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Introduction: Phe508del is the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene variant that results in the recessive genetic disorder cystic fibrosis (CF). The recent development of highly effective CFTR modulator therapies has led to significant health improvements in individuals with this mutation. While numerous animal models of CF exist, few have a CFTR mutation that is amenable to the triple combination therapy elexacaftor-tezacaftor-ivacaftor (ETI). Methods: To determine the responsiveness of Phe508del rats to ETI, a baseline nasal potential difference was measured. Subsequently, they received ETI daily for 14 days, after which post-treatment nasal potential difference, lung mechanics (via flexiVent) and lung ventilation (via X-ray Velocimetry) were assessed. Results: Chloride ion transport in nasal airways was restored in Phe508del rats treated with ETI, but neither lung mechanics nor ventilation were significantly altered. Discussion: These findings validate the usefulness of this rat model for future investigations of modulator therapy in CF.
RESUMO
Introduction: X-ray Velocimetry (XV) ventilation analysis is a 4-dimensional imaging-based method for quantifying regional ventilation, aiding in the assessment of lung function. We examined the performance characteristics of XV ventilation analysis by examining correlation to spirometry and measurement repeatability. Methods: XV analysis was assessed in 27 patients receiving thoracic radiotherapy for non-lung cancer malignancies. Measurements were obtained pre-treatment and at 4 and 12-months post-treatment. XV metrics such as ventilation defect percent (VDP) and regional ventilation heterogeneity (VH) were compared to spirometry at each time point, using correlation analysis. Repeatability was assessed between multiple runs of the analysis algorithm, as well as between multiple breaths in the same patient. Change in VH and VDP in a case series over 12 months was used to determine effect size and estimate sample sizes for future studies. Results: VDP and VH were found to significantly correlate with FEV1 and FEV1/FVC (range: -0.36 to -0.57; p < 0.05). Repeatability tests demonstrated that VDP and VH had less than 2% variability within runs and less than 8% change in metrics between breaths. Three cases were used to illustrate the advantage of XV over spirometry, where XV indicated a change in lung function that was either undetectable or delayed in detection by spirometry. Case A demonstrated an improvement in XV metrics over time despite stable spirometric values. Case B demonstrated a decline in XV metrics as early as 4-months, although spirometric values did not change until 12-months. Case C demonstrated a decline in XV metrics at 12 months post-treatment while spirometric values remained normal throughout the study. Based on the effect sizes in each case, sample sizes ranging from 10 to 38 patients would provide 90% power for future studies aiming to detect similar changes. Conclusions: The performance and safety of XV analysis make it ideal for both clinical and research applications across most lung indications. Our results support continued research and provide a basis for powering future studies using XV as an endpoint to examine lung health and determine therapeutic efficacy.
