Clinical characteristics of allergic bronchopulmonary mycosis caused by Schizophyllum commune.

BACKGROUND: Allergic bronchopulmonary mycosis (ABPM) is an allergic disease caused by type I and type III hypersensitivity to environmental fungi. Schizophyllum commune, a basidiomycete fungus, is one of the most common fungi that causes non-Aspergillus ABPM. OBJECTIVE: Herein, we attempted to clarify the clinical characteristics of ABPM caused by S. commune (ABPM-Sc) compared with those of allergic bronchopulmonary aspergillosis (ABPA). METHODS: Patients with ABPM-Sc or ABPA were recruited from a nationwide survey in Japan, a multicenter cohort, and a fungal database at the Medical Mycology Research Center of Chiba University. The definition of culture-positive ABPM-Sc/ABPA is as follows: (1) fulfills five or more of the 10 diagnostic criteria for ABPM proposed by Asano et al., and (2) positive culture of S. commune/Aspergillus spp. in sputum, bronchial lavage fluid, or mucus plugs in the bronchi. RESULTS: Thirty patients with ABPM-Sc and 46 with ABPA were recruited. Patients with ABPM-Sc exhibited less severe asthma and presented with better pulmonary function than those with ABPA (p = 0.008-0.03). Central bronchiectasis was more common in ABPM-Sc than that in ABPA, whereas peripheral lung lesions, including infiltrates/ground-glass opacities or fibrotic/cystic changes, were less frequent in ABPM-Sc. Aspergillus fumigatus-specific immunoglobulin (Ig)E was negative in 10 patients (34%) with ABPM-Sc, who demonstrated a lower prevalence of asthma and levels of total serum IgE than those with ABPM-Sc positive for A. fumigatus-specific IgE or ABPA. CONCLUSIONS: Clinical characteristics of ABPM-Sc, especially those negative for A. fumigatus-specific IgE, differed from those of ABPA.

A case of primary lung cancer requiring differentiation from metastatic cervical cancer.

p16 has been used as a surrogate marker for human papillomavirus (HPV)-related tumours. However, it remains unclear whether p16 is also a potential marker for pulmonary tumours. Herein, we report the case of an 80-year-old woman with a history of papillary squamous cell carcinoma of the uterine cervix, presenting with a left pulmonary tumour. A bronchoscopic biopsy revealed squamous cell carcinoma with a papillary pattern, which did not rule out pulmonary metastasis from the cervix. Immunohistochemical staining revealed that the cervical tumour was positive for p16, whereas the pulmonary tumour was negative and was effectively diagnosed as primary pulmonary carcinoma.

Pulmonary spindle cell carcinoma presenting with hemothorax.

Spontaneous hemothorax is less common. We report the case of an 83-year-old woman with spontaneous hemothorax caused by lung cancer with nontuberculous mycobacteriosis. She presented with chest pain and hemoptysis. Computed tomography revealed a tumor in the right middle lobe with middle syndrome and pleural effusion. Hemothorax was confirmed, and the right middle lobe was resected to control bleeding. The lung tumor invaded the mediastinal tissue, and tumor rupture was observed. Histological examination revealed pulmonary spindle cell carcinoma and epithelioid granulomas with caseous necrosis. Rapid tumor growth and mediastinal invasion could have led to intratumoral hemorrhage and tumor rupture.

Risk factors for pneumonitis in advanced extrapulmonary cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune-mediated pneumonitis has a high mortality rate; however, information regarding the related risk factors remains limited. This study aimed to analyze risk factors for pneumonitis, including smoking and lung metastasis (LM), in patients with extrapulmonary primary tumors. METHODS: Data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for treating extrapulmonary primary tumors at the Shiga University of Medical Science Hospital between January 2015 and December 2019 were retrospectively collected. The association between the onset of pneumonitis and treatment-related factors was analyzed by logistic regression. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Risk factors, such as the absence or presence of interstitial lung disease (ILD) and LM, or other clinical factors, including smoking status before ICI administration, were analyzed. RESULTS: Multivariate analyses indicated that the amount of smoking was significantly associated with an increase in the development of all-grade pneumonitis types (odds ratio (OR) = 20.33, 95% confidence interval (CI) = 20.03-20.66; p = 0.029). LM and ILD were significantly related to an increase in the development of symptomatic pneumonitis (≥ Grade 2) (OR = 10.08, 95% CI = 1.69-199.81; p = 0.076, and OR = 6.76, 95% CI = 1.13-40.63; p = 0.037, respectively). CONCLUSIONS: Pre-screening for ILD and LM and recognizing patients' smoking history is important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration.

Increased 18F-FDG accumulation in less-affected lung area in patients with non-small cell lung cancer and postoperative acute exacerbation of interstitial lung disease.

PURPOSE: To investigate whether or not 18F-FDG accumulation in normal or less-affected lung fields increased in non-small cell lung cancer (NSCLC) patients with postoperative acute exacerbation (PAE) of interstitial lung disease (ILD) MATERIAL AND METHODS: Thirty-six NSCLC patients with ILD and 50 patients without ILD (non-ILD patients) underwent pre-operative 18F-FDG-PET/CT at 2 institutions. Volume-of-interest (VOI) was placed to measure the mean standardized uptake value (SUVmean) in normal or less-affected lung fields at pre-defined 12 areas on ventral and dorsal locations of both lungs. SUVtissue fraction (TF) was defined as corrected SUVmean by using TF and mean computed tomography density on PET/CT. Harmonized SUVmean (hSUVmean) and SUVTF (hSUVTF) were calculated based on results of phantom study, which was performed to optimize the measured SUV difference among 2 institutions. Both the h-SUVmean and the h-SUVTF were compared between 8 patients with PAE of ILD (PAE group) or remaining 28 patients without PAE of ILD (non-PAE group) and non-ILD patients in each of the 12 areas. RESULTS: The hSUVmean in PAE group was higher in 9 out of 12 locations as compared with non-ILD patients, whereas the hSUVmean was mostly similar between non-PAE group and non-ILD patients. In contrast, the hSUVTF in non-PAE group was similar to that in PAE group, and higher than in non-ILD patients in most locations. CONCLUSION: 18F-FDG-PET/CT demonstrated increased SUVmean along with elevated SUVTF in normal or less-affected lung fields for NSCLC patients with PAE of ILD, which may reflect regional invisible fibrosis and inflammatory change.

Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study.

The constraint values of dose-volume histogram (DVH) parameters for radiation pneumonitis (RP) prediction have not been uniform in previous studies. We compared the differences between conventional DVH parameters and DVH parameters with high attenuation volume (HAV) in CT imaging in both esophageal cancer and lung cancer patients to determine the most suitable DVH parameters in predicting RP onset. Seventy-seven and 72 patients who underwent radiation therapy for lung cancer and esophageal cancer, respectively, were retrospectively assessed. RP was valued according to the Common Terminology Criteria for Adverse Events. We quantified HAV with quantitative computed tomography analysis. We compared conventional DVH parameters and DVH parameters with HAV in both groups of patients. Then, the thresholds of DVH parameters that predicted symptomatic RP and the differences in threshold of DVH parameters between lung cancer and esophageal cancer patient groups were compared. The predictive performance of DVH parameters for symptomatic RP was compared using the area under the receiver operating characteristic curve. Mean lung dose, HAV30% (the proportion of the lung with HAV receiving ≥30 Gy), and HAV20% were the top three parameters in lung cancer, while HAV10%, HAV5%, and V10 (the percentage of lung volume receiving 10 Gy or more) were the top three in esophageal cancer. By comparing the differences in the threshold for parameters predicting RP between the two cancers, we saw that HAV30% retained the same value in both cancers. DVH parameters with HAV showed narrow differences in the threshold between the two cancer patient groups compared to conventional DVH parameters. DVH parameters with HAV may have higher commonality than conventional DVH parameters in both patient groups tested.

Preoperative assessment of localized pleural adhesion: Utility of software-assisted analysis on dynamic-ventilation computed tomography.

PURPOSE: To assess the usefulness of software analysis using dynamic-ventilation CT for localized pleural adhesion (LPA). MATERIALS AND METHODS: Fifty-one patients scheduled to undergo surgery underwent both dynamic-ventilation CT and static chest CT as preoperative assessments. Five observers independently evaluated the presence and severity of LPA on a three-point scale (non, mild, and severe LPA) for 9 pleural regions (upper, middle, and lower pleural aspects on ventral, lateral, and dorsal areas) on the chest CT by three different methods by observing images from: static high-resolution CT (static image); dynamic-ventilation CT (movie image), and dynamic-ventilation CT while referring to the adhesion map (movie image with color map), which was created using research software to visualize movement differences between the lung surface and chest wall. The presence and severity of LPA was confirmed by intraoperative thoracoscopic findings. Parameters of diagnostic accuracy for LPA presence and severity were assessed among the three methods using Wilcoxon signed rank test in total and for each of the three pleural aspects. RESULTS: Mild and severe LPA were confirmed in 14 and 8 patients. Movie image with color map had higher sensitivity (56.9 ±â€¯10.7 %) and negative predictive value (NPV) (91.4 ±â€¯1.7 %) in LPA detection than both movie image and static image. Additionally, for severe LPA, detection sensitivity was the highest with movie image with color map (82.5 ±â€¯6.1 %), followed by movie image (58.8 ±â€¯17.0 %) and static image (38.8 ±â€¯13.9 %). For LPA severity, movie image with color map was similar to movie image and superior to static image in accuracy as well as underestimation and overestimation, with a mean value of 80.2 %. CONCLUSION: Software-assisted dynamic-ventilation CT may be a useful novel imaging approach to improve the detection performance of LPA.

Correction: Quantitative CT analysis of honeycombing area predicts mortality in idiopathic pulmonary fibrosis with definite usual interstitial pneumonia pattern: A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0214278.].

Quantitative CT analysis of honeycombing area predicts mortality in idiopathic pulmonary fibrosis with definite usual interstitial pneumonia pattern: A retrospective cohort study.

BACKGROUND: Honeycombing on high-resolution computed tomography (HRCT) images is a key finding in idiopathic pulmonary fibrosis (IPF). In IPF, honeycombing area determined by quantitative CT analysis is correlated with pulmonary function test findings. We hypothesized that quantitative CT-derived honeycombing area (HA) might predict mortality in patients with IPF. MATERIALS AND METHODS: Chest HRCT images of 52 IPF patients with definite usual interstitial pneumonia (UIP) pattern were retrospectively evaluated. Mortality data up to July 31, 2016, were recorded. Using a computer-aided system, HA and percentage of HA (%HA) were measured quantitatively. Predictors of 3-year mortality were evaluated using logistic regression models. RESULTS: The median %HA, %predicted forced vital capacity (FVC) and composite physiologic index (CPI) were 3.8%, 83.6%, and 33.6, respectively. According to GAP (gender, age, and physiology) stage, 20, 14, and 5 patients were classified under stages I-II-III, respectively. Percentage of HA was significantly correlated with %FVC, CPI, and GAP stage (all, p < 0.001). In univariate analysis, %HA, %FVC, and CPI were statistically significant predictors of mortality. In multivariate analysis using the stepwise regression method, only %HA (odds ratio [OR], 1.27; p = 0.011) was a significant independent predictors of mortality. Patients with %HA ≥ 4.8% had significantly lower survival rates than those with lesser %HA (median survival time, 1.3 vs 5.0 years; log-rank test; p < 0.001). CONCLUSION: Quantitative CT-derived HA might be an important and independent predictor of mortality in IPF patients with definite UIP pattern.

Nintedanib prevented fibrosis progression and lung cancer growth in idiopathic pulmonary fibrosis.

A 76-year-old man with a past history of acute exacerbation (AE) and idiopathic pulmonary fibrosis (IPF) was treated with nintedanib because of decline in his forced vital capacity over time. A new small nodular lesion was visible on a computed tomography scan of the chest before initiation of nintedanib. Disease progression in IPF and change in size of the nodular lesion were not detected during administration of nintedanib. Nine months after starting nintedanib, the patient was diagnosed with acute gangrenous appendicitis, and nintedanib treatment was discontinued. The nodular lesion increased in size four months after the cessation of nintedanib. The nodular lesion was diagnosed as squamous cell carcinoma. In this case, nintedanib inhibited the disease progression of IPF and lung cancer simultaneously. Nintedanib may play an important role in the treatment of IPF-associated lung cancer.

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and ß2-Adrenoceptor Agonists in Airway Smooth Muscle.

Long-acting muscarinic antagonists (LAMAs) and short-acting ß2-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 µM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K⁺ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between ß2-adrenoceptors and muscarinic receptors.

Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and ß2-adrenergic intrinsic efficacy.

Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and ß2-adrenergic receptor activity. Large-conductance Ca(2+)-activated K(+) (KCa) channels are activated by ß2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca(2+) influx passing through voltage-dependent Ca(2+) (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of ß2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between ß2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of ß2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between ß2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes ß2-adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of ß2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling.

A mixed phenotype of airway wall thickening and emphysema is associated with dyspnea and hospitalization for chronic obstructive pulmonary disease.

RATIONALE: Quantitative computed tomography (CT) has been used to phenotype patients with chronic obstructive pulmonary disease (COPD). A mixed phenotype is defined as the presence of both airway wall thickening and emphysema on quantitative CT. Little is known about patients with COPD with the mixed phenotype. OBJECTIVES: To propose a method of phenotyping COPD based on quantitative CT and to compare clinically relevant outcomes between patients with COPD with the mixed phenotype and those with other CT-based phenotypes. METHODS: Each of 427 male smokers (187 without COPD, 240 with COPD) underwent a complete medical interview, pulmonary function testing, and whole-lung CT on the same day. The percentage of low-attenuation volume at the threshold of -950 Hounsfield units (%LAV) and the square root of wall area of a hypothetical airway with an internal perimeter of 10 mm (Pi10) were measured. Patients with COPD were classified into four distinct phenotypes based on the upper limits of normal for %LAV and Pi10, which were derived from the data of smokers without COPD by using quantile regression. MEASUREMENTS AND MAIN RESULTS: Of 240 patients with COPD, 52 (21.7%) were classified as CT-normal phenotype, 39 (16.3%) as airway-dominant phenotype, 103 (42.9%) as emphysema-dominant phenotype, and 46 (19.2%) as mixed phenotype. Patients with COPD with the mixed phenotype were associated with more severe dyspnea than those with each of the remaining CT-based phenotypes (P < 0.01 for all comparisons). The number of hospitalizations for COPD exacerbations during the preceding year was 2.0 to 3.6 times higher in patients with the mixed phenotype than in those with each of the remaining CT-based phenotypes (P < 0.05 for all comparisons). Findings persisted after adjustment for age, pack-years of smoking, smoking status, body mass index, and FEV1. CONCLUSIONS: Patients with COPD with the mixed phenotype are associated with more severe dyspnea and more frequent hospitalizations than those with each of the remaining CT-based phenotypes. Thus, patients with COPD with the mixed phenotype may need more attention and interventions.

Mediastinitis and pericarditis after endobronchial ultrasound-guided transbronchial needle aspiration.

A 73-year-old man was admitted to our hospital for further investigation of multiple lung nodules and lymphadenopathy that were observed on chest radiography. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed to sample the lower paratracheal lymph node (4R), leading to a definitive diagnosis of squamous cell carcinoma of the lung. About 2 weeks after EBUS-TBNA, the patient had a high temperature, anterior chest pain, tachycardia, and hypotension. The diagnosis of infectious mediastinitis and pericarditis as complications of EBUS-TBNA, which were successfully treated with systemic antibiotics, was made after examinations. EBUS-TBNA is minimally invasive and useful for the diagnosis of hilar and mediastinum lesions particularly in determining the extent of lung cancer. With the increased employment of this method, critical complications may also increase. Clinicians should be aware of the rare but critical complications associated with EBUS-TBNA.

Airway wall area derived from 3-dimensional computed tomography analysis differs among lung lobes in male smokers.

BACKGROUND: It is time-consuming to obtain the square root of airway wall area of the hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10), a comparable index of airway dimensions in chronic obstructive pulmonary disease (COPD), from all airways of the whole lungs using 3-dimensional computed tomography (CT) analysis. We hypothesized that √Aaw at Pi10 differs among the five lung lobes and √Aaw at Pi10 derived from one certain lung lobe has a high level of agreement with that derived from the whole lungs in smokers. METHODS: Pulmonary function tests and chest volumetric CTs were performed in 157 male smokers (102 COPD, 55 non-COPD). All visible bronchial segments from the 3rd to 5th generations were segmented and measured using commercially available 3-dimensional CT analysis software. √Aaw at Pi10 of each lung lobe was estimated from all measurable bronchial segments of that lobe. RESULTS: Using a mixed-effects model, √Aaw at Pi10 differed significantly among the five lung lobes (R(2) = 0.78, P<0.0001). The Bland-Altman plots show that √Aaw at Pi10 derived from the right or left upper lobe had a high level of agreement with that derived from the whole lungs, while √Aaw at Pi10 derived from the right or left lower lobe did not. CONCLUSION: In male smokers, CT-derived airway wall area differs among the five lung lobes, and airway wall area derived from the right or left upper lobe is representative of the whole lungs.

Successful chemotherapy for small-cell lung cancer in an elderly patient undergoing continuous ambulatory peritoneal dialysis.

A standard treatment has not yet been established for elderly small-cell lung cancer patients, especially when they have end-stage renal disease. We report the first case of successful chemoradiotherapy in an elderly small-cell lung cancer patient undergoing continuous ambulatory peritoneal dialysis. A 77-year-old Japanese man on continuous ambulatory peritoneal dialysis was diagnosed as having limited disease small-cell lung cancer. He received four monthly cycles of chemotherapy consisting of carboplatin at 240 mg/m(2) on day 1 and etoposide at 40 mg/m(2) on days 1 and 3. He underwent additional hemodialysis on days 1 and 3, while continuous ambulatory peritoneal dialysis continued as usual on the other days. Following chemotherapy, he underwent hyperfractionated radiotherapy to a total dose of 45 Grey, resulting in complete remission of the disease. A pharmacokinetic study showed an area under the concentration-time curve of carboplatin of 3.41 to 4.88 mg.min/mL, increasing gradually over the first three cycles, while etoposide did not show this gradual increase. The increased area under the concentration-time curve of carboplatin may have reflected a worsened renal function during chemotherapy. Despite dose reductions and favorable areas under the concentration-ime curve of carboplatin, the patient suffered grade 3-4 hematological toxicities, necessitating transfusions and a further dose reduction. The patient died of recurrent small-cell lung cancer 19 months after diagnosis.