RESUMO
BACKGROUND: Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. METHODS: We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. RESULTS: Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. CONCLUSIONS: Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Genes ras , Neoplasias Pulmonares/metabolismo , Terapia de Alvo Molecular , Mutação , Transdução de Sinais , Ácido Aspártico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Ensaios Clínicos Fase II como Assunto , Cisteína , Intervalo Livre de Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Vetores Genéticos , Glicina , Humanos , Immunoblotting , Imunoprecipitação , Estimativa de Kaplan-Meier , Lentivirus , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Análise em Microsséries , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , ValinaRESUMO
BACKGROUND: Although laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) are the most common bariatric procedures performed in the past decade, little is known about their long-term (>5 years) outcomes. METHODS: A retrospective outcome study investigated 148 consecutive patients from a single practice who underwent LAGB from November 2000 to March 2002. The group was matched with 175 consecutive patients who underwent LRYGB from June 2000 to March 2005. Follow-up data for 5 years or longer was available for 127 LAGB patients (86%) and 105 LRYGB patients (60%). RESULTS: After an initial 4 years of progressive weight loss, body mass index (BMI) loss stabilized at 5-7 years at approximately 15 kg/m(2) for the LRYGB patients and at about 9 kg/m(2) for the LAGB patients with band in place (P < 0.01). At 7 years, the excess weight loss (EWL) was 58.6% for LRYGB and 46.3% for LAGB with band in place (P < 0.01). By 7 years, 19 LAGB patients (15%) had had their bands removed, bringing the failure rate for LAGB (including patients with less than 25% EWL) to 48.3% versus 10.7% for LRYGB (P < 0.01). By 10 years, 29 (22.8%) of the bands had been removed, bringing the total LAGB failure rate to 51.1%. In 10 years, 67 LAGB (52.8%) and 43 LRYGB (41%) adverse events had occurred. However, over time, the LRYGB group experienced 9 (8.6%) serious, potentially life-threatening complications, whereas the LAGB group had none (P < 0.001). One procedure-related death occurred in the LRYGB group. CONCLUSIONS: Over the long term, LRYGB had an approximate reduction of 15 kg/m(2) BMI and 60% EWL, a significantly better outcome than LAGB patients experienced with band intact. The main issue with LAGB was its 50% failure rate in the long term, as defined by poor weight loss and percentage of band removal. Nevertheless, LAGB had a remarkably safe course, and it may therefore be considered for motivated and informed patients.