RESUMEN
Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs.
Asunto(s)
Materiales Biomiméticos/farmacología , Células Madre Hematopoyéticas/citología , Nicho de Células Madre , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno/farmacología , Dimetilpolisiloxanos/farmacología , Femenino , Fibronectinas/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Masculino , Purinas/farmacología , Nicho de Células Madre/efectos de los fármacos , Ácido Valproico/farmacologíaRESUMEN
BACKGROUND: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center. PROCEDURE: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients. RESULTS: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each). CONCLUSION: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tumor de Wilms/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Niño , Preescolar , Terapia Combinada , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Lactante , Neoplasias Renales/diagnóstico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Acondicionamiento Pretrasplante , Vincristina/administración & dosificación , Vincristina/efectos adversos , Tumor de Wilms/diagnóstico , Tumor de Wilms/mortalidad , Tumor de Wilms/patologíaRESUMEN
BACKGROUND: Histone deacetylase inhibitors (HDACi) are promising antineoplastic agents, but their precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDACi-induced effects has not been fully elucidated. We investigated the anticancer effects of four structurally distinct HDACi, vorinostat, entinostat, apicidin and valproic acid, using isogenic HCT-116 colon cancer cell lines differing in p53 status. METHODS: Effects were assessed by MTT assay, flow-cytometric analyses of propidium iodide uptake, mitochondrial depolarisation and cell-cycle distribution, as well as by gene expression profiling. RESULTS: Vorinostat was equally effective in p53 wild-type and null cells, whereas entinostat was less effective in p53 null cells. Histone deacetylase inhibitors treatment suppressed the expression of MDM2 and increased the abundance of p53. Combination treatments showed that vorinostat enhanced the cytotoxic activity of TRAIL and bortezomib, independent of the cellular p53 status. Investigations into the effects of an inhibitor of the sirtuin class of HDAC, tenovin-1, revealed that tenovin-1-mediated cell death hinged on p53. CONCLUSION: These results demonstrate that vorinostat activates p53, but does not require p53 for inducing its anticancer action. Yet they also demonstrate that entinostat-induced cytotoxic effects partially depend on p53, indicating that different HDACi have a different requirement for p53.
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Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/administración & dosificación , Proteína p53 Supresora de Tumor/metabolismo , Benzamidas/administración & dosificación , Neoplasias del Colon/patología , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Ácidos Hidroxámicos/administración & dosificación , Péptidos Cíclicos/administración & dosificación , Proteínas Proto-Oncogénicas c-mdm2 , Piridinas/administración & dosificación , Proteína p53 Supresora de Tumor/genética , Ácido Valproico/administración & dosificación , VorinostatAsunto(s)
Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Calidad de Vida , Cloruro de Sodio/análisis , Sudor/química , Adolescente , Adulto , Alelos , Niño , Fibrosis Quística/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Estudios de Seguimiento , Genotipo , Humanos , Mediciones del Volumen Pulmonar , Pancreatitis/diagnóstico , Adulto JovenRESUMEN
The Upshaw Schulman syndrome (MIM #274150) is a hereditary deficiency of the von Willebrand factor cleaving protease (ADAMTS13) due to homozygous or compound heterozygous mutations in the ADAMTS13 gene. Patients are prone to bouts of thrombotic thrombocytopenic purpura. However, disease manifestation needs a second trigger event. Pregnancy is a known risk factor for TTP. Patients with USS may manifest during pregnancy and the postpartum period or relapse with a TTP bout. Before plasma therapy mortality for both the mother and the fetus was high, but even nowadays when plasma is delivered, therapy is challenging, still bearing a high risk for miscarriage or long term sequelae for the mother. In this report on pregnancies in three mothers with USS, plasma therapy was increased in frequency and amount given with regard to platelet count or ADAMTS13 activity, thus leading to a successful outcome.
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Intercambio Plasmático/métodos , Complicaciones Hematológicas del Embarazo/diagnóstico , Complicaciones Hematológicas del Embarazo/terapia , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , Adolescente , Adulto , Femenino , Humanos , Embarazo , Complicaciones Hematológicas del Embarazo/genética , Resultado del Embarazo , Púrpura Trombocitopénica Trombótica/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
In cystic fibrosis (CF), the most frequent life threatening inherited disease in Caucasians, sinonasal mucosa is regularly affected by defective mucociliary clearance. This facilitates pathogen colonization into CF airways and causes frequent symptoms of rhinosinusitis, including an impaired sense of smell. Despite probable effects on nutrition and overall health, CF-rhinosinusitis is little understood: CF-associated smelling deficiencies reported in literature vary between 12 and 71 %. The aim of this study was to assess olfactory and gustatory function in relation to sinonasal symptoms and sinonasal colonization, and lung function and nutrition. Thirty-five CF patients of different ages were compared to 35 age-matched healthy controls. Olfactory function was assessed by 'Sniffin'Sticks', gustatory qualities by "Taste-strips", and symptoms by sino-nasal outcome test 20 (SNOT-20). Normosmia was found in 62.8 % of healthy controls but only in 28.6 % of CF patients. In contrast the majority of CF patients exhibited a smell loss; almost 62.9 % of them were hyposmic, and 8.6 % functionally anosmic. Importantly, reduced olfactory function only affected odor thresholds, which were significantly increased in CF, not odor identification. This suggests that the olfactory dysfunction in CF results from the olfactory periphery due to either problems in conduction and/or a functional lesion due to the inflammatory process. SNOT-20 scores increased continuously from normosmic to hyposmic and anosmic CF patients (means 7.2/11.1/28.3 points). Neither sinonasal pathogen colonization, gender, pulmonary function, nor allergy or sinonasal surgery appeared to have significant effects on olfactory function and taste. Olfactory disorders are considerably more frequent in CF patients than in age-matched healthy controls. Assessing these parameters within CF-routine care should be considered because of their importance to nutrition and, thus, overall therapy outcome.
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Fibrosis Quística/fisiopatología , Trastornos del Olfato/etiología , Rinitis/etiología , Sinusitis/etiología , Trastornos del Gusto/etiología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Fibrosis Quística/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
After allogeneic hematopoietic stem cell transplantation (HSCT), viral infections/reactivations are a frequent complication, sometimes with fatal outcome. Thus, early diagnosis is recommended by screening of whole blood or plasma preparations using highly sensitive molecular techniques that test for the most common viral pathogens, such as Epstein-Barr virus, cytomegalovirus, and adenoviruses (ADVs). Despite this approach, not every reactivation/infection can be adequately detected or excluded, even with highly sensitive polymerase chain reaction. Particularly after toxic treatment, uncommon infections or infections resistant to first-line treatment can occur, even in unusual locations. Herein, we present the case of a child with Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic HSCT who suffered from 5 different viral reactivations/infections, including acyclovir-resistant herpes simplex virus type 1 esophagitis, human herpesvirus 6 encephalitis, rotavirus gastroenteritis, respiratory syncytial virus pneumonia, and ADV esophagitis, despite routinely performed blood examinations for viral pathogens remaining unrevealing at all times.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Virosis/diagnóstico , Virosis/virología , Adenovirus Humanos/aislamiento & purificación , Adolescente , Femenino , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Virus Sincitiales Respiratorios/aislamiento & purificación , Rotavirus/aislamiento & purificación , Trasplante Homólogo/efectos adversos , Activación Viral , Virosis/patologíaAsunto(s)
Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Mutación/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Cartilla de ADN/química , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Citometría de Flujo , Humanos , Lactante , Recién Nacido , Masculino , Complejo Represivo Polycomb 2 , Pronóstico , Adulto JovenRESUMEN
Infections with Pseudomonas aeruginosa can cause the hot-foot syndrome, presenting with painful plantar erythematous nodules. Particularly, the mechanically stressed areas of the foot are affected after contact with contaminated water from saunas, swimming pools, hot tubs, etc. We report an outbreak of hot-foot syndrome caused by Pseudomonas in 10 patients. The therapeutic regimens applied reached from local antiseptic therapy to systemic antibiotics.
Asunto(s)
Brotes de Enfermedades , Dermatosis del Pie/diagnóstico , Infecciones por Pseudomonas/diagnóstico , Pseudomonas aeruginosa , Adulto , Antiinfecciosos/administración & dosificación , Ceftazidima/administración & dosificación , Niño , Preescolar , Ciprofloxacina/administración & dosificación , Diagnóstico Diferencial , Femenino , Dermatosis del Pie/tratamiento farmacológico , Dermatosis del Pie/etiología , Gentamicinas/administración & dosificación , Humanos , Infusiones Intravenosas , Masculino , Pomadas , Povidona Yodada/administración & dosificación , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/transmisión , PiscinasRESUMEN
UNLABELLED: We report on two CF patients who received double lung transplantation (LTX) due to Pseudomonas aeruginosa related pulmonary destruction. Prior to LTX we detected P. aeruginosa in nasal lavages (NL) and sputum cultures from both patients. Donor lungs of patient 1 became colonized within four weeks with P. aeruginosa identical in genotype with isolates from his pre-transplant sputum cultures and pre- and post-transplant NL. In contrast, patient 2 remained P. aeruginosa free in lower airway samples (bronchial lavage/sputum) for now up to 30 months, despite persistent detection of P. aeruginosa that was identical in genotype with pre-transplant NL and sputum isolates in NL and even in throat swabs. For prevention of pulmonary re-colonization patient 2 has continuously inhaled Colomycin 1 MIU once daily during the preceding more than 36 months with the novel Pari Sinus™ nebulizer, which in scintigraphic studies was shown to deliver vibrating aerosols into paranasal sinuses, additional to bronchial antibiotic inhalation. DISCUSSION: Pulmonary colonization of transplanted donor lungs with identical clones previously colonizing the explanted lungs has been described previously and the upper airways were postulated as reservoir for descending colonization. However, this remained speculative, as upper airway sampling which does not belong to current standards, was not performed in these studies. Our report demonstrates persistence of identical P. aeruginosa genotypes in CF upper airways prior to and after LTX underlining risks of descending colonization of transplanted lungs with P. aeruginosa, which increases risks of graft dysfunction. Therefore, we recommend regular assessment of sinonasal colonization prior to and after LTX. Sinonasal inhalation with antimicrobials should be investigated in prospective trials.
Asunto(s)
Trasplante de Pulmón , Nariz/microbiología , Senos Paranasales/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Lavado Broncoalveolar , Femenino , Humanos , Masculino , Esputo/microbiología , Adulto JovenAsunto(s)
Antibacterianos/uso terapéutico , Fibrosis Quística/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Rinitis/tratamiento farmacológico , Sinusitis/tratamiento farmacológico , Tobramicina/uso terapéutico , Administración por Inhalación , Antibacterianos/administración & dosificación , Niño , Estudios de Seguimiento , Humanos , Masculino , Infecciones por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/aislamiento & purificación , Rinitis/microbiología , Sinusitis/microbiología , Tobramicina/administración & dosificación , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Mediciones del Volumen Pulmonar , Neumonía Bacteriana/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Infecciones por Pseudomonas/complicaciones , Antibacterianos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Comorbilidad , Relación Dosis-Respuesta a Droga , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Prednisona/efectos adversos , Prednisona/uso terapéutico , Pseudomonas aeruginosaRESUMEN
We report a case of acute hemorrhagic edema in a 10-year-old girl caused by adder bite. Therapy consisted of analgesics, antihistamines, corticosteroids. Antivenum serum was applied in a single dose due to severe spreading of the edema. The patient recovered almost completely after 10 days of treatment.
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Edema/etiología , Mordeduras de Serpientes/complicaciones , Venenos de Víboras/toxicidad , Viperidae , Analgésicos Opioides/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antivenenos/administración & dosificación , Brazo , Niño , Dimetindeno/administración & dosificación , Quimioterapia Combinada , Edema/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Mano , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Humanos , Meperidina/administración & dosificación , Prednisona/administración & dosificación , Venenos de Víboras/antagonistas & inhibidoresRESUMEN
We present the case of a 44-year-old wrestler suffering from persistent bronchitis and chronic rhinosinusitis which had been refractory to therapy. The patient underwent extensive diagnostic examinations throughout the disease. Recently, at the age of 42 years otorhinological controls led to presentation at a cystic fibrosis (CF) centre where CF with the genotype Fdel508/3849+10 kb C-->T was diagnosed despite borderline sweat tests. Atypical CF should be considered in chronic persistent rhinosinusitis even in patients with borderline sweat tests.
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Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Rinitis/diagnóstico , Rinitis/etiología , Sinusitis/diagnóstico , Sinusitis/etiología , Adulto , Enfermedad Crónica , Diagnóstico Diferencial , Humanos , MasculinoRESUMEN
RATIONALE: Lower airway (LAW) infection with Pseudomonas aeruginosa and Staphylococcus aureus is the leading cause of morbidity in cystic fibrosis (CF). The upper airways (UAW) were shown to be a gateway for acquisition of opportunistic bacteria and to act as a reservoir for them. Therefore, tools for UAW assessment within CF routine care require evaluation. OBJECTIVES: The aims of the study were non-invasive assessment of UAW and LAW microbial colonisation, and genotyping of P aeruginosa and S aureus strains from both segments. METHODS: 182 patients with CF were evaluated (age 0.4-68 years, median 17 years). LAW specimens were preferably sampled as expectorated sputum and UAW specimens by nasal lavage. P aeruginosa and S aureus isolates were typed by informative single nucleotide polymorphisms (SNPs) or by spa typing, respectively. RESULTS: Of the typable S aureus and P aeruginosa isolates from concomitant UAW- and LAW-positive specimens, 31 of 36 patients were carrying identical S aureus spa types and 23 of 24 patients identical P aeruginosa SNP genotypes in both compartments. Detection of S aureus or P aeruginosa in LAW specimens was associated with a 15- or 88-fold higher likelihood also to identify S aureus or P aeruginosa in a UAW specimen from the same patient. CONCLUSIONS: The presence of identical genotypes in UAW and LAW suggests that the UAW play a role as a reservoir of S aureus and P aeruginosa in CF. Nasal lavage appears to be suitable for non-invasive UAW sampling, but further longitudinal analyses and comparison with invasive methods are required. While UAW bacterial colonisation is typically not assessed in regular CF care, the data challenge the need to discuss diagnostic and therapeutic standards for this airway compartment. TRIAL REGISTRATION NUMBER: NCT00266474.
Asunto(s)
Fibrosis Quística/complicaciones , Infecciones por Pseudomonas/complicaciones , Pseudomonas aeruginosa/genética , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/genética , Adolescente , Adulto , Factores de Edad , Anciano , Técnicas de Tipificación Bacteriana/métodos , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Cavidad Nasal/microbiología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/microbiología , Polimorfismo de Nucleótido Simple , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Manejo de Especímenes/métodos , Esputo/microbiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/aislamiento & purificación , Irrigación TerapéuticaRESUMEN
We present the case of a female CF-patient with primary mild disease and pancreatic sufficiency. She did not attend any CF centres for long periods of time. With progression of the disease, she was referred to our thoracic surgery centre for lung transplantation (LTX) at the age of 16 years. 2? years previously, she had been diagnosed with CF in another CF centre. Follow-up in specialised centres was recommended, but was not followed. Nevertheless, the indication for LTX was questioned by the thoracic surgeons and she was referred to our CF centre. With CF-specific therapy according to the current standards, pulmonary function improved from initially FEV1 = 1.2 L (38 %) to 3.6 L (122 %). In parallel, the patient gained 13.1 kg in body weight. According to our case report and to recent data a significantly better pulmonary function and nutritional status is found in CF patients who had attended specialised centres. We discuss the special features of CF treatment. Our report underlines the necessity for CF patients to be treated in specialised centres.
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Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Adolescente , Fibrosis Quística/terapia , Femenino , Humanos , Insuficiencia Respiratoria/terapiaRESUMEN
Recent studies with very small numbers of patients showed that in some cases of childhood acute lymphoblastic leukemia (ALL), preleukemic cells are detectable on Guthrie cards that were used for newborn screening. We present here the largest series of ALL patients (n=32) in whom Guthrie cards were analyzed for the presence of preleukemic cells. Rearranged immunoglobulin heavy-chain genes were used as a marker for leukemic clones. We combined our set of patients with 17 previously published cases. Preleukemic cells were detected in 31 of all 49 patients (63%). Positive screening cards were not associated with patient's age at diagnosis but were almost always found in patients with hyperdiploidy (10/11; 91%; P=0.04). High birth weight is an established risk factor for childhood ALL. Positive screening cards were strongly associated with low birth weight (P=0.01). In conclusion, the majority of childhood B-precursor ALL arise prior to birth. In the search for causes of childhood leukemia we should concentrate on prenatal factors as well as postnatal factors. Our results suggest that autologous cord bloods could be a poor choice as the source of stem cells for transplantation in leukemia, which may contain preleukemic cells. Pending the development of suitable methods, childhood leukemia is a potentially screenable disease.
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Aneuploidia , Peso al Nacer , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Preleucemia/patología , Adolescente , Niño , Preescolar , Femenino , Reordenamiento Génico , Humanos , Cadenas Pesadas de Inmunoglobulina , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/embriología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios RetrospectivosRESUMEN
Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and pre-emptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, P<0.005). The probability of 3-year event-free survival (EFS) was 52% for all patients (n=81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n=62), and 28% for patients with increasing MC (n=19, P<0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n=15) compared to patients with increasing MC without intervention (pEFS 0%, n=4, P<0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients.
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Trasplante de Células Madre Hematopoyéticas , Inmunoterapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Quimera por Trasplante/genética , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Transfusión de Linfocitos , Masculino , Estudios Prospectivos , Factores de Riesgo , Donantes de Tejidos , Trasplante HomólogoAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Trombocitopenia/terapia , Síndrome de Wiskott-Aldrich/terapia , Antígeno AC133 , Antígenos CD , Trasplante de Médula Ósea , Separación Celular , Niño , Preescolar , Glicoproteínas/metabolismo , Humanos , Lactante , Masculino , Péptidos/metabolismo , Recuento de Plaquetas , Trombocitopenia/sangre , Trombopoyesis , Factores de Tiempo , Donantes de Tejidos , Quimera por Trasplante , Trasplante HomólogoRESUMEN
Allogeneic stem cell transplantation (allo-SCT) is a well-established treatment modality for children with severe aplastic anemia (SAA). Treatment failures are rare and mostly caused by graft rejection. Increasing mixed chimerism represents a stage at the very beginning of graft rejection, where immunological intervention might be an effective prophylactic approach. To substantiate this, we: (1) monitored peripheral blood cells from children with SAA after allo-SCT and performed pre-emptive immunotherapy in patients with increasing MC. In all, 23/34 courses of 32 children with SAA after allo-SCT showed a complete chimerism (CC) throughout and 10/34 developed different types of mixed chimerism (MC). Altogether, 4/10 with MC spontaneously developed decreasing MC, 2/10 courses persisted with low proportions of autologous cells below 30% (stable-MC), 4/10 developed increasing MC and one patient showed an autologous recovery. All patients with CC, decreasing MC or stable MC remained in continuous complete remission (CCR). In all, 2/4 patients with increasing MC developed graft rejection. Based on these observations, 2/4 new patients with increasing MC received low-dose DLIs prophylactically, and remained in CCR without any GVHD. These results substantiate that low-dose DLI in children with SAA and increasing MC can prevent graft rejection with a calculable risk to induce severe GVHD.