RESUMEN
The survival rate of cancer patients has increased considerably in the last 20 years owing to significant efforts made in prevention, early detection protocols, combined chemotherapy regimens, targeted therapies, refined radiotherapy and cancer vaccines. However, metastasis and acquired resistance to current therapies represent two major challenges for achieving long-term cure. Therefore, new treatment strategies must be developed. One promising alternative is epigenetic-based therapies, of which miRNAs are at the forefront. MicroRNAs are endogenous small non-coding RNAs, often deregulated in cancer, which regulate gene expression by specific binding to the 3'-UTR of target genes. They are excellent candidates for therapy since miRNAs can regulate multiple targets of the same or different pathways, thereby minimizing the risk of resistance development or compensatory mechanisms. In this review, the mechanisms that lead to miRNA deregulation in cancer, their feasibility as therapeutic tools and the different strategies for the pharmacological manipulation of miRNAs in preclinical animal models are discussed.
Asunto(s)
Marcación de Gen/métodos , Terapia Genética/métodos , MicroARNs/genética , Neoplasias/terapia , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Terapia Combinada , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/biosíntesis , Neoplasias/genéticaRESUMEN
We aimed at assessing the clinical significance of the levels of acute lymphoblastic leukemia (ALL) cells in samples of cerebrospinal fluid (CSF) during therapy. We studied 990 CSF samples from 108 patients, at the time of diagnosis (108) and at each time of intrathecal therapy (882). The proportions of leukemic cells in CSF samples were assessed by flow cytometry (FCM). Patients with central nervous system (CNS) involvement at diagnosis (FCM+) showed predominantly a T-ALL, and higher percentages of known negative prognostic factors: high risk group, higher white blood cell counts, normal karyotype, and the BCR-ABL fusion gene. No differences in relapse free survival (RFS) and overall survival (OS) were observed between FCM+ versus FCM- at diagnosis. Patients with CNS involvement during therapy showed significantly older age, and higher frequencies of T-cell leukemia. We found a significantly higher RFS in patients with FCM+ during therapy. The detection of subclinical CNS disease by FCM during maintenance was associated with significantly lower 3-years RFS and 3-years OS. A sensitive methodology like FCM can be applied for a close follow-up of the levels of ALL in CFS samples, and may identify a group of patients at high risk for relapse.
Asunto(s)
Neoplasias Meníngeas/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Estudios de Cohortes , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inyecciones Espinales , Quimioterapia de Mantención , Masculino , Neoplasias Meníngeas/epidemiología , Neoplasias Meníngeas/secundario , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/fisiopatología , Pronóstico , Estudios Prospectivos , Recurrencia , Factores de Riesgo , España/epidemiología , Análisis de SupervivenciaRESUMEN
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
BACKGROUND: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. OBJECTIVE: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. METHODS: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. RESULTS: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. CONCLUSIONS: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
Asunto(s)
Fragilidad Cromosómica , Anemia de Fanconi/genética , Reactivos de Enlaces Cruzados/farmacología , Compuestos Epoxi/farmacología , Anemia de Fanconi/diagnóstico , Humanos , Mitomicina/farmacología , Mosaicismo , FenotipoRESUMEN
Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.
Asunto(s)
Proteína del Grupo de Complementación A de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación A de la Anemia de Fanconi/fisiología , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Mutación , Adolescente , Edad de Inicio , Secuencia de Bases , Técnicas de Cultivo de Célula , Células Cultivadas , Niño , Preescolar , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Análisis Mutacional de ADN , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiología , Proteína del Grupo de Complementación A de la Anemia de Fanconi/metabolismo , Frecuencia de los Genes , Humanos , Lactante , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Fenotipo , España/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVE: The objective was to analyze the clinical profile of Differentiated Thyroid Carcinoma in children (DTC) and the predisposing factors to suffering the disease. MATERIAL AND METHOD: Eighty children with DTC were studied retrospectively. They all underwent total/near total thyroidectomy and 75 cases underwent ablative iodine therapy. Patients were controlled periodically with clinical, laboratory and imaging tests follow-up. RESULTS: Twenty eight patients were male and 52 female (mean age: 13.43+/-3.6 y). The 87.5% of patients had an increased cervical perimeter as the first clinical symptom, 65% of them corresponding to a thyroid nodule with a predominance of females. The papillary histological pattern was more frequent than the follicular pattern, and it was associated with the presence of lymph involvement and metastasis. About 56.4% of patients showed advanced disease at the time of diagnosis. 9 patients had previous irradiation. Surgical complications appeared in 32.5% of patients. At the end of follow-up (mean: 10.79+/-5.69 y) 9 patients had persistent disease with a significant relation with stage 4. CONCLUSIONS: DTC presents a higher incidence in females than in males. Cervical node is the most frequent form of initial presentation. The papillary type is more prevalent than the follicular type, and it is frequently associated with lymph node involvement and metastatic spread.