RESUMEN
BACKGROUND: The Accreditation Council for Graduate Medical Education's Next Accreditation System endorsed specialty-specific milestones as the foundation of an outcomes-based resident evaluation process. These milestones represent five competency levels (entry level to expert), and graduating residents will be expected to meet Level 4 on all 23 milestones. Limited validation data on these milestones exist. It is unclear if higher levels represent true competencies of practicing emergency medicine (EM) attendings. OBJECTIVE: Our aim was to examine how practicing EM attendings in academic and community settings self-evaluate on the new EM milestones. METHODS: An electronic self-evaluation survey outlining 9 of the 23 EM milestones was sent to a sample of practicing EM attendings in academic and community settings. Attendings were asked to identify which level was appropriate for them. RESULTS: Seventy-nine attendings were surveyed, with an 89% response rate. Sixty-one percent were academic. Twenty-three percent (95% confidence interval [CI] 20%-27%) of all responses were Levels 1, 2, or 3; 38% (95% CI 34%-42%) were Level 4; and 39% (95% CI 35%-43%) were Level 5. Seventy-seven percent of attendings found themselves to be Level 4 or 5 in eight of nine milestones. Only 47% found themselves to be Level 4 or 5 in ultrasound skills (p = 0.0001). CONCLUSIONS: Although a majority of EM attendings reported meeting Level 4 milestones, many felt they did not meet Level 4 criteria. Attendings report less perceived competence in ultrasound skills than other milestones. It is unclear if self-assessments reflect the true competency of practicing attendings. The study design can be useful to define the accuracy, precision, and validity of milestones for any medical field.
Asunto(s)
Acreditación/normas , Competencia Clínica , Evaluación Educacional/métodos , Medicina de Emergencia/educación , Competencia Clínica/normas , Educación de Postgrado en Medicina/normas , Humanos , Internado y Residencia/normas , Estudios ProspectivosRESUMEN
BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
Asunto(s)
Receptores ErbB/genética , Mutación Missense , Quinazolinas/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Receptores ErbB/química , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Células 3T3 NIH , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fosforilación , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Quinazolinas/química , Quinazolinas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.