RESUMO
While long-term survival rates for early-stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early-stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for our study. After RNA was extracted, the expressions of FPR1 and a reference gene were quantified by an automated one-step Taqman RT-PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off-the-shelf equipment and reagents. Further work is justified to explain the source of this biomarker.
Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , RNA Mensageiro , Receptores de Formil Peptídeo/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Estudos de Casos e Controles , Comorbidade , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Curva ROCRESUMO
BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
Assuntos
DNA de Neoplasias/análise , Genes p53 , Glioma/genética , Mutação , Adolescente , Adulto , Idoso , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Análise por Conglomerados , Feminino , Glioblastoma/genética , Glioma/metabolismo , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Análise de Sequência de DNA , Transdução de SinaisRESUMO
OBJECTIVE: To compare thin-layer endometrial cytology to endometrial biopsy and surgical pathology in women with abnormal uterine bleeding. STUDY DESIGN: We performed a prospective study of 103 women. Patients underwent endometrial cytologic evaluation using an endometrial brush, followed by either endometrial biopsy, hysteroscopy with dilation and curettage, or hysterectomy, as clinically indicated. Test performance characteristics and adequacy of cytology and endometrial biopsy were assessed. Ki-67 immunocytochemical expression was evaluated in a random subset of 60 specimens. RESULTS: Cytologic sampling demonstrated a sensitivity of 78%, a specificity of 96%, a positive predictive value of 78% and a negative predictive value of 96% for the detection of endometrial abnormalities. The unsatisfactory rate of uterine cytology was 15% as compared to 26% for endometrial biopsy. Of adenocarcinoma cases, 83% expressed Ki-67, as compared to 30% in benign cases. CONCLUSION: Endometrial cytology may be useful in the detection of endometrial hyperplasia and neoplasia and provides adequate material for the assessment of Ki-67.
