Interstitial lung disease with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis in elderly patients.

Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) occurs in elderly people, and patients with anti-myeloperoxidase autoantibodies (MPO-ANCA)-positive AAV are often complicated with interstitial lung disease (ILD). This study aimed to evaluate the age-related clinical features of elderly patients with MPO-ANCA-positive AAV-ILD. This study retrospectively investigated 63 patients with MPO-ANCA-positive AAV-ILD, all of whom were 65 years or older at diagnosis. Clinical characteristics, causes of death and survival rates among three groups stratified by age (65-74 years, n = 29; 75-79 years, n = 18; over 80 years, n = 16) were compared. This study also examined the association with severe infections in these patients. Among the three age groups, there were significant differences in sex (P = 0.032), serum Krebs von den Lungen-6 (P < 0.01), and total ground-glass opacity score (P = 0.011). The causes of death were mainly severe infections and complications of ILD. Kaplan-Meier curve analysis showed a significantly lower 5-year survival rate in the oldest group (P < 0.01). Regarding severe infections in these patients, the 5-year cumulative incidence of severe infections was higher in the patients receiving steroid pulse therapy (P = 0.034). The clinical characteristics of MPO-ANCA-positive AAV-ILD differ with age in elderly patients, with age being an important poor prognostic factor in these patients. The administration of steroid pulse therapy is a significant risk factor of severe infection in MPO-ANCA-positive elderly patients with AAV-ILD.

Association between lung ultrasound B-lines and exercise-induced pulmonary hypertension in patients with connective tissue disease.

BACKGROUND: Identification of elevation in pulmonary pressures during exercise may provide prognostic and therapeutic implications in patients with connective tissue disease (CTD). Interstitial lung disease (ILD) is common in CTD patients and subtle interstitial abnormalities detected by lung ultrasound could predict exercise-induced pulmonary hypertension (PH). METHODS AND RESULTS: Echocardiography and lung ultrasound were performed at rest and bicycle exercise in CTD patients (n = 41) and control subjects without CTD (n = 24). Ultrasound B-lines were quantified by scanning four intercostal spaces in the right hemithorax. We examined the association between total B-lines at rest and the development of exercise-induced PH during ergometry exercise. Compared to controls, the number of total B-lines at rest was higher in CTD patients (0 [0, 0] vs 2 [0, 9], P < .0001) and was correlated with radiological severity of ILD assessed by computed tomography (fibrosis score, r = .70, P < .0001). Pulmonary artery systolic pressure (PASP) was increased with ergometry exercise in CTD compared to controls (48 ± 14 vs 35 ± 13 mm Hg, P = .0006). The number of total B-lines at rest was highly correlated with higher PASP (r = .52, P < .0001) and poor right ventricular pulmonary artery coupling (tricuspid annular plane systolic excursion/PASP ratio, r = -.31, P = .01) during peak exercise. The number of resting B-lines predicted the development of exercise-induced PH with an area under the curve .79 (P = .0003). CONCLUSIONS: These data may suggest the value of a simple resting assessment of lung ultrasound as a potential tool for assessing the risk of exercise-induced PH in CTD patients.

Glasgow prognostic score and body mass index predict short-term discontinuation of the antifibrotic agents pirfenidone and nintedanib.

BACKGROUND: The antifibrotic agents pirfenidone and nintedanib have been shown to be effective in patients with idiopathic pulmonary fibrosis (IPF). However, discontinuation of antifibrotic drugs is a major clinical concern because of the lack of alternative treatment options. Therefore, we identified factors that may be useful for predicting the termination of antifibrotic agents. METHODS: We retrospectively recruited 280 IPF patients treated with antifibrotic drugs between 2009 and 2018 from seven regional core hospitals in Gunma prefecture, Japan. RESULTS: At four months, the short-term discontinuation group exhibited a significantly worse prognosis in the pirfenidone group and a poorer prognosis in the nintedanib group compared to that in the continuation group. The discontinuation group of pirfenidone at 4 months exhibited lower albumin and higher C-reactive protein (CRP) levels in the sera compared to the group that continued treatment for more than 4 months. In multivariate analysis, the Glasgow prognostic score (GPS), well known as a predictor of cancer prognosis, which comprises serum CRP and albumin levels, predicted early discontinuation and prognosis in the pirfenidone group, whereas the body mass index (BMI) predicted early discontinuation of nintedanib. A high GPS, with both albumin <3.5 g/dL and CRP >1.0 mg/dL, was associated with a poorer prognosis in the pirfenidone group. CONCLUSION: GPS and BMI were significant factors for short-term pirfenidone and nintedanib discontinuation, respectively. Initial evaluation of GPS and BMI prior to antifibrotic therapy may contribute to less interrupted IPF management, thus leading to better prognostic outcomes in patients with IPF.

Opioids impair nivolumab outcomes: a retrospective propensity score analysis in non-small-cell lung cancer.

OBJECTIVES: Opioids are often administered for cancer-related pain relief. However, few reports have evaluated the association between opioids and immune checkpoint inhibitor treatment for patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to reveal the effect of opioids on the prognosis of patients harbouring NSCLC treated with nivolumab. METHODS: The medical records of consecutive patients with NSCLC receiving nivolumab at our institution were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment initiation. Propensity score matching (PSM) was performed to minimise potential selection bias. We compared clinical outcomes with and without baseline opioid use. RESULTS: Of the 296 patients identified in the study, after PSM, 38 cases with opioid use and matched 38 cases without opioid use were selected. The overall response rate was significantly lower in patients with opioid use than in those without (2.63%, 95% CI 0.47% to 13.49%, vs 21.05%, 95% CI 11.07% to 36.35%; p=0.0284). The median progression-free survival in patients with opioid use was significantly shorter than that in patients without (1.17, 95% CI 0.93 to 1.73 months, vs 2.07 95% CI 1.23 to 4.73 months; p=0.002). The median overall survival in patients with opioid use was significantly shorter than that in patients without (4.20, 95% CI 2.53 to 6.20 months, vs 9.57, 95% CI 2.23 to not reached months; p=0.018). CONCLUSIONS: Patients with NSCLC receiving regular opioid administration at nivolumab treatment initiation had a worse nivolumab treatment outcome than patients without opioid use.

Clinical differences among patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive interstitial lung disease.

INTRODUCTION: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD. METHOD: This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). RESULTS: Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD. CONCLUSIONS: The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

Retrospective analysis of long-term survival factors in patients with advanced non-small cell lung cancer treated with nivolumab.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC). However, factors associated with long-term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long-term survival in NSCLC patients treated with nivolumab, using real-world data. METHODS: We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long-term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong-term survivors and long-term survivors and performed univariate and multivariate analyses of factors associated with long-term survival. RESULTS: Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG-PS ≤1 were included in the study. Young age, ECOG-PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil-to-lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long-term survival. Long-term survivors had significantly higher response and disease control rates than nonlong-term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long-term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months). CONCLUSIONS: ΔNLR <1 was a significant long-term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab.

Differential Discontinuation Profiles between Pirfenidone and Nintedanib in Patients with Idiopathic Pulmonary Fibrosis.

Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, p < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, p = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.

Quantitative CT analysis of interstitial pneumonia in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: a single center, retrospective study.

INTRODUCTION: This study aimed to assess the utility of quantitative high-resolution computed tomography (HRCT) for determining the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). METHOD: This study retrospectively analyzed the data of 34 patients with MDA5+ ILD to determine the association between the clinical findings and extent of ILD via quantitative CT analysis at baseline and short-term follow-up. Quantified HRCT scores were evaluated as the lung severity score (LSS), percentage of opacity, and percentage of high opacity. RESULTS: Thirty-four patients underwent follow-up CT scans 35 (range: 14-78) days after diagnosis. Patients who died of rapidly progressive ILD had higher LSS (p < 0.01), percentage of opacity (p < 0.01), percentage of high opacity (p = 0.01), total ground-glass opacity score (p = 0.01), serum C-reactive protein (CRP) (p = 0.03), and alveolar-arterial oxygen difference (Aa-DO2) (p = 0.01) at follow-up than those who survived. Quantified HRCT scores correlated with serum CRP and Aa-DO2 levels at follow-up. LSS at follow-up (AUC = 0.844, p < 0.01) was the best predictor of death in MDA5+ ILD patients. Patients with an LSS of > 6.5 at follow-up had higher mortality than those with an LSS of ≤ 6.5, especially when receiving triple therapy. In multivariate analysis, an LSS of > 6.5 at follow-up was significantly associated with a poor outcome. CONCLUSIONS: Quantitative CT analysis of MDA5+ ILD is useful for the objective assessment of respiratory status and disease activity. Short-term HRCT evaluation, particularly LSS, is most important in predicting its clinical course during triple therapy. Key Points • Quantitative CT analysis plays an important role in evaluating the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). • Quantified HRCT scores, particularly lung severity score, at short-term intervals from diagnosis can help to predict prognosis after triple therapy in MDA5+ ILD.

Influence of obesity in interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies.

BACKGROUND: Obesity is a major risk factor for developing various respiratory diseases. Patients with anti-aminoacyl tRNA synthetase (ARS) antibodies often have interstitial lung disease (ILD). The present study was conducted to evaluate the association between obesity and outcomes of anti-ARS antibody-related ILD (ARS-ILD). METHODS: We retrospectively investigated 58 patients with ARS-ILD and compared the clinical characteristics, treatment, and prognoses between obese (body mass index [BMI] ≥25 kg/m2) and nonobese (BMI <25 kg/m2) patients. Chest fat was quantified via computed tomography (CT). Thoracic subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured at diagnosis and first relapse of ILD. RESULTS: Sixteen patients were obese. Obese patients had lower percentages of predicted diffusing capacity of the lungs for carbon monoxide and higher high-resolution CT scores and SAT and VAT indexes than did nonobese patients. The ILD relapse rate was higher in obese patients (P < 0.01), especially among those with high SAT indexes (P < 0.01). The SAT and VAT indexes increased significantly from diagnosis until first relapse. Among clinical parameters at first relapse, SAT and VAT indexes were correlated with serum Krebs von den Lungen-6 levels (r = 0.720, P = 0.008) and total ground-glass attenuation scores (r = 0.620, P = 0.024), respectively. CONCLUSIONS: Obesity and high SAT indexes are risk factors for ILD relapse in patients positive for anti-ARS antibodies. Evaluating and quantifying patients' chest fat on CT is important for predicting ILD relapse.

Limitations of End-Tidal CO2 Measured with a Portable Capnometer to Estimate PaCO2 for Patients with Respiratory Disease.

OBJECTIVE: This study evaluated the relationship between end-tidal carbon dioxide (EtCO2) measured with a portable capnometer and PaCO2 in respiratory disease patients. MATERIAL AND METHODS: We retrospectively reviewed patients whose EtCO2, measured with a portable capnometer using a mouthpiece, and PaCO2 were simultaneously assessed at a single center from August 2017 to September 2018. The primary outcome was the relationship between EtCO2 and PaCO2. We conducted subgroup analyses in patients with interstitial lung disease (ILD), with and without O2 supplementation. The relationship between EtCO2 and PaCO2 was analyzed using Spearman's rank test and Bland-Altman analysis. RESULTS: A total of 100 patients were registered in this study. There was a moderate correlation between EtCO2 and PaCO2 (rho = 0.41). The Bland-Altman plot showed that the mean bias was 0.32 mmHg (95% CI: -1.28 to 1.92), the limits of agreement (LOA) were -15.48 and 16.13 mmHg, and the percent error was 38.49%. The LOA in patients with ILD were -15.12 and 13.75 mmHg. In patients with O2 supplementation, the mean bias was greater, and the LOA were wider than in those without O2 supplementation (mean bias: 7.17 vs. -1.18 mmHg, respectively; LOA: -14.29 and 28.62 mmHg vs. -13.82 and 11.46 mmHg, respectively). CONCLUSION: In the clinical setting, the relationship between EtCO2 and PaCO2 was poor in patients with respiratory disease, especially in those receiving O2 supplementation, compared with that reported in previous studies. It may be difficult to precisely estimate PaCO2 in patients with respiratory disease based on measurements of EtCO2.

Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer.

PURPOSE: This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). PATIENTS/METHODS: Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. RESULTS: Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). CONCLUSIONS: No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD.

Efficacy and Safety of Carbon-Ion Radiotherapy for Stage I Non-Small Cell Lung Cancer with Coexisting Interstitial Lung Disease.

Interstitial lung disease (ILD) is a risk factor both for the development and treatment failure of lung cancer. In this retrospective study, we analyzed the outcome of carbon-ion radiotherapy (CIRT) in 124 patients with clinical stage I non-small cell lung cancer (NSCLC), of whom 26 (21%) had radiological signs of pre-existing ILD. ILD was diagnosed retrospectively by a pulmonologist based on critical review of CT-scans. Ninety-eight patients were assigned to the non-ILD group and 26 patients (21.0%) to the ILD group. There were significant differences in pre-treatment KL-6 values between the two groups. The three year overall survival and cause-specific survival rates were 83.2% and 90.7%, respectively, in the non-ILD group, and 59.7% and 59.7%, respectively, in the ILD group (between-group differences, p = 0.002 and p < 0.001). Radiation pneumonitis worse than Grade 2 was observed in three patients (3.0%) in the non-ILD group and two patients (7.6%) in the ILD group (p = 0.29). There were no cases of acute exacerbation in the ILD group. CIRT for stage I NSCLC was as safe in the ILD group as in the non-ILD group. Coexisting ILD was a poor prognostic factor in CIRT for clinical stage I lung cancer.

Predictive factors for progression-free survival in non-small cell lung cancer patients receiving nivolumab based on performance status.

BACKGROUND: Nivolumab has promising efficacy for the treatment of non-small cell lung cancer (NSCLC). Various predictive factors for nivolumab response in those with NSCLC have been reported, including performance status (PS). The objective of this retrospective study was to determine the predictive factors for nivolumab response in those with NSCLC with good PS and those with poor PS. METHODS: We retrospectively collected pretreatment clinical data of 296 consecutive patients with NSCLC treated with nivolumab. We investigated the relationship between progression-free survival (PFS) and patient characteristics and analyzed predictive factors associated with good PS (PS 0-1) or poor PS (PS 2-4). RESULTS: The median age of patients was 70 years; 206 patients were male, and 224 were classified as having good PS (PS 0-1). The median PFS was 3.0 months, 3.7 months, and 1.2 months for all patients, patients with good PS, and patients with poor PS respectively. Multivariate analysis showed that never smoking (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.15-2.75), high C-reactive protein (CRP) (HR, 1.39; 95% CI, 1.00-1.93), liver metastasis (HR, 1.95; 95% CI, 1.24-3.07), pleural effusion (HR, 1.45; 95% CI, 1.06-2.00), and steroid use (HR, 2.85; 95% CI, 1.65-4.94) were associated with significantly shorter PFS in patients with good PS. A high advanced lung cancer inflammation index (ALI) was significantly associated with longer PFS in patients with poor PS (HR, 0.24; 95% CI, 0.08-0.79). CONCLUSIONS: In patients with NSCLC treated with nivolumab, the factors found to be predictive of shorter PFS in patients with good PS were never smoking, high CRP, liver metastasis, pleural effusion, and steroid administration, whereas high ALI was predictive of longer PFS in patients with poor PS.

Poor effect of osimertinib on EGFR exon 20 insertion-positive lung adenocarcinoma: A case report.

INTRODUCTION: The clinical efficacy of osimertinib for patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations is unclear. Few case reports exist on the successful treatment of such tumors with osimertinib. We report a case wherein osimertinib administration had no effect in a patient with EGFR exon 20 insertion-positive lung adenocarcinoma. PATIENT CONCERNS: A 48-year-old never-smoking woman was referred to our hospital for chronic cough. Computed tomography (CT) and positron emission tomography-CT revealed a nodule in the right middle lobe, consolidation in the right upper lobe, multiple lymph node metastases, liver metastasis, and multiple bone metastases. DIAGNOSIS: On the basis of further examination using transbronchial lung biopsy, the patient was diagnosed with cT1N3M1 stage IVB lung adenocarcinoma. An EGFR exon 20 insertion, without any additional mutations, was identified. INTERVENTIONS: Daily oral administration of 80 mg osimertinib was initiated to treat the EGFR exon 20 insertion-positive lung adenocarcinoma. OUTCOMES: Although the disease appeared to be stable 2.5 months after the administration of osimertinib, the tumor started to grow 3 months after administration, and carcinoembryonic antigen levels became higher than those before treatment. Thus, osimertinib was discontinued, and treatment with carboplatin as well as pemetrexed and bevacizumab was started, which the patient responded to. CONCLUSION: EGFR exon 20 insertion mutations must be classified in more detail to assess the efficacy of EGFR tyrosine kinase inhibitors. Osimertinib doses that provide favorable therapeutic windows should be considered. Further clinical research is required to clarify the efficacy of osimertinib and other drugs for exon 20 insertion mutations.