Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39-91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0-1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50-74%, 75-89%, and 90-100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0-1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05-2.72; p = 0.03138), CRP/Alb (<0.3 vs. ≥0.3: HR: 1.92, 95.0% CI: 1.28-2.87; p = 0.00153), steroid usage (not usage vs. usage: HR: 2.94, 95.0% CI: 1.45-5.95; p = 0.00267), and PD-L1 TPS (50-89% vs. 90-100%: HR: 0.65, 95.0% CI: 0.43-1.00; p = 0.04984) were significantly and independently correlated with PFS of pembrolizumab. Conclusion The results confirm the efficacy and safety of pembrolizumab in real-world patients. Poor PS and steroid usage at the time of commencing pembrolizumab treatment indicate poor outcomes. First-line pembrolizumab particularly benefits patients with PD-L1 TPS ≥90% or low inflammatory states (CRP/ALB<0.3).

Levels of Antibody against Glycopeptidolipid Core as a Marker for Monitoring Treatment Response in Mycobacterium avium Complex Pulmonary Disease: a Prospective Cohort Study.

The diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) is sometimes complicated and time-consuming. A serodiagnostic kit that measures the serum levels of IgA antibodies against the glycopeptidolipid (GPL) core is commercially available and has good diagnostic accuracy for MAC-PD. However, the significance of measurement of GPL core IgA antibody levels in monitoring for chemotherapy response in patients with MAC-PD was not well investigated. Thirty-four treatment naive MAC-PD patients who were started on multidrug chemotherapy were enrolled. Their antibody levels were prospectively measured at regular intervals. The relationships between their antibody levels and the therapeutic outcomes were examined. The patients were classified into three groups (conversion, recurrence, and nonconversion) based on the bacteriological outcomes after chemotherapy. There were no significant differences in the antibody levels before treatment between the culture conversion (n = 19), recurrence (n = 7), and nonconversion (n = 8) groups (P = 0.9881). The levels decreased significantly after the chemotherapy (P < 0.0001). Recurrence and/or worsening of chest radiography findings were observed in cases whose antibody levels subsequently increased after cessation of the chemotherapy. No significant difference in the percent decrease in antibody levels by the chemotherapy was observed between the culture conversion and recurrence groups (P = 0.9338). The initial antibody levels are not a predictor of therapeutic outcomes, and also the percent decrease in antibody levels is not a sufficient indicator of the cessation of chemotherapy. However, serial measurements of antibody levels may allow objective monitoring of disease activity in individual MAC-PD patients.

Clinical analysis of 71 spontaneous pneumomediastinum cases: an observational study from a tertiary care hospital in Japan.

BACKGROUND: Spontaneous pneumomediastinum is characterized by the presence of interstitial air in the mediastinum without any underlying disease. Some cases of spontaneous pneumomediastinum have been reported in the past, although only few reports are available, and its management remains uncertain. This study reviewed our experience in the diagnosis and treatment of spontaneous pneumomediastinum. METHODS: A retrospective study of 71 cases treated for spontaneous pneumomediastinum at the Yodogawa Christian Hospital between April 2005 and March 2020 was conducted. RESULTS: The patients' mean age was 19.3 years (range, 7-48 years). A triggering event was noted in 69% of the cases. Seventy-six percent of the patients were admitted to the hospital, and 24% were outpatients. Treatment included analgesia, rest, antibiotics, and/or oxygen therapy. Thirty-six patients (51%) were treated with antibiotics. None of the cases presented any complications, including mediastinitis or worsening respiratory condition. Two patients (3%) had a recurrence of spontaneous pneumomediastinum. CONCLUSIONS: All the patients, with or without antimicrobial treatment and hospitalization, had favorable outcomes. We should therefore reconsider the need for hospitalization and antimicrobial therapy for patients with mediastinitis prophylaxis.

Association Between Early Immune-related Adverse Events and Clinical Outcomes in Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

INTRODUCTION: Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non-small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes. PATIENTS AND METHODS: We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS). RESULTS: In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts. CONCLUSION: Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.

Three Cases of Idiopathic Diffuse Pulmonary Ossification.

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

Monitoring antibody binding to T cells in a pembrolizumab-treated patient with lung adenocarcinoma on hemodialysis.

Recent clinical trials have demonstrated that anti-PD-1 blocking antibodies showed remarkable clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non-small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti-PD-1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD.

Dyspnea and the Varying Pathophysiologic Manifestations of Chronic Obstructive Pulmonary Disease Evaluated by Cardiopulmonary Exercise Testing With Arterial Blood Analysis.

Background: Patients with chronic obstructive pulmonary disease (COPD) show varying mechanisms of exertional dyspnea with different exercise capacities. Methods: To investigate the pathophysiologic conditions related to exertional dyspnea, 294 COPD patients were evaluated using cardiopulmonary exercise testing (CPET) with arterial blood analyses, with the patients classified into two groups according to their exercise limitation: the leg fatigue group (n = 58) and the dyspnea group (n = 215). The dyspnea group was further subdivided into four groups based on peak oxygen uptake ( V ° O 2 in mL/min/kg): group A (< 11), group B (11 to < 15), group C (15 to < 21), and group D (≥21). Results: In the dyspnea group, group A (n = 28) showed the following findings: (i) the forced expiratory volume in 1 s was not correlated with the peak V ° O 2 (p = 0.288), (ii) the arterial oxygen tension (PaO2) slope (peak minus resting PaO2/Δ V ° O 2 ) was the steepest (p < 0.0001) among all subgroups, (iii) reduced tidal volume (VT) was negatively correlated with respiratory frequency at peak exercise (p < 0.0001), and (iv) a break point in exertional VT curve was determined in 17 (61%) patients in group A. In these patients, there was a significant negative correlation between bicarbonate ion ( HCO 3 - ) levels at peak exercise and VT level when the VT-break point occurred (p = 0.032). In group D (n = 46), HCO 3 - levels were negatively correlated with plasma lactate levels (p < 0.0001). In all subgroups, the HCO 3 - level was negatively correlated with minute ventilation. The dyspnea subgroups showed no significant differences in the overall mean pH [7.363 (SD 0.039)] and Borg scale scores [7.4 (SD, 2.3)] at peak exercise. Conclusions: During exercise, ventilation is stimulated to avoid arterial blood acidosis and hypoxemia, but ventilatory stimulation is restricted in the setting of reduced respiratory system ability. These conditions provoke the exertional dyspnea in COPD. Although symptom levels were similar, the exertional pathophysiologic conditions differed according to residual exercise performance; moreover, COPD patients showed great inter-individual variability. An adequate understanding of individual pathophysiologic conditions using CPET is essential for proper management of COPD patients.

Radiation Pneumonitis with Eosinophilic Alveolitis in a Lung Cancer Patient.

A 59-year-old woman suffering from dry cough and dyspnea was admitted to our hospital. She had undergone concurrent chemo-radiotherapy five months earlier. Chest computed tomography revealed bilateral ground-glass opacities extending outside the irradiated lung field. Her eosinophil numbers were increased in both the peripheral blood and the bronchoalveolar lavage fluid; therefore, she was diagnosed with radiation pneumonitis accompanied by eosinophilic alveolitis. Steroid therapy promptly improved the pneumonitis. Radiation pneumonitis accompanied by eosinophilic alveolitis extending outside the irradiated field is rare. Bronchoalveolar lavage is useful for a diagnosis, and steroid therapy is effective for treatment.

Pulmonary rehabilitation for COPD improves exercise time rather than exercise tolerance: effects and mechanisms.

BACKGROUND: COPD patients undergoing pulmonary rehabilitation (PR) show various responses. The purpose of this study was to investigate the possible mechanisms and predictors of the response to PR in COPD patients. METHODS: Thirty-six stable COPD patients underwent PR including a 4-week high-intensity exercise training program, and they were evaluated by cardiopulmonary exercise testing. All patients (mean age 69 years, severe and very severe COPD 94%) were classified into four groups by whether the exercise time (Tex) or the peak oxygen uptake [Formula: see text] increased after PR: two factors increased (both the Tex and the peak [Formula: see text] increased); two factors decreased; time only increased (the Tex increased, but the peak [Formula: see text] economized); and [Formula: see text] only increased (the Tex decreased, but the peak [Formula: see text] increased). Within all patients, the relationships between baseline variables and the post-to-pre-change ratio of the time-slope, Tex/(peak minus resting [Formula: see text]), were investigated. RESULTS: Compared with the two factors increased group (n=11), in the time only increased group (n=18), the mean differences from pre-PR at peak exercise in 1) minute ventilation [Formula: see text] (P=0.004), [Formula: see text] (P<0.0001), and carbon dioxide output [Formula: see text] (P<0.0001) were lower, 2) [Formula: see text]/ [Formula: see text] (P=0.034) and [Formula: see text]/ [Formula: see text] (P=0.006) were higher, and 3) the dead space/tidal volume ratio (VD/VT) and the dyspnea level were similar. After PR, there was no significant difference in the ratio of the observed peak heart rate (HR) to the predicted peak HR (220 - age [years]) between the two groups. A significant negative correlation with the baseline time-slope (r=-0.496, P=0.002) and a positive correlation with the baseline body mass index (BMI) (r=0.496, P=0.002) were obtained. CONCLUSIONS: PR in COPD patients improves Tex rather than exercise tolerance, economizing oxygen requirements, resulting in reduced ventilatory requirements without cardiac loads followed by reduced exertional dyspnea. In addition, the time-slope and BMI could be used to predict PR responses beforehand.