[A CASE OF SUSPECTED ALLERGIC BRONCHOPULMONARY MYCOSIS CAUSED BY SCEDOSPORIUM APIOSPERMUM THAT SHOWED CLINICAL IMPROVEMENT AFTER BRONCHOSCOPIC REMOVAL OF A MUCUS PLUG].

A 69-year-old woman presented with a persistent cough and high fever. Thoracic computed tomography revealed atelectasis and high-attenuation mucus. The blood test results showed eosinophils at 18.2%, an absolute eosinophil count of 980 cells/µL, and a total serum immunoglobulin E of 1980IU/mL. Bronchoscopy revealed a mucous plug, which upon photomicrograph examination, showed eosinophils. A culture study of the mucus yielded Scedosporium apiospermum, leading to the suspicion of allergic bronchopulmonary mycosis (ABPM) caused by the fungus. After the bronchoscopic removal of the mucous plug, her symptoms quickly diminished. She was successfully treated without medication, and ABPM has not recurred for 2 years. To our knowledge, ABPM caused by Scedosporium apiospermum is rare, and close follow-up was effective without the administration of systemic steroids or antifungal drugs.

Clinical Impact of Pre-Existing Autoantibodies in Patients With SCLC Treated With Immune Checkpoint Inhibitor: A Multicenter Prospective Observational Study.

Introduction: Although pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC. Methods: A multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies. Results: PFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups. Conclusions: Vigilance is required against the development of irAEs in pretreatment antibody-positive patients.

Pneumonia Caused by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza Virus: A Multicenter Comparative Study.

BACKGROUND: Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. METHODS: A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. RESULTS: Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. CONCLUSIONS: Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings.

The validity and reliability of four-meter gait speed test for stable interstitial lung disease patients: the prospective study.

BACKGROUND: The 4-m gait speed test is a simple functional performance measure for older adults or patients with chronic obstructive lung disease. However, limited data exist regarding these measures for patients with interstitial lung disease. We evaluated the correlation between the 4-m gait speed and 6-min walk distance tests for interstitial lung disease patients and examined their underlying physiological factors. METHODS: The 4-m gait speed and 6-min walk tests were prospectively conducted for 51 patients with interstitial lung disease. Other measurements included health-related quality of life, modified Medical Research Council score, arterial blood gas levels, pulmonary function, muscle strength according to the skeletal muscle mass index and physical activity. RESULTS: Thirty-five patients were male (68.6%). Thirty-four patients had idiopathic pulmonary fibrosis (66.7%). There were significant correlations between the 4-m gait speeds and 6-min walk distances (r=0.57; P<0.001). Multivariate analyses showed that both the 4-m gait speed and 6-min walk distance were correlated with the modified Medical Research Council score. In addition, the 6-min walk distance was correlated with age and the percentage of the predicted diffusion capacity of carbon monoxide. CONCLUSIONS: The 4-m gait speed test is a simple, easy to perform and reliable functional performance measure for interstitial lung disease patients.

Respiratory management of acute exacerbation of interstitial pneumonia using high-flow nasal cannula oxygen therapy: a single center cohort study.

BACKGROUND: The role of high-flow nasal cannula oxygen therapy (HFNC) in respiratory management of acute exacerbation of interstitial pneumonia (AE-IP) is unknown. METHODS: We retrospectively reviewed patients with AE-IP who were admitted to our hospital from June 2009 - May 2015 and compared mortality, complications, sedatives and analgesia use, and oral intake between cohorts before (pre-HFNC: June 2009 - May 2012) and after (post-HFNC: June 2012 - May 2015) the introduction of HFNC. In the pre-HFNC cohort, standard oxygen therapy, noninvasive ventilation (NIV), and invasive mechanical ventilation (IMV) were used for respiratory management of AE-IP. In the post-HFNC cohort, HFNC was also used as an alternative to NIV in patients (I) who had refused NIV; (II) unable to cooperate, (III) intolerant to NIV, or (IV) who improved in respiratory parameters after NIV treatment for weaning. RESULTS: Fifty-three pre-HFNC patients and 43 post-HFNC patients were enrolled. Neither the baseline characteristics at admission nor the major pharmacotherapy for AE-IP differed between the two cohorts. Twenty-eight (52.8%) patients and 19 (44.2%) patients required any respiratory support, in pre- and post-HFNC cohort, respectively (P=0.40). After introduction of HFNC, it was used in 40% of the patients who required respiratory support and NIV use was significantly reduced from 49.1% to 16.3% (P<0.001). The post-HFNC cohort had significantly lower in-hospital mortality than the pre-HFNC cohort (27.9% vs. 49.1%, P=0.04). The incidence of complications was not significantly different between the two cohorts. The use of sedoanalgesia during respiratory support and the number of patients who discontinued oral intake for >24 hours were decreased after the introduction of HFNC (78.6% vs. 31.6%, P<0.001; 52.8% vs. 23.3%, P=0.003). CONCLUSIONS: HFNC might be a feasible option in respiratory management of AE-IP.

Pulmonary artery enlargement predicts poor outcome during acute exacerbations of fibrotic interstitial lung disease.

BACKGROUND AND OBJECTIVE: In fibrotic interstitial lung disease (f-ILD), pulmonary artery diameter to ascending aorta diameter ratio (PA/A) ≥ 1 during the stable stage is associated with worse outcomes; however, the effect of acute exacerbation (AE) on the PA/A is unknown. METHODS: Patients with a diagnosis of AE of f-ILD and with a computed tomography (CT) scan performed during stable period to confirm background fibrosis, as well as a CT scan at admission, were included. The pulmonary arterial diameter, ascending aortic diameter and PA/A were measured using CT during AE and CT prior to AE, when available, to evaluate the changes. Demographic data, co-morbidities and clinical outcome (90-day mortality) were analysed. RESULTS: Of the 123 patients included, 45 had a PA/A ≥ 1 during AE and compared to the PA/A < 1 group, they were younger, had lower % vital capacity (VC) and % forced vital capacity (FVC), required more long-term oxygen therapy and other treatments, and had lower PaO2 /FiO2 (P/F) ratios. During AE, the PA/A increased from that during stable periods (P < 0.001), and a PA/A ≥ 1 was significantly associated with 90-day mortality both before and after adjustment for age, the P/F ratio at admission, long-term oxygen therapy usage and the type of background f-ILD (P = 0.018 and 0.025). CONCLUSION: To the best of our knowledge, this is the first longitudinal examination of the PA/A ratio and evaluation during AE of f-ILD. Our data show that a PA/A ≥ 1 during AE predicted poor survival outcome in f-ILD.

Clinical Characteristics and Prognosis of Patients With Advanced Non-Small-cell Lung Cancer Who Are Ineligible for Clinical Trials.

BACKGROUND: Most patients with non-small-cell lung cancer (NSCLC) are ineligible for clinical trials. However, few studies have reported on the profiles and treatment outcomes for these patients. Therefore, we investigated the characteristics, outcomes, and survival of patients with advanced NSCLC who were ineligible for clinical trials. MATERIALS AND METHODS: We analyzed the data from a retrospective cohort of 786 consecutive patients with a diagnosis of advanced NSCLC. We reviewed the criteria of phase 1 to 3 clinical trials and classified patients according to the common first-line eligibility criteria for lung cancer. RESULTS: Of the 786 patients, 469 (60%) were ineligible for clinical trials. The main reasons for ineligibility were brain metastasis (41%), poor performance status (25%), and respiratory disease (24%). For all patients, ineligibility was identified as an independent predictor of overall survival (hazard ratio, 0.78; 95.0% confidence interval, 0.65-0.93; P = .008), even in those with a good performance status who had received chemotherapy (hazard ratio, 0.80; 95.0% confidence interval, 0.65-0.99; P = .037). In the subgroup analysis of ineligible patients, survival varied depending on the reasons for ineligibility. In particular, a history of cancer was not associated with a poor outcome, although this was a common reason for ineligibility. CONCLUSION: Most patients were ineligible for clinical trials and had a shorter overall survival, although this varied depending on the reason for their ineligibility. These results should be considered when applying clinical trial outcomes to real-world patients. Further studies of ineligible patients are needed to improve the treatment decisions in clinical settings.

Programmed Cell Death Ligand 1 Expression in Non-Small-cell Lung Cancer Patients With Interstitial Lung Disease: A Matched Case-control Study.

BACKGROUND: Programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have demonstrated antitumor activity, and immunohistochemical analysis of PD-L1 expression has been used to identify the response in patients with non-small-cell lung cancer (NSCLC). Recently, considerable interest has ensued toward extending the benefit of these inhibitors to high-risk patients, such as those with NSCLC and interstitial lung disease (ILD). However, no studies have compared PD-L1 expression in NSCLC patients with and without ILD. Therefore, we conducted a case-control study to evaluate PD-L1 expression and stromal CD8+ lymphocyte density in these patients. MATERIALS AND METHODS: The data from patients with pathologic stage I or II NSCLC who had undergone surgery from January 2007 to January 2016 were analyzed. RESULTS: We identified 62 patients with pathologic stage I or II NSCLC and ILD. We compared these patients with 1:1-matched cohort. In both groups with and without ILD, approximately 60% were PD-L1+. Tumor cell PD-L1 expression was similar between the groups (median, 1%; interquartile range, 0%-5%; vs. median, 1%; interquartile range, 0%-5%; P = .49). The proportion of patients with positive (≥ 1%) and strongly positive (≥ 50%) PD-L1 expression was also similar between the 2 groups (P = .46 and P = 1.00, respectively). Additionally, the CD8+ lymphocyte density did not differ between patients with and without ILD. CONCLUSION: PD-L1 expression and stromal CD8+ lymphocyte density were comparable between the NSCLC patients with and without ILD. PD-1 axis inhibitors might be effective for NSCLC patients with ILD.

Reduced Tumour Proportion Scores for Programmed Cell Death Ligand 1 in Stored Paraffin Tissue Sections.

BACKGROUND/AIM: We evaluated the effects of storage of formalin-fixed, paraffin-embedded (FFPE) sections on the tumour proportion score (TPS) for programmed cell death ligand 1 (PD-L1), as indicator in non-small cell lung cancer (NSCLC) tissues of treatment efficacy. MATERIALS AND METHODS: NSCLC postoperative specimens with PD-L1 TPS ≥50% were obtained and cut into five serial sections. One section was stained immediately, and four were stored at 4°C for 2, 4, 6, or 8 weeks. Slides were subjected to PD-L1 immunohistochemistry using the anti-PD-L1 clone 28-8. PD-L1 TPS were blindly evaluated by two independent pathologists. RESULTS: Twelve specimens (60 slides) were evaluated. After slide storage for 2, 4, 6, and 8 weeks, a TPS of <50% was obtained in five (41%), four (33%), seven (58%), and eight (67%) patients, respectively. CONCLUSION: TPS values for PD-L1 were reduced by long-term slide storage of FFPE specimens. Sectioned slides should be stained for PD-L1 without delay.

What Is the Impact of Mildly Altered Consciousness on Acute Hypoxemic Respiratory Failure with Non-invasive Ventilation?

Objective A severely altered level of consciousness (ALC) is considered to be a possible contraindication to non-invasive ventilation (NIV). We investigated the association between mild ALC and NIV failure in patients with hypoxemic respiratory failure. Methods A retrospective study was conducted by reviewing the medical charts of patients with de novo hypoxemic respiratory failure who received NIV treatment. The clinical background and the outcomes of patients with and without ALC were compared. Patients Patients who were admitted to our hospital for acute hypoxemic respiratory failure between July 2011 and May 2015 were included in the present study. Results Sixty-six of the 148 patients had ALC. In comparison to the patients without ALC, the patients with ALC were older (median: 72 vs. 78 years, p=0.02), had a higher Acute Physiology and Chronic Health Evaluation II score (18 vs. 19, p=0.02), and received a higher level of inspiratory pressure (8 cmH2O vs. 8, p<0.01). The median Glasgow Coma Scale score of the patients with ALC was 14 (interquartile range, 11-14). There were no significant differences between the groups in the rates of NIV failure (24% vs. 30%, p=0.4) and in-hospital mortality (13% vs. 16%, p=0.3). Conclusion NIV may be successfully applied to treat acute hypoxemic respiratory failure with mild ALC. NIV may be performed, with careful attention to the appropriate timing for intubation.

Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. METHODS: We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%-49%), or negative (TPS <1%). RESULTS: A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1-stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted κ coefficient 0.64-0.71), whereas the SP142 assay showed lower concordance with other assays (weighted κ coefficient 0.39-0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve 0.75-0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). CONCLUSIONS: The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients.

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study.

INTRODUCTION: Retrospective studies have shown immune-related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy. METHODS: We conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals. RESULTS: A total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1-positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression-free survival than those without (6.4 months [95% confidence interval: 2.5-not reached] versus 1.5 months [95% confidence interval: 1.2-2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment. CONCLUSIONS: Early irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia.

INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP. METHODS: Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly. RESULTS: Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response. CONCLUSIONS: Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037).

Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

PURPOSE: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC). METHODS: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group). RESULTS: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients. CONCLUSIONS: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

An Atypical Clinical Course of Anti-MDA5 Antibody-positive Interstitial Lung Disease in a Patient with Three Deteriorations in 9 years.

Anti-MDA5 antibody-positive patients with clinically amyopathic dermatomyositis (CADM) are at high risk of developing rapidly progressive interstitial lung disease (ILD), which is associated with a high mortality rate. Approximately half of the patients with ILD recover; however, the long-term clinical course of these patients has not been fully reported and is not completely understood. This report describes the atypical clinical course of an anti-MDA5 antibody-positive CADM patient who experienced three deteriorations of ILD in 9 years. These findings indicate that the ILD in anti-MDA5 antibody-positive patients may not only be rapidly progressive, but may also be chronic and recurrent.