RESUMO
UNLABELLED: Activated anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases, through gene fusions, have been found in lung adenocarcinomas and are highly sensitive to selective kinase inhibitors. This study aimed at identifying the presence of these rearrangements in human colorectal adenocarcinoma specimens using a 4-target, 4-color break-apart FISH assay to simultaneously determine the genomic status of ALK and ROS1. Among the clinical colorectal cancer specimens analyzed, rearrangement-positive cases for both ALK and ROS1 were observed. The fusion partner for ALK was identified as EML4 and the fusion partner for one of the ROS1-positive cases was SLC34A2, the partner for the other ROS1-positive case remains to be identified. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. In addition, rearrangements were detected in samples that also harbored KRAS and BRAF mutations in two of the three cases. Interestingly, the ALK-positive specimen displayed marked intratumoral heterogeneity and rearrangement was also identified in regions of high-grade dysplasia. Despite the additional oncogenic events and tumor heterogeneity observed, elucidation of the first cases of ROS1 rearrangements and confirmation of ALK rearrangements support further evaluation of these genomic fusions as potential therapeutic targets in colorectal cancer. IMPLICATIONS: ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Proteínas de Ciclo Celular/genética , Feminino , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas Recombinantes de Fusão/genética , Serina Endopeptidases/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Proteínas ras/genéticaRESUMO
BACKGROUND: Patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) respond to ALK inhibitors. Clinically, the presence of ≥15% cells with rearrangements identified on break-apart fluorescence in situ hybridization (FISH) classifies tumors as positive. Increases in native and rearranged ALK copy number also occur. METHODS: In total, 1426 NSCLC clinical specimens (174 ALK-positive specimens and 1252 ALK-negative specimens) and 24 ALK-negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH. RESULTS: Clinical specimens with 0% to 9%, 10% to 15%, 16% to 30%, 31% to 50%, and >50% ALK-positive cells were identified in 79.3%, 8.5%, 1.4%, 2.7%, and 8.1%, respectively. An increased native ALK copy number (≥3 copies per cell in ≥40% of cells) was detected in 19% of ALK-positive tumors and in 62% of ALK-negative tumors. In ALK-negative tumors, abundant, focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in approximately 6% of tumors. The mean native ALK copy number ranged from 2.1 to 6.9 copies in cell lines and was not correlated with crizotinib sensitivity (50% inhibitory concentration, 0.34-2.8 µM; r = 0.279; P = .1764). Neither native or rearranged ALK copy number nor the percentage of positive cells correlated with extra-central nervous system progression-free survival in ALK-positive patients who were receiving crizotinib. CONCLUSIONS: Overall, 8.5% of tumors fell below the established positivity threshold by ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone were not associated with sensitivity to ALK inhibition in vitro. However, rare, complex patterns of increased native ALK in patients should be studied further; because, otherwise, atypical rearrangements contained within these may be missed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Crizotinibe , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
Difficulty in managing the airway is a major contributor to the morbidity and mortality of the trauma patient. The video laryngoscope, with its camera at the distal tip of the intubation blade, allows the practitioner an improved view of the glottic opening during intubation. The image from this viewer is transmitted to a monitor, allowing the intubating practitioner to "see around the corner" of a patient's airway. The purpose of the present study was to assess and compare the video quality of commercially available video laryngoscopy systems. It was found that between the STORZ C-MAC and the Verathon GlideScope® there was little difference between the video quality; the difference came down to user preference.