FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.

Objective: To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.Methods: STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.Results: STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation via the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.Conclusions: Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells via the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.

Post-COVID-19 interstitial lung disease presenting with profound hypoxemia: Report of three cases demonstrating a good response to high-dose corticosteroid therapy.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to critical pneumonia, although the clinical courses vary. In some cases, COVID-19 pneumonia causes secondary pulmonary fibrosis, which can retain radiological changes and prolong respiratory symptoms. Interstitial lung disease (ILD) secondary to COVID-19 is thought to be caused by multiple pathologies, such as excessive cytokines and abnormal repair processes elaborated by lung cells (epithelium, mesenchyme, and alveolar macrophages) after lung injury rather than viral invasion itself. Immunosuppression therapy may improve chronic respiratory symptoms and radiological changes in post-COVID-19 ILD, although the treatment is not yet established. Herein, we report three patients with post-COVID-19 ILD who presented with profound hypoxemia that had a good response to high-dose corticosteroid therapy. Further and larger studies are needed to establish post-COVID-19 ILD.

Serine Protease Imbalance in the Small Airways and Development of Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), a transcription factor, is required for lung maturation during development, and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that Spink5 (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model. Finally, we showed that daily antiprotease treatment counteracted the phenotypes of C/EBPα-knockout mice. In human studies, CEBPA (CCAAT/enhancer binding protein-α) gene expression in the lung was downregulated in patients with emphysema, and six smokers with centrilobular emphysema (CLE) showed a significant reduction in LEKTI in the small airways compared with 22 smokers without CLE. LEKTI downregulation in the small airways was associated with disease development during murine small airway injury and CLE in humans, suggesting that LEKTI might be a key factor linking small airway injury to the development of emphysema.

Accelerated Loss of Antigravity Muscles Is Associated with Mortality in Patients with COPD.

BACKGROUND: Low antigravity muscle mass is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, the significance of longitudinal changes in antigravity muscle mass remains unclear in patients with COPD. OBJECTIVES: The aims of this study were to investigate the factors associated with the longitudinal loss of antigravity muscles and whether the accelerated loss of these muscles has a negative impact on prognosis. METHODS: This study was part of a prospective observational study at Kyoto University. We enrolled stable male patients with COPD who underwent longitudinal quantitative CT analysis of the cross-sectional area of the erector spinae muscles (ESMCSA) at an interval of 3 years. The associations between the rate of change in ESMCSA (%ΔESM) and clinical parameters, such as anthropometry, symptoms, lung function, exacerbation frequency, and all-cause mortality, were investigated. RESULTS: In total, 102 stable male COPD patients were successfully evaluated in this study (71.3 ± 8.3 years, GOLD stage I/II/III/IV = 20/47/28/7 patients). ESMCSA significantly decreased from 30.53 to 28.98 cm2 (p < 0.0001) in 3 years, and the mean %ΔESM was 5.21 ± 7.24%. The rate of survival during the observation period was 85.3% (87/102). Patients with an accelerated decline in ESMCSA (n = 31; more than double the mean rate of decline) had a significantly higher frequency of moderate-to-severe exacerbations during the interval (p = 0.015). They also had significantly worse survival (p = 0.035 by log-rank test). A multivariate Cox proportional hazard model showed that lower ESMCSA and greater %ΔESM decline were independently and significantly associated with mortality. CONCLUSIONS: Frequent exacerbations were related to the loss of antigravity muscles in COPD patients. The accelerated loss of antigravity muscles was associated with a poor prognosis.

Annual decline in arterial blood oxygen predicts development of chronic respiratory failure in COPD with mild hypoxaemia: A 6-year follow-up study.

BACKGROUND AND OBJECTIVE: Chronic respiratory failure (CRF) with hypoxaemia is an important pathophysiology in patients with chronic obstructive pulmonary disease (COPD), and existing mild hypoxaemia may be a sign of future CRF development. However, little is known about the trajectory of partial arterial pressure of oxygen (PaO2 ) decline in patients with COPD. We assessed decline in PaO2 and the impact of short-term reductions in PaO2 to predict future decline in PaO2 . METHODS: A total of 172 outpatients with COPD from a prospective cohort study were enrolled. Pulmonary function tests and arterial blood gas (ABG) analyses were conducted at baseline and 1 year after enrolment and changes in PaO2 (ΔPaO2 ) and other parameters were calculated. Survival and incidence of CRF (as assessed by prescription of long-term home oxygen therapy) were monitored for 6 years. RESULTS: A total of 164 patients completed the observation period and 101 patients had mild hypoxaemia (PaO2 < 80 Torr) at baseline. No patients with normal PaO2 (≥80 Torr) developed CRF, and 10 patients with mild hypoxaemia developed CRF in 6 years. Baseline airflow limitation and diffusion capacity were significantly associated with development of CRF. Receiver-operating characteristic curve analysis showed that ΔPaO2 of -3.05 Torr/year is a useful cut-off value to predict development of CRF in 6 years (hazard ratio (HR): 12.6, 95% CI: 3.48-58.73, P < 0.0001). CONCLUSION: Patients with COPD and mild hypoxaemia may benefit from repeat ABG after 1 year. Although PaO2 trajectories widely varied, significant annual changes in PaO2 of at least -3.0 Torr/year were predictive of CRF development.

Perspectives on End-of-Life Treatment among Patients with COPD: A Multicenter, Cross-sectional Study in Japan.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Since patients with severe COPD may experience exacerbations and eventually face mortality, advanced care planning (ACP) has been increasingly emphasized in the recent COPD guidelines. We conducted a multicenter, cross-sectional study to survey the current perspectives of Japanese COPD patients toward ACP. "High-risk" COPD patients and their attending physicians were consecutively recruited. The patients' family configurations, understanding of COPD pathophysiology, current end-of-life care communication with physicians and family members, and preferences for invasive life-sustaining treatments including mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) were evaluated using a custom-made, structured, self-administered questionnaire. Attending physicians were also interviewed, and we evaluated the patient-physician agreement. Among the 224 eligible "high-risk" patients, 162 participated. Half of the physicians (54.4%) thought they had communicated detailed information; however, only 19.4% of the COPD patients thought the physicians did so (κ score = 0.16). Less than 10% of patients wanted to receive invasive treatment (MV, 6.3% and CPR, 9.4%); interestingly, more than half marked their decision as "refer to the physician" (MV 42.5% and CPR 44.4%) or "refer to family" (MV, 13.8% and CPR, 14.4%). Patients with less knowledge of COPD were less likely to indicate that they had already made a decision. Although ACP is necessary to cope with severe COPD, Japanese "high-risk" COPD patients were unable to make a decision on their preferences for invasive treatments. Lack of disease knowledge and communication gaps between patients and physicians should be addressed as part of these patients' care.

Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation.

BACKGOUND: Alveolar type 2 (AT2) cells play important roles in maintaining adult lung homeostasis. AT2 cells isolated from the lung have revealed the cell-specific functions of AT2 cells. Comprehensive molecular and transcriptional profiling of purified AT2 cells would be helpful for elucidating the underlying mechanisms of their cell-specific functions. To enable the further purification of AT2 cells, we aimed to discriminate AT2 cells from non-AT2 lung epithelial cells based on surface antigen expression via fluorescence activated cell sorting (FACS). METHODS: Single-cell suspensions obtained from enzymatically digested murine lungs were labeled for surface antigens (CD45/CD31/epithelial cell adhesion molecule (EpCAM)/ major histocompatibility complex class II (MHCII)) and for pro-surfactant protein C (proSP-C), followed by FACS analysis for surface antigen expression on AT2 cells. AT2 cells were sorted, and purity was evaluated by immunofluorescence and FACS. This newly developed strategy for AT2 cell isolation was validated in different strains and ages of mice, as well as in a lung injury model. RESULTS: FACS analysis revealed that EpCAM+ epithelial cells existed in 3 subpopulations based on EpCAM and MHCII expression: EpCAMmedMHCII+ cells (Population1:P1), EpCAMhiMHCII- cells (P2), and EpCAMlowMHCII- cells (P3). proSP-C+ cells were enriched in P1 cells, and the purity values of the sorted AT2 cells in P1 were 99.0% by immunofluorescence analysis and 98.0% by FACS analysis. P2 cells were mainly composed of ciliated cells and P3 cells were composed of AT1 cells, respectively, based on the gene expression analysis and immunofluorescence. EpCAM and MHCII expression levels were not significantly altered in different strains or ages of mice or following lipopolysaccharide (LPS)-induced lung injury. CONCLUSIONS: We successfully classified murine distal lung epithelial cells based on EpCAM and MHCII expression. The discrimination of AT2 cells from non-AT2 epithelial cells resulted in the isolation of pure AT2 cells. Highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis.

Chronic Kidney Disease Predicts Survival in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age as with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We assessed the prevalence of CKD (stages 3-5) and investigated the relationship of CKD to clinical features and outcomes in patients with IPF. METHODS: This study comprised 123 patients with IPF; 61 subjects with chronic obstructive pulmonary disease (COPD), which was reportedly associated with CKD, were also enrolled as a disease control. CKD (stages 3-5) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Thirty-seven patients (30%) with IPF and 14 controls (23%) with COPD were diagnosed with CKD, and these frequencies were not significantly different. The patients with IPF and CKD were older (p < 0.01) and had a higher frequency of hypertension (p = 0.048) and ischemic heart disease (p = 0.02) than those with IPF but without CKD. Furthermore, the diffusing capacity of the lung for carbon monoxide (DLCO) and the 6-min walking distance in the patients with CKD were significantly lower (40.0 ± 13.2 vs. 45.9 ± 14.4%, p = 0.04, and 416 ± 129 vs. 474 ± 84 m, p = 0.01, respectively) than in the patients without CKD. The outcome of the patients with CKD showed significantly worse survival compared with the patients without CKD (p = 0.04). Moreover, eGFR remained an independent predictor of survival after adjusting for age and pulmonary function data. CONCLUSION: A substantial percentage of IPF patients have CKD. CKD with a low eGFR was associated with decreased survival in IPF.

Emphysema and airway disease affect within-breath changes in respiratory resistance in COPD patients.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by a mixture of emphysema and airway disease. The forced oscillation technique (FOT) has been applied to COPD patients to clarify changes in respiratory mechanics; dynamic changes in respiratory resistance (Rrs) during breathing (within-breath changes in Rrs, ΔRrs) are characteristic of COPD. However, the pathophysiological significance of these changes is unknown. The aim of this study was to assess how emphysema and airway disease influence ΔRrs in COPD patients. METHODS: In this cross-sectional study, stable COPD patients were recruited and underwent respiratory impedance measurements with a commercially available FOT device. Rrs was recorded during tidal breathing and then analyzed as whole-breath Rrs (Rrs at 5 Hz, R5; Rrs at 20 Hz, R20; and their difference, R5-R20) or as ΔRrs, the difference between the expiratory and inspiratory Rrs (ΔR5, ΔR20 and ΔR5-R20). The percentage of the low attenuation area (LAA%) and airway wall area (WA%) was quantified by computed tomography analysis, and their contributions to ΔRrs were examined. RESULTS: Seventy-five COPD patients were recruited. LAA% was negatively correlated with ΔR5 and ΔR5-R20 (P = 0.0002 and P = 0.0033, respectively); meanwhile, WA% in B(10) was positively correlated with ΔR5 and ΔR5-R20 (P = 0.0057 and P < 0.0001, respectively). Multivariate analysis revealed that the contribution of both LAA% and WA% in B(10) to ΔRrs was independent of the severity of airflow limitations. CONCLUSION: This study shows that emphysema suppresses ΔRrs in COPD patients, while airway disease increases ΔRrs in these patients.

A case report of Birt-Hogg-Dubé syndrome associated with severe airway obstruction in a 62-year-old female smoker.

Birt-Hogg-Dubé syndrome (BHD) typically does not manifest airway obstruction despite the presence of multiple lung cysts. However, the long-term effects of cigarette smoking on lung function among individuals with BHD are unknown. We report a case of a smoking individual diagnosed with BHD syndrome complicated by spontaneous pneumothorax and severe airway obstruction. The patient presented with chronic dyspnea and productive cough. Further work-up revealed severe obstructive airflow limitation, and multiple lung cysts in both lungs, accompanied centrilobular emphysematous changes. Genetic testing confirmed a heterozygous deletion of exons 6-8 in the folliculin gene, confirming the diagnosis of BHD.

Efficacy of the combination of baricitinib, remdesivir, and dexamethasone in hypoxic adults with COVID-19: A retrospective study.

BACKGROUND: Remdesivir with dexamethasone and remdesivir with baricitinib are effective in coronavirus disease 2019 (COVID-19) patients. However, there has been few evidence regarding the efficacy of the combination of baricitinib, remdesivir, and dexamethasone in hypoxic COVID-19 patients. METHODS: Consecutive patients who required oxygen therapy at the time of admission and received remdesivir and dexamethasone at Kishiwada City Hospital between March 1, 2021 and May 31, 2021 were retrospectively analyzed. RESULTS: A total of 90 patients were investigated, including 30 receiving a combination of remdesivir, dexamethasone, and baricitinib (baricitinib group) and 60 receiving remdesivir and dexamethasone (control group). The use of direct oral anticoagulants, the level of C-reactive protein, and chest X-ray abnormalities were significantly higher in the baricitinib group than in the control group. Patients in the baricitinib group recovered a median of four days faster than those in the control group (median, 7 days vs. 11 days; Gray's test, p < 0.001). The recovery rate was 90.0% in the baricitinib group and 63.3% in the control group (p = 0.011). Fine and Gray regression analysis showed that adjusted rate ratio for recovery with the baricitinib combination therapy was 5.26 (95% confidential interval, 1.99-13.9; p < 0.001). The incidence of new onset of bacterial infection was 6.7% in the baricitinib group and 16.7% in the control group (p = 0.324). CONCLUSIONS: Our study suggests that the combination of baricitinib, dexamethasone, and remdesivir is effective and tolerable in hypoxic patients with COVID-19.

Aluminium Gauze Reduces SARS-CoV-2 Viral Load in Non-Woven Masks Worn by Patients with COVID-19.

BACKGROUND: Aluminium reduces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) survival in experimental settings. It is unknown whether adding an aluminium gauze to a mask reduces the SARS-CoV-2 RNA load in the mask and whether SARS-CoV-2 is detectable in the breath that permeates through such a mask in clinical settings. METHODS: Patients admitted to Kishiwada City Hospital, Osaka, Japan, between July 2021 and September 2021 were enrolled in the study. Non-woven masks comprising filters with 99% viral filtration efficacy and aluminium and cotton gauzes attached to plastic collection cases were developed. All participants wore the experimental mask models for three hours. RESULTS: Twenty-nine patients who wore the final model masks were analysed in this study. The Ct values of the nucleocapsid gene and envelope gene of SARS-CoV-2 were significantly higher in the aluminium gauze than in the cotton gauze. SARS-CoV-2 RNA was detected in the masks of 8 out of 12 vaccinated patients (66.7%). Although breath condensates were collected behind both aluminium and cotton gauzes, SARS-CoV-2 RNA was not detected in these condensates. CONCLUSIONS: Our study indicated that non-woven masks with an aluminium gauze may obstruct SARS-CoV-2 transmission in clinical settings better than non-woven masks with cotton gauzes.

The safety and efficacy of durvalumab consolidation therapy in the management of patients with stage III non-small-cell lung cancer and preexisting interstitial lung disease.

BACKGROUND: Some lung cancer patients have preexisting interstitial lung disease (ILD), which is considered a risk factor for lung cancer treatment. This study investigated the safety and efficacy of durvalumab consolidation therapy for patients with stage III non-small-cell lung cancer (NSCLC) and preexisting ILD. METHODS: Fifty consecutive patients who were judged to be tolerable to concurrent chemoradiotherapy (CCRT) for stage III NSCLC were enrolled. Differences in the incidence rate of radiation pneumonitis (RP) and progression-free survival (PFS) were assessed in patients with or without ILD of which CT showed non-usual interstitial pneumonia pattern between the durvalumab consolidation group and chemotherapy (combination of carboplatin and paclitaxel [CP]) consolidation group. RESULTS: The incidence of RP was higher in patients with preexisting ILD (40% and 20% in the durvalumab and CP groups, respectively) than in those without ILD (26% and 8% in the durvalumab and CP groups, respectively). Univariate analysis showed that durvalumab therapy tended to increase the incidence of RP; however, preexisting ILD did not significantly increase the incidence of RP. The condition of all patients who developed RP improved with the administration of oral prednisolone. Among patients without ILD, the median PFS was 17 and 16 months in the durvalumab and CP groups, respectively. Among patients with preexisting ILD, median PFS was not achieved in the durvalumab group and was 8 months in the CP group. CONCLUSIONS: Although durvalumab consolidation therapy tended to increase the incidence of RP, it might be tolerable in stage III NSCLC patients with preexisting ILD.

Successful treatment with metronidazole and paromomycin for fulminant amoebic colitis during cytotoxic chemotherapy in a patient with small-cell lung cancer.

We report the case of a 64-year-old man with advanced small-cell lung cancer who developed fulminant amoebic colitis during cytotoxic chemotherapy. During the first cycle of carboplatin/etoposide treatment, febrile neutropenia and grade 4 neutropenia developed. Because diarrhea, abdominal pain, and bloody stool were observed, abdominal computed tomography was performed, showing intussusception, and extensive colectomy and colostomy were performed. Histopathology of the colon revealed gastrointestinal necrosis and perforation due to Entamoeba histolytica infection. Amoebiasis improved after treatment with metronidazole and paromomycin. The second cycle of carboplatin/etoposide with dose reduction was completed, resulting in a partial response to small-cell lung cancer. The results of this case suggest that paromomycin is an additional option for amoebiasis during cytotoxic chemotherapy, and persistent diarrhea during cytotoxic chemotherapy should alert clinicians to consider the development of amoebiasis.

Low serum free light chain is associated with risk of COPD exacerbation.

BACKGROUND: Most exacerbations of chronic obstructive pulmonary disease (COPD) are triggered by respiratory tract infections. Adaptive immunity via antibody production is important in preventing infections. Impaired antibody production is reported to be associated with an increased risk of exacerbations of COPD. In the present study, we elucidated whether reduced free light chains (FLCs), which are excessive amounts of light chains produced during antibody synthesis and can be used to estimate systemic antibody production, may be a promising biomarker to predict the risk of exacerbations of COPD. METHODS: We enrolled stable male patients with COPD and prospectively observed them for 2 years. At baseline, serum combined FLC (cFLC; sum of kappa and lambda values) and pulmonary function were evaluated. Exacerbation was defined as a worsening of symptoms requiring treatments with antibiotics, corticosteroids or both. RESULTS: 63 patients with stable COPD were enrolled (72.8±8.1 years, GOLD A/B/C/D=24/28/6/5), and 51 patients completed the 2-year follow-up. Serum cFLC was 31.1 mg·L-1 on average and ranged widely (1.4 to 89.9 mg·L-1). The patients with low cFLC (below the mean-sd, n=6) experienced a significantly shorter time to the first exacerbation of COPD (p<0.0001 by the log-rank test). A multivariate Cox proportional hazard model, including the COPD assessment test score, % predicted forced expiratory volume in 1 s (FEV1 % pred), and number of previous exacerbations demonstrated that low cFLC and low FEV1 % pred were independently and significantly correlated with the risk for exacerbations of COPD. CONCLUSION: Low cFLC may be a B-cell-associated novel biomarker associated with risk of COPD exacerbation.

Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model.

The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of alectinib resistance. Combinatorial therapy against Src and MET significantly restored alectinib sensitivity in vitro (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size in vivo. To confirm the generality, a conventional alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in alectinib-resistant patients. IMPLICATIONS: This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.

Gastroesophageal reflux symptoms and nasal symptoms affect the severity of bronchitis symptoms in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cough and sputum production (symptoms of bronchitis) are common in chronic obstructive pulmonary disease (COPD). Extrapulmonary comorbidities, such as gastroesophageal reflux disease (GERD) and post-nasal drip, also cause bronchitis symptoms. The impact of extrapulmonary comorbidities on the severity of bronchitis symptoms in COPD is unknown. The aim of this study was to quantify bronchitis symptoms and assess the impact of GERD and nasal symptoms on the severity of bronchitis symptoms in COPD. METHODS: In this cross-sectional study, stable COPD patients were recruited and completed the COPD assessment test (CAT) and Cough and Sputum Assessment Questionnaire (CASA-Q) to quantify bronchitis symptoms. To evaluate extrapulmonary comorbidities, the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and nasal symptom questionnaire were completed. The impact of these comorbidities on the severity of bronchitis symptoms was analyzed. RESULTS: Ninety-nine COPD patients were recruited. The presence of GERD symptoms (24.2% in the study population) was associated with more sputum symptoms. The presence of nasal discharge (43.4%) was associated with more cough and sputum symptoms, whereas post-nasal drip (13.1%) was associated with more sputum symptoms. On multivariate analyses, nasal discharge was associated with more cough symptoms. GERD and post-nasal drip were associated with more sputum symptoms. CONCLUSION: This study showed that the presence of GERD and/or nasal symptoms is associated with an increase in bronchitis symptoms. Careful assessment of extrapulmonary comorbidities is necessary in the evaluation of bronchitis symptoms in COPD patients.

Complementary regional heterogeneity information from COPD patients obtained using oxygen-enhanced MRI and chest CT.

BACKGROUND: The heterogeneous distribution of emphysema is a key feature of chronic obstructive pulmonary disease (COPD) patients that typically is evaluated using high-resolution chest computed tomography (HRCT). Oxygen-enhanced pulmonary magnetic resonance imaging (OEMRI) is a new method to obtain information regarding regional ventilation, diffusion, and perfusion in the lung without radiation exposure. We aimed to compare OEMRI with HRCT for the assessment of heterogeneity in COPD patients. METHODS: Forty patients with stable COPD underwent quantitative HRCT, OEMRI, and pulmonary function tests, including arterial blood gas analysis. OEMRI was also performed on nine healthy control subjects. We measured the severity of emphysema (percent low attenuation volume; LAV%) in whole lungs and the standard deviations (SDs) of the LAV% values of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal heterogeneity. Similarly, relative enhancement ratios of oxygen (RERs) in whole lungs from OEMRI and SD-RER were analyzed. RESULTS: COPD patients showed a lower mean RER than control subjects (12.6% vs 22.0%, p<0.01). The regional heterogeneity of the RERs was not always consistent with the LAV distribution. Both the HRCT (LAV% and SD-LAV) and the OEMRI (RER and SD-RER) indices were significantly associated with the diffusion capacity (DLCO) and partial pressure of oxygen in arterial blood (PaO2). The PaO2 was associated only with the heterogeneity index of HRCT (SD-LAV) (R2 = 0.39); however, the PaO2 was associated with both the mean RER and heterogeneity (SD-RER) in the multivariate analysis (R2 = 0.38). CONCLUSIONS: OEMRI-derived parameters were directly associated with oxygen uptake in COPD patients. Although the OEMRI-derived parameters were not identical to the HRCT-derived parameters, the cranial-caudal heterogeneity in HRCT or OEMRI was complementary to that in evaluations of oxygen uptake in the lungs. Functional imaging seems to provide new insights into COPD pathophysiology without radiation exposure.

Quantitative Assessment of Erector Spinae Muscles in Patients with Chronic Obstructive Pulmonary Disease. Novel Chest Computed Tomography-derived Index for Prognosis.

RATIONALE: Loss of skeletal muscle mass and physical inactivity are important manifestations of chronic obstructive pulmonary disease (COPD), and both are closely related to poor prognoses in patients with COPD. Antigravity muscles are involved in maintaining normal posture and are prone to atrophy with inactivity. The erector spinae muscles (ESM) are one of the antigravity muscle groups, and they can be assessed by chest computed tomography (CT). OBJECTIVES: We hypothesized that the cross-sectional area of ESM (ESMCSA) visualized on chest CT images may serve as a predictor of mortality in patients with COPD. METHODS: This study was part of the prospective observational study undertaken at Kyoto University Hospital. ESMCSA was measured on a single-slice axial CT image at the level of the 12th thoracic vertebra in patients with COPD. The cross-sectional area of the pectoralis muscles (PMCSA) was also measured. We evaluated the relationship between ESMCSA and clinical parameters, including mortality, in patients with COPD. Age- and height-matched smoking control subjects were also evaluated. MEASUREMENTS AND MAIN RESULTS: In total, 130 male patients and 20 smoking control males were enrolled in this study. ESMCSA was significantly lower in patients with COPD than in the smoking control subjects and was significantly correlated with disease severity. There was a significant but only moderate correlation between ESMCSA and PMCSA. ESMCSA was significantly correlated with previously reported prognostic factors, such as body mass index, dyspnea (modified Medical Research Council dyspnea scale score), FEV1 percent predicted value, inspiratory capacity to total lung capacity ratio, and emphysema severity (percentage of the lung field occupied by low attenuation area). Compared with PMCSA, ESMCSA was more strongly associated with mortality in patients with COPD. Stepwise multivariate Cox proportional hazards analysis revealed that, among these known prognostic factors, ESMCSA was the strongest risk factor for mortality (hazard ratio, 0.85; 95% confidence interval, 0.79-0.92; P < 0.001) and mMRC dyspnea scale score was an additional factor (hazard ratio, 2.35; 95% confidence interval, 1.51-3.65; P < 0.001). CONCLUSIONS: ESMCSA assessed by chest CT may be a valuable clinical parameter, as ESACSA correlates significantly with physiological parameters, symptoms, and disease prognosis.