Idiopathic pleuroparenchymal fibroelastosis: three-dimensional computed tomography assessment of upper-lobe lung volume.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterised by predominant upper-lobe fibrosis involving the pleura and subpleural lung parenchyma. Despite its poor prognosis, there is no consensus on prognostic determinants of iPPFE to date. Because volume loss in the upper lobe is a distinct feature of iPPFE, we hypothesised that the lung volume of the bilateral upper lobes (upper-lobe volume) accurately indicates disease severity and mortality risk in iPPFE patients. METHODS: This retrospective study assessed two cohorts of 132 patients with iPPFE (69 in Hamamatsu cohort; 63 in Seirei cohort) and 45 controls. Each lobe volume was quantitatively measured using three-dimensional computed tomography at the time of iPPFE diagnosis and standardised using predicted forced vital capacity. RESULTS: The standardised upper-lobe volume in iPPFE patients was less than half that of controls, whereas the lower-lobe volume did not decrease. iPPFE patients with lower standardised upper-lobe volume had significantly shorter survival rates than those with higher volume (median survival: 6.08 versus 2.48 years, p<0.001). In multivariate analysis, the lower standardised upper-lobe volume was significantly associated with increased mortality adjusting for age, sex and forced vital capacity (HR 0.939). A composite scoring model, including age, sex and standardised upper-lobe volume, better predicted risk of death than the gender-age-physiology model. CONCLUSION: Assessment of upper-lobe volume provides useful information for managing iPPFE by evaluating disease severity and mortality risk in clinical practice.

Combined assessment of the GAP index and body mass index at antifibrotic therapy initiation for prognosis of idiopathic pulmonary fibrosis.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas.

Genotyping epidermal growth factor receptor (EGFR) is an essential process to indicate lung adenocarcinoma patients for the most appropriate treatment. Liquid biopsy using circulating tumor DNA (ctDNA) potentially complements the use of tumor tissue biopsy for identifying genotype-specific mutations in cancer cells. We assessed the performance of a high-fidelity sequencing method that uses molecular barcodes called the nonoverlapping integrated read sequencing system (NOIR-SS) for detecting EGFR L858R-mutated alleles in 33 advanced or recurrent patients with L858R mutation-positive lung adenocarcinoma revealed by matched tissue biopsy. We compared NOIR-SS with site-specific droplet digital PCR (ddPCR), which was taken as the reference, in terms of sensitivity and ability to quantify L858R variant allele fractions (VAFs). NOIR-SS and ddPCR had sensitivities of 87.9% (29/33) and 78.8% (26/33) for detecting L858R alleles, respectively. The VAFs measured by each assay were strongly correlated. Notably, one specimen was positive with a VAF of 30.12% for NOIR-SS but marginally positive with that of 0.05% for ddPCR because of a previously poorly recognized mechanism: two-base substitution-induced L858R (c.2573_2574delinsGA). These results indicate that NOIR-SS is a useful method for detecting ctDNA, potentially overcoming a limitation of ddPCR which highly depends on the binding ability of primers to specific targeting sequences.

Assessment of Immune-Related Interstitial Lung Disease in Patients With NSCLC Treated with Immune Checkpoint Inhibitors: A Multicenter Prospective Study.

INTRODUCTION: Programmed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting. METHODS: This is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed. RESULTS: Among the 138 patients with NSCLC who received anti-programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29-147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development. CONCLUSIONS: The incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC.

Comprehensive assessment of myositis-specific autoantibodies in polymyositis/dermatomyositis-associated interstitial lung disease.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) are associated with clinical phenotypes in polymyositis/dermatomyositis (PM/DM). No study has investigated the clinical features based on comprehensive MSA assessment in PM/DM-associated interstitial lung disease (ILD). We aimed to determine the practical significance of MSAs in PM/DM-ILD. METHODS: Sixty consecutive PM/DM-ILD patients were retrospectively analysed. Serum MSAs were comprehensively measured using immunoprecipitation assay. Clinical features and prognosis were compared among MSA subgroups. RESULTS: Twenty-six (43.3%) PM/DM-ILD patients were anti-aminoacyl tRNA-synthetase antibody-positive (anti-ARS-positive), 15 (25.0%) were anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5-positive), 3 (5%) were anti-signal recognition particle antibody-positive, 1 (1.7%) was anti-transcriptional intermediary factor 1-gamma antibody-positive, and 15 (25%) were MSA-negative. There were significant differences in clinical features, including ILD form, serum ferritin and surfactant protein-D levels at ILD diagnosis, and high-resolution CT pattern among the anti-ARS-positive, anti-MDA5-positive and MSA-negative groups. The anti-MDA5-positive group showed the lowest 90-day survival rate (66.7%, anti-MDA5-positive; 100%, anti-ARS-positive; 100%, MSA-negative; P < 0.01). The anti-ARS-positive group had the highest 5-year survival rate (96%, anti-ARS-positive; 66.7%, anti-MDA5-positive; 68.3%, MSA-negative, P = 0.02). Univariate analysis revealed that anti-ARS antibody was associated with better prognosis (HR = 0.45; 95% CI, 0.18-0.89; P = 0.02), whereas anti-MDA5 antibody was associated with poorer prognosis (HR = 1.90; 95% CI, 1.02-3.39; P = 0.04). CONCLUSIONS: The comprehensive MSA assessment demonstrated that anti-ARS and anti-MDA5 antibodies were two major MSAs, and the clinical features differed depending on MSA status in PM/DM-ILD. Assessment of anti-ARS and anti-MDA5 antibodies is practically useful for predicting clinical course and prognosis in PM/DM-ILD patients.

Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.