First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

Intrinsic clarithromycin heteroresistance in Mycobacterium avium.

BACKGROUND: Mycobacterium avium is associated with pulmonary disease in otherwise healthy adults. Several clarithromycin-refractory cases have been reported, including some cases caused by clarithromycin-susceptible strains. OBJECTIVES: To characterize the reason for the discrepancy between clinical response and antibiotic susceptibility results. METHODS: We conducted population analysis of clarithromycin-tolerant and heteroresistant subpopulations of M. avium cultured in vitro and in homogenates of infected lungs of mice. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for 28 M. avium and two M. kansasii strains. Mice were intranasally infected with M. avium and treated with or without clarithromycin (100 mg/kg) thrice weekly. They were sacrificed on day 35 and the bacteria in lung homogenates were tested for clarithromycin resistance. Population analysis assays were performed based on colony growth on plates containing two-fold dilutions of clarithromycin. RESULTS: The MBC/MIC ratios were ≥8 in all 28 strains of M. avium tested. In the population analysis assay, several colonies were observed on the plates containing clarithromycin concentrations above the MIC (2-64 mg/L). No growth of M. kansasii colonies was observed on the plates containing clarithromycin concentrations ≥2 mg/L. M. avium in the homogenates of infected lungs showed clearer clarithromycin-resistant subpopulations than in vitro, regardless of clarithromycin exposure. CONCLUSION: M. avium shows intrinsic heterogeneous resistance (heteroresistance) to clarithromycin. This may explain the observed discrepancies between clarithromycin susceptibility testing results and clinical response to clarithromycin treatment. Further studies are needed to confirm a link between heteroresistance and clinical outcomes.

Effectiveness of Amikacin liposome inhalation suspension for refractory Mycobacterium avium complex pulmonary disease at 6 months post initiation.

BACKGROUND: Amikacin  liposome inhalation suspension (ALIS) improved sputum culture conversion rate at 6 months for patients with refractory Mycobacterium avium complex pulmonary disease (MAC-PD) in an international phase 3 trial. Patient characteristics and chest high-resolution CT (HRCT) findings associated with ALIS effectiveness are poorly documented. OBJECTIVE: We aimed to clarify ALIS effectiveness for refractory MAC-PD at 6 months, elucidating associated patient characteristics and chest CT findings. METHODS: We reviewed medical records of 12 patients with refractory MAC-PD for whom ALIS treatment was initiated at Toho University Omori Medical Center from November 2021 through September 2022. All patients demonstrated treatment persistence for at least 3 months. They were divided into culture conversion and non-conversion groups using sputum culture conversion status after 6-month ALIS treatment initiation. Clinical and radiological characteristics were compared. RESULTS: Seven of the 12 patients (58.3%) achieved sputum culture conversion within 6 months. The culture conversion group had shorter pre-ALIS initiation treatment duration [21 months (16-25) vs. 62 months (32-69); p = 0.045]; lower cavitary lesion incidence on HRCT (28.6% vs. 100%; p = 0.028); and fewer clarithromycin (CLA)-resistant strains [0/7 (0%) vs. 3/5 (60%); p = 0.045]. Chest HRCT findings improved in 4 of 7 (57.1%) and 1 of 5 (20%) patients in the culture conversion and non-conversion groups, respectively. CONCLUSION: ALIS facilitated sputum culture conversion within 6 months in 58.3% of patients with refractory MAC-PD. Sputum culture conversion was significantly more frequent for CLA-susceptible strains and patients with fewer cavitary lesions. Improved CT findings after ALIS did not always correspond to sputum culture conversion.

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407.

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.

Clinical significance of dispersion imaging by shear wave elastography in the treatment and diagnosis of pancreatic cancer.

BACKGROUND AND AIM: Recently, dispersion imaging by shear wave elastography has been developed to visualize a tissue viscosity-related factor by measuring the dispersion slope. However, clinical significance of dispersion imaging in the field of pancreatic cancer is unknown. This study aimed to investigate the clinical significance of dispersion imaging in the treatment and diagnosis of pancreatic cancer. METHODS: We measured shear wave dispersion slope (SWD) (m/s/kHz) and shear wave elasticity (SWE) (kPa) in patients with pancreatic ductal adenocarcinoma (PDA). The primary endpoint was the relationship between the changes in SWD and SWE values before and after chemotherapy and the response to chemotherapy. Secondary endpoints included SWD and SWE values in relation to differences between PDA and non-PDA sites and histopathological scores of stroma, inflammation, fibrosis, and necrosis in endoscopic ultrasound-guided fine-needle aspiration specimens. RESULTS: Fifty-six patients were included, 30 of whom underwent chemotherapy. There was no relationship between the changes of SWD and SWE values and chemotherapy responses. In 56 patients, the median SWD value was 12.20 m/s/kHz (interquartile range [IQR]: 10.88-13.61) at PDA sites and 13.57 m/s/kHz (IQR: 12.28-16.20) at non-PDA sites (P = 0.005). The median SWE value was 8.18 kPa (IQR: 7.00-9.74) at PDA sites and 6.14 kPa (IQR: 5.40-6.77) at non-PDA sites (P < 0.001). Histopathological evaluation revealed that inflammation scores were correlated with SWD values (rs  = 0.42, P < 0.001). CONCLUSIONS: Dispersion imaging in pancreatic cancer would be useful for diagnosis and assessing inflammation.

Efficacy of three sputum specimens for the diagnosis of Mycobacterium avium complex pulmonary disease.

BACKGROUND: In Mycobacterium avium complex pulmonary disease (MAC-PD), diagnosis requires a positive culture from at least two separate expectorated sputum specimens. The optimal number of sputum examinations remains unclear. OBJECTIVE: This study sought to elucidate the diagnostic yield of acid-fast bacilli in MAC-PD using 3 sputum specimens and to clarify the clinical characteristics of patients with MAC-PD diagnosed using 3 sputum specimens. Furthermore, we investigated the correlation between increased number of sputum specimens and diagnostic yield. METHODS: We reviewed the medical records of 139 patients with MAC-PD diagnosed at Toho University Omori Medical Center for whom at least three sputum specimens were examined before treatment from November 2014 through June 2021. Patients were classified into the 3-sputum diagnosed and the non-3 sputum diagnosed groups based on diagnostic procedure; clinical and radiological characteristics were compared. We also assessed diagnostic yield with the increased number of sputum specimens. RESULTS: Diagnostic yield with 3 sputum specimens was 16.5% (23/139). The 3-sputum diagnosed group had a lower body mass index [18.6(17-19.5) vs. 19.5(18-21.5); p = 0.014], and higher chest CT score [9(6.5-13) vs. 6(4-9); p = 0.011] including cavitary lesions (39.1% vs. 19%; p = 0.037) compared with the non-3 sputum diagnosed group. When the number of sputum specimens was increased to 6, the diagnostic yield increased to 23.7% (33/139). CONCLUSION: Diagnostic yield with 3 sputum specimens was 16.5%. Patients diagnosed using 3 sputum specimens had more severe chest CT findings including cavitary lesions. Increasing the number of sputum specimens to 6 improved diagnostic yield by 7.2%.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1-2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1-45.6%). The best overall response was 25.0% (95% confidence interval: 9.8-46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4-58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7-17.5) for the former and 4.4 months (95% confidence interval: 3.0-N.E.) for the latter, with no statistically significant difference (P = 0.74).

Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation.

BACKGROUND: The impact of co-infection with other pathogenic microorganisms after initiation of treatment for Mycobacterium avium complex pulmonary disease (MAC-PD) has not been clearly described. This study sought to clarify the clinical outcomes of co-infection with MAC after antimycobacterial therapy for MAC. METHODS: Co-infection status was defined as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment. Chest computed tomography (CT) findings and culture results were compared between co-infection and MAC alone groups. RESULTS: The co-infection and MAC alone groups comprised 12 and 36 patients, respectively. The proportion of patients with sputum culture positive for MAC after 24 months of therapy did not differ significantly between the two groups [25% (3/12) vs. 16.7% (6/36); p = 0.671]. The proportion of patients with improved chest CT score after 24 months of starting treatment compared to baseline was significantly lower for the co-infection group than for the MAC alone group [16.7% (2/12) vs. 79.4% (27/34); p < 0.001]. In the co-infection group, median CT score values at 12 and 24 months did not differ from baseline. However, the MAC alone group showed significant improvement at 12 and 24 months compared with baseline. CONCLUSIONS: In the patient group with co-infection of other pathogenic microorganisms after treatment initiation for MAC there was no impact on therapeutic efficacy compared to the MAC alone group. However, therapeutic intervention interfered with improvement in chest CT findings such as nodule formation, bronchiectasis, infiltration, and cavitary lesions.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.

Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial.

BACKGROUND: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. METHODS: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. RESULTS: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. CONCLUSIONS: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Severe spruelike enteropathy and collagenous colitis caused by olmesartan.

BACKGROUND: Olmesartan, which is an angiotensin II receptor blocker, reportedly causes spruelike enteropathy, with intestinal villous atrophy as its typical histopathological finding. Interestingly, collagenous and/or lymphocytic gastritis and colitis occur in some patients. We report the case of a 73-year-old Japanese man with a 2-month clinical history of severe diarrhea and weight loss. There were few reports in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. CASE PRESENTATION: We report a case of a 73-year-old man with a 2-month clinical history of severe diarrhea and weight loss. He had taken olmesartan for hypertension treatment for 5 years. Endoscopic examination with biopsies revealed intestinal villous atrophy and collagenous colitis. Suspecting enteropathy caused by olmesartan, which was discontinued on admission because of hypotension, we continued to stop the drug. Within 3 weeks after olmesartan discontinuation, his clinical symptoms improved. After 3 months, follow-up endoscopy showed improvement of villous atrophy but not of the thickened collagen band of the colon. However, the mucosa normalized after 6 months, histologically confirming that the preexistent pathology was finally resolved. CONCLUSIONS: This report presents a case in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. In unexplained cases of diarrhea, medication history should be reconfirmed and this disease should be considered a differential diagnosis.

Bronchial Brushing and Diagnosis of Pulmonary Nontuberculous Mycobacteria Infection.

BACKGROUND: The optimal bronchoscopy procedure for diagnosis of pulmonary nontuberculous mycobacteria (NTM) infection is unclear. OBJECTIVE: This study investigated the usefulness of bronchial brushing in bronchoscopy for diagnosis of pulmonary NTM infection in patients with suspected NTM lung disease and nodular bronchiectasis on chest computed tomography (CT) images. METHODS: Bronchoscopy was prospectively performed for 69 patients with clinically suspected pulmonary NTM infection on chest CT from December 2017 through December 2019. Before and after bronchial brushing, bronchial washing was performed with 20 or 40 mL of normal sterile saline at the same segmental or subsegmental bronchi. Before and after bronchial brushing, samples of the washing fluid (pre- and postbrushing samples) and brush deposits (brush samples) were obtained and cultured separately. RESULTS: NTM was detected in 37 of the 69 (53.6%) patients (Mycobacterium avium in 27, Mycobacterium intracellulare in 7, M. abscessus in 2, and M. kansasii in 2). NTM was detected in 34 (49.3%) prebrushing samples, in 27 (39.1%) postbrushing samples, and in 20 (29.0%) brush samples from the 69 patients. In 2 (2.9%) patients, NTM was detected only in postbrushing samples; in 1 (1.4%) patient, NTM was detected only in a brush sample. As compared with bronchial washing only, additional bronchial brushing increased the NTM culture-positive rate by 4.3% (3/69). Bronchial brushing caused bleeding, requiring hemostasis in 5 (7.2%) patients. CONCLUSION: Additional bronchial brushing increased the NTM culture-positive rate by only 4.3% (3/69), as compared with bronchial washing alone. Thus, the usefulness of brushing appears to be limited.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Efficacy of early antifibrotic treatment for idiopathic pulmonary fibrosis.

BACKGROUND: Although antifibrotic drugs, including nintedanib and pirfenidone, slow the progression of idiopathic pulmonary fibrosis (IPF), there is little data about the timing of start of antifibrotic treatment in real-world clinical practice. The present study aimed to clarify the efficacy of nintedanib and pirfenidone in patients with early-stage IPF. METHODS: We compared survival and disease progression between patients with IPF with Japanese Respiratory Society (JRS) disease severity system stage I with and without oxygen desaturation on the 6-min walk test (6MWT) and increased the gender-age-physiology (GAP) staging. We examined the efficacy of antifibrotic drugs in patients with early-stage IPF. RESULTS: The severity of stage I IPF (n = 179) according to the JRS criteria consisted of the following GAP staging criteria: stage I, 111 cases; stage II, 58 cases; stage III, 10 cases. The duration from the initial visit to disease progression and survival time was significantly shorter in JRS stage I patients with oxygen desaturation on the 6MWT or with increased GAP staging (unfavorable group) compared with patients without those factors. In the unfavorable group, the relative decline in percentage predicted forced vital capacity (%FVC) over 6 months was significantly lower in patients undergoing antifibrotic treatment compared with non-treated patients. CONCLUSION: Antifibrotic drugs have a beneficial effect on the decline in %FVC in Japanese patients with early-stage IPF who have oxygen desaturation on the 6MWT or increased GAP staging.

Appendicular Skeletal Muscle Mass Correlates with Patient-Reported Outcomes and Physical Performance in Patients with Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF), an incurable lung disease of unknown cause, often presents with losses of skeletal muscle mass. IPF requires comprehensive care, but it has not been investigated which skeletal muscle mass index reflects holistic management factors: pulmonary function, patient-reported outcomes (PROs), and physical performance. We compared three representative indices of skeletal muscle mass with holistic management factors in IPF patients. Twenty-seven mild to severe IPF patients (21 male) with the mean age of 76.1 ± 5.9 years were enrolled. The three indices were appendicular skeletal muscle mass index (ASMI), cross-sectional area of pectoralis major (PMCSA), and cross-sectional area of erector spinae muscles (ESMCSA). ASMI is considered as a gold standard for sarcopenia assessment, while PMCSA and ESMCSA are frequently used in IPF. As PROs, we assessed breathlessness with the modified Medical Research Council dyspnea scale (mMRC), symptoms with the chronic obstructive pulmonary disease assessment test (CAT), and health-related quality of life with St. George's Respiratory Questionnaire (SGRQ). For physical performance, peripheral muscle strength and 6-min walk distance (6MWD) were investigated. In this cross-sectional study, ASMI showed the greatest number of significantly correlated indices, such as pulmonary function, peripheral muscle strength, 6MWD, mMRC, and SGRQ. PMCSA showed the next greatest number of correlations, with peripheral muscle strength, 6MWD, and mMRC, whereas ESMCSA showed no significant correlations with any index. Thus, ASMI correlated with both PROs and physical performance, and PMCSA correlated mainly with physical performance. In conclusion, assessing ASMI is helpful for the comprehensive care of patients with IPF.

Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis.

Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.

Selection of Oral Antifungals for Initial Maintenance Therapy in Chronic Pulmonary Aspergillosis: A Longitudinal Analysis.

BACKGROUND: There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). METHODS: We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. RESULTS: Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively). CONCLUSIONS: Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients. CLINICAL TRIALS REGISTRATION: UMIN000007055.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.

A phase I and extension study of S-1 and carboplatin for previously untreated patients aged 75 years or more with advanced non-small cell lung cancer -TCOG 1101.

PURPOSE: Combination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient. METHODS: Eligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0-1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m2/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed. RESULTS: A total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m2/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12-54%] and the disease control rate was 90.0% (95% CI 68-99%). Thrombocytopenia and neutropenia were major adverse events. CONCLUSIONS: The recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m2/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.

Characteristics of non-small-cell lung cancer with interstitial pneumonia: variation in cancer location, histopathology, and frequency of postoperative acute exacerbations in interstitial pneumonia.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated. METHODS: We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining. RESULTS: Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group. CONCLUSIONS: The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.