RESUMEN
Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.
Asunto(s)
Aminopiridinas/administración & dosificación , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Morfolinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Adulto , Anciano , Aminopiridinas/farmacocinética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Femenino , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Morfolinas/farmacocinética , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Poli(ADP-Ribosa) Polimerasas/genéticaRESUMEN
Skin significantly contributes to water turnover excreting 300-600 ml/Day, this aliquot being under the control of several factors, including psychologic factors. The cutaneous evaporimetry offers semeiological parameters useful to study water balance. Our work is an extension of the classic experiments of G.E. Nilsson and coworkers. In the present report evaporimetric measurements are related to 15 normal subjects at ours climatic conditions.
Asunto(s)
Sudoración , Pérdida Insensible de Agua , Adulto , Presión Atmosférica , Peso Corporal , Femenino , Humanos , Humedad , Masculino , Temperatura , VolatilizaciónRESUMEN
Some modification are proposed to standardize better the staining technique of lipoprotein fractions. These modifications facilitate greatly the procedure originally reported by Colfs and Verheyden.
Asunto(s)
Lipoproteínas/análisis , Coloración y Etiquetado/métodos , Electroforesis en Acetato de Celulosa , HumanosRESUMEN
The aim of this work is the recognition, if any, of connection of arterial hypertension and some risk factors in obese children. In the schools of two little towns of our Region 114 subjects were selected, 57 males and 57 females, aged between 6, 5 and 15 years, with a body weight superior to that corresponding to the 95th percentils in the same age class. The blood pressure values were related to age and height and it was decided to consider hypertese those children whose pressure values corresponded to 95th and 97, 5th, respectively in the same class of age and height. The number of hypertese children in our group demonstrate that diastolic pressure in the height scale results especially increased among the age group 13-15 years in connection to size (females 75%, males 41, 7%). The connection between family diabetes and family hypertension have been shown significant. It can be pointed out that the risk factors for hypertension may be: age over 13 years, feminine, sex, family diabetes, family hypertension.
Asunto(s)
Hipertensión/etiología , Obesidad/complicaciones , Adolescente , Factores de Edad , Presión Sanguínea , Niño , Femenino , Humanos , Hipertensión/genética , Masculino , Obesidad/genética , Riesgo , Factores SexualesRESUMEN
The effect of a combined test (insulin, TRH, LHRH) on plasma concentrations of LH, FSH, PRL, Cortisol was studied in 18 normal subjects in prepubescent state and in 65 patients in prepubescent state with short stature. In 6 subjects with short stature there was no change of LH, and in 7 subjects with short stature there was no change of FSH. In conclusion the combined test for pituitary stimulation provides an useful method for localizing the lesion in disorders of hypothalamo-pituitary axis.
Asunto(s)
Enanismo Hipofisario/diagnóstico , Hormona Folículo Estimulante/sangre , Hidrocortisona/sangre , Hormona Luteinizante/sangre , Pruebas de Función Hipofisaria , Adenohipófisis/fisiopatología , Prolactina/sangre , Tirotropina/sangre , Niño , Preescolar , Enanismo Hipofisario/fisiopatología , Femenino , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina , Humanos , Hidrocortisona/metabolismo , Insulina , Hormona Luteinizante/metabolismo , Masculino , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Prolactina/metabolismo , Pubertad , Estimulación Química , Hormona Liberadora de TirotropinaRESUMEN
We have investigated the possible influence of auricolar puncture over hormonal secretion. We have studied in 5 subjects the course of hormonal incretion determinable by only auricolar puncture and the second time making the same methodology united with the test of hypophyseal stimulation by "LH-RH-insulina-TRH". The results show that it is not get any changes of the plasmatic rates of hypophiseal hormones, while we have observed a decrease of the plasmatic hydrocortisone rate when it was practised the only auricolar puncture.