Abnormal saturated fatty acids and sphingolipids metabolism in asthma.

Recent advances in fatty acid analysis have highlighted the links between lipid disruption and disease development. Lipid abnormalities are well-established risk factors for many of the most common chronic illnesses, and their involvement in asthma is also becoming clear. Here, we review research demonstrating the role of abnormal lipid metabolism in asthma, with a focus on saturated fatty acids and sphingolipids. High levels of palmitic acid, the most abundant saturated fatty acid in the human body, have been found in the airways of asthmatic patients with obesity, and were shown to worsen eosinophilic airway inflammation in asthma model mice on a high-fat diet. Aside from being a building block of longer-chain fatty acids, palmitic acid is also the starting point for de novo synthesis of ceramides, a class of sphingolipids. We outline the three main pathways for the synthesis of ceramides, which have been linked to the severity of asthma and act as precursors for the dynamic lipid mediator sphingosine 1-phosphate (S1P). S1P signaling is involved in allergen-induced eosinophilic inflammation, airway hyperresponsiveness, and immune-cell trafficking. A recent study of mice with mutations for the elongation of very long-chain fatty acid family member 6 (Elovl6), an enzyme that elongates fatty acid chains, has highlighted the potential role of palmitic acid composition, and thus lipid balance, in the pathophysiology of allergic airway inflammation. Elovl6 may be a potential therapeutic target in severe asthma.

Control of pleural effusion with prednisolone in a patient with yellow nail syndrome: A case report.

Yellow nail syndrome (YNS) can induce bilateral exudative pleural effusion; however, to the best of our knowledge, no standard treatment for YNS has been established. The present study describes a patient with YNS for whom the pleural effusion was controlled by prednisolone. A 73-year-old man was referred to the University of Tsukuba Hospital (Ibaraki, Japan) complaining of shortness of breath, which was diagnosed as being due to bilateral pleural effusion. Based on the presence of yellowing and growth retardation of the toenails, lymphedema, bilateral exudative pleural fluid of unknown etiology, and lymphatic congestion on lymphoscintigraphy, the patient was diagnosed with YNS. The pleural fluid was predominantly lymphocytic and responded to systemic steroid administration [prednisolone 30 mg/day (0.5 mg/kg) for 2 weeks, with subsequent weekly tapering]. The general condition of the patient and their dyspnea also improved with treatment. These findings indicated that systemic steroid administration should be considered as one of the treatment options for patients with YNS who are reluctant to undergo chest drainage or pleurodesis due to the potential for a decrease in their ability to perform daily activities and respiratory function.

Clinical Benefits of Targeting Treatable Traits in Asthma and Chronic Obstructive Pulmonary Disease.

Asthma and chronic obstructive pulmonary disease (COPD) have long been debated regarding their similarities and differences in clinical presentation and pathology. There has also been a discussion about how common therapeutics should be used differently for each disease. Traditionally, a "one size fits all" stepwise treatment has been chosen based on the severity of each case after categorizing the diseases, such as asthma or COPD. However, recently, the need for a precise approach for the treatment of individual patients beyond the disease category has been emphasized, especially in severe cases. To achieve precise personalized therapy, it has become necessary to focus on the individual phenotypes and underlying causal molecular mechanisms (endotypes) and to identify key therapeutic targets, which are called treatable traits. This review discusses the evidence for the importance of identifying treatable traits and therapeutic strategies based on the broader perspective of chronic obstructive airway disease rather than on individual diseases such as asthma or COPD.

Patient Age and EGFR-positive Non-small Cell Lung Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: The median age of subjects in many clinical trials of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor conducted to date has been approximately 60 years. However, it is not uncommon to encounter EGFR gene-positive patients in their 70s or 80s. Based on information obtained from these clinical trials, EGFR gene-positive non-small cell lung cancer (NSCLC) patients are considered to be younger than EGFR-negative patients. In this study, we analyzed clinical data to identify whether this assumption is true. PATIENTS AND METHODS: We retrospectively reviewed the medical records of NSCLC patients diagnosed in a multicenter clinical practice from 2009 to 2023. Patients included all cases of non-advanced and advanced NSCLC. RESULTS: Information on 2,540 patients, including 605 EGFR gene-positive patients, was collected. The median age of EGFR-positive and EGFR-negative patients was 72 years and 71 years, respectively, and there was no significant difference in the age of patients between these two groups (p=0.7887). The most common age in these two groups was 70 years. Among the EGFR gene subtypes, the frequency of exon 19 deletion decreased with age, whereas that of EGFR L858R increased. CONCLUSION: Patients in their 70s and 80s with non-small cell lung cancer were relatively frequently EGFR gene-positive. To avoid missing out on treatment opportunities, EGFR gene testing should also be performed on patients in this age group.

High-efficiency EGFR genotyping using cell-free DNA in bronchial washing fluid.

BACKGROUND: EGFR mutation testing is required for treatment of lung adenocarcinoma using epidermal growth factor receptor-tyrosine kinase inhibitor. However, the amounts of tumor tissue or tumor cells obtained by bronchoscopy are often insufficient. Bronchial washing fluid, obtained by lavage with saline after tumor biopsy or brushing, and the supernatant of bronchial washing fluid are thought to contain cell-free DNA that would be potentially applicable for EGFR testing. METHODS: From among patients with suspected adenocarcinoma or non-small cell lung carcinoma diagnosed from biopsy or surgical specimens at the University of Tsukuba Hospital between 2015 and 2019, cell-free DNAs from 80 specimens of supernatant of bronchial washing fluid (50 with EGFR mutation and 30 with wild type EGFR) and 8 blood serum samples were examined for EGFR mutation using droplet digital PCR. RESULTS: Among the 50 patients harboring EGFR mutation, the rate of positivity for cell-free DNA extracted from supernatant of bronchial washing fluid was 80% (40/50). In nine of the EGFR mutation-positive cases, tumor cells were not detected by either biopsy or cytology, but the mutation was detected in four cases (4/9, 44%). Comparison of the cell-free DNA mutation detection rate between supernatant of bronchial washing fluid and blood serum in six cases showed that mutations were detected from the former in all cases (6/6, 100%), but from the latter in only one case (1/6, 17%). CONCLUSIONS: Using supernatant of bronchial washing fluid samples, the detection rate of EGFR mutation was high, and EGFR mutations were detectable even when no tumor cells had been detectable by biopsy or cytology. Supernatant of bronchial washing fluid might be an effective sample source for EGFR mutation testing.

Centrilobular emphysema and airway dysanapsis: factors associated with low respiratory function in younger smokers.

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised. Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan. Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively). Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers.

Common Pathogeneses Underlying Asthma and Chronic Obstructive Pulmonary Disease -Insights from Genetic Studies.

Neither asthma nor chronic obstructive pulmonary disease (COPD) is a single disease consisting of a uniform pathogenesis; rather, they are both syndromes that result from a variety of basic distinct pathogeneses. Many of the basic pathogeneses overlap between the two diseases, and multiple basic pathogeneses are simultaneously involved at varying proportions in individual patients. The specific combination of different basic pathogeneses in each patient determines the phenotype of the patient, and it varies widely from patient to patient. For example, type 2 airway inflammation and neutrophilic airway inflammation may coexist in the same patient, and quite a few patients have clinical characteristics of both asthma and COPD. Even in the same patient, the contribution of each pathogenesis is expected to differ at different life stages (eg, childhood, adolescence, middle age, and older), during different seasons (eg, high seasons for hay fever and rhinovirus infection), and depending on the nature of treatments. This review describes several basic pathogeneses commonly involved in both asthma and COPD, including chronic non-type 2 inflammation, type 2 inflammation, viral infections, and lung development. Understanding of the basic molecular pathogeneses in individual patients, rather than the use of clinical diagnosis, such as asthma, COPD, or even asthma COPD overlap, will enable us to better deal with the diversity seen in disease states, and lead to optimal treatment practices tailored for each patient with less disease burden, such as drug-induced side effects, and improved prognosis. Furthermore, we can expect to focus on these molecular pathways as new drug discovery targets.

The primary ciliary dyskinesia-related genetic risk score is associated with susceptibility to adult-onset asthma.

BACKGROUND: Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes. METHODS: Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset. RESULTS: Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15). CONCLUSION: Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance.

Inflammatory myofibroblastic tumor directly invading the right first rib treated with oral steroids: a case report.

BACKGROUND: We present a case of an inflammatory myofibroblastic tumor cured with a short period of steroid administration, a treatment previously unreported for such cases. CASE PRESENTATION: A 49-year-old man had a chief complaint of chest pain for more than 3 days. Computed tomography (CT) revealed a tumoral lesion suspected to have infiltrated into the right first rib and intercostal muscles, with changes in lung parenchymal density around the lesion. The maximal standardized uptake value on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography was high (16.73), consistent with tumor presence. CT-guided biopsy revealed an inflammatory myofibroblastic tumor with no distant metastases. Surgery was indicated based on the disease course. However, he had received an oral steroid before the preoperative contrast-enhanced CT scan due to a history of bronchial asthma, and subsequent CT showed that the tumor shrank in size after administration; he has been recurrence-free for more than a year. CONCLUSIONS: Surgery is still the first choice for inflammatory myofibroblastic tumors, as the disease can metastasize and relapse; however, this condition can also be cured with a short period of steroid therapy.

Long­term control in a patient with lung adenocarcinoma, nonbacterial thrombotic endocarditis and multiple systemic emboli: A case report.

Systemic emboli are not uncommon in patients with advanced non-small cell lung cancer. The present study describes a rare case of long-term control in a patient with lung adenocarcinoma, nonbacterial thrombotic endocarditis and multiple systemic emboli. Briefly, a 56-year-old man was diagnosed with metastatic lung adenocarcinoma and was treated with pembrolizumab, which was discontinued due to the appearance of a pulmonary immune-related adverse event. During the clinical course, the patient developed pseudo-progression of a brain tumor, repeated thromboembolism in multiple organs and a small vegetation attached to the aortic valve. These lesions were controlled with apixaban after heparin therapy for >3 years. Lung cancer was subsequently treated with pemetrexed and bevacizumab; however, this treatment was terminated due to a complete response and the patient's request to discontinue treatment. More than 3 years have passed since the diagnosis of lung adenocarcinoma, and the patient has been followed up at the hospital without signs of cancer recurrence. Although unusual, the patient's course may provide useful suggestions for the treatment of other patients with a similar evolution.

Organizing Pneumonia in a Case of cold Agglutinin Disease with Pulmonary Thrombosis.

Cold agglutinin disease is a subtype of autoimmune hemolytic anemia that occurs via the activation of specific anti-red blood cell antibodies (agglutinins) at low temperatures. Autoimmune hemolytic anemia has been reported to cause interstitial pneumonia; however, the underlying mechanism remains unclear. We herein report a 46-year-old man diagnosed with cold agglutinin disease complicated by pulmonary thrombosis and organizing pneumonia. Treatment with prednisolone improved the course of cold agglutinin disease and organizing pneumonia in a similar manner. To our knowledge, this is the first report of cold agglutinin associated with organizing pneumonia, suggesting a potential link between the two.

Atezolizumab for EGFR-mutated Non-small Cell Lung Cancer Patients: An Observation Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab, an anti-programed death-ligand 1 monoclonal antibody, targets programed death-ligand 1 expressed on cancer cells and antigen-presenting cells and is now commonly used in combination with chemotherapy. We conducted a study to clarify the efficacy of atezolizumab in epidermal growth factor receptor (EGFR)-mutated patients who are considered less responsive to immune checkpoint inhibitors. PATIENTS AND METHODS: A retrospective review of patients with advanced non-small cell lung cancer (NSCLC) who received atezolizumab-containing therapy at 11 hospitals from April 2018 to March 2023 was performed. RESULTS: Median progression-free survival and overall survival in 33 EGFR-mutated patients treated with atezolizumab monotherapy were 2.0 and 9.0 months, respectively, and those in 19 patients who received combined atezolizumab plus chemotherapy were 12.0 and 17.0 months, respectively. When comparing EGFR-mutated and EGFR-negative patients after propensity score matching, there were no significant differences in progression-free survival and overall survival between the two groups, whether atezolizumab monotherapy or combined atezolizumab plus chemotherapy. Among EGFR-mutated patients, being male was a significant favorable factor in both atezolizumab treatment groups. None of the EGFR-mutated patients had grade 5 immune-related adverse events. CONCLUSION: Efficacy of atezolizumab in EGFR-mutated NSCLC patients could be comparable to that for EGFR-negative patients. To prolong the survival of EGFR-mutated NSCLC patients, appropriate selection and sequencing of EGFR for tyrosine kinase inhibitors, as well as immune checkpoint inhibitors, anti-tumor agents, and anti-angiogenic agents are important.

Patient profiling to predict response to bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty is the only device-based nonpharmacological treatment approach for severe asthma. Current guidelines are cautious in recommending bronchial thermoplasty because of unknown patient response prediction. Recent research on bronchial thermoplasty includes up-to-date, state-of-the-art, and recent-advances reviews. However, these reviews provide a broad and general discussion on equipment, technique, patient selection, and patient management, with little evaluation of the predictors of a beneficial response. Predicting an optimal response to bronchial thermoplasty in patients with severe asthma remains elusive. The lack of reliable predictive markers means that bronchial thermoplasty remains a last-line treatment and makes profiling for predicting the response or efficacy a topic of study. Genetic changes are associated with airway remodeling. A gap in the literature exists regarding patient profiling to predict the response to bronchial thermoplasty in patients with severe asthma. Therefore, recently published omics data and genetic associations regarding the response to bronchial thermoplasty therapy should be reviewed. We present an up-to-date review of recent publications profiling the response to bronchial thermoplasty in patients with severe asthma.

Flk1 Deficiency and Hypoxia Synergistically Promote Endothelial Dysfunction, Vascular Remodeling, and Pulmonary Hypertension.

BACKGROUND: The mechanisms underlying pulmonary hypertension (PH) remain largely unknown; further, why advanced vascular remodeling preferentially occurs in arterioles is yet to be answered. VEGF (vascular endothelial growth factor) regulates angiogenesis through Flk1 (fetal liver kinase 1) and Flt1 (fms-like tyrosine kinase 1) on endothelial cells (ECs), which may be related to PH pathogenesis. However, spatiotemporal expression patterns of Flk1 and Flt1 in the pulmonary vascular system and the role of endothelial Flk1 in PH development remain poorly understood. METHODS: We analyzed multiple reporter mice, including Flk1-GFP (green fluorescent protein) bacterial artificial chromosome transgenic (Tg), Flt1-DsRed bacterial artificial chromosome Tg, and Flk1-GFP/Flt1-DsRed double Tg mice, to determine the spatiotemporal expression of Flk1 and Flt1 in hypoxia-induced PH. We also used Cdh5CreERT2/Flk1f/f/Tomato (Flk1-KO [knockout]) mice to induce EC-specific Flk1 deletion and lineage tracing in chronic hypoxia. RESULTS: Flk1 was specifically expressed in the ECs of small pulmonary vessels, including arterioles. Conversely, Flt1 was more broadly expressed in the ECs of large- to small-sized vessels in adult mouse lungs. Intriguingly, Flk1+ ECs were transiently increased in hypoxia with proliferation, whereas Flt1 expression was unchanged. Flk1-KO mice did not exhibit pulmonary vascular remodeling nor PH in normoxia; however, the arteriolar ECs changed to a cuboidal shape with protrusion. In hypoxia, Flk1 deletion exacerbated EC dysfunction and reduced their number via apoptosis. Additionally, Flk1 deletion promoted medial thickening and neointimal formation in arterioles and worsened PH. Mechanistically, lineage tracing revealed that neointimal cells were derived from Flk1-KO ECs. Moreover, RNA sequencing in pulmonary ECs demonstrated that Flk1 deletion and hypoxia synergistically activated multiple pathways, including cell cycle, senescence/apoptosis, and cytokine/growth factor, concomitant with suppression of cell adhesion and angiogenesis, to promote vascular remodeling. CONCLUSIONS: Flk1 and Flt1 were differentially expressed in pulmonary ECs. Flk1 deficiency and hypoxia jointly dysregulated arteriolar ECs to promote vascular remodeling. Thus, dysfunction of Flk1+ ECs may contribute to the pathogenesis of advanced vascular remodeling in pulmonary arterioles.

Atezolizumab Monotherapy for Non-small Cell Lung Cancer Patients: An Observational Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab is a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) expressed on cancer cells derived from various organs and antigen-presenting cells and is currently commonly used in combination with chemotherapy. We conducted a study to clarify the current status of response to atezolizumab monotherapy in clinical practice and clarify the factors that contribute to long-term response and survival. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy from April 2018 to March 2023 at 11 Hospitals. RESULTS: The 147 patients evaluated had a progression-free survival (PFS) of 3.0 months and an overall survival of 7.0 months. Immune-related adverse events of any grade were observed in 13 patients (8.8%), grade 3 or higher in nine patients (6.1%), and grade 5 with pulmonary toxicity in one patient (0.7%). Favorable factors related to PFS were 'types of NSCLC other than adenocarcinoma'. Favorable factors for overall survival were 'performance status 0-1' and 'treatment lines up to 3'. There were 16 patients (10.9%) with PFS >1 year. No characteristic clinical findings were found in these 16 patients compared to the remaining 131 patients. CONCLUSION: Efficacy and immune-related adverse events of NSCLC patients associated with atezolizumab monotherapy were comparable to those of previous clinical trial results. Knowledge of characteristics of patients who are most likely to benefit from atezolizumab monotherapy is a crucial step towards implementing appropriate prescribing.

Consideration on size, velocity and path of droplets emitted during running.

BACKGROUND: People began to wear face masks during physical activities due to spread of COVID-19. There are no previous studies about the need for wearing masks while running. METHODS: Assuming a citizen runner who runs full marathon in 4 hours, we verified the path and the amount of droplet dispersal, setting a humanoid mannequin with a mask in simulated running environment (Experiment 1). We also had six adults exercise in the same environment to examine droplet behaviors when not wearing a face mask (Experiment 2). Average droplet size was determined, and repeated measures ANOVA was carried out to examine statistical significance. To evaluate observed droplet behaviors, theoretical solutions of the downfall motion of large droplets were then derived, taking air resistance into consideration. RESULTS: Experiment 1: wearing a face mask caused more droplets to adhere to the face; Experiment 2: droplets were emitted in conversation, coughing or sneezing, and they fell within social distancing. Average droplet size was not sensitive to the wind velocity. It could vary with a significant difference for time and wind velocity. Observed velocity and path of droplet can be expressed by the theoretical solutions. CONCLUSIONS: Velocity and path of large droplets can be expressed by the theoretical solution of particles in downfall motion under air resistance. We therefore conclude that wearing a mask while running gives adverse effects in preventing infection. Possibility of droplet transmission while running is considered low even when not wearing a face mask, as long as social distancing is ensured.

Risk factors for clinical progression in patients with pulmonary Mycobacterium avium complex disease without culture-positive sputum: a single-center, retrospective study.

OBJECTIVES: Limited data are available on the progression of pulmonary Mycobacterium avium complex (MAC) disease without culture-positive sputum. The aim of this study was to identify the risk factors associated with clinical progression of pulmonary MAC disease diagnosed by bronchoscopy. METHODS: A single-center, retrospective, observational study was conducted. Pulmonary MAC patients diagnosed by bronchoscopy without culture-positive sputum from January 1, 2013, to December 31, 2017 were analyzed. Clinical progression after diagnosis was defined as having culture-positive sputum at least once or initiation of guideline-based therapy. Then, clinical characteristics were compared between clinically progressed patients and stable patients. RESULTS: Ninety-three pulmonary MAC patients diagnosed by bronchoscopy were included in the analysis. During the 4-year period after diagnosis, 38 patients (40.9%) started treatment, and 35 patients (37.6%) had new culture-positive sputum. Consequently, 52 patients (55.9%) were classified into the progressed group, and 41 patients (44.1%) were classified into the stable group. There were no significant differences between the progressed and the stable groups in age, body mass index, smoking status, comorbidities, symptoms, or species isolated from bronchoscopy. On multivariate analysis, male sex, monocyte to lymphocyte ratio (MLR) ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were risk factors for clinical progression. CONCLUSIONS: Some patients with pulmonary MAC disease without culture-positive sputum progress within 4 years. Therefore, pulmonary MAC patients, especially male patients, having higher MLR or lesions in the middle (lingula) and lower lobes might need careful follow-up for a longer time.