RESUMEN
Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of care was evaluated by the Measure of Processes of Care questionnaire. Sixty-three HS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, -2.4 [range, -3.5 to -1.6]; median global functioning z score, -3.2 [range, -4.8 to -1.8]). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 [range, -0.7 to 0.8]). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.
RESUMEN
Neuroblastoma, a paediatric malignancy of the sympathetic nervous system, accounts for 15 % of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat partly due to the development of multidrug resistance. There is thus a compelling demand for new treatment strategies that can bypass resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various tumour models. We have previously reported that PBOX compounds induce apoptosis in drug sensitive and multidrug resistant neuroblastoma cells and synergistically enhance apoptosis induced by chemotherapeutics such as carboplatin. In this study we present further data concerning the molecular basis of PBOX-induced apoptosis in neuroblastoma. We demonstrate that PBOX-6 induced AMP-activated protein kinase (AMPK) activation and downstream acetyl-CoA carboxylase phosphorylation. Increased reactive oxygen species (ROS) appeared to serve as the upstream signal for AMPK activation as pretreatment of cells with the antioxidant N-acetylcysteine inhibited both AMPK activation and PBOX-induced apoptosis. Furthermore, activation of AMPK by PBOX-6 was found to inhibit mTOR complex 1 (mTORC1) signalling. Finally, we demonstrate the efficacy of PBOX-6 in an in vivo xenograft model of neuroblastoma. This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further supports their future use as novel anti-cancer agents for the treatment of neuroblastoma.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Oxazepinas/farmacología , Pirroles/farmacología , Moduladores de Tubulina/farmacología , Acetil-CoA Carboxilasa/metabolismo , Acetilcisteína/farmacología , Animales , Antineoplásicos/uso terapéutico , Antioxidantes/farmacología , Carboplatino/uso terapéutico , Línea Celular Tumoral , Femenino , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patología , Oxazepinas/uso terapéutico , Fosforilación/efectos de los fármacos , Pirroles/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Moduladores de Tubulina/uso terapéutico , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors. METHODS: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics. RESULTS: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings. CONCLUSIONS: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H.
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Progresión de la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Luxación de la Cadera/fisiopatología , Mucopolisacaridosis I/terapia , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Luxación de la Cadera/diagnóstico por imagen , Luxación de la Cadera/etiología , Humanos , Masculino , Modelos Estadísticos , Mucopolisacaridosis I/complicaciones , Variaciones Dependientes del Observador , Pronóstico , Radiografía , Reproducibilidad de los Resultados , Estudios Retrospectivos , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: After successful hematopoietic stem cell transplantation, maintaining function and mobility have become key goals in the management of patients with Hurler syndrome, (mucopolysaccharoidosis type 1H). The aim of this study was to establish the functional and radiologic outcomes after hip surgery in patients with this condition who had reached skeletal maturity. METHODS: We prospectively followed 13 mucopolysaccharoidosis type 1H patients with closed triradiate cartilages who had undergone hip surgery in a single institution (Our Lady's Children's Hospital, Crumlin) in early childhood, after successful hematopoietic stem cell transplantation. Functional assessment was performed using the Harris Hip Score. Acetabular and femoral head morphology were defined using a pelvic radiograph. RESULTS: The average age at follow-up was 18.6 years (range, 13.2 to 23.8 y). The average length of follow-up from surgical intervention was 14.6 years (range, 10.3 to 21.6 y). The average Harris Hip Score at follow-up was 61.0 (range, 19 to 91). At follow-up, 4 patients were either wheelchair bound or required a walking frame to mobilize in the community. At follow-up, all hips were in-joint with an average center edge angle of 37.7 degrees (range, 0 to 63 degrees). All hips displayed characteristic medial flattening of the femoral head. Ten hips (of 26 hips) showed radiologic degenerative changes with loss of joint space <2 mm. CONCLUSIONS: Despite the surgical provision of stable well-covered hips, active intervention did not prevent the development of radiologic deterioration and clinically significant hip arthritis. We recommend that pediatric hip surgery in Hurler syndrome be designed with the possibility of early hip replacement in mind. LEVEL OF EVIDENCE: Level III.
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Artroplastia de Reemplazo de Cadera , Predicción , Luxación de la Cadera/cirugía , Articulación de la Cadera/cirugía , Mucopolisacaridosis I/complicaciones , Rango del Movimiento Articular/fisiología , Adolescente , Niño , Preescolar , Femenino , Luxación de la Cadera/diagnóstico por imagen , Luxación de la Cadera/etiología , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/fisiopatología , Humanos , Lactante , Masculino , Estudios Prospectivos , Radiografía , Resultado del TratamientoRESUMEN
Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis I/terapia , Adolescente , Adulto , Niño , Desarrollo Infantil , Preescolar , Cognición , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Masculino , Mucopolisacaridosis I/epidemiología , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis I/psicología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Neuroblastoma, a malignancy of neuroectoderrmal origin, accounts for 15% of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat. A major obstacle in the effective treatment of neuroblastoma is the development of multidrug resistance (MDR). There is thus a compelling demand for new treatment strategies for this cancer that can bypass such resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various cancer cell lines, ex vivo patient samples and in vivo cancer models. In this study we examined the ability of two members, PBOX-6 and -15, to exhibit anti-cancer effects in a panel of drug sensitive and MDR neuroblastoma cell lines. The PBOX compounds potently reduced the viability of all neuroblastoma cells examined and exhibited a lower fold resistance in MDR cells when compared to standard chemotherapeutics. In addition, the PBOX compounds synergistically enhanced apoptosis induced by etoposide, carboplatin and doxorubicin. Exposure of drug sensitive and resistant cell lines to PBOX-6/carboplatin induced cleavage of Bcl-2, a downregulation of Mcl-1 and a concomitant increase in Bak. Furthermore, activation of caspase-3, -8 and -9 was demonstrated. Finally, gene silencing of Mcl-1 by siRNA was shown to sensitise both drug sensitive and multidrug resistant cells to carboplatin-induced apoptosis demonstrating the importance of Mcl-1 downregulation in the apoptotic pathway mediated by the PBOX compounds in neuroblastoma. In conclusion, our findings indicate the potential of the PBOX compounds in enhancing chemosensitivity in neuroblastoma.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carboplatino/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neuroblastoma/patología , Oxazepinas/farmacología , Pirroles/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/fisiología , Carboplatino/uso terapéutico , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Sinergismo Farmacológico , Humanos , Neuroblastoma/tratamiento farmacológico , Oxazepinas/uso terapéutico , Pirroles/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
Throughout the United States, government and private payers are exploring new payment models such as accountable care organizations and shared savings agreements. These models are widely based on the construct of the Triple Aim, a set of three principles for health services reform: improving population-based outcomes, improving patient care experiences, and reducing costs through better delivery systems. Wound programs may adapt to the new health financing environment by incorporating initiatives known to promote the Triple Aim, such as diabetes amputation reduction and pressure ulcer prevention programs, and by rethinking how health services can best be delivered to meet these new criteria. The existing literature supports that programmatic approaches can improve care, quality, and cost, especially in the field of diabetic foot ulcers. Wound healing programs have opportunities to develop new business plan models that provide quality, cost-efficient care to their patient population and to be leaders in the development of new types of partnerships with payers and health delivery organizations.
Asunto(s)
Administración Financiera/organización & administración , Modelos Económicos , Cicatrización de Heridas , HumanosRESUMEN
INTRODUCTION: The use of complementary and alternative medicine (CAM) in the Irish pediatric cancer setting has not previously been established. METHODS: To investigate the prevalence and predictors of CAM use in this group of patients, an anonymous cross-sectional survey was offered to all carers of patients either on or off treatment for malignancy at a single pediatric cancer center over an 8-week period. RESULTS: Of a total of 220 questionnaires distributed, 98 (43%) were returned. Six were excluded because of inadequate data. A total of 58% of children were male and the mean age was 9 years. The most common cancer diagnosis was leukemia (45%). Fifty-two respondents (57%) said their child had used or was using CAM, and 55% of whom had started since their cancer diagnosis. The most common types of CAM used were vitamins and minerals (18%), reflexology (11%), dietary supplements (11%), faith healers (9%), and energy therapies (9%). The most common reason for CAM use was to improve physical well-being (31%). A total of 65% of CAM users had not told their doctor that they were doing so. Of the 52 CAM users, 30 (58%) were using oral CAM medication. A total of 86% of CAM users reported benefit from the treatment, and no respondent reported side effects.There was no significant relationship between sex, tumor type, age, income, previous treatment, and CAM use. Where parents had a higher level of education, children were more likely to use CAM (P=0.035.) There was a statistically significant relationship between respondents rating of conventional therapy and CAM use (P=0.007). Interestingly, parents who were satisfied with conventional therapy were more likely to use CAM. CONCLUSION: The high prevalence of CAM use demonstrated in this study and particularly the high use of CAM medication therapies underlines the importance of physicians asking routinely about CAM use in this population.
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Terapias Complementarias , Neoplasias/terapia , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Irlanda , Masculino , Neoplasias/epidemiología , Prevalencia , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
BACKGROUND: After successful hematopoietic stem cell transplantation maintaining function and mobility has become the key goal in the management of patients with mucopolysaccharoidosis type 1 (MPS-1). We detail the foot and ankle pathology in 18 patients with MPS-1 managed in our unit. METHODS: Functional assessment was performed using the Oxford Foot and Ankle Questionnaire for children (OxAFQ-C). Morphologic assessment was performed by means of a mirrored foot photograph box, the Foot Posture Index (FPI), and clinical photography. Standardized radiologic investigations were sought when clinically warranted. Average lateral talus-first metatarsal angle, anteroposterior and lateral talocalcaneal angles, and lateral distal tibial angle (LDTA) were determined. RESULTS: The average patient-reported OxAFQ-C score was 44.7 (range, 10 to 60). The average proxy-reported OxAFQ-C score was 45.7 (range, 11 to 60). Ten of the 18 patients wore customized footwear. Of the 36 feet examined 11 were found scored as "highly pronated" (FPI>+9), 12 feet had a "pronated posture" (FPI +6 to +9), and 13 feet were found to have a "normal posture" (FPI 0 to +5). Thirteen of the 18 (72%) patients studied had curly toes. The average talus-first metatarsal angle recorded was 10.7 degrees (range, -7 to 30 degrees). The average lateral and anteroposterior talocalcaneal angles were 45.8 degrees (range, 16 to 62 degrees) and 31 degrees (range, 1 to 51 degrees), respectively. The average LDTA was found to be 70.6 degrees (range, 48 to 82 degrees). A single-sample Student t test shows significant divergence of measured LDTA, OxAFQ-C, and FPI from normal populations (P<0.005). CONCLUSIONS: MPS-1 is associated with a significant degree of foot and ankle pathology that has not been previously described. We found a high incidence of curly toes, ankle valgus, functional foot, and ankle disability and a requirement for customized footwear among our cohort. We recommend that careful assessment of foot and ankle pathology should be routine in the interdisciplinary management of patients with MPS-1. LEVEL OF EVIDENCE: Level III.
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Tobillo/patología , Pie/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Mucopolisacaridosis I/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Mucopolisacaridosis I/terapia , Fenotipo , Estudios Prospectivos , Zapatos , Adulto JovenRESUMEN
PURPOSE: The purpose of this study is to examine the impact of a Care Management Organization (CMO) Diabetes Disease Management Program (DDMP) in improving diabetes outcomes among high-risk patients with type 2 diabetes (T2DM) in the Bronx, New York. METHODS: An interventional, nonrandomized study design was used to assess the effectiveness of the DDMP. Patients older than 18 years who had T2DM and an A1C persistently 8% or greater or with a cardiovascular comorbidity were characterized as high risk and received intensive disease management. Patients served as their own controls, with data collection and analysis occurring 12 months prior to and 12 months after enrollment in DDMP. Data collection included screening rates for A1C, low-density lipoprotein (LDL) cholesterol, depression, smoking status, and annual influenza vaccine administration. Changes in A1C and LDL cholesterol were also analyzed. Statistical analyses were conducted using Minitab. McNemar's chi-square and paired t tests were used to assess within-group changes from baseline to final outcomes. RESULTS: Significant improvements in screening rates for A1C, LDL, depression, smoking status, and annual influenza vaccine administration were found among high-risk/intensively managed patients in the DDMP. Improvements in clinical measures were also achieved in this group. Provider and patient satisfaction surveys were positive, with 92% of patients believing that the program helped them better understand their disease. CONCLUSIONS: A DDMP among high-risk patients has shown promise in improving the quality of care for patients with diabetes. This program has relevance for other integrated delivery systems that are developing accountable care approaches.
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Centros Médicos Académicos , Diabetes Mellitus Tipo 2/terapia , Accesibilidad a los Servicios de Salud/organización & administración , Necesidades y Demandas de Servicios de Salud , Atención Primaria de Salud/organización & administración , Población Urbana , Centros Médicos Académicos/organización & administración , Citas y Horarios , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Procesos de Grupo , Humanos , Comunicación Interdisciplinaria , Masculino , New York/epidemiología , Evaluación de Procesos, Atención de Salud , Evaluación de Programas y Proyectos de Salud , Mejoramiento de la Calidad , Calidad de la Atención de Salud , Años de Vida Ajustados por Calidad de Vida , Factores de RiesgoRESUMEN
A 2-year-old female with Hurler syndrome (mucopolysaccharidosis type 1) died suddenly within 3 months of successful unrelated fully matched cord blood transplant, having received weekly enzyme replacement therapy (ERT) prior to transplant. Though an infectious aetiology was clinically suspected to be the cause of her unanticipated acute deterioration and untimely demise, autopsy findings suggested that a combination of pre-existing but sub-clinical Hurler related cardiopulmonary pathology and superimposed transplant related pulmonary venopathy as the basis of her death. This case highlights the limitations of ERT in ameliorating cardiorespiratory disease and the failure of standard pre-transplant investigations to detect significant abnormality related to her underlying condition. It also reinforces the importance of autopsy in explaining unanticipated events.
RESUMEN
We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Mucopolisacaridosis I/terapia , Agonistas Mieloablativos/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adolescente , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Mucopolisacaridosis I/epidemiología , Mucopolisacaridosis I/mortalidad , Agonistas Mieloablativos/efectos adversos , Estudios Retrospectivos , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Acondicionamiento Pretrasplante/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Forty percent of renal cell carcinomas (RCCs) in childhood are characterized by translocation involving transcription factor E3 (TFE3) family members. Here, we describe a case of TFE3-positive RCC in which metastatic relapse to the mediastinal lymph nodes and pulmonary nodules was treated with single-agent sunitinib, a multitargeted tyrosine inhibitor. Complete radiologic remission was achieved after only 3 courses of treatment, and surgical exploration of metastases failed to identify any residual viable disease. The published experience of sunitinib in TFE-RCC is limited, and prospective evaluation of its activity in a larger number of patients is warranted.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirroles/uso terapéutico , Translocación Genética/genética , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Niño , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metástasis Linfática , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Inducción de Remisión , Sunitinib , Tomografía Computarizada por Rayos XRESUMEN
To describe the incidence, risk factors, and treatment of autoimmune diseases (ADs) occurring after cord blood transplantation (CBT), we analyzed both CBT recipients reported to EUROCORD who had developed at least 1 new AD and those who had not. Fifty-two of 726 reported patients developed at least 1 AD within 212 days (range, 27-4267) after CBT. Cumulative incidence of ADs after CBT was 5.0% +/- 1% at 1 year and 6.6% +/- 1% at 5 years. Patients developing ADs were younger and had more nonmalignant diseases (P < .001). ADs target hematopoietic (autoimmune hemolytic anemia, n = 20; Evans syndrome, n = 9; autoimmune thrombocytopenia, n = 11; and immune neutropenia, n = 1) and other tissues (thyroiditis, n = 3; psoriasis, n = 2; Graves disease, n 1; membranous glomerulonephritis, n = 2; rheumatoid arthritis, n = 1; ulcerative colitis, n = 1; and systemic lupus erythematosus, n = 1). Four patients developed 2 ADs (3 cases of immune thrombocytopenia followed by autoimmune hemolytic anemia and 1 Evans syndrome with rheumatoid arthritis). By multivariate analysis, the main risk factor for developing an AD was nonmalignant disease as an indication for CBT (P = .0001). Hematologic ADs were most often treated with steroids, rituximab, and cyclosporine. With a median follow-up of 26 months (range, 2-91), 6 of 52 patients died as a consequence of ADs. We conclude that CBT may be followed by potentially life-threatening, mainly hematologic ADs.
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Enfermedades Autoinmunes/etiología , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Medición de Riesgo/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Niño , Preescolar , Ciclosporina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Lactante , Masculino , Persona de Mediana Edad , Análisis Multivariante , Evaluación de Resultado en la Atención de Salud/métodos , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Rituximab , Esteroides/uso terapéutico , Análisis de Supervivencia , Adulto JovenRESUMEN
A previously healthy 9-year-old girl presented with a 10-day history of slowly progressive unsteadiness, slurred speech, and behavior change. On examination there was cerebellar ataxia and dysarthria, excessive blinking, subtle perioral myoclonus, and labile mood. The finding of oligoclonal bands in the cerebrospinal fluid prompted paraneoplastic serological evaluation and search for an occult neural crest tumor. Antineuronal nuclear autoantibody type 1 (anti-Hu) and voltage-gated potassium channel complex antibodies were detected in serum. Metaiodobenzylguanidine scan and computed tomography scan of the abdomen showed a localized abdominal mass in the region of the porta hepatis. A diagnosis of occult neuroblastoma was made. Resection of the stage 1 neuroblastoma and treatment with pulsed corticosteroids resulted in resolution of all symptoms and signs. Excessive blinking has rarely been described with neuroblastoma, and, when it is not an isolated finding, it may be a useful clue to this paraneoplastic syndrome. Although voltage-gated potassium channel complex autoimmunity has not been described previously in the setting of neuroblastoma, it is associated with a spectrum of paraneoplastic neurologic manifestations in adults, including peripheral nerve hyperexcitability disorders.
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Neoplasias Abdominales/diagnóstico , Neoplasias Abdominales/inmunología , Anticuerpos Antinucleares/sangre , Parpadeo/inmunología , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/inmunología , Disartria/diagnóstico , Disartria/inmunología , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/inmunología , Neuroblastoma/diagnóstico , Neuroblastoma/inmunología , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/inmunología , Canales de Potasio con Entrada de Voltaje/inmunología , Niño , Diagnóstico Diferencial , Femenino , Humanos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING: Gentium SpA, European Group for Blood and Marrow Transplantation.
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Fibrinolíticos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/prevención & control , Polidesoxirribonucleótidos/uso terapéutico , Adolescente , Bilirrubina/sangre , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/epidemiología , Humanos , Incidencia , Lactante , Infusiones Intravenosas , Masculino , Insuficiencia Multiorgánica/epidemiología , Insuficiencia Renal/epidemiologíaRESUMEN
BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies. METHODS: A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus. RESULTS: Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT. CONCLUSIONS: This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.
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Terapia de Reemplazo Enzimático/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Mucopolisacaridosis I/terapia , Preescolar , Terapia Combinada , Europa (Continente) , Humanos , Iduronidasa/administración & dosificación , Iduronidasa/uso terapéutico , Lactante , Resultado del TratamientoRESUMEN
PURPOSE: Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. PATIENTS AND METHODS: The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. RESULTS: In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. CONCLUSION: Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation.
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Técnicas de Apoyo para la Decisión , Recurrencia Local de Neoplasia , Nomogramas , Selección de Paciente , Rabdomiosarcoma/terapia , Terapia Recuperativa , Distribución de Chi-Cuadrado , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Oportunidad Relativa , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/patología , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
We report a case of an 8-month-old child with a primitive myxoid mesenchymal tumor of infancy arising in the thenar eminence. The lesion recurred after conservative excision and was ultimately nonresponsive to chemotherapy, necessitating partial amputation. The patient remains free of disease 5 years after this radical surgery. This is the 1st report of such a tumor since it was initially described by Alaggio and colleagues in 2006. The pathologic differential diagnosis is discussed.
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Mesenquimoma/patología , Neoplasias de los Tejidos Blandos/patología , Amputación Quirúrgica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Mano/patología , Humanos , Inmunohistoquímica , Lactante , Mesenquimoma/terapia , Recurrencia Local de Neoplasia/terapia , Neoplasias de los Tejidos Blandos/terapiaRESUMEN
BACKGROUND: Hurler Syndrome is associated with a deficiency of a specific lysosomal enzyme involved in the degradation of glycosaminoglycans. Hematopoietic stem cell transplantation (HSCT) in early infancy is undertaken to help prevent the accumulation of glycosaminoglycans and improve organ function. AIM: To investigate the oral features and dental health of patients with Hurler Syndrome who have undergone successful HSCT. MATERIALS AND METHODS: Twenty-five patients (median age 8.6 years) post-HSCT (mean age 9.4 months) underwent oral assessment (mean of 7.5 years post-HSCT). RESULTS: Dental development was delayed. Numerous occlusal anomalies were noted including: open-bite, class III skeletal base, dental spacing, primary molar infra-occlusion and ectopic tooth eruption. Dental anomalies included hypodontia, microdontia, enamel defects, thin tapering canine crowns, pointed molar cusps, bulbous molar crowns and molar taurodontism. Tooth roots were usually short/blunted/spindle-like in permanent molars. The prevalence of dental caries was low in the permanent dentition (mean DMFT 0.7) but high in the primary dentition (mean dmft 2.4). Oral hygiene instruction with plaque and or calculus removal was indicated in 71% of those that were dentate. CONCLUSION: Patients with Hurler Syndrome post-HSCT are likely to have delayed dental development, a malocclusion, and dental anomalies, particularly hypodontia and microdontia.