RESUMEN
DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.
Asunto(s)
Histonas , Células Madre Pluripotentes Inducidas , Animales , ADN , Reparación del ADN , Células Endoteliales/metabolismo , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismoRESUMEN
The incidence and the burden of cardiovascular disease (CVD), coronary heart disease (CHD), type 2 diabetes mellitus (T2DM), and the metabolic syndrome are greatly increasing in our societies. Together, they account for 31% of all deaths worldwide. This chapter focuses on the role of two revolutionary discoveries that are changing the future of medicine, induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 technology, in the study, and the cure of cardiovascular and metabolic diseases.We summarize the state-of-the-art knowledge about the possibility of editing iPSC genome for therapeutic applications without hampering their pluripotency and differentiation, using CRISPR/Cas technology, in the field of cardiovascular and metabolic diseases.
Asunto(s)
Sistema Cardiovascular , Diabetes Mellitus Tipo 2 , Células Madre Pluripotentes Inducidas , Enfermedades Metabólicas , Humanos , Edición Génica , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/terapiaRESUMEN
The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. We retrospectively analyzed 361 acute leukaemia patients, who underwent allogeneic SCT in the Hadassah's bone marrow transplantation department between the years 2005 and 2012 and identified 84 patients with active leukaemia at transplantation. Median age was 34 years. Sixty four patients were diagnosed with acute myeloid leukaemia (AML), 18 patients with acute lymphoblastic leukaemia and two with biphenotypic leukaemia. The majority of patients were diagnosed with de-novo AML and transplanted at relapse. In the surviving patients, median follow up was 15 months. One year OS was 20%. At time of last follow up, 13 patients were alive (15.5%): ten patients with AML and two patients with acute lymphoblastic leukaemia. In the univariate analysis, factors associated with significantly better overall survival were as follows: matched unrelated donor (p = 0.006), matched donor (p = 0.014) and occurrence of acute graft-versus-host disease (aGVHD) (p = 0.019). Karnofsky performance score at SCT and occurrence of cGVHD were found to be borderline significant. Only matched unrelated donor and aGVHD were found to affect overall survival significantly in the multivariate analysis. Other than performance score at SCT, none of the pretransplant patients' characteristics were found to influence survival. In conclusion, as none of the pretransplant characteristics were found to influence the ability to select the patients that will benefit from HSC transplantation, this work supports offering HSCT to all active leukaemia eligible patients with reasonable performance status. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. METHODS: This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/Lâ×âh). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. FINDINGS: 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. INTERPRETATION: This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. FUNDING: None.
Asunto(s)
Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/administración & dosificación , Suero Antilinfocítico/administración & dosificación , Busulfano/administración & dosificación , Niño , Preescolar , Quimioterapia Combinada , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA , Humanos , Inmunosupresores/administración & dosificación , Lactante , Estudios Prospectivos , Quimera por Trasplante/fisiología , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
We examined the rate, clinical impact, and risk factors of cytomegalovirus (CMV) drug resistance in 561 patients who underwent 616 hematopoietic stem cell transplantations (HSCTs) over 5 years. Drug resistance was exclusively identified in haploidentical (haplo)-HSCT recipients receiving preemptive therapy, among whom the rate was 14.5%. Resistance appeared after prolonged treatment (median, 70 days), was associated with higher preceding viral load (P < .001), and was the strongest predictor for disease by multivariate analysis. The high rate of drug resistance as interlinked with severe disease in haplo-HSCT recipients suggests the potential advantage of prophylactic over preemptive treatment in high-risk patients and highlights the need for better-tolerable anti-CMV drugs.
Asunto(s)
Antivirales/administración & dosificación , Infecciones por Citomegalovirus/prevención & control , Citomegalovirus/aislamiento & purificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Niño , Citomegalovirus/genética , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Farmacorresistencia Viral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Estudios ProspectivosRESUMEN
Cyclosporine (CSA) is the most commonly used medication for GVHD prophylaxis. The initiation time varies from day -4 to day 0. Initially, we gave CSA starting on day -1. However, since 2003 we have changed CSA initiation timing policy in most of our protocols to day -4, to achieve stable and controlled pretransplant CSA levels. Here, we assessed if initiation time impact the outcome of allogeneic stem-cell transplantation (allo-SCT). Data of 261 patients who underwent allo-SCT for hematological malignancies from a fully matched donor, treated with CSA as a single agent for GVHD prophylaxis were prospectively collected. Patients were divided according to CSA initiation time and analyzed for outcome. The acute GVHD severity, cGVHD extent, GVHD-associated mortality were significantly lower in the CSA -4 group. There was no difference in the rate and timing of acute or chronic GVHD. Overall survival did not differ between the groups. We conclude that the initiation of CSA at day -4 reduced the severity of aGVHD, extent of cGVHD, and GVHD-associated mortality without impact on overall survival.
Asunto(s)
Ciclosporina/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Neoplasias Hematológicas/cirugía , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Vidarabina/uso terapéuticoRESUMEN
In the mid-1990s, we introduced a fludarabine (Flu)-based conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with Fanconi anemia (FA).The aim of this study is to compare Flu-based conditioning to alternative regimens in patients with FA. Forty-one patients with FA (aged 0.5-31, median, 10.3 years) who underwent allogeneic HSCT were included in this retrospective study. Hospital records were reviewed for conditioning regimens, engraftment data, and toxicity. The median (range) follow-up was 32 (0.5-149) months. Flu-based conditioning regimens were used in 24 patients: 17 patients were treated with alternative conditioning regimens including a radiation-based regimen/cyclophosphamide and busulfan regimen. The disease-free survival (DFS) after Flu-based regimens is 83% (20/24) versus 35% (6/17) for the alternative regimens (P = .002). Toxicity was significantly lower in patients who received Flu-based conditioning (modified Bearman toxicity score [P = .001]). Seven patients received transplants from matched unrelated donors without irradiation (5 of whom are currently alive and well). All patients who survived are disease free and in good clinical condition. We conclude that a combination of fludarabine with antithymocyte globulin (ATG) and low-dose cyclophosphamide (Cy) and/or busulfan (Bu) is safe, demonstrates low rejection rates, and is well tolerated by FA patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea/métodos , Anemia de Fanconi/terapia , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Suero Antilinfocítico/uso terapéutico , Busulfano/uso terapéutico , Niño , Preescolar , Ciclofosfamida/uso terapéutico , Supervivencia de Injerto , Humanos , Lactante , Estudios Retrospectivos , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin's lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad de Hodgkin/genética , Proteínas Tirosina Quinasas/genética , Trasplante Homólogo/inmunología , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/patología , Preescolar , Codón sin Sentido , Muerte , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/terapia , Femenino , Herpesvirus Humano 4/crecimiento & desarrollo , Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/terapia , Homocigoto , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfohistiocitosis Hemofagocítica/mortalidad , Linfohistiocitosis Hemofagocítica/patología , Masculino , Linaje , Proteínas Tirosina Quinasas/inmunología , Inducción de RemisiónRESUMEN
We report a successful umbilical cord blood transplantation (UCBT) in an 8-month male with Wiskott-Aldrich syndrome (WAS) and congenital cytomegalovirus (CMV) infection. The child presented at 3 months of age with symptomatic thrombocytopenia and CMV infection. Despite appropriate antiviral treatment no rise in the platelet count was observed. Genetic analysis confirmed the diagnosis of WAS. The clinical course was complicated by severe CMV retinitis with bilateral retinal hemorrhages and renal vasculitis. He underwent unrelated UCBT resulting in a rapid resolution of autoimmunity and thrombocytopenia.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/cirugía , Síndrome de Wiskott-Aldrich/cirugía , Infecciones por Citomegalovirus/fisiopatología , Humanos , Lactante , Masculino , Trasplante Homólogo , Síndrome de Wiskott-Aldrich/fisiopatologíaRESUMEN
The aim of this study was to validate the 2005-2006 National Institutes of Health (NIH) scale for patient's self-reporting and clinical manifestations of oral chronic graft-versus-host disease (cGVHD). Numerical parameters of the NIH scale were analyzed for their construct validity (correlation of the NIH scale with numerical rating scale [NRS] for pain) and internal consistency reliability (correlation between different parameters of the same scale). Categoric parameters were analyzed by comparison between severity subgroups defined by the oral manifestation (lichenoid/erythema/ulceration). Analysis included data of 75 evaluations. The total NIH score and the NRS for pain were found to be moderately correlated (r=0.449). Cronbach's alpha reliability coefficient was .718. Strong correlations were found between the total NIH score and both erythema and ulceration scores (r=0.746 and r=0.926, respectively). The difference between the 2 "severe" subgroups (ie, lichenoid and erythema/ulceration) was significant (P=.025). The difference between the moderate-erythema/ulceration subgroup and the severe-lichenoid subgroup was nonsignificant (total NIH score and NRS for pain: P=.276 and .291, respectively). The correlation between the total NIH score and the NRS for pain is only moderate. The internal consistency reliability analysis yielded good reliability, especially for erythema and ulceration. Analysis of categoric parameters suggests that the NIH scale disproportionately differentiates between moderate-erythema/ulceration and severe-lichenoid cGVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/clasificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades de la Boca/diagnóstico , Mucosa Bucal , Medicina Oral/instrumentación , Dolor/clasificación , Índice de Severidad de la Enfermedad , Adulto , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/fisiopatología , Humanos , Israel , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/etiología , National Institutes of Health (U.S.) , Úlceras Bucales/etiología , Dolor/etiología , Dimensión del Dolor/métodos , Estadística como Asunto , Estados Unidos , Adulto JovenRESUMEN
The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin's lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma de Células B/terapia , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Linfoma de Células B/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab , Prevención Secundaria , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Children with Down syndrome (DS) have a unique form of acute megakaryocytic leukemia (AMKL) characterized by the presence of mutations in the GATA1 gene leading to increased chemosensitivity and a favorable outcome. We describe an 8-month-old male with DS who was diagnosed with AMKL without a mutation in the GATA1 gene. The patient was treated according to the DS-AML-regimen but his disease progressed and he succumbed 9 months later. This rare case of DS AMKL without a GATA1 mutation with an unfavorable outcome suggests that GATA1 testing may play a useful role in initial stratification.
Asunto(s)
Síndrome de Down/complicaciones , Factor de Transcripción GATA1/genética , Leucemia Megacarioblástica Aguda/complicaciones , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Resultado Fatal , Humanos , Lactante , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Masculino , MutaciónRESUMEN
We describe a 12-year-old boy male who presented with an expressive dysphasia after completion of treatment for unifocal Ewing sarcoma. CNS vasculitis was diagnosed by MRI/MRA and cerebral angiography. Extensive rheumatologic work-up failed to identify an underlying primary process. Restaging studies showed no evidence of tumor. Complete neurologic recovery was achieved on prednisone. Four months later the patient developed overt, extensive metastases, confirmed by biopsy to represent recurrent Ewing sarcoma. Despite intensive therapy the patient succumbed 6 months later. This case demonstrates the unique finding of isolated CNS vasculitis as a presenting sign of Ewing sarcoma.
Asunto(s)
Síndromes Paraneoplásicos del Sistema Nervioso/etiología , Sarcoma de Ewing/complicaciones , Vasculitis del Sistema Nervioso Central/etiología , Afasia/etiología , Angiografía Cerebral , Niño , Resultado Fatal , Humanos , Imagen por Resonancia Magnética , Masculino , Recurrencia , Sarcoma de Ewing/patologíaRESUMEN
The failure of allogeneic stem cell transplant (allo-SCT) is cumbersome. We analyzed our experience in a second allo-SCT. Between the years 1981 and 2007, 144 patients underwent 2 or more allo-SCT. The first to second transplant interval ranged from 18 days to 13.25 years (median 98 days). The most frequent indications for the second SCT were activity of the basic disease (78), rejection (37), and engraftment failure (25). Twenty-nine of the 144 (20%) patients transplanted survived more then a year with treatment-related mortality of 45.5% as the leading cause of death. Interestingly, despite the low rate of graft-versus-host disease (GVHD) prophylaxis used, only 51 and 16 of the patients developed acute and chronic GVHD (aGVHD, cGVHD), respectively. Factors indicating higher likelihood for survival were nonmalignant disease, a nonrelapse indication for the second SCT, full HLA-matching, and the use of reduced-intensity conditioning (RIC). Age at transplantation, time interval between transplants, the development of GVHD, conditioning regimen, GVHD prophylaxis, or graft source were not shown to influence the prognosis. With a median follow-up of 4.5 years, 25 patients (17.2%) are alive, and 18 are disease-free. We conclude that although toxic, a second allo-SCT can lead to long-term survival.
Asunto(s)
Rechazo de Injerto/mortalidad , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
BACKGROUND AIMS: We have shown previously that alefacept is effective in acute steroid resistant/dependent and chronic extensive graft versus host disease (GvHD) with a protocol using timings similar to those used for psoriasis treatment. In this study, we describe the use of an alefacept induction (e.g. for 7 consecutive days) followed by a bi-weekly maintenance treatment in combination with tacrolimus for acute steroid resistant/dependent GvHD 1, 3. METHODS: Sixteen patients were treated in this cohort, most with refractory GvHD. The pre-treatment GvHD grade ranged from 2 to 4 (median 3), involving the skin 16, gut 11 and liver 5. RESULTS: Twelve out of the 16 patients showed a response. As with the first protocol, the response of GvHD in the skin was fastest. In contrast to our previous protocol, however, the gastro-intestinal (GI) GvHD response was faster (P=0.05 compared with the first cohort). A hepatic response was seen in 4/6 patients and was complete in three. All responses were durable, including mucocutaneous, gut and liver GvHD. In all responding patients we were able to decrease the steroid dose significantly and in seven it was completely withdrawn. CONCLUSION: Alefacept induction is safe in acute steroid resistant/dependent GvHD and may be more effective therapeutically than our previous alefacept protocol. We speculate that alefacept initiates an allo-versus-allo cellular effect through its Fc receptor.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Tacrolimus/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Alefacept , Niño , Preescolar , Protocolos Clínicos , Fármacos Dermatológicos/efectos adversos , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes de Fusión/efectos adversos , Tacrolimus/efectos adversos , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed.
Asunto(s)
Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/terapia , Niño , Enfermedad Injerto contra Huésped , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas , Humanos , Factores Inmunológicos/administración & dosificación , Inmunoterapia , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Masculino , Proteínas RecombinantesRESUMEN
This is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with a newly identified foscarnet-resistant and ganciclovir-resistant DNA polymerase L776M mutation. Artesunate treatment resulted in a 1.7-2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9-1.9 days, indicating a highly effective block in viral replication.
Asunto(s)
Artemisininas/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/métodos , Antivirales/farmacología , Antivirales/uso terapéutico , Artemisininas/farmacología , Artesunato , Niño , Citomegalovirus/efectos de los fármacos , Infecciones por Citomegalovirus/etiología , Farmacorresistencia Viral , Foscarnet/farmacología , Foscarnet/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Resultado del TratamientoRESUMEN
The effect of ABO-incompatibility on transplantation outcome remains a controversial issue, with many of the reported studies showing conflicting results. In this study, we evaluate: the association between ABO-incompatibility and myeloid engraftment; the incidence and severity of acute and chronic graft-versus-host disease (GVHD); non-relapse mortality (NRM); GVHD-associated mortality, relapse and overall survival (OS). Our study includes 221 patients with malignant diseases treated in the same institution with the same reduced intensity regimen. Other variables known to affect the transplantation outcome such as age, disease, disease risk, and donor characteristics were well-balanced between ABO-matched and ABO-mismatched transplants. Analysis of our data shows increased incidence of NRM during the first months after transplantation in the groups of patients with major and minor ABO-incompatibility. Although neither incidence nor severity of GVHD differed significantly among the different groups, we found increased mortality associated with GVHD in the major ABO-incompatible groups. Long-term OS and relapse rate were not different, although we observed a trend for decreased OS during the first year post transplantation in the group of patients with major ABO-incompatibility. Our study showed that ABO-incompatibility has an adverse impact on the transplantation outcome.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Incompatibilidad de Grupos Sanguíneos , Enfermedad Injerto contra Huésped/fisiopatología , Neoplasias/terapia , Trasplante de Células Madre/métodos , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Leucemia/terapia , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Recurrencia , Estudios RetrospectivosRESUMEN
Toxoplasmosis is a rare and often fatal complication of hematopoietic stem cell transplantation (HSCT). The diagnosis of toxoplasmosis is usually made at autopsy because of the variety of systemic manifestations and the difficulty of diagnosis by serologic methods in the severely immunocompromised patient. Cutaneous toxoplasmosis in this setting is extremely rare and is difficult to diagnose with certainty because of the morphologic similarity of Toxoplasma gondii to other organisms, such as Leishmania and Histoplasma species. We report a patient who developed systemic toxoplasmosis, manifested as encephalitis and cutaneous lesions, after HSCT. Findings of a skin biopsy led to a tentative histologic diagnosis of toxoplasmosis, confirmed by polymerase chain reaction (PCR) examination of the skin biopsy and cerebrospinal fluid. This is, to our knowledge, the first report of cutaneous toxoplasmosis diagnosed by skin biopsy confirmed by PCR and sequencing. This disease may be more common than is generally appreciated in severely immunocompromised patients. PCR is a valuable adjunct to diagnosis.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Complicaciones Neoplásicas del Embarazo/terapia , Complicaciones Parasitarias del Embarazo/diagnóstico , Enfermedades Cutáneas Parasitarias/diagnóstico , Toxoplasmosis/diagnóstico , Adulto , Animales , Infecciones por Citomegalovirus/diagnóstico , ADN Protozoario/análisis , Encefalitis Viral/diagnóstico , Resultado Fatal , Femenino , Humanos , Huésped Inmunocomprometido , Leucemia Mieloide Aguda/terapia , Reacción en Cadena de la Polimerasa , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Enfermedades Cutáneas Parasitarias/etiología , Toxoplasma/genética , Toxoplasmosis/líquido cefalorraquídeo , Toxoplasmosis/etiologíaRESUMEN
Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of acute myelogenous leukemia (AML). Cellular microparticles, submicron vesicles shed from the plasma membrane of various cells, are also associated with human pathology. In the present study, we investigated the putative relationships between the SDF-1/CXCR4 axis and microparticles in AML. We detected CXCR4-expressing microparticles (CXCR4(+) microparticles) in the peripheral blood and bone marrow plasma samples of normal donors and newly diagnosed adult AML patients. In samples from AML patients, levels of CXCR4(+) microparticles and total SDF-1 were elevated compared with normal individuals. The majority of CXCR4(+) microparticles in AML patients were CD45(+), whereas in normal individuals, they were mostly CD41(+). Importantly, we found a strong correlation between the levels of CXCR4(+) microparticle and WBC count in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, levels of functional, noncleaved SDF-1 were reduced in these patients compared with normal individuals and also strongly correlated with the WBC count. Furthermore, our data indicate NH(2)-terminal truncation of the CXCR4 molecule in the microparticles of AML patients. However, such microparticles were capable of transferring the CXCR4 molecule to AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID/beta2m(null) mice. The CXCR4 antagonist AMD3100 reduced these effects. Our findings suggest that functional CXCR4(+) microparticles and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional diagnostic AML variable.