RESUMEN
BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Quinazolinas/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/patología , Neoplasias de la Mama/secundario , Progresión de la Enfermedad , Femenino , Humanos , Lapatinib , Persona de Mediana Edad , Receptor ErbB-2/biosíntesis , Trastuzumab , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Adrenocorticotrophic hormone (ACTH) and corticosteroids have no maintenance values for inflammatory bowel disease but serve to reduce the severity of disease. The effectiveness of intravenous corticotrophin versus hydrocortisone in ulcerative colitis has been determined including whether previous steroid therapy influenced the better response to one rather than the other, but no such studies have ever been done in Crohn's disease. Eighty-eight patients hospitalized with moderate-to-severe Crohn's disease (Present-Korelitz [P-K] Index -3 to -2 and the International Organisation for the Study of Inflammatory Bowel Disease-Crohn's & Colitis Foundation of America [IOIBD-CCFA] Index, mean 14, range 5-23) were treated in a prospective, randomized, double-blind clinical trial to receive either continuous intravenous infusion of 120 U/day of ACTH (44 patients) or hydrocortisone 300 mg/day (44 patients). Patients were also subdivided into those who received oral steroids during the 30 days prior to intravenous therapy and those who had not. Response was followed on a daily basis and tabulated at 3, 5, and 10 days. Patients were followed from 1-3 years to determine the later status. After 10 days of intravenous therapy 36 of 44 patients (82%) who received ACTH and 41 of 44 patients (93%) who received hydrocortisone fully responded (P-K index +3 and IOIBD-CCFA Index mean of 3). At the end of the study, response to intravenous ACTH and hydrocortisone was not statistically different whether or not patients received oral steroids during the 30 days prior to admission, although the response to IV ACTH tended to be faster at 3 days in those who had received previous steroid therapy. Intravenous ACTH and hydrocortisone are equally effective in achieving therapeutic goals in patients with Crohn's disease who have not achieved results with oral medications. Moreover the response rate was high (mean 88%), serving to buy time for establishment of successful maintenance programs of treatment with oral 5-ASA and immunosuppressive drugs for 69% of patients at 1-3 years.
Asunto(s)
Hormona Adrenocorticotrópica/uso terapéutico , Antiinflamatorios/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Hidrocortisona/uso terapéutico , Administración Oral , Método Doble Ciego , Estudios de Seguimiento , Hospitalización , Humanos , Infusiones Intravenosas , Prednisona/uso terapéutico , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
We have examined the expression of the vav protooncogene during mouse embryogenesis using RNase protection assays, in situ hybridization, and immunocytochemical analysis. vav gene transcripts were first detected in E11.5 embryos in the blood-forming islands and megakaryocytes of the fetal liver. During diversification of hematopoietic activity in the embryo, vav gene expression became down-regulated in the liver and activated in thymus and spleen. In newborn animals, vav expression was also confined to hematopoietic tissues, with the exception of the ameloblastic cell layer at the latest stages of tooth morphogenesis. In the adult, vav transcripts were found in spleen, thymus, lymph nodes, and bone marrow, but not in liver. In spleen, vav transcripts were concentrated in the white pulp areas, whereas in the red pulp, the vav transcripts appeared to be primarily localized in the megakaryocytes. In thymus, vav expression was found to be more abundant in the cortical areas than in the medulla. In agreement with these observations, purified thymic lymphocytes showed heterogeneous immunoreactivity against the Vav protein, whereas splenic lymphocytes and bone marrow-derived cells displayed rather uniform levels of expression. These observations suggest that the vav protooncogene plays an important role in the signal transduction pathways that regulate the development and maintenance of the hematopoietic system.