisiología , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptor TIE-2
10.
Pediatr Transplant ; 14(7): 896-902, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20642490

RESUMEN

PTLD is a major complication after transplantation. Treatment options for PTLD are not standardized, usually sequential, starting with reduction in immunosuppression. Recently, we have used a dual combination of rituximab and reduced dose chemotherapy (R/C) directly after failed RI. We retrospectively identified 30 pediatric PTLD cases across four organ systems at our center from 1995 to 2008. We assessed recent outcomes of PTLD in children, comparing the responses to different regimens. Two-yr failure-free survival was best in renal and heart recipients (80-88%), followed by liver (57%) and lung (0%). Of note, two patients were Epstein-Barr peripheral blood viral load low positive but tumor EBER negative. Three patients had no detectable viral load but were EBER positive. The R/C regimen (n = 8) had the highest CR rate (100%), low recurrence (12%) and lowest mortality (12%). Interferon (n = 4) had 75% CR, 33% recurrence and 25% mortality. Rituximab/prednisone (n = 5) had 80% CR, 50% recurrence and 20% mortality. Other chemotherapy (n = 7, including all 4 T-cell PTLDs) had 57% CR, 0% recurrence and 14% mortality. Direct dual R/C combination therapy after failed RI is effective and offers another treatment option for B-cell PTLD.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Trasplante de Órganos/efectos adversos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Herpesvirus Humano 4/metabolismo , Humanos , Masculino , Recurrencia , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Carga Viral
11.
Healthcare (Basel) ; 8(4)2020 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-33066571

RESUMEN

Chemotherapy for acute lymphoblastic leukemia (ALL) patients is complex and intense, resulting in a high readmission rate. We aimed to identify the incidence, causes, and risk factors of readmission following inpatient chemotherapy among ALL patients, using 2016 National Readmission Database. We applied three different definitions of 30-day readmission: (1) nonelective readmission based on readmission type, (2) unplanned readmission defined by CMS, and (3) unintentional readmission, combining (1) and (2). We used unweighted multivariable Poisson regression with robust variance estimates for risk factors analysis, including patient-, hospital-, and admission-related characteristics. Percentage for nonelective, unplanned, and unintentional readmission were 33.3%, 22.4%, and 18.5%, respectively. The top three causes for unplanned readmissions were neutropenia/agranulocytosis (27.8%), septicemia (15.3%), and pancytopenia (11.5%). Risk ratios for unintentional readmission were 1.21 (1.08-1.36) for nonelective vs. elective admission, 1.19 (1.06-1.33) for public vs. private insurance enrollees, 0.96 (0.95-0.98) for each day of hospital stay, 0.77 (0.62-0.95) for large teaching and 0.87 (0.70-1.08) for small teaching vs. nonteaching hospitals. Possible strategies to reduce readmission among ALL patients could be shortening the gap in quality of care among teaching vs. non-teaching hospitals, understanding the difference between privately vs. publicly insured patients, and avoiding aggressive discharge after chemotherapy.

12.
Radiol Case Rep ; 15(7): 1110-1114, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32477441

RESUMEN

Primary pulmonary artery sarcoma (PAS) is extremely rare in children. Nevertheless, distinguishing primary PAS from pulmonary embolism is critical to a child's survival. Primary PAS is commonly misdiagnosed as a pulmonary embolism due to similar presenting symptoms and radiographic findings. However, compared to adults, pulmonary embolism is rare in children, especially in patients who do not have predisposing factors or hypercoagulable state. We present a child with primary PAS which mimicked pulmonary embolism on presentation but eventually was resected and is doing well 5 years after resection. In the absence of predisposing factors or hypercoagulable state, solid tumors such as primary PAS should be considered when assessing a pediatric patient with presumed pulmonary embolism.

13.
Int J Part Ther ; 6(4): 11-16, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32582815

RESUMEN

BACKGROUND: Local relapse is a predominant form of recurrence among pediatric patients with Hodgkin lymphoma (PHL). Although PHL radiotherapy doses have been approximately 20 Gy, adults with Hodgkin lymphoma receiving 30 to 36 Gy experience fewer in-field relapses. We investigated the dosimetric effect of such a dose escalation to the organs at risk (OARs). MATERIALS AND METHODS: Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT21Gy) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT30Gy), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRTboost), and delivering 30 Gy to the residual ISRT target only (rISRT30Gy). Radiation doses to the OARs were compared. RESULTS: The ISRT30Gy escalated the dose to the target by 42% but also to the OARs. The rISRTboost escalated the residual target dose by 42%, and the OAR dose by only 17% to 26%. The rISRT30Gy escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%. CONCLUSION: Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT21Gy. Studies should evaluate these strategies to improve outcomes and minimize the late effects.

14.
Exp Hematol ; 36(9): 1143-1156, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18718416

RESUMEN

OBJECTIVE: Bone marrow sinusoids remain predominantly host-derived following bone marrow transplantation. Systematic analysis was conducted at the cellular level to investigate how the host sinusoidal structures survived after lethal irradiation. MATERIALS AND METHODS: Apoptosis and cell proliferation assays were performed on bone marrow sections at various time points during the first 2 weeks postirradiation to study the extent of damage to sinusoidal endothelial cells from lethal irradiation and to determine whether cell proliferation contributes to the recovery of the sinusoidal system. RESULTS: Phosphorylated H2AX was present in both hematopoietic and sinusoidal endothelial cells 3 hours after irradiation demonstrating DNA damage. Three days after irradiation, some sinusoidal endothelial cells became terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling -positive, but were caspase-3 and in situ oligo ligation -negative, suggesting nonapoptotic DNA fragmentation. Clusters of sinusoidal endothelial cells that expressed Ki67 appeared 3 days after irradiation, and increased through day 7. These Ki67-positive endothelial cells were host-derived. Bromodeoxyuridine-positive endothelial cells were present in the Ki67-positive areas confirming endothelial cell replication. Twenty percent of the sinusoidal endothelial cells were lost by day 3 after irradiation. The total number of endothelial cells remained relatively unchanged between day 3 and day 14. These results demonstrate that lethal irradiation resulted in limited, nonapoptotic sinusoidal endothelial cell loss, followed by proliferation of preexisting host-derived mature sinusoidal endothelial cells. Our data suggest that DNA repair mechanisms and proliferation of host endothelial cells within the sinusoids are involved in maintenance of the structural integrity of the bone marrow vascular niche following lethal irradiation.


Asunto(s)
Células de la Médula Ósea/efectos de la radiación , Médula Ósea/efectos de la radiación , Células Endoteliales/efectos de la radiación , Traumatismos Experimentales por Radiación/patología , Animales , Biomarcadores , Médula Ósea/irrigación sanguínea , Células de la Médula Ósea/patología , Trasplante de Médula Ósea , Muerte Celular , División Celular , ADN/efectos de la radiación , Roturas del ADN , Reparación del ADN , Células Endoteliales/patología , Femenino , Histonas/metabolismo , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación , Procesamiento Proteico-Postraduccional , Quimera por Radiación , Factores de Tiempo
15.
Curr Gene Ther ; 19(1): 40-53, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30444200

RESUMEN

INTRODUCTION: Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design. METHODS: Here, we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay. RESULTS: The results showed that the CD28/IL-15Rα co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-γ, TNFα and IL-2 upon interaction with the target cells. CONCLUSION: In a follow-up clinical study, an acute lymphoblastic leukemia (ALL) patient, who experienced multiple relapses of central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Rα-modified CART cells in cancer patients.


Asunto(s)
Inmunoterapia/métodos , Subunidad alfa del Receptor de Interleucina-15/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/trasplante , Receptor Toll-Like 9/inmunología , Adulto , Estudios de Casos y Controles , Células Cultivadas , Citocinas/metabolismo , Humanos , Subunidad alfa del Receptor de Interleucina-15/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Receptor Toll-Like 9/genética
16.
Blood Adv ; 3(12): 1837-1847, 2019 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-31208955

RESUMEN

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2, IDH1/2, ASXL1, and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.


Asunto(s)
Biología Computacional/métodos , Genómica/instrumentación , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Biología Computacional/estadística & datos numéricos , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Dioxigenasas , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/terapia , Ensayos Clínicos Controlados no Aleatorios como Asunto , Medicina de Precisión/instrumentación , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sensibilidad y Especificidad , Factores de Transcripción/genética , Resultado del Tratamiento
17.
Hum Gene Ther ; 19(4): 376-83, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18370591

RESUMEN

Although conventional recombinant single-stranded adeno-associated virus serotype 2 (ssAAV2) vectors have been shown to efficiently transduce numerous cells and tissues such as brain and muscle, their ability to transduce primary hematopoietic stem cells (HSCs) has been reported to be controversial. We have previously documented that among the ssAAV serotype 1 through 5 vectors, ssAAV1 vectors are more efficient in transducing primary murine HSCs, but that viral second-strand DNA synthesis continues to be a rate-limiting step. In the present studies, we evaluated the transduction efficiency of several novel serotype vectors (AAV1, AAV7, AAV8, and AAV10) and documented efficient transduction of HSCs in a murine serial bone marrow transplantation model. Self-complementary AAV (scAAV) vectors were found to be more efficient than ssAAV vectors, and the use of hematopoietic cell-specific enhancers/promoters, such as the human beta-globin gene DNase I-hypersensitive site 2 enhancer and promoter (HS2-betap) from the beta-globin locus control region (LCR), and the human parvovirus B19 promoter at map unit 6 (B19p6), allowed sustained transgene expression in an erythroid lineage-restricted manner in both primary and secondary transplant recipient mice. The proviral AAV genomes were stably integrated into progenitor cell chromosomal DNA, and did not lead to any overt hematological abnormalities in mice. These studies demonstrate the feasibility of the use of novel scAAV vectors for achieving high-efficiency transduction of HSCs as well as erythroid lineage-restricted expression of a therapeutic gene for the potential gene therapy of beta-thalassemia and sickle cell disease.


Asunto(s)
Trasplante de Médula Ósea , Linaje de la Célula , Dependovirus/genética , Expresión Génica , Vectores Genéticos/genética , Células Madre Hematopoyéticas/metabolismo , Transgenes/genética , Animales , Células Sanguíneas/citología , ADN Recombinante/genética , Femenino , Ingeniería Genética , Células Madre Hematopoyéticas/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Factores de Tiempo , Transducción Genética
18.
Hum Gene Ther ; 19(3): 267-78, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18303957

RESUMEN

We previously reported that among single-stranded adeno-associated virus (ssAAV) vectors, serotypes 1 through 5, ssAAV1 is the most efficient in transducing murine hematopoietic stem cells (HSCs), but viral second-strand DNA synthesis remains a rate-limiting step. Subsequently, using double-stranded, self-complementary AAV (scAAV) vectors, serotypes 7 through 10, we observed that scAAV7 vectors also transduce murine HSCs efficiently. In the present study, we used scAAV1 and scAAV7 shuttle vectors to transduce HSCs in a murine bone marrow serial transplant model in vivo, which allowed examination of the AAV proviral integration pattern in the mouse genome, as well as recovery and nucleotide sequence analyses of AAV-HSC DNA junction fragments. The proviral genomes were stably integrated, and integration sites were localized to different mouse chromosomes. None of the integration sites was found to be in a transcribed gene, or near a cellular oncogene. None of the animals, monitored for up to 1 year, exhibited pathological abnormalities. Thus, AAV proviral integration-induced risk of oncogenesis was not found in our study, which provides functional confirmation of stable transduction of self-renewing multipotential HSCs by scAAV vectors as well as promise for the use of these vectors in the potential treatment of disorders of the hematopoietic system.


Asunto(s)
ADN Viral/genética , Dependovirus/genética , Vectores Genéticos , Células Madre Hematopoyéticas/virología , Transducción Genética , Integración Viral , Animales , Bleomicina , ADN Viral/metabolismo , Dependovirus/metabolismo , Femenino , Terapia Genética , Genoma Viral , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Provirus/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transgenes
19.
Hum Gene Ther ; 19(4): 365-75, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18399730

RESUMEN

Therapeutic levels of expression of the beta-globin gene have been difficult to achieve with conventional retroviral vectors without the inclusion of DNase I-hypersensitive site (HS2, HS3, and HS4) enhancer elements. We generated recombinant adeno-associated viral (AAV) vectors carrying an antisickling human beta-globin gene under the control of either the beta-globin gene promoter/enhancer or the erythroid cell-specific human parvovirus B19 promoter at map unit 6 (B19p6) without any enhancer, and tested their efficacy in a human erythroid cell line (K-562) and in primary murine hematopoietic progenitor cells (c-kit(+)lin()). We report here that (1) self-complementary AAV serotype 2 (scAAV2)-beta-globin vectors containing only the HS2 enhancer are more efficient than single-stranded AAV (ssAAV2)-beta-globin vectors containing the HS2+HS3+HS4 enhancers; (2) scAAV2-beta-globin vectors recombine with scAAV2-HS2+HS3+HS4 vectors after dual-vector transduction, leading to transgene expression; (3) scAAV2-beta-globin as well as scAAV1-beta-globin vectors containing the B19p6 promoter without the HS2 enhancer element are more efficient than their counterparts containing the HS2 enhancer/beta-globin promoter; and (4) scAAV2-B19p6-beta-globin vectors in K-562 cells, and scAAV1-B19p6-beta-globin vectors in murine c-kit(+)lin() cells, yield efficient expression of the beta-globin protein. Thus, the combined use of scAAV vectors and the parvovirus B19 promoter may lead to expression of therapeutic levels the beta-globin gene in human erythroid cells, which has implications in the use of these vectors in gene therapy of beta-thalassemia and sickle cell disease.


Asunto(s)
Dependovirus/genética , Terapia Genética , Vectores Genéticos/genética , Globinas/genética , Transducción Genética , Transgenes/genética , Animales , Línea Celular , Elementos de Facilitación Genéticos/genética , Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Parvovirus B19 Humano , Regiones Promotoras Genéticas/genética
20.
Stem Cells ; 25(11): 2945-55, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17656638

RESUMEN

Bone marrow sinusoids maintain homeostasis between developing hematopoietic cells and the circulation, and they provide niches for hematopoietic progenitors. Sinusoids are damaged by chemotherapy and radiation. Hematopoietic stem cells (HSCs) have been shown to produce endothelial progenitor cells that contribute to the repair of damaged blood vessels. Because HSCs home to the marrow during bone marrow transplant, these cells may play a role in repair of marrow sinusoids. Here, we explore the role of donor HSCs in the repair of damaged sinusoids following hematopoietic stem cell transplant. We used three methods to test this role: (a) expression of platelet endothelial cell adhesion molecule to identify endothelial progenitors and the presence of the Y chromosome to identify male donor cells in female recipients; (b) presence of the Y chromosome to identify male donor cells in female recipients, and expression of the panendothelial marker mouse endothelial cell antigen-32 to identify sinusoidal endothelium; and (c) use of Tie-2/green fluorescent protein mice as donors or recipients and presence of Dil-Ac-LDL to identify sinusoids. We found that sinusoids were predominantly host-derived posttransplant. Donor cells spread along the marrow vasculature early post-transplant in a pattern that matched stromal-derived factor-1 expression. Furthermore, these engrafting progenitors were positioned to provide physical support, as well as growth and survival signals in the form of vascular-endothelial growth factor-A. Occasionally, donor cells provide cellular "patches" in the damaged sinusoids, although this occurred at a low level compared with hematopoietic engraftment. Donor support for the repair of the marrow vascular niche may be a critical first step of hematopoietic engraftment.


Asunto(s)
Médula Ósea/fisiología , Trasplante de Células Madre Hematopoyéticas/métodos , Donantes de Tejidos , Cicatrización de Heridas/fisiología , Animales , Médula Ósea/cirugía , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
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