RESUMEN
INTRODUCTION: Monoclonal gammopathies are common over the age of 50. Patients are usually asymptomatic. However, some patients present with secondary clinical manifestations, which are now grouped under the entity « Monoclonal Gammopathy of Clinical Significance ¼ (MGCS). CASE REPORT: Here, we report two rare cases of MGCS: an acquired von Willebrand syndrome (AvWS) and an acquired angioedema (AAE). CONCLUSION: The discovery of a decrease in von Willebrand activity (vWF:RCo) or angioedema in a patient over 50 years of age, in the absence of a family history, should prompt a search for a hemopathy and in particular, a monoclonal gammopathy.
Asunto(s)
Angioedema , Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Enfermedades de von Willebrand , Humanos , Persona de Mediana Edad , Paraproteinemias/complicaciones , Paraproteinemias/diagnóstico , Enfermedades de von Willebrand/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Factor de von WillebrandRESUMEN
Five MRI patterns of marrow involvement (diffuse, focal, combined diffuse and focal, variegated, and normal) are observed in patients with a marrow proliferative disorder including MM. The wide range of marrow involvement patterns in monoclonal plasma cell proliferative disorders mirrors that of their natural histories that can vary from indolent to rapidly lethal. MRI of the axial bone marrow contributes to stage these disorders, but it should not be obtained for disease detection and characterization because of its limited specificity and sensitivity. At MRI, diffuse benign hematopoietic marrow hyperplasia and marrow heterogeneities in elderly patients mimic the diffuse and variegated patterns observed in MM patients. Careful analysis of fat- and fluid-sensitive MR images and quantitative marrow assessment by using MRI and FDG-PET can contribute in differentiating these changes from those associated with neoplastic marrow infiltration, with some residual overlapping findings.
Asunto(s)
Enfermedades de la Médula Ósea , Mieloma Múltiple , Anciano , Médula Ósea/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Mieloma Múltiple/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/mortalidad , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Leucemia Mieloide Aguda/patología , Masculino , Síndromes Mielodisplásicos/patología , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To evaluate the cost-effectiveness of five prenatal screening strategies for trisomies (13/18/21) and other unbalanced chromosomal abnormalities (UBCA), following the introduction of cell-free DNA (cfDNA) analysis. METHODS: A model-based cost-effectiveness analysis was performed to estimate prevalence, safety, screening-program costs and healthcare costs of five different prenatal screening strategies, using a virtual cohort of 652 653 pregnant women in France. Data were derived from the French Biomedicine Agency and published articles. Uncertainty was addressed using one-way sensitivity analysis. The five strategies compared were: (i) cfDNA testing for women with a risk following first-trimester screening of ≥ 1/250; (ii) cfDNA testing for women with a risk of ≥ 1/1000 (currently recommended); (iii) cfDNA testing in the general population (regardless of risk); (iv) invasive testing for women with a risk of ≥ 1/250 (historical strategy); and (v) invasive testing for women with a risk of ≥ 1/1000. RESULTS: In our virtual population, at similar risk thresholds, cfDNA testing compared with invasive testing was cheaper but less effective. Compared with the historical strategy, cfDNA testing at the ≥ 1/1000 risk threshold was a more expensive strategy that detected 158 additional trisomies, but also 175 fewer other UBCA. Implementation of cfDNA testing in the general population would give an incremental cost-effectiveness ratio of 9 166 689 per additional anomaly detected compared with the historical strategy. CONCLUSION: Extending cfDNA to lower risk thresholds or even to all pregnancies would detect more trisomies, but at greater expense and with lower detection rate of other UBCA, compared with the historical strategy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Relación costo-eficacia de cinco estrategias de cribado prenatal para trisomías y otras anomalías cromosómicas no equilibradas: un análisis basado en modelos OBJETIVO: Evaluar la eficacia en función de los costos de cinco estrategias de cribado prenatal para trisomías (13/18/21) y otras anomalías cromosómicas no equilibradas (UBCA, por sus siglas en inglés), tras la introducción del análisis de ADN fetal (cfDNA, por sus siglas en inglés). MÉTODOS: Se realizó un análisis de la relación costo-eficacia basado en modelos para estimar la prevalencia, la seguridad, los costos de los programas de cribado y los costos sanitarios de cinco estrategias diferentes de cribado prenatal, para lo cual se usó una cohorte virtual de 652 653 mujeres embarazadas en Francia. Los datos se obtuvieron de la Agencia Francesa de Biomedicina y de artículos publicados. La incertidumbre se abordó mediante un análisis de sensibilidad unidireccional. Las cinco estrategias comparadas fueron: (i) pruebas de cfDNA para mujeres con un riesgo ≥1/250 después del examen del primer trimestre; (ii) pruebas de cfDNA para mujeres con un riesgo ≥1/1000 (las recomendadas actualmente); (iii) pruebas de cfDNA en la población general (independientemente del riesgo); (iv) pruebas invasivas para mujeres con un riesgo ≥1/250 (estrategia histórica); y (v) pruebas invasivas para mujeres con un riesgo ≥1/1000. RESULTADOS: En esta población virtual, con umbrales de riesgo similares, la prueba de cfDNA fue más barata pero menos efectiva en comparación con la prueba invasiva. En comparación con la estrategia histórica, la prueba de cfDNA para el umbral de riesgo de ≥1/1000 fue una estrategia más costosa que detectó 158 trisomías adicionales, pero también 175 menos de otras UBCA. La aplicación de las pruebas de cfDNA en la población general daría una relación costo-eficacia incremental de 9 166 689 EUR por cada anomalía adicional detectada en comparación con la estrategia histórica. CONCLUSIÓN: Extender las pruebas de cfDNA a umbrales de riesgo más bajos o incluso a todos los embarazos detectaría más trisomías, pero a un costo mayor y con una tasa de detección más baja de otras UBCA, en comparación con la estrategia histórica.
Asunto(s)
Ácidos Nucleicos Libres de Células/economía , Síndrome de Down/diagnóstico , Diagnóstico Prenatal/economía , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 18/diagnóstico , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/normas , Aberraciones Cromosómicas/estadística & datos numéricos , Estudios de Cohortes , Síndrome de Down/epidemiología , Síndrome de Down/genética , Femenino , Francia/epidemiología , Humanos , Embarazo , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/normas , Sensibilidad y Especificidad , Síndrome de la Trisomía 13/epidemiología , Síndrome de la Trisomía 13/genética , Síndrome de la Trisomía 18/epidemiología , Síndrome de la Trisomía 18/genéticaRESUMEN
BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre de Sangre Periférica , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nucleofosmina , Recurrencia , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Asunto(s)
Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Diagnóstico Prenatal/métodos , Adolescente , Adulto , Aneuploidia , Cromosomas Humanos/genética , Femenino , Edad Gestacional , Humanos , Edad Materna , Medida de Translucencia Nucal , Embarazo , Estudios Retrospectivos , Adulto JovenRESUMEN
Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Nucleofosmina , Medicina de Precisión/métodos , Inducción de Remisión , Medición de Riesgo , Tasa de Supervivencia , Secuencias Repetidas en Tándem , Acondicionamiento Pretrasplante/métodos , Adulto JovenRESUMEN
The Xq25 duplications syndrome has recently emerged as a distinct clinical entity. We report here on six new patients belonging to two unrelated families and harbouring an Xq25 microduplication detected by array CGH. Similarly to previously reported cases, the phenotype of our patients is characterized by delayed milestones, speech disturbance, intellectual disability, abnormal behaviours and a characteristic facial dysmorphism. The common duplicated interval allowed further refinement of the shortest region of overlap to 173 kb, including only one gene, STAG2, which encodes a component of the cohesin complex. We suggest that increased STAG2 gene copy number and dysregulation of its downstream target genes may be responsible for the specific clinical findings of this syndrome. Therefore, the Xq25 microduplication could be considered as a novel cohesinopathy, thus increasing the group of these disorders.
Asunto(s)
Antígenos Nucleares/genética , Fenotipo , Trisomía/diagnóstico , Trisomía/genética , Adolescente , Adulto , Encéfalo/metabolismo , Encéfalo/fisiopatología , Proteínas de Ciclo Celular , Niño , Preescolar , Cromosomas Humanos X/genética , Hibridación Genómica Comparativa , Electroencefalografía , Facies , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Imagen por Resonancia Magnética , Masculino , Aberraciones Cromosómicas Sexuales , Inactivación del Cromosoma X , Adulto JovenRESUMEN
OBJECTIVE: By-the-book implementation of non-invasive prenatal test and clinical validation for trisomy 21. STUDY DESIGN: Publicly funded prospective study of 225 cases. Women at risk for trisomy 21 > 1/250 based on combined ultrasound and serum markers during first or second trimester were eligible following an informed consent. The technique was established from the available literature and performed on 10 mL of venous blood collected prior to chorionic villus sampling or amniocentesis. Investigators were blinded to the fetal karyotype. Results were expressed in Z-scores of the percentage of each chromosome. RESULTS: Among 976 eligible cases, 225 were processed: 8 were used for pretesting phase and 23 to build a reference set. One hundred thirty six euploid cases and 47 with trisomy 21 were then run randomly. Eleven cases yielded no result (4.8%). Z-scores were above 3 (7.58+/-2.41) for chromosome 21 in all 47 trisomies and in none of the euploid cases (0.11+/-1.0). Z-scores were within normal range for the other chromosomes in both groups. Using a cut-off of 3, sensitivity and specificity were of 100% 95% CI [94.1, 100] and 100% 95% CI [98, 100], respectively. CONCLUSION: Non-invasive prenatal test for trisomy 21 is a robust strategy that can be translated from seminal publications. Publicly funded studies should refine its indications and cost-effectiveness in prenatal screening and diagnosis. © 2015 John Wiley & Sons, Ltd.
Asunto(s)
ADN/sangre , Síndrome de Down/sangre , Adulto , Amniocentesis , Muestra de la Vellosidad Coriónica , Estudios de Cohortes , Síndrome de Down/diagnóstico , Femenino , Humanos , Cariotipificación , Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Diagnóstico Prenatal , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de RiesgoRESUMEN
The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.
Asunto(s)
Leucemia Mieloide Aguda/terapia , Adulto , Antineoplásicos/química , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Inducción de Remisión , Riesgo , Factores de Tiempo , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.
Asunto(s)
Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Neoplasia Residual , Nucleofosmina , Pronóstico , Análisis de Regresión , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The aim of the present study was to show the feasibility and describe the first results of a 3D reconstruction of the venous network of the lower limbs in human fetus using the computer-assisted anatomical dissection (CAAD) technique. MATERIALS AND METHODS: We used limbs from two human fetuses, respectively, 14 and 15 weeks gestation old. Specimens were fixed in 10% formalin, embedded in paraffin wax and serially sectioned at 10 m. The histological slices were stained using HES and Masson Trichrome for soft tissues identification. Immunolabeling techniques using the Protein S-100 marker and the D2-40 marker were used to identify nerves and vessels, respectively. Stained slices were aligned manually, labeled and digitalized. The segmentation of all anatomical structures was achieved using the WinSurf(®) software after manual drawing. RESULTS: A 3D interactive vectorial model of the whole leg, including skin, bone, muscles, arteries, veins, and nerves was obtained. In all limbs, we observed the presence of a big axial vein traveling along the sciatic nerve. In addition, the femoral vein appeared as a small plexus. Although this is a common anatomical feature at the end of organogenesis, this feature is observed in only 9% of adults. Usually interpreted as an "anatomical variation of the femoral vein" it should be considered as a light truncular malformation. These observations bring further support to our proposed "angio-guiding nerves" hypothesis. CONCLUSION: This preliminary study shows that the CAAD technique provided an accurate 3D reconstruction of the fetal leg veins anatomy. It should bring a new insight for the understanding of the different steps of development of the human venous system.
Asunto(s)
Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Extremidad Inferior/anatomía & histología , Extremidad Inferior/irrigación sanguínea , Venas/anatomía & histología , Cadáver , Disección/métodos , Vena Femoral/anatomía & histología , Vena Femoral/diagnóstico por imagen , Vena Femoral/embriología , Feto , Humanos , Extremidad Inferior/diagnóstico por imagen , Flebografía/métodos , Vena Safena/anatomía & histología , Vena Safena/diagnóstico por imagen , Vena Safena/embriología , Cirugía Asistida por Computador/métodos , Venas/embriologíaRESUMEN
Discordant chromosomal anomalies in monozygotic twins may be caused by various timing issues of erroneous mitosis and twinning events. Here, we report a prenatal diagnosis of heterokaryotypic monozygotic twins discordant for phenotype. In a 28-year-old woman, ultrasound examination performed at 26 weeks of gestation, detected intrauterine growth restriction and unilateral cleft lip and palate in twin B, whereas twin A had normal fluid, growth and anatomy. Molecular karyotyping in twin B identified a 18q21.2qter deletion, further confirmed by FISH analysis on amniocytes. Interestingly, in twin A, cytogenetic studies (FISH analysis and karyotype) on amniocytes were normal. Genotyping with microsatellite markers confirmed the monozygosity of the twins. At 32 weeks of gestation, selective termination of twin B was performed by umbilical cord coagulation and fetal blood samples were taken from the umbilical cord in both twins. FISH analyses detected mosaicism in both twins with 75% of cells being normal and 25% harboring the 18qter deletion. After genetic counseling, the parents elected to terminate the second twin at 36 weeks of gestation. In postmortem studies, FISH analyses revealed mosaicism on several tissues in both twins. Taking into account this observation, we discuss the difficulties of genetic counseling and management concerning heterokaryotypic monozygotic twins.
Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos Par 18/genética , Enfermedades en Gemelos/diagnóstico , Mosaicismo , Diagnóstico Prenatal , Gemelos Monocigóticos/genética , Adulto , Líquido Amniótico , Trastornos de los Cromosomas/genética , Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Hibridación Genómica Comparativa , Enfermedades en Gemelos/genética , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Humanos , Repeticiones de Microsatélite , Fenotipo , EmbarazoAsunto(s)
Anomalías Múltiples/genética , Cuerpos Basales/patología , Enfermedades Cerebelosas/genética , Cilios/patología , Anomalías del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Renales Quísticas/genética , Mutación , Síndromes Orofaciodigitales/genética , Proteínas/genética , Retina/anomalías , Anomalías Múltiples/patología , Adolescente , Cuerpos Basales/metabolismo , Enfermedades Cerebelosas/patología , Cerebelo/anomalías , Niño , Preescolar , Cilios/metabolismo , Anomalías del Ojo/patología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Genotipo , Humanos , Recién Nacido , Enfermedades Renales Quísticas/patología , Masculino , Síndromes Orofaciodigitales/patología , Fenotipo , Retina/patología , Adulto JovenRESUMEN
Although discordant phenotypes in monozygotic twins with developmental disorder are not an exception, underlying genetic discordance is rarely reported. Here, we report on the clinical and cytogenetic details of 4-year-old female monozygotic twins with discordant phenotypes. Twin 1 exhibited global developmental delay, overweight and hyperactivity. Twin 2 had an autistic spectrum disorder. Molecular karyotyping in twin 1 identified a 2p25.3 deletion, further confirmed by Fluorescence in situ hybridization (FISH) analysis on leukocytes. Interestingly, array comparative genomic hybridization was normal in twin 2 but FISH analysis using the same probe as twin 1 showed mosaicism with one-third of cells with a 2p25.3 deletion, one-third of cells with a 2p25.3 duplication, and one-third of normal cells. Genotyping with microsatellite markers confirmed the monozygosity of the twins. We propose that the chromosome imbalance may be due to a mitotic non-allelic recombination occurring during blastomeric divisions of a normal zygote. Such event will result in three distinct cell populations, whose proportion in each embryo formed after separation from the zygote may differ, leading to discordant chromosomal anomalies between twins. We also discuss that the MYTL1L and the SNTG2 genes within the reported region could probably relate to the phenotypic discordance of the monozygotic twins.
Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 2 , Discapacidades del Desarrollo/genética , Enfermedades en Gemelos/genética , Proteínas de la Membrana/genética , Mosaicismo , Proteínas Musculares/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Gemelos Monocigóticos/genética , Trastorno Autístico/fisiopatología , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/fisiopatología , Enfermedades en Gemelos/fisiopatología , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Fenotipo , Recombinación GenéticaRESUMEN
The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Ácidos Borónicos/administración & dosificación , Bortezomib , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Pirazinas/administración & dosificación , Estudios Retrospectivos , Análisis de Supervivencia , Talidomida/administración & dosificación , Resultado del TratamientoRESUMEN
Preimplantation genetic diagnosis (PGD) is authorized in France since 1999. After 10 years, technical results are encouraging. With the development of new technologies, our team is able to diagnosis the large majority of chromosome translocations and 75 monogenic diseases. However, PGD remains limited because of the growing augmentation of demands causing an increasing delay for the first procedure of more than 18 months. Since 2006, 19 couples asked for a PGD with HLA typing. In January 2011, 11 couples have already been included in our PGD program. The birth of the first child after PGD with HLA typing offers new perspectives of treatment for these couples.