RESUMEN
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.
Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Trastornos de Fallo de la Médula Ósea/genética , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación/genética , Fenotipo , Aplasia Pura de Células Rojas/genética , Vasculitis/genéticaRESUMEN
Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman-Bodian-Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.
Asunto(s)
Enfermedades Autoinmunes/genética , Inflamación/genética , Proteínas/genética , Síndrome de Shwachman-Diamond/genética , Adolescente , Adulto , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/patología , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Niño , Preescolar , Sistema Endocrino/patología , Femenino , Humanos , Inflamación/diagnóstico , Inflamación/patología , Lipomatosis/diagnóstico , Lipomatosis/genética , Lipomatosis/patología , Masculino , Mutación/genética , Fenotipo , Proteómica , Síndrome de Shwachman-Diamond/diagnóstico , Síndrome de Shwachman-Diamond/patología , Adulto JovenRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1. METHODS: All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes. RESULTS: Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months. CONCLUSIONS: The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Niño , Preescolar , Tumor Desmoplásico de Células Pequeñas Redondas , Femenino , Estudios de Seguimiento , Humanos , Irinotecán/administración & dosificación , Masculino , Pronóstico , Estudios Retrospectivos , Temozolomida/administración & dosificación , Factores de Tiempo , Vincristina/administración & dosificaciónRESUMEN
Identification of genetic causes of neutropenia informs precision medicine approaches to medical management and treatment. Accurate diagnosis of genetic neutropenia disorders informs treatment options, enables risk stratification, cancer surveillance, and attention to associated medical complications. The rapidly expanding genetic testing options for the evaluation of neutropenia have led to exciting advances but also new challenges. This review provides a practical guide to germline genetic testing for neutropenia.
Asunto(s)
Pruebas Genéticas/estadística & datos numéricos , Leucemia/diagnóstico , Linfoma/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Proteínas de Neoplasias/genética , Neutropenia/diagnóstico , Manejo de la Enfermedad , Expresión Génica , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Leucemia/complicaciones , Leucemia/genética , Leucemia/terapia , Linfoma/complicaciones , Linfoma/genética , Linfoma/terapia , Tamizaje Masivo/métodos , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Proteínas de Neoplasias/metabolismo , Neutropenia/complicaciones , Neutropenia/genética , Neutropenia/terapia , Guías de Práctica Clínica como Asunto , Medicina de Precisión/métodos , Medición de RiesgoAsunto(s)
Anemia de Diamond-Blackfan/genética , Enfermedades de la Médula Ósea/genética , Pruebas Genéticas , Lipomatosis/etiología , Anemia de Diamond-Blackfan/complicaciones , Anemia de Diamond-Blackfan/diagnóstico , Enfermedades de la Médula Ósea/diagnóstico , Humanos , Lipomatosis/genética , Enfermedades PancreáticasRESUMEN
Hematopoietic stem cell transplant (HSCT) can prevent progression of several genetic disorders. Although a subset of these disorders are identified on newborn screening panels, others are not identified until irreversible symptoms develop. Genetic testing is an efficient methodology to ascertain pre-symptomatic children, but the penetrance of risk-associated variants in the general population is not well understood. We developed a list of 127 genes associated with disorders treatable with HSCT. We identified likely pathogenic or pathogenic (LP/P) and loss-of-function (LoF) variants in these genes in the Genome Aggregation Database (gnomAD), a dataset containing exome and genome sequencing data from 141,456 healthy adults. Within gnomAD, we identified 59 individuals with a LP/P or LoF variant in 15 genes. Genes were associated with bone marrow failure syndromes, bleeding disorders, primary immunodeficiencies, osteopetrosis, metabolic disorders, and epidermolysis bullosa. In conclusion, few ostensibly healthy adults had genotypes associated with pediatric disorders treatable with HSCTs. Given that most of these disorders do not have biomarkers that could be cheaply and universally assessed on a standard newborn screen, our data suggest that genetic testing may be a complementary approach to traditional newborn screening methodology that has the potential to improve mortality and is not expected to lead to a high burden of false-positive results.
RESUMEN
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.
Asunto(s)
Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Enfermedades Hematológicas , Adolescente , Adulto , Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , Niño , Preescolar , Estudios de Cohortes , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Enfermedades Hematológicas/complicaciones , Humanos , Lactante , Persona de Mediana Edad , Síndrome de Shwachman-Diamond , Adulto JovenRESUMEN
Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.
Asunto(s)
Anemia Aplásica , Adulto , Humanos , Anemia Aplásica/genética , Anemia Aplásica/patología , Alelos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA-B/genética , Antígenos HLA/genéticaRESUMEN
Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.
Asunto(s)
Anemia de Fanconi , Metformina , Niño , Anemia de Fanconi/tratamiento farmacológico , Anemia de Fanconi/genética , Humanos , Metformina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: An isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q), are the most frequent anomalies in the bone marrow of patients with Shwachman-Diamond syndrome, which is caused in most cases by mutations of the SBDS gene. These clonal changes imply milder haematological symptoms and lower risk of myelodysplastic syndromes and acute myeloid leukaemia, thanks to already postulated rescue mechanisms. RESULTS: Bone marrow from fourteen patients exhibiting either the i(7)(q10) or the del(20)(q) and coming from two large cohorts of patients, were subjected to chromosome analyses, Fluorescent In Situ Hybridization with informative probes and array-Comparative Genomic Hybridization. One patient with the i(7)(q10) showed a subsequent clonal rearrangement of the normal chromosome 7 across years. Four patients carrying the del(20)(q) evolved further different del(20)(q) independent clones, within a single bone marrow sample, or across sequential samples. One patient with the del(20)(q), developed a parallel different clone with a duplication of chromosome 3 long arm. Eight patients bore the del(20)(q) as the sole chromosomal abnormality. An overall overview of patients with the del(20)(q), also including cases already reported, confirmed that all the deletions were interstitial. The loss of material varied from 1.7 to 26.9 Mb and resulted in the loss of the EIF6 gene in all patients. CONCLUSIONS: Although the i(7)(q) and the del(20)(q) clones are frequent and clinically benign in Shwachman Diamond-syndrome, in the present work we show that they may rearrange, may be lost and then reconstructed de novo, or may evolve with independent clones across years. These findings unravel a striking selective pressure exerted by SBDS deficiency driving to karyotype instability and to specific clonal abnormalities.
RESUMEN
Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-ß pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.
Asunto(s)
Anemia de Fanconi , Animales , Médula Ósea , Daño del ADN , Anemia de Fanconi/genética , Células Madre Hematopoyéticas , Humanos , Ratones , Factor de Crecimiento Transformador betaRESUMEN
Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor ß (TGFß) pathway, regulated by the TGFß1, TGFß2, and TGFß3 ligands. Accordingly, the TGFß pathway is an attractive therapeutic target for FA. While inhibition of TGFß1 and TGFß3 promotes blood cell expansion, inhibition of TGFß2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFß1- and TGFß3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA.
Asunto(s)
Anemia de Fanconi/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta3/antagonistas & inhibidores , Adolescente , Adulto , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Niño , Preescolar , Anemia de Fanconi/metabolismo , Anemia de Fanconi/fisiopatología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismoRESUMEN
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
Asunto(s)
Hematopoyesis Clonal/genética , Hematopoyesis Clonal/fisiología , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Adulto , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/metabolismo , Niño , Preescolar , Factores Eucarióticos de Iniciación/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Ribosomas/genética , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
BACKGROUND: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. METHODS: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. FINDINGS: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. INTERPRETATION: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome. FUNDING: National Institute of Health.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Síndromes Mielodisplásicos/mortalidad , Síndrome de Shwachman-Diamond/mortalidad , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Pronóstico , Estudios Retrospectivos , Síndrome de Shwachman-Diamond/patología , Síndrome de Shwachman-Diamond/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca(2+) transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+) in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N(G)-nitro-l-arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+), thereby reducing myocardial dysfunction and mortality in murine models of septic shock.
Asunto(s)
Cardiotónicos/metabolismo , Corazón/fisiopatología , Miocitos Cardíacos/enzimología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Choque Séptico/fisiopatología , Citoesqueleto de Actina , Alopurinol/farmacología , Animales , Calcio/metabolismo , Proteínas de Unión al Calcio/metabolismo , Endotoxemia/enzimología , Endotoxemia/fisiopatología , Endotoxinas/farmacología , Inhibidores Enzimáticos/farmacología , Corazón/efectos de los fármacos , Cardiopatías/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Contracción Miocárdica/efectos de los fármacos , Miocardio/enzimología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Retículo Sarcoplasmático/metabolismo , Choque Séptico/inducido químicamente , Choque Séptico/mortalidad , Xantina Oxidasa/metabolismoRESUMEN
Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by clonal hematopoiesis with a propensity to evolve into acute myeloid leukemia. MDS presenting in children and young adults is associated with features clinically and biologically distinct from MDS arising in older adults. MDS presenting in children and young adults is associated with a higher likelihood of an underlying genetic predisposition; however, genetic predisposition is increasingly recognized in a subset of older adults. The diagnosis of a genetic predisposition to MDS informs clinical care and treatment selection. Early diagnosis allows a tailored approach to management and surveillance. Genetic testing now offers a powerful diagnostic approach but also poses new challenges and caveats. Clinical expertise in these disorders together with scientific expertise regarding the affected genes is essential for diagnosis. Understanding the basic mechanisms of genetic predisposition to myeloid malignancies may inform surveillance strategies and lead to novel therapies. The cases presented in this article illustrate challenges to the diagnosis of germline genetic predisposition to MDS and how the diagnosis affects clinical management and treatment.
Asunto(s)
Predisposición Genética a la Enfermedad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Femenino , Pruebas Genéticas , Mutación de Línea Germinal/genética , Humanos , Masculino , Síndromes Mielodisplásicos/diagnósticoRESUMEN
BACKGROUND: Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin. METHODS AND RESULTS: A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3-/-), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57+/-2% to 47+/-1% (P<0.001) in WT mice. Compared with WT mice, fractional shortening was greater in NOS3-/- and less in NOS3-TG after doxorubicin (55+/-1% and 35+/-2%; P<0.001 for both). Cardiac tissue was harvested from additional mice at 24 hours after doxorubicin administration for measurement of cell death and reactive oxygen species production. Doxorubicin induced cardiac cell death and reactive oxygen species production in WT mice, effects that were attenuated in NOS3-/- and were more marked in NOS3-TG mice. Finally, WT and NOS3-/- mice were treated with a lower dose of doxorubicin (4 mg/kg) administered weekly over 5 weeks. Sixteen weeks after beginning doxorubicin treatment, fractional shortening was greater in NOS3-/- than in WT mice (45+/-2% versus 28+/-1%; P<0.001), and mortality was reduced (7% versus 60%; P<0.001). CONCLUSIONS: These findings implicate NOS3 as a key mediator in the development of left ventricular dysfunction after administration of doxorubicin.
Asunto(s)
Doxorrubicina/toxicidad , Óxido Nítrico Sintasa de Tipo II/fisiología , Disfunción Ventricular Izquierda/prevención & control , Animales , Apoptosis/efectos de los fármacos , Cateterismo Cardíaco , Doxorrubicina/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Miocardio/enzimología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/deficiencia , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo III , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes de Fusión/fisiología , Superóxidos/metabolismo , Ultrasonografía , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/patologíaRESUMEN
Development of hematologic malignancies is driven by mutations that may be somatic or germline. Availability of next-generation DNA sequencing technologies has facilitated the development of individualized diagnostic evaluations and tailored treatment strategies. Until now, such personalized medical approaches have largely centered on prognostic stratification and treatment strategies informed by acquired somatic mutations. The role of germline mutations in children and adults with hematologic malignancies was previously underappreciated. Diagnosis of an inherited predisposition to hematologic malignancy informs choice of therapy, risk of treatment-related complications, donor selection for hematopoietic stem cell transplantation, evaluation of comorbidities, and surveillance strategies to improve clinical outcomes. The recognition that patients with inherited hematologic malignancy syndromes may present without classic clinical stigmata or suspicious family history has led to increased reliance on genetic testing, which, in turn, has raised new diagnostic challenges. Genomic testing is a rapidly evolving field with an increasing number of choices for testing for the practicing clinician to navigate. This review will discuss general approaches to diagnosis and management of patients with germline predisposition to hematology malignancies and will consider applications and limitations of genomic testing in clinical practice.
Asunto(s)
Mutación de Línea Germinal , Neoplasias Hematológicas/genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , HumanosRESUMEN
Purpose Despite advances in childhood cancer care, some patients die soon after diagnosis. This population is not well described and may be under-reported. Better understanding of risk factors for early death and scope of the problem could lead to prevention of these occurrences and thus better survival rates in childhood cancer. Methods We retrieved data from SEER 13 registries on 36,337 patients age 0 to 19 years diagnosed with cancer between 1992 and 2011. Early death was defined as death within 1 month of diagnosis. Socioeconomic status data for each individual's county of residence were derived from Census 2000. Crude and adjusted odds ratios and corresponding 95% CIs were estimated for the association between early death and demographic, clinical, and socioeconomic factors. Results Percentage of early death in the period was 1.5% (n = 555). Children with acute myeloid leukemia, infant acute lymphoblastic leukemia, hepatoblastoma, and malignant brain tumors had the highest risk of early death. On multivariable analysis, an age younger than 1 year was a strong predictor of early death in all disease groups examined. Black race and Hispanic ethnicity were both risk factors for early death in multiple disease groups. Residence in counties with lower than median average income was associated with a higher risk of early death in hematologic malignancies. Percentages of early death decreased significantly over time, especially in hematologic malignancies. Conclusion Risk factors for early death in childhood cancer include an age younger than 1 year, specific diagnoses, minority race and ethnicity, and disadvantaged socioeconomic status. The population-based disease-specific percentages of early death were uniformly higher than those reported in cooperative clinical trials, suggesting that early death is under-reported in the medical literature. Initiatives to identify those at risk and develop preventive interventions should be prioritized.
Asunto(s)
Neoplasias/mortalidad , Adolescente , Niño , Preescolar , Estudios de Cohortes , Humanos , Lactante , Neoplasias/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Programa de VERF , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Vitamin B12 deficiency is classically encountered in the adult Caucasian population and manifests as a subacute combined degeneration in the presence or absence of macrocytic anemia. However, B12 deficiency is extremely rare in children in developed countries, and pernicious anemia is even rarer etiology of this deficiency. The clinical presentation of B12 deficiency in children is not as easily recognizable or well-characterized and may result in missed or delayed diagnosis. PATIENT DESCRIPTION: We describe a previously healthy adolescent girl who presented with emotional lability, mental status changes, hyperreflexia, and ataxia. She was found to have megaloblastic anemia and subacute combined degeneration secondary to B12 deficiency caused by pernicious anemia. CONCLUSION: Though B12 deficiency is uncommon in pediatrics, it is important to maintain a high index of suspicion because early recognition and treatment of B12 deficiency are key to preventing long-term neurological sequelae.