Cystic Lung Research Articles

Tumor cavitation in patients with non-small-cell lung cancer receiving anti-angiogenic therapy with apatinib.

Cavities have been reported in approximately 20% of lung cancer after anti-angiogenesis treatments. However, the effect of which on treatment outcomes remains unclear. This study sought to investigate the incidence and radiographic patterns of tumor cavitation in patients with non-small cell lung cancer (NSCLC) treated with apatinib, and its associations with patients' clinical characteristics and outcomes. A total of 300 patients with NSCLC treated with apatinib were retrospectively identified. Baseline and follow-up chest computed tomography scans were reviewed to identify tumor cavitation, and the subsequent filling-in of the cavitation. A multivariate logistic regression analysis was conducted to identify the factors associated with tumor cavitation. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Of the 300 patients, 51 (17.0%) developed lung cavitation after initiating apatinib therapy. The results of the multivariate analysis showed that apatinib combination therapy (vs. apatinib monotherapy, odds ratio: 0.593, 95% confidence interval: 0.412-0.854, P=0.005) was significantly associated with tumor cavitation. Patients with tumor cavitation had significantly longer progression-free survival (PFS) than those without cavitation (8.2 vs. 5.2 months, P<0.01). Of the patients, 18 had cavity filling after progression, while 13 had persistent cavities after progression. The corresponding median PFS times were 11.9 and 3.2 months in patients with filled and persistent cavities after disease progression, respectively (P<0.001). Tumor cavitation occurred in 17% of the NSCLC patients treated with apatinib and was associated with better PFS. Patients who had cavities filled after progression had a better prognosis than those with persistent cavities.

Clinical Trial Validation of Automated Segmentation and Scoring of Pulmonary Cysts in Thoracic CT Scans.

In cystic lung diseases such as lymphangioleiomyomatosis (LAM), a CT-based cyst score that measures the percentage of the lung volume occupied by cysts is a common index of the cyst burden in the lungs. Although the current semi-automatic measurement of the cyst score is well established, it is susceptible to human operator variabilities. We recently developed a fully automatic method incorporating adaptive features in place of manual adjustments. In this clinical study, the automatic method is validated against the standard method in several aspects. These include the agreement between the cyst scores of the two methods, the agreement of each method with independent tests of pulmonary function, and the temporal consistency of the measurements in the consecutive visits of the same patients. We found that the automatic method agreed with the standard method as well as the agreement between two trained operators running the same standard method; both methods obtained the same level of correlation with laboratory pulmonary function tests; the automated method had better temporal consistency than the standard method (p < 0.0001). The study indicates that the automatic method could replace the standard method and provide better consistency in assessing the extent of cystic changes in the lungs of patients.

Integrative metagenomic, transcriptomic, and proteomic analysis reveal the microbiota-host interplay in early-stage lung adenocarcinoma among non-smokers

BackgroundThe incidence of early-stage lung adenocarcinoma (ES-LUAD) is steadily increasing among non-smokers. Previous research has identified dysbiosis in the gut microbiota of patients with lung cancer. However, the local microbial profile of non-smokers with ES-LUAD remains largely unknown. In this study, we systematically characterized the local microbial community and its associated features to enable early intervention.MethodsA prospective collection of ES-LUAD samples (46 cases) and their corresponding normal tissues adjacent to the tumor (41 cases), along with normal lung tissue samples adjacent to pulmonary bullae in patients with spontaneous pneumothorax (42 cases), were subjected to ultra-deep metagenomic sequencing, host transcriptomic sequencing, and proteomic sequencing. The obtained omics data were subjected to both individual and integrated analysis using Spearman correlation coefficients.ResultsWe concurrently detected the presence of bacteria, fungi, and viruses in the lung tissues. The microbial profile of ES-LUAD exhibited similarities to NAT but demonstrated significant differences from the healthy controls (HCs), characterized by an overall reduction in species diversity. Patients with ES-LUAD exhibited local microbial dysbiosis, suggesting the potential pathogenicity of certain microbial species. Through multi-omics correlations, intricate local crosstalk between the host and local microbial communities was observed. Additionally, we identified a significant positive correlation (rho > 0.6) between Methyloversatilis discipulorum and GOLM1 at both the transcriptional and protein levels using multi-omics data. This correlated axis may be associated with prognosis. Finally, a diagnostic model composed of six bacterial markers successfully achieved precise differentiation between patients with ES-LUAD and HCs.ConclusionsOur study depicts the microbial spectrum in patients with ES-LUAD and provides evidence of alterations in lung microbiota and their interplay with the host, enhancing comprehension of the pathogenic mechanisms that underlie ES-LUAD. The specific model incorporating lung microbiota can serve as a potential diagnostic tool for distinguishing between ES-LUAD and HCs.

CT features associated with contralateral recurrence of spontaneous pneumothorax.

Spontaneous pneumothorax recurs in 30 to 54% of patients without surgery. Identifying individuals likely to suffer a recurrence, who might benefit from pre-emptive surgery, is challenging. Previous meta-analysis suggested a relationship between contralateral recurrence and specific computed tomography (CT) findings. We analysed CT images and recurrence rates 243 patients seen by our tertiary referral pneumothorax service. We validated the meta-analysis observation that contralateral lung cysts are associated with a higher risk of contralateral recurrence in younger individuals. Furthermore, we observed the size of contralateral cysts to be associated with increased contralateral recurrence in younger patients. The detection of contralateral lung cysts might therefore help identify younger patients more likely to benefit from pre-emptive surgery.

Interpretation of inflammatory markers in lung cyst hydatid disease.

Studies on alterations in inflammatory markers and risk factors for perforation in hydatid cysts of the lung are rare. In our study, we planned to investigate the effect of inflammatory markers on prognosis of hydatid cyst disease. 37 patients underwent surgery for pulmonary hydatid cyst between February 2022 and October 2023 and analyzed retrospectively. Inflammatory markers were calculated from preoperative and postoperative 3rd-month peripheral blood results. Cyst size was 58.5 ± 28.0mm, 5 patients had bilateral cysts and 11 patients had multifocal cysts. Preoperative white blood cell, white blood cell difference, preoperative and postoperative eosinophils, preoperative neutrophils, neutrophils difference, preoperative systemic immune inflammatory index, systemic immune inflammatory index difference and preoperative eosinophil lymphocyte ratio were higher in patients with perforated cysts, the cut-off value for preoperative white blood cell for perforation was 10,535, preoperative cut-off value for eosinophils was 230, preoperative cut-off value for neutrophils was 8815, the cut-off value for preoperative systemic immune inflammatory index was 1129.83 and the cut-off value for preoperative eosinophil-lymphocyte ratio was 0.09. In patients with preoperative eosinophil, neutrophil, white blood cell, eosinophil-lymphocyte ratio and systemic immune inflammatory index values above the cut-off value, the probability of perforation increased 7.5, 13.6, 6.3, 9.6, and 9.3 times, respectively.

Interstitial lung diseases : From imaging to treatment

The role of radiology in the diagnosis of interstitial lung diseases (ILDs) has evolved over time, in part replacing histology. Radiology now represents a pillar of diagnostics and monitoring in ILDs. To what extent does radiology influence diagnostics and treatment in ILDs? Aliterature review was conducted, and current findings were discussed in the context of clinical data. Radiology plays acrucial role in the diagnosis of ILDs. Within the framework of the multidisciplinary conference, it provides specific CT patterns such as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP), or helps in identifying cystic lung diseases. Multicompartment diseases can be detected, and pulmonary hypertension or extrapulmonary involvement of the respective diseases can be suspected. Progressive pulmonary fibrosis requires radiologic assessment as one of the required criteria. Interstitial lung abnormalities are usually detected by radiological studies performed for an unrelated indication. Radiology plays an important role within the multidisciplinary conference to determine both diagnosis and treatment with antifibrotic or anti-inflammatory drugs, or a combination of both.

Granulomatosis with polyangiitis masquerading as disseminated tuberculosis in presence of bilateral lung cavities and hemorrhagic infarct

Lung cavitations with constitutional symptoms are usually associated with pulmonary tuberculosis due to its high prevalence and are the most common infectious cause in India. Granulomatosis with polyangiitis (GPA) with the systemic pulmonary disease will have different radiological presentations such as nodule, mass, and consolidation with or without cavitation. In this case report, we have reported a 40-year-old female presented with cough, fever, and weight loss of 6 months duration with chest imaging suggestive of bilateral cavitary lung disease. She was labeled as a case of disseminated tuberculosis due to involvement of the central nervous system and empirically treated with anti-tuberculosis treatment (ATT) without microbiological evidence of tuberculosis in smear and cartridge-based nucleic acid amplification tests. The absence of clinical response and radiological worsening to empirical ATT gives a clue for an alternate diagnosis. Bronchoscopy workup documented Aspergillus colonization and vasculitis workup in the presence of cavitary lung disease documented abnormally raised proteinase 3 anti-neutrophil cytoplasmic antibodies titers. She was treated with a combination of systemic methylprednisolone and azathioprine with voriconazole. Her clinical response was observed in 4 weeks and radiological response with complete radiological clearance of pulmonary cavitations was documented after 6 months of treatment. We recommend prompt workup and ruling out GPA in all cases with pulmonary cavitations with negative microbiological workup and no empirical ATT should be given in the era of rapid microbiological tests with good sensitivity and specificity.

Comparative sensitivity of early cystic fibrosis lung disease detection tools in school aged children

BackgroundEffective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children. Methods50 CF subjects (mean±SD 11.2 ± 3.5y, range 5–18y) with early lung disease (FEV1≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT). ResultsCT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82 %, MBWTG RV 78 %, LCI 74 %, MBWTG IC 68 % and Sacin 51 %. CPET VO2peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r = 0.55–0.64, p < 0.001) and AT (r = 0.73–0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %. ConclusionsSignificant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting.

Hydropneumothorax as a rare manifestation of primary pulmonary hydatid disease

Echinococcosis, alternatively referred to as hydatid disease, is caused by the larvae of the tapeworm Echinococcus. The primary agents of human infections are Echinococcus granulosus and Echinococcus multilocularis. The present case report pertains to an individual who relocated from an endemic region to the United Arab Emirates and subsequently manifested symptoms of hydropneumothorax. The 44-year-old male patient presented with a 4-day fever and right-sided chest pain, accompanied by cough and breathlessness for 2 weeks. Computed tomography (CT) of the chest revealed right hydropneumothorax and a ruptured hydatid cyst with consolidation. The patient was diagnosed with a ruptured pulmonary hydatid cyst based on a strongly positive hydatid serology and the presence of hydatid tissue on histopathological examination. The patient underwent surgical decortication with cyst removal and received medical treatment with ceftriaxone and albendazole. He was discharged in good condition after a 10-day hospitalisation period. Echinococcosis is a parasitic disease that most often affects the liver and lungs. Although more than half of the patients do not show any symptoms, the main symptoms observed during presentation include dry cough, haemoptysis, and chest pain. Plain radiographs or chest CT scans are used for diagnosis. Surgery is considered the primary treatment for pulmonary hydatid cysts and medical treatment with benzimidazoles (albendazole and mebendazole) is recommended. Complicated pulmonary hydatid disease can manifest in various ways, including hydropneumothorax, as observed in the present case. Early diagnosis, surgical intervention combined with medical treatment, and multidisciplinary teamwork can significantly improve patient outcomes.

Diaphragmatic Herniation with Pneumothorax Due to Barotrauma – Lessons to Learn: A Case Report

Diaphragmatic hernia is usually congenital or follows thoracoabdominal injury. Diaphragmatic hernia combined with pneumothorax is a rare combination in the clinical setting, where pneumothorax is usually secondary to hollow viscera perforation in the long-term complications of diaphragmatic herniation or rupture of ectopic endometrium over the diaphragm during menstruation. Unlike the aforementioned conditions, we describe a 67-year-old man with chronic diaphragmatic hernia who suffered from pneumothorax and pneumoperitoneum secondary to pulmonary bulla by barotrauma during mechanical ventilation. Computed tomography showed scattered free gas in the thoracic and abdominal cavities, while there was no tenderness and rebound tenderness. The patient was managed conservatively with low PEEP and a lung-protective mechanical ventilation strategy. Finally, the oxygenation index gradually rose from 58 to 107. Unfortunately, in light of the patient’s poor clinical status and significant comorbidities, the patient passed away peacefully 3 weeks after hospital admission. Diaphragmatic hernia combined with pneumothorax should be differentiated from tension pneumothorax. Whether to intubate chest drainage depends on the cause of pneumothorax and pneumoperitoneum, as well as the risks and benefits of chest drainage. Additionally, mechanical ventilation should be applied cautiously, and respiratory parameters should be adjusted reasonably in patients at high risk of pneumothorax.

Examples of surgical treatment of pulmonary echinococosis in adults and children

ABSTRACT. The article presents a modern view of the diagnosis and treatment of pulmonary echinococcosis. The etiology, pathogenesis, clinical picture, ways of diagnosis and available methods of treatment of this pathology are highlighted. The purpose of the work was to acquaint doctors of various specialties with clinical cases of pulmonary echinococcosis. Two clinical cases of pulmonary echinococcosis became the object of the work. The first clinical example concerned a 17-year-old boy who had a typical course of echinococcosis and who underwent left lower lobectomy. The second clinical example concerned a young woman in whom pulmonary echinococcosis had an atypical course and was diagnosed only intraoperatively. It was concluded that the most effective method of treatment of echinococcal lung cysts is surgical operation. The volume of surgical intervention depends on many factors and is decided individually in each specific case. In the postoperative period, preventive anthelmintic therapy is mandatory.

Computer-aided diagnosis of cystic lung diseases using CT scans and deep learning.

Auxiliary diagnosis of different types of cystic lung diseases (CLDs) is important in the clinic and is instrumental in facilitating early and specific treatments. Current clinical methods heavily depend on accumulated experience, restricting their applicability in regions with less developed medical resources. Thus, how to realize the computer-aided diagnosis of CLDs is of great clinical value. This work proposed a deep learning-based method for automatically segmenting the lung parenchyma in computed tomography (CT) slice images and accurately diagnosing the CLDs using CT scans. A two-stage deep learning method was proposed for the automatic classification of normal cases and five different CLDs using CT scans. Lung parenchyma segmentation is the foundation of CT image analysis and auxiliary diagnosis. To meet the requirements of different sizes of the lung parenchyma, an adaptive region-growing and improved U-Net model was employed for mask acquisition and automatic segmentation. The former was achieved by a self-designed adaptive seed point selection method based on similarity measurement, and the latter introduced multiscale input and multichannel output into the original U-Net model and effectively achieved the lightweight design by adjusting the structure and parameters. After that, the middle 30 consecutive CT slice images of each sample were segmented to obtain lung parenchyma, which was employed for training and testing the proposed multichannel parallel input recursive MLP-Mixer network (MPIRMNet) model, achieving the computer-aided diagnosis of CLDs. A total of 4718 and 16290 CT slice images collected from 543 patients were employed to validate the proposed segmentation and classification methods, respectively. Experimental results showed that the improved U-Net model can accurately segment the lung parenchyma in CT slice images, with the Dice, precision, volumetric overlap error, and relative volume difference of 0.96±0.01, 0.93±0.04, 0.05±0.02, and 0.05±0.03, respectively. Meanwhile, the proposed MPIRMNet model achieved appreciable classification effect for normal cases and different CLDs, with the accuracy, sensitivity, specificity, and F1 score of 0.8823±0.0324, 0.8897±0.0325, 0.9746±0.0078, and 0.8831±0.0334, respectively. Compared with classical machine learning and convolutional neural networks-based methods for this task, the proposed classification method had a preferable performance, with a significant improvement of accuracy of 10.74%. The work introduced a two-stage deep learning method, which can achieve the segmentation of lung parenchyma and the classification of CLDs. Compared to previous diagnostic tasks targeting single CLD, this work can achieve various CLDs' diagnosis in the early stage, thereby achieving targeted treatment and increasing the potential and value of clinical applications.

Large Pulmonary Bullae, Resulting from Tuberculosis, in the Context of Extensive Pneumothorax Caused by a Penetrating Chest Wound

Pulmonary bullae typically occur either idiopathically or in the context of chronic obstructive pulmonary disease and pulmonary infections. Clinical manifestations of pulmonary bullae include cough, shortness of breath, and chest pain. In some cases, they may be asymptomatic. Differentiating between pneumothorax and pulmonary bullae can be challenging when they coexist. Therefore, obtaining a detailed patient history, conducting a physical examination, performing laboratory tests, and utilizing radiology studies are essential diagnostic tools that should be employed simultaneously. In this case report, we present a patient who developed a wide pneumothorax due to a penetrating chest wound caused by a knife. Initially, the large lung cavity, which had already formed due to tuberculosis, was misdiagnosed as a loculated pneumothorax.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry

BackgroundPleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic...

Complicated Liver Cystic Echinococcosis-A Comprehensive Literature Review and a Tale of Two Extreme Cases.

Cystic echinococcosis is a zoonotic parasitic disease that affects the liver in more than 70% of cases, and there is still an underestimated incidence in endemic areas. With a peculiar clinical presentation that ranges from paucisymptomatic illness to severe and possibly fatal complications, quality imaging and serological studies are required for diagnosis. The mainstay of treatment to date is surgery combined with antiparasitic agents. The surgical armamentarium consists of open and laparoscopic procedures for selected cases with growing confidence in parenchyma-sparing interventions. Endoscopic retrograde cholangiopancreatography (ERCP) is extremely useful for the diagnosis and treatment of biliary fistulas. Recent relevant studies in the literature are reviewed, and two complex cases are presented. The first patient underwent open surgery to treat 11 liver cysts, and during the follow-up, a right pulmonary cyst was diagnosed that was treated by minimally invasive surgery. The second case is represented by the peritoneal rupture of a giant liver cyst in a young woman who underwent laparoscopic surgery. Both patients developed biliary fistulas that were managed by ERCP. Both patients exhibited a non-specific clinical presentation and underwent several surgical procedures combined with antiparasitic agents, highlighting the necessity of customized treatment in order to decrease complications and successfully cure the disease.

Ruptured pulmonary Echinococcus granulosus cyst: A rare cause of severe pneumogenic sepsis

Parasitic infections by Echinococcus granulosus are rare in Germany, and predominantly affect individuals with a migration background. Liver and lungs are the most commonly affected organs. Pulmonary cysts often remain asymptomatic until rupture, at which point symptoms may manifest. The diagnostic approach typically involves a combination of imaging modalities and serological tests, occasionally supplemented by molecular genetic methods. Given the global movements of migration, considerations of the epidemiology of common diseases in the country of origin should also be taken into account in the differential diagnosis. We present the unusual case of a pneumogenic sepsis in a young man from Syria, where the combination of medical history alongside radiological, serological, and molecular genetic investigations ultimately led to the diagnosis of a severe pulmonary echinococcosis with rupture.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts.

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

A Novel Mutation as a Rare Cause of Pneumothorax in a Soldier.

Birt-Hogg-Dube (BHD) is a rare cause of spontaneous pneumothorax caused by an autosomal-dominant mutation in the folliculin gene (FLCN). The syndrome can have widely variable presentations and is associated with recurrent pneumothorax, cystic lung disease, characteristic skin lesions, and renal tumors. Lung cysts have been described in over 80% of cases, and roughly 24 to 38% of patients have at least one pneumothorax and over 75% have multiple pneumothoraces. One of the defining features of this condition is fibrofolliculomas, which are benign tumors of the hair follicle. Given its rarity, the diagnosis is often missed and/or delayed for many years. This delay has clinical implications as screening for renal cancer is recommended in both the patient and affected family members. Increased recognition of this syndrome can lead to more patients receiving definitive treatment for their first pneumothorax, and being screened for renal cancers. We present a rare case of Birt-Hogg-Dubé with a never before described mutation in the FLCN gene, leading to spontaneous pneumothorax in an active duty male soldier.

WS06.01 CFTR transgene expression in airway epithelial cells following aerosolized administration of the AAV-based gene therapy 4D-710 to adults with cystic fibrosis lung disease

WS06.01 CFTR transgene expression in airway epithelial cells following aerosolized administration of the AAV-based gene therapy 4D-710 to adults with cystic fibrosis lung disease