RESUMO
OBJECTIVES: Designing cancer screening trials for multi-cancer early detection (MCED) tests presents a significant methodology challenge, as natural histories of cell-free DNA-shedding cancers are not yet known. A microsimulation model was developed to project the performance and utility of an MCED test in cancer screening trials. METHODS: Individual natural history of preclinical progression through cancer stages for 23 cancer classes was simulated by a stage-transition model under a broad range of cancer latency parameters. Cancer incidences and stage distributions at clinical presentation in simulated trials were set to match the data from Surveillance, Epidemiology, and End Results program. One or multiple rounds of annual screening using a targeted methylation-based MCED test (Galleriâ) was conducted to detect preclinical cancers. Mortality benefit of early detection was simulated by a stage-shift model. RESULTS: In simulated trials, accounting for healthy volunteer effect and varying test sensitivity, positive predictive value in the prevalence screening round reached 48% to 61% in 6 natural history scenarios. After 3 rounds of annual screening, the cumulative proportions of stage I/II cancers increased by approximately 9% to 14%, the incidence of stage IV cancers was reduced by 37% to 46%, the reduction of stages III and IV cancer incidences was 9% to 24%, and the reduction of mortality reached 13% to 16%. Greater reductions of late-stage cancers and cancer mortality were achieved by five rounds of MCED screening. CONCLUSIONS: Simulation results guide trial design and suggest that adding this MCED test to routine screening in the United States may shift cancer detection to earlier stages, and potentially save lives.
Assuntos
Detecção Precoce de Câncer , Neoplasias , Humanos , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/mortalidade , Simulação por Computador , Feminino , Masculino , Ensaios Clínicos como AssuntoRESUMO
Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from â¼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Terapia Neoadjuvante , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
Hepatic fibrosis stage is the most important determinant of outcomes in patients with nonalcoholic fatty liver disease (NAFLD). There is an urgent need for noninvasive tests that can accurately stage fibrosis and determine efficacy of interventions. Here, we describe a novel cell-free (cf)-mRNA sequencing approach that can accurately and reproducibly profile low levels of circulating mRNAs and evaluate the feasibility of developing a cf-mRNA-based NAFLD fibrosis classifier. Using separate discovery and validation cohorts with biopsy-confirmed NAFLD (n = 176 and 59, respectively) and healthy subjects (n = 23), we performed serum cf-mRNA RNA-Seq profiling. Differential expression analysis identified 2,498 dysregulated genes between patients with NAFLD and healthy subjects and 134 fibrosis-associated genes in patients with NAFLD. Comparison between cf-mRNA and liver tissue transcripts revealed significant overlap of fibrosis-associated genes and pathways indicating that the circulating cf-mRNA transcriptome reflects molecular changes in the livers of patients with NAFLD. In particular, metabolic and immune pathways reflective of known underlying steatosis and inflammation were highly dysregulated in the cf-mRNA profile of patients with advanced fibrosis. Finally, we used an elastic net ordinal logistic model to develop a classifier that predicts clinically significant fibrosis (F2-F4). In an independent cohort, the cf-mRNA classifier was able to identify 50% of patients with at least 90% probability of clinically significant fibrosis. We demonstrate a novel and robust cf-mRNA-based RNA-Seq platform for noninvasive identification of diverse hepatic molecular disruptions and for fibrosis staging with promising potential for clinical trials and clinical practice.NEW & NOTEWORTHY This work is the first study, to our knowledge, to utilize circulating cell-free mRNA sequencing to develop an NAFLD diagnostic classifier.
Assuntos
Ácidos Nucleicos Livres/genética , Perfilação da Expressão Gênica , Hepatopatia Gordurosa não Alcoólica/genética , RNA Mensageiro/genética , RNA-Seq , Transcriptoma , Biópsia , Ácidos Nucleicos Livres/sangue , Estudos de Viabilidade , Humanos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Mensageiro/sangue , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
The aim of this study was to explore factors influencing children's (7-13 years) tonsillectomy experiences and outcomes. A prospective, repeated measures, design was used to investigate the effect of age, gender, ethnicity, time, and previous pain, hospitalization and surgery on children's (N = 60) perceptions of anxiety, pain intensity, quality of pain and sleep, and oral intake. The relationship between postoperative pain and anxiety was also examined. Using a diary, three days of data were collected. Descriptive statistics, Pearson correlation coefficient, and a mixed linear regression model were used for analysis. Children's tonsillectomy experiences and outcomes were affected by time, previous experience, age, and anxiety. Moderate correlations were found between level of anxiety and pain intensity. These findings provide clinicians with additional knowledge to guide their perioperative practice and care of children.
Assuntos
Satisfação do Paciente , Tonsilectomia/psicologia , Adolescente , Ansiedade , Criança , Humanos , Medição da Dor , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Estados UnidosRESUMO
OBJECTIVE: To examine the effects of pre-operative tonsillectomy pain education on children's (7-13 years) self-reported pre-operative anxiety and post-operative clinical outcomes (i.e., anxiety, pain intensity, quality of pain and sleep, oral intake, perceptions of pre-operative education, and pain expectation). METHOD: A prospective, repeated measures, quasi-experimental design using an age appropriate pain education booklet (n = 30) and a standard care comparison group (n = 30) was employed to investigate children's pre- and post-education anxiety and post-operative tonsillectomy with or without adenoidectomy subjective experiences in the hospital and home settings. Group comparisons were performed using the Wilcoxon test, Fisher's exact test, repeated measures analysis of variance, and mixed model regression. RESULTS: There were no significant differences between groups for measures of anxiety, pain intensity, quality of pain and sleep, oral intake, or expected pain. There was no change in anxiety before or after pre-operative education (P = 0.85). Ninety-six percent (n = 25) of the children in the intervention group reported that pre-operative pain education helped with their post-operative pain and 72% (n = 16) in the control group stated that it would be helpful to learn about pain before surgery. The majority of children in both the intervention and control groups (96%, 91%, respectively) stated learning about the 0-10 numeric pain intensity scale helped or would be helpful to learn pre-operatively. CONCLUSION: Pre-operative pain education did not affect anxiety. Children valued pre-operative pain education. Pre-operative pain education may influence children's perceptions of medical care.