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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) predominantly occurs in adults ≥60 years old; 10-20% of cases are pediatric or adolescent/young adult (AYA) patients. Tagraxofusp (TAG, Elzonris®) is the only approved treatment for BPDCN; in the United States it is approved for patients aged ≥2 years. Data on treating pediatric and AYA BPDCN patients are limited. We present a case series of pediatric and AYA patients with BPDCN treated with TAG. Eight patients (five newly diagnosed; three relapsed/refractory [R/R]), aged 2-21 years, received 12 mcg/kg TAG. Seven patients were female; most had skin (n = 6) and/or bone marrow (n = 4) involvement. No new safety signals were identified. Grade 3 adverse events were headache (n = 1) and transaminitis (n = 2). Three patients with newly diagnosed BPDCN achieved complete response, one achieved partial response, and one had stable disease (SD). One patient with R/R BPDCN achieved a minor response; one had SD. Seven patients (88%) were bridged to stem cell transplant: 80% of newly diagnosed patients and 100% of R/R patients. Five patients remained alive at last follow-up. These cases highlight the efficacy and safety of TAG in pediatric and AYA patients for whom there is no other approved BPDCN therapy.
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BACKGROUND/AIM: This study explored the mechanisms of the allogeneic graft versus leukemia effect in acute lymphoblastic leukemia (ALL) cells by examining whether they change gene expression in the post-transplant environment containing cytokines and the immunosuppressant cyclosporine, and if such changes affect ALL cell survival. MATERIALS AND METHODS: RNASeq was used to assess leukemia global gene expression and flow cytometry to measure ALL survival in the presence of T cells, NK cells, cytokines, and cyclosporine. RESULTS: A total of 4,805 genes were differentially expressed. Gene set enrichment analysis demonstrated up-regulation of biological processes related to cytokine responses, control of viral infection, and regulation of leukocyte function including proliferation. Down-regulated genes were related to mesenchymal tissue morphogenesis. ALL cells exposed to cytokines and cyclosporine retained susceptibility to T and NK cell killing, and also exhibited increased cell death without exposure to killer cells. CONCLUSION: A significant portion of the graft versus leukemia effect may be mediated by cytokines and cyclosporine.
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Sobrevivência Celular/genética , Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Criança , Ciclosporina/farmacologia , Citocinas/sangue , Citocinas/fisiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transplante HomólogoRESUMO
The present report describes work examining the manner in which nonmalignant bone marrow stromal cells prevent acute lymphoblastic leukemia (ALL) cell death. The initial focus was on the role of stromal cell-derived C-X-C motif chemokine 12 (CXCL12). Interference with CXCL12 production by stroma or blockade of its interactions with ALL by plerixafor did increase ALL cell death and in sensitive ALLs there was synergistic effect with conventional chemotherapy drugs. However, in contrast to most reports, there was considerable heterogeneity regarding the effect between 7 unique primary ALLs, with several exhibiting no sensitivity to CXCL12 blockade. The diversity in effect was not explained by differences in the expression of ALL cell surface receptors for CXCL12. The modest and variable effects of interference with CXCL12 on ALL led to the assessment of gene expression profiles of stromal cells and ALL cells. Gene set enrichment analysis identified pathways associated with metabolism and redox reactions as potentially important in the stromal cell: leukemia cell interaction. Exploratory imaging studies demonstrated bidirectional transfer of intracellular calcien-labelled molecules and also bidirectional transfer of mitochondria between stromal cells and ALL cells, providing potential means of metabolic interdependence of stromal cells and ALL cells.
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Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare cause of bone marrow failure in children. We report two children who presented with pancytopenia, and were diagnosed with PNH with severe aplastic anemia. Both children underwent upfront, successful hematopoietic stem cell transplantation with reduced-intensity conditioning. One patient had a syngeneic donor, and one patient had a 10/10 matched unrelated donor. Neither patient developed graft versus host disease, infections, or recurrent PNH. Reduced-intensity conditioning hematopoietic stem cell transplantation is a reasonable therapy for PNH with marrow failure in children.
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Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/terapia , Condicionamento Pré-Transplante , Adolescente , Humanos , MasculinoRESUMO
BACKGROUND: Pediatric cancer is rare and its symptoms are often ambiguous. The aims of this study were to investigate the time needed to make a diagnosis, assess the frequency of misdiagnosis, and to determine whether these factors affected survival. METHODS: A review of records of 364 pediatric patients diagnosed with cancer at the University of Rochester Golisano Children's Hospital between 2004 and 2012 was conducted. Data were extracted on patient and health care system-related factors and clinical outcomes. RESULTS: The median time from symptom onset to diagnosis was shortest for leukemia (18.5 d) and longest for bone tumors (86.5 d). Tumor type was the only factor associated with time to diagnosis. In 52% of cases an incorrect nononcological diagnosis was initially made. Soft tissue sarcomas and brain tumors were misdiagnosed most often. Neither prolonged time to diagnosis nor initial misdiagnosis was associated with reduced survival. Tumor type and presence of metastatic disease at diagnosis were significantly associated with survival. CONCLUSIONS: There is significant variation in the time from symptom onset to diagnosis of pediatric cancers, and incorrect initial diagnostic impressions are common. Despite this there is no impact of prolonged time to diagnosis on survival.
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Erros de Diagnóstico/mortalidade , Neoplasias/diagnóstico , Adolescente , Neoplasias Ósseas/diagnóstico , Criança , Pré-Escolar , Diagnóstico Tardio/mortalidade , Detecção Precoce de Câncer/mortalidade , Feminino , Humanos , Lactente , Leucemia/diagnóstico , Masculino , Neoplasias/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
Sickle cell disease is a severe hemoglobinopathy caused by mutations in the beta globin genes. The disorder has protean manifestations and leads to severe morbidity and early mortality. Acute chest syndrome (ACS) is a common complication and in the USA is the leading cause of death in patients with sickle cell disease. Care of patients with sickle cell disease is complex and typically involves both primary care physicians and hematology subspecialists. The purpose of this study was first to attempt to validate in a pediatric sickle cell patient cohort associations between ACS and sickle cell disease genotype and between ACS and asthma as a comorbidity. The second purpose of the study was to study in a typical community the frequency with which asthma associated with ACS was addressed in terms of electronic medical record integration, pulmonary subspecialty consultation for management of asthma, and completion of pulmonary function testing (PFTs). A retrospective study of the electronic medical record of a children's hospital that provides most of the medical care for children in a portion of western New York state was performed. We found that ACS was more common in the sickle cell disease genotypes SS and S/beta-thalassemia-null, and that ACS was more frequent in patients treated for asthma. We also found that despite the use of a comprehensive electronic medical record, there was poor documentation of ACS and asthma episodes in the problem lists of patients with sickle cell disease, and that most patients with sickle cell disease with ACS or asthma failed to receive formal consultation services from pediatric pulmonary subspecialists.
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Síndrome Torácica Aguda/etiologia , Anemia Falciforme/complicações , Asma/complicações , Síndrome Torácica Aguda/genética , Adolescente , Anemia Falciforme/genética , Criança , Pré-Escolar , Feminino , Genótipo , Doença da Hemoglobina SC/complicações , Doença da Hemoglobina SC/genética , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Stem cell antigen-1 (Ly6a/Sca-1) is a gene that is expressed in activated lymphocytes, hematopoietic stem cells and stem cells of a variety of tissues in mice. Despite decades of study its functions remain poorly defined. These studies explored the impact of expression of this stem cell associated gene in acute lymphoid leukemia. Higher levels of Ly6a/Sca-1 expression led to more aggressive leukemia growth in vivo and earlier death of hosts. Leukemias expressing higher levels of Ly6a/Sca-1 exhibited higher levels of matrix metalloproteinases. The results suggest the hypothesis that the more aggressive behavior of Ly6a/Sca-1 expressing leukemias is due at least in part to greater capacity to degrade microenvironmental stroma and invade tissues.
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Antígenos Ly/metabolismo , Proteínas de Membrana/metabolismo , Metaloproteases/metabolismo , Invasividade Neoplásica/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Microambiente Tumoral/fisiologia , Animais , Western Blotting , Linhagem Celular Tumoral , Colágeno , Combinação de Medicamentos , Citometria de Fluxo , Vetores Genéticos/genética , Laminina , Camundongos , Camundongos Endogâmicos C57BL , Proteoglicanas , Estatísticas não ParamétricasRESUMO
BACKGROUND: Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. METHODOLOGY/PRINCIPAL FINDINGS: In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. CONCLUSIONS/SIGNIFICANCE: These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.
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Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Antidrepanocíticos/uso terapêutico , Hemoglobina Fetal/genética , Hidroxiureia/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Anemia Falciforme/metabolismo , Antidrepanocíticos/administração & dosagem , Criança , Feminino , Hemoglobina Fetal/metabolismo , Genótipo , Humanos , Hidroxiureia/administração & dosagem , Masculino , Estudos ProspectivosAssuntos
Trato Gastrointestinal/imunologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fígado/imunologia , Metilprednisolona/administração & dosagem , Adulto , Criança , Resistência a Medicamentos , Feminino , Glucocorticoides/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Injeções Intra-Arteriais , Masculino , Prontuários Médicos , Metilprednisolona/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.
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Anti-Infecciosos/administração & dosagem , Doenças Transmissíveis/tratamento farmacológico , Febre de Causa Desconhecida/tratamento farmacológico , Neoplasias/complicações , Neutropenia/complicações , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Canadá , Humanos , Neutropenia/induzido quimicamente , Estados UnidosRESUMO
This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.
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Anti-Infecciosos/administração & dosagem , Doenças Transmissíveis/tratamento farmacológico , Febre de Causa Desconhecida/tratamento farmacológico , Neoplasias/complicações , Neutropenia/complicações , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Canadá , Humanos , Neutropenia/induzido quimicamente , Estados UnidosRESUMO
Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analysed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Feminino , Citometria de Fluxo , Humanos , Interferon-alfa/farmacologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Análise de Sobrevida , Linfócitos T Citotóxicos/imunologia , Transplante Homólogo , Irradiação Corporal TotalRESUMO
These experiments explored mechanisms of control of acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation using a murine model of MHC-matched, minor histocompatibility antigen-mismatched transplantation. The central hypothesis examined was that addition of active vaccination against leukemia cells would substantially increase the effectiveness of allogeneic donor lymphocyte infusion (DLI) against ALL present in the host after transplantation. Although vaccination did increase the magnitude of type I T cell responses against leukemia cells associated with DLI, it did not lead to substantial improvement in long-term survival. Analysis of immunologic mechanisms of leukemia progression demonstrated that the failure of vaccination was not because of antigen loss in leukemia cells. However, analysis of survival provided surprising findings that, in addition to very modest type I T cell responses, a B cell response that produced antibodies that bind leukemia cells was found in long-term survivors. The risk of death from leukemia was significantly lower in recipients that had higher levels of such antibodies. These studies raise the hypothesis that stimulation of B cell responses after transplantation may provide a novel way to enhance allogeneic graft-versus-leukemia effects associated with transplantation.
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Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Anticorpos Antineoplásicos/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Histocompatibilidade , Leucemia Experimental/imunologia , Leucemia Experimental/prevenção & controle , Leucemia Experimental/terapia , Masculino , Camundongos , Camundongos Endogâmicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevenção & controle , Análise de Sobrevida , Linfócitos T/imunologia , Transplante HomólogoRESUMO
The effectiveness of allogeneic graft-versus-leukemia (GVL) activity in control of acute lymphoblastic leukemia is generally regarded as poor. One possible factor is dynamic adaptation of the leukemia cell to the allogeneic environment. This work tested the hypothesis that the pattern of gene expression in acute lymphoblastic leukemia cells in an allogeneic environment would differ from that in a non-allogeneic environment. Expression microarray studies were performed in murine B lineage acute lymphoblastic leukemia cells recovered from mice that had undergone allogeneic MHC-matched but minor histocompatibility antigen mismatched transplants. A limited number of genes were found to be differentially expressed in ALL cells surviving in the allogeneic environment. Functional analysis demonstrated that genes related to immune processes, antigen presentation, ubiquitination and GTPase function were significantly enriched. Several genes with known immune activities potentially relevant to leukemia survival (Ly6a/Sca-1, TRAIL and H2-T23) were examined in independent validation experiments. Increased expression in vivo in allogeneic hosts was observed, and could be mimicked in vitro with soluble supernatants of mixed lymphocyte reactions or interferon-gamma. The changes in gene expression were reversible when the leukemia cells were removed from the allogeneic environment. These findings suggest that acute lymphoblastic leukemia cells respond to cytokines present after allogeneic transplantation and that these changes may reduce the effectiveness of GVL activity.
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Biomarcadores Tumorais/genética , Transplante de Medula Óssea , Sobrevivência de Enxerto/fisiologia , Efeito Enxerto vs Leucemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animais , Biomarcadores Tumorais/metabolismo , Western Blotting , Sistemas de Liberação de Medicamentos , Perfilação da Expressão Gênica , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo , Células Tumorais CultivadasRESUMO
BACKGROUND: Thrombosis in neonates is a rare but serious occurrence, usually associated with central catheterization. The objective of this study was to investigate the risk factors associated with catheter related thrombosis in very low birth weight (VLBW) infants. PROCEDURE: The present retrospective study was performed using data from a randomized trial of duration of umbilical venous catheters (UVC) placement among infants <1,250 g birth weight. Twenty-two cases of UVC-associated thrombosis were identified in this sample. The remaining study sample (n = 188) served as the comparison group. Data on thrombosis, platelets, gestational age, birth weight, hematocrit, serum sodium, maternal preeclampsia, blood group, infant of diabetic mother (IDM) and demographic factors were collected using database and record review. RESULTS: Among the total subjects (n = 210), 112 (53%) were males and 126 (60%) were Caucasians, with mean gestational age of 27.7 +/- 2.1 weeks (standard deviation) and mean birth weight of 923 +/- 195 g. Bivariate analysis revealed significant association of thrombosis with hematocrit >55% in the first week (odds ratio [OR] 5.4; 95% confidence interval [CI] 2.0-14.6; P = 0.0003), being small for gestational age (SGA) (OR, 2.9; 95% CI, 1.2-7.4; P = 0.02) and maternal preeclampsia (OR, 3.97; 95% CI, 1.6-9.84; P = 0.0017). In multivariate logistic regression analysis, only hematocrit >55% was independently associated with thrombus (OR, 3.7; 95% CI 1.1-11.8; P = 0.03). CONCLUSIONS: This study demonstrates a significant, independent association between elevated hematocrit and development of UVC-associated thrombosis. Careful monitoring for catheter-associated thrombosis may be indicated in VLBW infants who have hematocrit >55% in the first week of life.
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Cateterismo Venoso Central/efeitos adversos , Hematócrito/efeitos adversos , Recém-Nascido de muito Baixo Peso , Trombose/etiologia , Veias Umbilicais , Feminino , Humanos , Recém-Nascido , Masculino , Nascimento Prematuro , Estudos Retrospectivos , Fatores de RiscoRESUMO
INK4A/ARF mutations are acquired in bcr/abl(+) lymphoid blast phase chronic myelogenous leukemia (CML) and bcr/abl(+) acute lymphoblastic leukemia (ALL). Donor lymphocyte infusion and graft-versus-leukemia (GVL) are generally ineffective in such ALLs, whereas GVL is highly active against bcr/abl(+) CML, which does not have a lesion in the INK4A/ARF locus. The mechanisms for the ineffectiveness of GVL are not fully known, and it is possible that intrinsic resistance of acute lymphoid leukemias to immune effectors associated with allogeneic GVL may contribute to ineffectiveness. This work tested the hypothesis that INK4A/ARF mutations that are associated with transformation of bcr/abl(+) CML to an ALL phenotype, and that are associated with increased resistance to apoptosis render ALL cells insensitive to allogeneic immune responses to minor histocompatibility antigens (mHA). Murine acute pre-B ALLs were induced by transfer of the human p210 bcr/abl gene into bone marrow of INK4A/ARF null mice. These ALL lines were then studied in a murine model of MHC-matched, mHA-mismatched allogeneic BMT. In vivo growth of these ALLs was inhibited in allogeneic transplants characterized by active allogeneic immune responses compared to their behavior in syngeneic transplants. In vitro ALLs with INK4A/ARF, p210 bcr/abl, or p190 bcr/abl mutations remained sensitive to anti-mHA cytolytic T cells. In addition, the ALLs were capable of inducing primary immune responses to mHAs in vivo. Thus, ALLs with INK4A/ARF or bcr/abl mutations are not intrinsically resistant to allogeneic T cell responses, suggesting that active immunotherapies against mHA have the potential to control such acute lymphoblastic leukemias.
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Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas de Fusão bcr-abl/genética , Efeito Enxerto vs Leucemia/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Apoptose/imunologia , Transplante de Medula Óssea , Células Cultivadas/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Progressão da Doença , Genes abl , Genes p16 , Humanos , Células Matadoras Naturais/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/cirurgia , Quimera por Radiação , Subpopulações de Linfócitos T/transplante , Linfócitos T Citotóxicos/transplante , Transplante Homólogo/imunologiaRESUMO
The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient. However, our prior studies have not critically addressed the question of whether a similar process of acquisition of unresponsiveness to or tolerance of antigens present on minimal residual disease also occurs. The present study tested the hypothesis that unresponsiveness to antigens present on minimal residual disease present at the time of HSCT would also occur. The answer to this question would have a significant effect on the potential efficacy of post-transplantation tumor vaccines. In a murine model of major histocompatibility complex matched, minor histocompatibility antigen mismatched HSCT (C3.SW female donors and C57BL/6 female recipients), we tested whether transplant recipients would acquire unresponsiveness to antigens present on small numbers of residual leukemia/lymphoma cells. We employed a male C57BL/6 lymphoid malignancy with an immunoglobulin/c-myc oncogene in these studies using as a model of tumor-restricted antigen the well-characterized male (HY) antigen system present only on the tumor but not present as ubiquitous minor antigens in the recipient. After HSCT, recipients did not mount immune responses to the ubiquitously distributed immunodominant recipient strain H7 minor histocompatibility antigen, but did retain the capacity to mount significant T cell responses to HY antigens present on small numbers of HY+ tumor cells present at transplantation. Additional studies using small numbers of nonmalignant recipient male B cells or dendritic cells as models of minimal residual disease also demonstrated that the transplant recipients retained their capacity to mount anti-HY T cell responses. After HSCT, recipients may retain the capacity to mount effective T cell responses to antigens present on minimal residual disease and still acquire relative tolerance to ubiquitously distributed immunodominant minor antigens that are related to graft-versus-host disease.