RESUMEN
Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been controversial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that several of these specifically recognize EPOR by Western blot, immunoprecipitation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment.
Asunto(s)
Anticuerpos Monoclonales/biosíntesis , Proteínas de Neoplasias/inmunología , Receptores de Eritropoyetina/inmunología , Secuencia de Aminoácidos , Animales , Técnicas de Química Sintética/métodos , Citometría de Flujo/métodos , Técnica del Anticuerpo Fluorescente , Silenciador del Gen , Humanos , Inmunoprecipitación , Ratones , Datos de Secuencia Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ratas , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Medición de Riesgo/métodos , Terminología como Asunto , Células Tumorales Cultivadas/metabolismoAsunto(s)
Antineoplásicos/uso terapéutico , Asma Inducida por Ejercicio/diagnóstico , Errores Diagnósticos , Disnea/etiología , Leucemia Mieloide de Fase Crónica/complicaciones , Síndromes Paraneoplásicos/etiología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Linfocitos B/metabolismo , Benzamidas , Tos/tratamiento farmacológico , Tos/etiología , Disnea/sangre , Disnea/tratamiento farmacológico , Disnea/fisiopatología , Ejercicio Físico , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crónica/sangre , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/fisiopatología , Leucotrieno C4/metabolismo , Masculino , Síndromes Paraneoplásicos/sangre , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/tratamiento farmacológico , Síndromes Paraneoplásicos/fisiopatología , Inducción de RemisiónRESUMEN
To address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology.
Asunto(s)
Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/etiología , Leucemia Linfocítica Crónica de Células B/genética , Ambiente , Salud de la Familia , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Mutación , FenotipoRESUMEN
Three sets of diagnostic criteria for polycythaemia vera (PV); the Polycythaemia Vera Study Group (PVSG) criteria (1975), the British Committee for Standards in Haematology (BCSH) criteria (1996) and the World Health Organisation (WHO) criteria (2001) have been described. We compared the ability of each set of criteria to accurately diagnose PV and differentiate it from secondary, apparent and idiopathic erythrocytosis. A cohort was drawn from a clinical database of erythrocytosis patients currently attending the Belfast City Hospital and the relevant information from the time of diagnosis for each patient was assessed according to each set of criteria, with the BCSH criteria used as a comparator. Sufficient data was available on 71 patients: 46 PV, 8 idiopathic, 8 apparent and 9 secondary erythrocytosis. The BCSH criteria classified 34 of 46 patients (73.9%) as PV and the WHO criteria had a sensitivity and specificity of 100% for classifying PV. For idiopathic and apparent erythrocytosis, the specificity of the WHO criteria, compared to the BCSH criteria, declined to 66.7 and 87.5%, respectively. The PVSG criteria were limited by the unavailability of required data for some patients resulting in a sensitivity and specificity of 50% for PV and specificity of 100% for all other groups. The Janus kinase 2 (JAK2) V617F mutation was present in 34 (85.3%) PV, 2 (50%) IE, 1 (50%) apparent and no secondary erythrocytosis cases. We concluded that the BCSH criteria were the most accurate diagnostic criteria for PV as they had an acceptable level of sensitivity and could differentiate between PV and other erythrocytoses.
Asunto(s)
Policitemia Vera/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Estudios de Cohortes , Bases de Datos Factuales , Volumen de Eritrocitos , Femenino , Frecuencia de los Genes , Hematócrito , Hemoglobinas/análisis , Hospitales Urbanos/estadística & datos numéricos , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Mutación Missense , Irlanda del Norte , Mutación Puntual , Policitemia/diagnóstico , Policitemia/etiología , Policitemia Vera/sangre , Policitemia Vera/genética , Valor Predictivo de las Pruebas , Estándares de Referencia , Estudios Retrospectivos , Sensibilidad y Especificidad , Sociedades Médicas , Organización Mundial de la SaludAsunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/patología , Anciano , Biopsia , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Persona de Mediana Edad , Resultado del Tratamiento , Vejiga Urinaria/patologíaAsunto(s)
Antineoplásicos/uso terapéutico , Aberraciones Cromosómicas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas , Humanos , Mesilato de Imatinib , Cromosoma FiladelfiaRESUMEN
A 78-year-old man presented with a 5-day history of epistaxis and spontaneous bruising, and a 2-day history of acute dysphagia. Barium swallow, computerized tomography scan of the chest and upper gastrointestinal endoscopy were suggestive of an upper oesophageal tumour, although biopsies failed to confirm this. Investigations including a raised activated partial thromboplastin time led to the detection of an inhibitor causing functional factor VIII deficiency. Following treatment with intravenous human immunoglobulin, oral prednisolone and oral cyclophosphamide, the patient's dysphagia resolved. There was a resolution of the findings seen at the initial endoscopy and on computerized tomography scan of the chest, consistent with an oesophageal haematoma. Follow-up endoscopy failed to detect recurrence or an aetiological factor.