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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA) associated bone marrow failure (BMF)/aplastic anemia (AA) and hematological malignancy. We performed a retrospective multicenter study on 813 FA children undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years (interquartile range, 3.4-4.0). Median age at transplant was 8.8 years (6.5-18.1). Overall survival (OS), event-free survival (EFS) and GvHD-free, relapse-free survival (GRFS) at 5 years were 83% (80-86%), 78% (75-81%) and 70% (67-74%) respectively. OS was comparable between matched family donor (MFD, n=441, 88%) and matched unrelated donor (MUD, n=162, 86%) and was superior to that of mismatched family or unrelated donor (MMFD/MMUD, n=144, 72%) and haploidentical donor (HID) (n=66, 70%, p<0.001). In multivariable analysis, a transplant indication of acute myeloid leukaemia/myelodysplastic syndrome compared to AA/BMF, use of MMFD/MMUD and HID compared to MFD, Fludarabine-Cyclophosphamide (FluCy) + other conditioning compared to FluCy independently predicted inferior OS, while alemtuzumab compared to ATG was associated with better OS. Age ï³ 10 years was associated with worse EFS and GRFS. Cumulative incidences (CIN) of primary and secondary graft failure were 2% (1-3%) and 3% (2-4%) respectively. CIN of grade II-IV acute GvHD, grade III-IV acute GvHD and chronic GvHD were 23% (20-26%), 12% (10-15%) and 8% (6-10%) respectively. The 5-year CIN of secondary malignancy was 2% (1-3%). These data suggest that HSCT should be offered to Fanconi Anemia patients with AA/BMF at a younger age in the presence of a well-matched donor.
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BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in PRKDC define the scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far. OBJECTIVE: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human. METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material. RESULTS: We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4+CD45RA+ T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y). CONCLUSION: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.
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Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
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Bronquiectasia , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Bronquiectasia/etiología , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
Major histocompatibility complex class II (MHC-II) deficiency or bare lymphocyte syndrome (BLS) is a rare, early-onset, autosomal recessive, and life-threatening inborn error of immunity. We aimed to assess the demographic, clinical, laboratory, follow-up, and treatment characteristics of patients with MHC-II deficiency, together with their survival. We retrospectively investigated 21 patients with MHC-II deficiency. Female/male ratio was 1.63. The median age at diagnosis was 16.3 months (5 months-9.7 years). Nineteen patients (90.5%) had parental consanguinity. Pulmonary diseases (pneumonia, chronic lung disease) (81%), diarrhoea (47.6%), and candidiasis (28.6%) were common. Four (19%) had autoimmunity, two developed septic arthritis, and three (14%) developed bronchiectasis in the follow-up. Three patients (14%) had CMV viraemia, one with bilateral CMV retinitis. Eight (38.1%) had lymphocytopenia, and four (19%) had neutropenia. Serum IgM, IgA, and IgG levels were low in 18 (85.7%), 15 (71.4%), and 11 (52.4%) patients, respectively. CD4+ lymphocytopenia, a reversed CD4+/CD8+ ratio, and absent/low HLA-DR expressions were detected in 93.3%, 86.7%, and 100% of the patients, respectively. Haematopoietic stem cell transplantation (HSCT) was performed on nine patients, and four died of septicaemia and ARDS after HSCT. The present median age of patients survived is 14 years (1-31 years). Genetic analysis was performed in 10 patients. RFX5 homozygous gene defect was found in three patients (P1, P4 and P8), and RFXANK (P2 and P14) and RFXAP (P18 and P19) heterozygous gene defects were found in each two patients, respectively. This large cohort showed that BLS patients have severe combined immunodeficiency (SCID)-like clinical findings. Flow cytometric MHC-II expression study is crucial for the diagnosis, differential diagnosis with SCID, early haematopoietic stem cell transplantation (HSCT), and post-HSCT follow-up. Genetic studies are required first for matched family donor evaluation before HSCT and then for genetic counselling.
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Infecciones por Citomegalovirus , Linfopenia , Inmunodeficiencia Combinada Grave , Humanos , Femenino , Masculino , Adolescente , Turquía , Estudios RetrospectivosRESUMEN
BACKGROUND: Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. OBJECTIVES: The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. METHOD: In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. RESULTS: The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. CONCLUSION: While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , COVID-19/epidemiología , COVID-19/terapia , COVID-19/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Masculino , Femenino , Estudios Retrospectivos , Adolescente , Turquía/epidemiología , Preescolar , Factores de Riesgo , SARS-CoV-2 , Lactante , Trasplante Homólogo , Índice de Severidad de la EnfermedadRESUMEN
Bone marrow (BM) niches are special microenvironments that work in harmony with each other for the regulation and maintenance of hematopoiesis. Niche investigations have thus far been limited to various model organisms and animal studies; therefore, little is known about different niches in healthy humans. In this study, a special harvesting method for the collection of BM from two different anatomical regions in the iliac crest of humans was used to investigate the presence of different niches in BM. Additionally, metabolomic and transcriptomic profiles were compiled using comparative 'omics' technologies, and the main cellular pathways and corresponding transcripts and metabolites were identified. As a result, we found that the energy metabolism between the regions was different. This study provides basic broad data for regenerative medicine in terms of the design of the appropriate microenvironment for in vitro hematopoietic niche modeling, and identifies the normal reference values that can be compared in hematological disease.
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Médula Ósea , Nicho de Células Madre , Animales , Células de la Médula Ósea , Perfilación de la Expresión Génica , Hematopoyesis/genética , Células Madre Hematopoyéticas , Humanos , Metaboloma/genética , Nicho de Células Madre/genéticaRESUMEN
BACKGROUND: This study aimed to determine incidence of kidney complications in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients. METHODS: Pediatric allogeneic HSCT patients were included. Post-transplantation urinary system complications were collected from medical records and glomerular filtration rates at last visit compared with clinical parameters. Additionally, 24-h ambulatory blood pressure monitoring was performed. RESULTS: The study included 165 pediatric patients. Acute kidney injury (AKI) developed in 125 (75.8%) patients of whom 54 (43.2%) had stage 1, 36 (28.8%) stage 2, and 35 (28%) stage 3 AKI. Primary malignant disease and viral infection post-HSCT were associated with increased risk of AKI (OR: 4; 95%CI: 1.2-13, p = 0.022 and OR: 2.9; 95%CI: 1.2-6.8, p = 0.014, respectively). Mean duration of post-HSCT follow-up was 4.4 ± 2.5 years, during which time 8 patients had chronic kidney disease (CKD) (stage 1, 4 patients; stage 2, 3 patients; stage 3, 1 patient). CKD incidence was higher in patients in whom stem cell product was bone marrow + cord blood and mobilized peripheral blood, compared to bone marrow alone (40-37.5% versus 5.1%, p = 0.002). Based on 24-h ABPM, 14.7% and 7.4% of patients with normal office blood pressure had pre-hypertension and hypertension, respectively. In patients with albuminuria/severe albuminuria, daytime and nighttime systolic SDS scores were higher than those without albuminuria/severe albuminuria (p = 0.010 and p = 0.004, respectively). CONCLUSIONS: Incidence of AKI is higher in pediatric HSCT patients with primary malignant disease and those with documented viral infection. Our study highlights the beneficial role of 24-h ABPM as a routine part of standard care of pediatric HSCT recipients.
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Lesión Renal Aguda , Trasplante de Células Madre Hematopoyéticas , Hipertensión , Neoplasias , Insuficiencia Renal Crónica , Humanos , Niño , Albuminuria/etiología , Monitoreo Ambulatorio de la Presión Arterial , Estudios Retrospectivos , Riñón/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hipertensión/etiología , Insuficiencia Renal Crónica/complicaciones , Lesión Renal Aguda/etiología , Neoplasias/complicaciones , Factores de RiesgoRESUMEN
Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n = 18), followed by CD40 Ligand (CD40L) (n = 14) and CD40 (n = 3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p = .001 and p = .008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p = .002 and 77.8%, p = .002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n = 4, CD40 deficiency n = 2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.
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Síndrome de Inmunodeficiencia con Hiper-IgM , Neutropenia , Humanos , Ligando de CD40/genética , Cambio de Clase de Inmunoglobulina , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Inmunoglobulina M , Neutropenia/genética , Citidina DesaminasaRESUMEN
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) alters the diversity of the intestinal bacterial microbiota. This study aimed to evaluate human mycobiota composition pre-HSCT and post-HSCT in children with thalassemia. METHOD: Ten children with thalassemia undergoing allogeneic HSCT were enrolled. The stool samples were collected before the transplantation regimen, before the transplant day, and +15, +30 days, and three months after transplantation. Stool samples were also collected from the donor and the patient's caregivers. Gut mycobiota composition was evaluated with metagenomic analysis. RESULTS: Pretransplant mycobiota of children with thalassemia (the predominant genus was Saccharomyces, 64.1%) has been shown to approximate the diverse mycobiota compositions of healthy adult donors but becomes altered (lower diversity) following transplant procedures. Three months after HSCT, phyla Ascomycota and Basidiomycota were 83.4% and 15.6%, respectively. The predominant species were Saccaharomyces_uc and Saccharomyces cerevisiae (phylum Ascomycota); we also observed Malassezia restricta and Malassezia globosa (phylum Basidiomycota) (â¼13%). On day 90 after HSCT, we observed 65.3% M. restricta and 18.4% M. globosa predominance at the species level in a four-year-old boy with acute graft-versus-host disease (GVHD) (skin and gut involvement) 19 days after transplantation included. CONCLUSION: The mycobiota composition of children with thalassemia altered after HSCT. We observed Malassezia predominance in a child with GVHD. Further studies in children with GVHD will identify this situation.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Talasemia , Preescolar , Humanos , Masculino , Trasplante HomólogoRESUMEN
BACKGROUND: We aimed to evaluate hematopoietic stem cell transplantation (HSCT) related outcomes of patients with severe combined immunodeficiency (SCID). METHODS: We retrospectively collected data from SCID patients who were diagnosed, followed up and survived at least 2 years after HSCT. RESULTS: Forty four SCID patients were included in the study. Median age of HSCT and follow-up period after HSCT were 7.1 months and 8.7 years, respectively. Human leukocyte antigen (HLA) identical donors were used in 77.3% (n = 34) of the patients (23 siblings, six fathers, two mothers, three extended family donors), HLA 1-2 mismatched family donors in 11.3% (n = 5), and haploidentical family donors in 11.3% (n = 5). CD3 and CD19 counts were normal in more than 90% and in 45.4% at last follow-up, respectively. Intravenous immunoglobulin (IVIG) could be stopped in 72.7% (n = 32) after HSCT. B+ SCID patients had better CD19 counts than B- (p < .001). T cell numbers, lymphocyte proliferation, IVIG need, immunoglobulin levels, antibody responses did not differ among B- and B+ immunophenotypes. Acute graft-versus-host disease (GVHD) was less in bone marrow transplanted patients (19.4%) than peripheral stem cell (58.3%) transplanted ones (p = .024). There was no correlation between age at transplantation and immune reconstitution. At the last follow-up, 70.2% and 78.3% of the patients had body weight and height above 3rd percentile, respectively. CONCLUSION: The immune reconstitution and the growth were normal in the majority of SCID patients after HSCT. It may be rational to use bone marrow instead of peripheral stem cell, as acute GVHD was less in bone marrow transplanted patients.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunoglobulinas Intravenosas , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/etiología , Inmunodeficiencia Combinada Grave/terapiaRESUMEN
Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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Subunidad alfa del Receptor de Interleucina-21/deficiencia , Subunidad alfa del Receptor de Interleucina-21/genética , Adolescente , Linfocitos B/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Niño , Preescolar , Criptosporidiosis/genética , Criptosporidiosis/inmunología , Cryptosporidium/inmunología , Femenino , Genómica/métodos , Humanos , Inmunidad Humoral/genética , Inmunidad Humoral/inmunología , Lactante , Subunidad alfa del Receptor de Interleucina-21/inmunología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Células B de Memoria/inmunología , Infección Persistente/genética , Infección Persistente/inmunología , Fenotipo , Transducción de Señal/genética , Transducción de Señal/inmunología , Adulto JovenRESUMEN
Although G-CSF mobilized peripheral blood stem cell (PBSC) transplantation is commonly used in adults, bone marrow (BM) is still the preferred stem cell source in pediatric stem cell transplantation. Despite the fact that G-CSF is increasingly being used to enhance the hematopoietic stem/progenitor cell (HSPC) yield in BM transplantation (G-BM), the direct effects of G-CSF on the pediatric BM microenvironment have never been investigated. The BM hematopoietic niche provides the physical space where the HSPCs reside. This BM niche regulates HSPC quiescence and proliferation through direct interactions with other niche cells, including Mesenchymal Stromal Cells (MSCs). These cells have been shown to secrete a wide range of hematopoietic cytokines (CKs) and growth factors (GFs) involved in differentiation, retention and homing of hematopoietic cells. Here, we assessed changes in the BM microenvironment by measuring levels of 48 different CKs and GFs in G-BM and control BM (C-BM) plasma from pediatric donors. In addition, the effect of G-CSF on cell numbers and characteristics of HSPCs and MSCs was assessed. IL-16, SCGF-b, MIP-1b (all >1000 pg/mL) and RANTES (>10.000 pg/mL) were highly expressed in healthy donor pediatric BM plasma. Levels of IL-3, IL-18, GROa, MCP-3 (p<0.05) were increased in G-BM, whereas levels of RANTES (p<0.001) decreased after G-CSF treatment. We found a negative correlation with increasing age for IL2-Ra and LIF (p<0.05). In addition, a concomitant increase in the number of both hematopoietic and fibroblast colony forming units was observed, indicating that G-CSF affects both HSPC and MSC numbers. In conclusion, G-CSF treatment of healthy pediatric donors affects the hematopoietic BM microenvironment by expansion of HSPC and MSC numbers and modifying local CK and GF levels.
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Células de la Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Células Madre Mesenquimatosas/efectos de los fármacos , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Niño , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Donantes de TejidosRESUMEN
Lysosomal storage disorders (LSDs) are rare inborn errors of metabolism caused by defects in lysosomal function. These diseases are characterized by accumulation of completely or partially degraded substrates in the lysosomes leading to cellular dysfunction of the affected cells. Currently, enzyme replacement therapies (ERTs), treatments directed at substrate reduction (SRT), and hematopoietic stem cell (HSC) transplantation are the only treatment options for LSDs, and the effects of these treatments depend strongly on the type of LSD and the time of initiation of treatment. However, some of the LSDs still lack a durable and curative treatment. Therefore, a variety of novel treatments for LSD patients has been developed in the past few years. However, despite significant progress, the efficacy of some of these treatments remains limited because these therapies are often initiated after irreversible organ damage has occurred.Here, we provide an overview of the known effects of LSDs on stem cell function, as well as a synopsis of available stem cell-based cell and gene therapies that have been/are being developed for the treatment of LSDs. We discuss the advantages and disadvantages of use of hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and induced pluripotent stem cell (iPSC)-related (gene) therapies. An overview of current research data indicates that when stem cell and/or gene therapy applications are used in combination with existing therapies such as ERT, SRT, and chaperone therapies, promising results can be achieved, showing that these treatments may result in alleviation of existing symptoms and/or prevention of progression of the disease. All together, these studies offer some insight in LSD stem cell biology and provide a hopeful perspective for the use of stem cells. Further development and improvement of these stem cell (gene) combination therapies may greatly improve the current treatment options and outcomes of patients with a LSD.
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Enfermedades por Almacenamiento Lisosomal , Terapia de Reemplazo Enzimático , Terapia Genética , Células Madre Hematopoyéticas , Humanos , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Enfermedades por Almacenamiento Lisosomal/terapia , LisosomasRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.
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Anemia de Fanconi , Trasplante de Células Madre Hematopoyéticas , Leucemia , Síndromes Mielodisplásicos , Enfermedad Aguda , Aloinjertos , Supervivencia sin Enfermedad , Anemia de Fanconi/complicaciones , Anemia de Fanconi/mortalidad , Anemia de Fanconi/terapia , Femenino , Estudios de Seguimiento , Humanos , Leucemia/etiología , Leucemia/mortalidad , Leucemia/terapia , Masculino , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The bone marrow (BM) hematopoietic niche is the microenvironment where in the adult hematopoietic stem and progenitor cells (HSPCs) are maintained and regulated. This regulation is tightly controlled through direct cell-cell interactions with mesenchymal stromal stem (MSCs) and reticular cells, adipocytes, osteoblasts and endothelial cells, through binding to extracellular matrix molecules and through signaling by cytokines and hematopoietic growth factors. These interactions provide a healthy environment and secure the maintenance of the HSPC pool, their proliferation, differentiation and migration. Recent studies have shown that innervation of the BM and interactions with the peripheral sympathetic neural system are important for maintenance of the hematopoietic niche, through direct interactions with HSCPs or via interactions with other cells of the HSPC microenvironment. Signaling through adrenergic receptors (ARs), opioid receptors (ORs), endocannabinoid receptors (CRs) on HSPCs and MSCs has been shown to play an important role in HSPC homeostasis and mobilization. In addition, a wide range of neuropeptides and neurotransmitters, such as Neuropeptide Y (NPY), Substance P (SP) and Tachykinins, as well as neurotrophins and neuropoietic growth factors have been shown to be involved in regulation of the hematopoietic niche. Here, a comprehensive overview is given of their role and interactions with important cells in the hematopoietic niche, including HSPCs and MSCs, and their effect on HSPC maintenance, regulation and mobilization.
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Células de la Médula Ósea/citología , Neuropéptidos/metabolismo , Neurotransmisores/metabolismo , Nicho de Células Madre/fisiología , Diferenciación Celular , Células Madre Hematopoyéticas/citología , Humanos , Células Madre Mesenquimatosas/citologíaRESUMEN
Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (Pâ¯=â¯.02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (Pâ¯=â¯.03 and Pâ¯=â¯.04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.
Asunto(s)
Busulfano/análogos & derivados , Gónadas/metabolismo , Trasplante de Células Madre Hematopoyéticas , Pubertad Precoz , Adolescente , Adulto , Aloinjertos , Busulfano/administración & dosificación , Busulfano/efectos adversos , Niño , Preescolar , Femenino , Gónadas/patología , Humanos , Masculino , Pubertad Precoz/inducido químicamente , Pubertad Precoz/metabolismo , Pubertad Precoz/patología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.
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Proteínas Adaptadoras Transductoras de Señales/deficiencia , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/etiología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Síndrome Linfoproliferativo Autoinmune/complicaciones , Síndrome Linfoproliferativo Autoinmune/terapia , Biomarcadores , Niño , Preescolar , Terapia Combinada , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/terapia , Enfermedades Transmisibles/etiología , Femenino , Estudios de Asociación Genética/métodos , Sitios Genéticos , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Masculino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Secuenciación del Exoma , Adulto JovenRESUMEN
OBJECTIVE: To analyze the development of psychopathology in recipients along with their donor and nondonor siblings and the relationship with the bone marrow transplantation (BMT) process. METHODS: All children were interviewed using the Kiddie Schedule for Affective Disorders and Schizophrenia to assess psychopathology. The depression and anxiety symptoms and self-esteem of children and adolescents were evaluated using the Children's Depression Inventory, State-Trait Anxiety Inventory for Children, State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. RESULTS: In this study, the depressive symptom level was found significantly higher in the donor group compared with the nondonor group. State anxiety symptoms were higher in the BMT group (P < .05). There were no significant differences in trait anxiety symptoms. Self-respect was higher in children in the donor group compared with those in the BMT group (P < .05). During the transplant process, children with bone marrow transplants had a higher prevalence of depression, anxiety disorder, and attention-deficit/hyperactivity disorder, and nondonor siblings had a higher prevalence of depressive disorder, anxiety disorder, and attention-deficit/hyperactivity disorder compared with society in general. CONCLUSION: Physicians should deal with the family as a whole, not just their patient, and should be aware of the psychiatric risk of other siblings during the assessment.
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Ansiedad/psicología , Trasplante de Médula Ósea/psicología , Depresión/psicología , Hermanos/psicología , Adolescente , Niño , Femenino , Humanos , Masculino , Inventario de Personalidad , Psicopatología , AutoimagenRESUMEN
There are limited data available regarding effectiveness of exercise training in children undergoing hematopoietic stem cell transplantation (HSCT). We aimed to investigate effects of multimodal exercise program on clinical status and patient-reported outcomes including pain, fatigue, depression, and quality of life (QOL) level of children and their parents' QOL level. Twenty-six children undergoing HSCT participated in this study. Clinical status, pain, fatigue, depression, and QOL level of children were assessed three times: before HSCT, at discharge, and one month later. For intervention group (IG, n = 15), multimodal exercise program was performed five days a week, throughout hospitalization and children were advised to continue exercise program at home. For control group (CG, n = 11), being active as much as possible was advised. The number of painful day and pain intensity was significantly lower in IG than in CG during hospitalization (p < .05). Depression level decreased in IG at the time points (p Ë .05); however, there was no significantly difference between groups. The QOL level was higher in IG than CG only at control measurements (p Ë .05). In addition, QOL level of the parents decreased in both groups (p Ë .05). There was no statistically difference between groups in terms of other clinical variables. The multimodal supervised exercise program has positive effects on children's pain and QOL level. Exercise program was also well tolerated by children during hospitalization. In addition, QOL levels of the parents were also negatively affected during hospitalization, and interventions aiming to increase QOL level of the parents should be considered.
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Terapia por Ejercicio , Trasplante de Células Madre Hematopoyéticas , Calidad de Vida , Adolescente , Aloinjertos , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.