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Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Trastornos de Deglución/patología , Disartria/patología , Parálisis Facial/patología , Proteinopatías TDP-43/patología , Anciano , Encéfalo/metabolismo , Trastornos de Deglución/metabolismo , Disartria/metabolismo , Parálisis Facial/metabolismo , Femenino , Humanos , Proteinopatías TDP-43/metabolismoRESUMEN
BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10â¯years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (ageâ¯≥â¯10â¯years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.
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Polimorfismo de Nucleótido Simple/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Tromboembolia Venosa/etiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de RiesgoRESUMEN
Chronic traumatic encephalopathy (CTE) is a long-term neurodegenerative consequence of repetitive head impacts which can only be definitively diagnosed in post-mortem. Recently, the consensus neuropathological criteria for the diagnosis of CTE was published requiring the presence of the accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in an irregular pattern as the mandatory features. The clinical diagnosis and antemortem prediction of CTE pathology remain challenging if not impossible due to the common co-existing underlying neurodegenerative pathologies and the lack of specific clinical pointers and reliable biomarkers. This review summarizes the historical evolution of CTE as a neuropathological entity and highlights the latest advances and future directions of research studies on the topic of CTE.
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Encéfalo/patología , Encefalopatía Traumática Crónica/patología , Envejecimiento , Animales , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/metabolismo , Encefalopatía Traumática Crónica/complicaciones , Encefalopatía Traumática Crónica/diagnóstico , Encefalopatía Traumática Crónica/metabolismo , Encefalitis/complicaciones , Humanos , Neuronas/metabolismo , Neuronas/patología , Factores de Riesgo , Proteínas tau/metabolismoAsunto(s)
Encéfalo/patología , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Atrofia de Múltiples Sistemas/patología , Resultado Fatal , Demencia Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/diagnósticoRESUMEN
BACKGROUND: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy. METHODS: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.
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Envejecimiento/patología , Encefalopatías/diagnóstico por imagen , Encefalopatías/patología , Imagen por Resonancia Magnética/métodos , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Bancos de Tejidos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted.
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Encéfalo/patología , Trastornos del Conocimiento/patología , Cognición/fisiología , Atrofia de Múltiples Sistemas/patología , Degeneración Nerviosa/patología , Neuronas/patología , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/complicaciones , Degeneración Nerviosa/complicacionesRESUMEN
AIMS: Since the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardson's syndrome (PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS. METHODS: We sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions. RESULTS: In addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a 'cortical' PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups. CONCLUSIONS: A better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies.
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Ganglios Basales/patología , Corteza Cerebral/patología , Parálisis Supranuclear Progresiva/patología , Proteínas tau/metabolismo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Parálisis Supranuclear Progresiva/diagnóstico , SíndromeRESUMEN
Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Prospectivos , Inducción de Remisión , Factores de Riesgo , Trasplante Homólogo , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
AIMS: Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. METHODS: All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. RESULTS: All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. CONCLUSIONS: These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.
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Ganglios Basales/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , alfa-Sinucleína/metabolismo , Adulto , Ganglios Basales/patología , Niño , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , Neurodegeneración Asociada a Pantotenato Quinasa/genética , Neurodegeneración Asociada a Pantotenato Quinasa/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Adulto Joven , Proteínas tau/metabolismoRESUMEN
Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal degeneration and cerebellar ataxias. Dystonia shares many clinical features with these conditions but research in general, has been unrewarding in providing information on disease processes. Neuropathological studies are few in number and only limited morphological abnormalities have been described. In the genetic literature, dystonia loci are represented as DYT and are assigned ascending numerals chronologically as they are identified. This review will concentrate on the neuropathology of primary pure dystonia, focusing on DYT1 and DYT6 and the correlation between clinical and genetic findings. Research in this area is incomplete and confounded by the rarity of post mortem brain tissue. However, recent findings, indicating a direct interaction between the torsinA (TOR1A) gene responsible for DYT1 and the thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene responsible for DYT6, have important implications in understanding these two entities and also for other members of this group of disorders.
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Encéfalo/patología , Trastornos Distónicos/genética , Trastornos Distónicos/patología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Humanos , Chaperonas Moleculares/genética , Proteínas Nucleares/genéticaAsunto(s)
Proteínas del Tejido Nervioso/genética , Ataxias Espinocerebelosas , Edad de Inicio , Animales , Electrofisiología , Salud de la Familia , Femenino , Humanos , Persona de Mediana Edad , Neuroimagen , Ataxias Espinocerebelosas/clasificación , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatologíaRESUMEN
Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.
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Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/fisiopatología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.
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Imagen por Resonancia Magnética/métodos , Núcleo Subtalámico/anatomía & histología , Anciano , Anciano de 80 o más Años , Cadáver , Colorantes , Imagen Eco-Planar , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Adhesión en Parafina , Reproducibilidad de los Resultados , Técnicas Estereotáxicas , Núcleo Subtalámico/patología , Fijación del TejidoRESUMEN
BACKGROUND: Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of α-synuclein. We investigated the relationship between cumulative lifetime dose of l-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). METHODS: Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with well-documented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. RESULTS: Mean lifetime dose of L-dopa correlated significantly (p < 0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p = 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density. CONCLUSION: Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities.
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Antiparkinsonianos/farmacología , Levodopa/farmacología , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Adulto , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/uso terapéutico , Recuento de Células , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Levodopa/uso terapéutico , Cuerpos de Lewy/efectos de los fármacos , Cuerpos de Lewy/patología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuronas/patología , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Sustancia Negra/metabolismoRESUMEN
AIMS: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. METHODS: To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. RESULTS: Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi-quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. CONCLUSIONS: Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD.
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Encéfalo/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Encéfalo/patología , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Mutación , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
BACKGROUND: Paediatric oncology patients with febrile neutropenia are usually hospitalised and treated with empirical broad-spectrum antibiotic therapy to counter the risk of infection. However, there is currently no method available to rapidly identify bacteremia in these patients. T-helper-type-1 (Th1) cytokines are required for effective immune response to many pathogenic organisms and T regulatory cells are known suppressors of Th1 cells. We hypothesized that characterization of reduced intracellular Th1 cytokines and increased T regulatory cells (Tregs) may prove useful in identifying infection in childhood oncology patients with febrile neutropenia. METHODS: Intracellular Th 1 cytokines and Tregs were enumerated in peripheral blood from a group of childhood oncology patients with febrile neutropenia using multiparameter flow cytometry. RESULTS: There was a significant increase in the percentage of CD25(+) CD127(-) CD8(-) CD3(+) Tregs and a significant decrease in Th1 intracellular cytokines IFNγ, IL-2 and TNFα in the blood of culture positive patients compared with culture negative patients. CONCLUSIONS: Enumeration of Tregs and intracellular Th1 cytokines may provide a sensitive, specific test for determining infection in childhood oncology patients before blood culture results become available.
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Citocinas/sangre , Neoplasias/sangre , Neutropenia/sangre , Linfocitos T Reguladores/metabolismo , Bacteriemia/sangre , Bacteriemia/etiología , Complejo CD3/metabolismo , Antígenos CD8/metabolismo , Células Cultivadas , Niño , Fiebre/sangre , Fiebre/etiología , Citometría de Flujo , Humanos , Mediadores de Inflamación/sangre , Interferón gamma/sangre , Interleucina-2/sangre , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Recuento de Linfocitos , Neoplasias/complicaciones , Neutropenia/etiología , Células TH1/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Relapse of pediatric acute lymphoblastic leukemia (ALL) remains the main cause of treatment failure after allogeneic stem cell transplantation (alloSCT). A high level of minimal residual disease (MRD) before alloSCT has been shown to predict these relapses. Patients at risk might benefit from a preemptive alloimmune intervention. In this first prospective, MRD-guided intervention study, 48 patients were stratified according to pre-SCT MRD level. Eighteen children with MRD level >or=1 x 10(-4) were eligible for intervention, consisting of early cyclosporine A tapering followed by consecutive, incremental donor lymphocyte infusions (n=1-4). The intervention was associated with graft versus host disease >or=grade II in only 23% of patients. Event-free survival in the intervention group was 19%. However, in contrast with the usual early recurrence of leukemia, relapses were delayed up to 3 years after SCT. In addition, several relapses presented at unusual extramedullary sites suggesting that the immune intervention may have altered the pattern of leukemia recurrence. In 8 out of 11 evaluable patients, relapse was preceded by MRD recurrence (median 9 weeks, range 0-30). We conclude that in children with high-risk ALL, immunotherapy-based regimens after SCT are feasible and may need to be further intensified to achieve total eradication of residual leukemic cells.