Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial.

Background: The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. Methods: This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. Clinical trial registration: ClinicalTrials.gov, identifier NCT05578222.

Impact of chronic obstructive pulmonary disease on the efficacy and safety of neoadjuvant immune checkpoint inhibitors combined with chemotherapy for resectable non-small cell lung cancer: a retrospective cohort study.

BACKGROUND: Neoadjuvant immune checkpoint inhibitors(ICIs) combined with chemotherapy can improve non-small cell lung cancer(NSCLC) patients' pathological responses and show promising improvements in survival. Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease, and its associated abnormal inflammatory response affects not only the immunotherapy efficacy but also immune-related adverse events. It remains unclear whether NSCLC patients with COPD can benefit from neoadjuvant ICIs combined with chemotherapy. METHODS: A retrospective observational clinical study was conducted on 105 consecutive NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy at the Department of Thoracic Surgery of Tianjin Chest Hospital between April 2020 and April 2023. RESULTS: A total of 74 NSCLC patients were included in the study, including 30 patients with COPD and 44 patients without COPD. The percentage of patients with a pathological complete response (PCR) was higher in the COPD group than in the non-COPD group (43.3% vs. 20.5%, P = 0.042). Multivariate logistic regression analysis of factors associated with PCR showed that the adjusted odds ratio (OR) was statistically significant for presence of COPD (OR = 3.020, 95%CI: 1.042-8.757; P = 0.042). Major pathological response (66.7% vs. 50%, P = 0.155), R0 resection rate (96.7% vs.93.2%, P = 0.642), N2 lymph node downstaging(92.3% vs. 66.7%, P = 0.182) and objective response rate (70% vs. 63.6%, P = 0.57) were not significantly different between the groups. Progression-free survival(PFS) was not reached in the COPD group and 17 months (95%CI: 12.1-21.9) in the non-COPD group, with statistically significance (χ2 = 6.247, P = 0.012). Multivariate Cox's regression analysis showed that the adjusted hazard ratio (HRadj) was statistically significant for presence of COPD (HRadj = 0.321, 95%CI: 0.111-0.930; P = 0.036). The grade 3 and grade 4 adverse events in the COPD group were leukopenia (3.3%, 6.7%), neutropenia (3.3%, 6.7%), fatigue (6.7%, 0%), gastrointestinal reactions (3.3%, 0%), and hypothyroidism (3.3%, 0%). In the non-COPD group, the corresponding adverse events were leukopenia (6.8%, 6.8%), neutropenia (3.3%, 6.8%), fatigue (2.3%, 0%), gastrointestinal reactions (2.3%, 0%), and hypothyroidism (2.3%, 0%), respectively. CONCLUSIONS: The present study indicates that the presence of COPD may improve PCR, prolong PFS, and have an acceptable safety profile in NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy.

Catechin regulates miR-182/GGPPS1 signaling pathway and inhibits LPS-induced acute lung injury in mice.

AIM: Acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS) are detrimental inflammatory disease associated with high rates of morbidity and mortality due to a lack of effective treatment options. Previous study has demonstrated that an inhibition of geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1) show a protective effect against ALI. METHOD: In this study, by using connective map (CMAP), we identified catechin as a potential drug to exhibit similar effects to inhibit GGPPS1. Furthermore, we detected the protective effect of catechin on lipopolysaccharide (LPS)-induced ALI and delineated the underlying mechanism. RESULTS: We found that catechin effectively ameliorated LPS-induced lung inflammation and alleviated the release of cytokines into alveolar space. Notably, miR-182/GGPPS1 signaling pathway was reactivated upon catechin administration, which was essential for the catechin-induced protective effect against ALI. CONCLUSION: catechin regulates miR-182/GGPPS1 signaling pathway and efficaciously ameliorates LPS-induced acute lung injury in mice model, which provided a promising therapeutic strategy in ALI and ARDS.

Impact of severe-to-very severe chronic obstructive pulmonary disease on the prognosis of patients with non-small cell lung cancer who received chemotherapy.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. There are limited data about the impact of severe-to-very severe COPD on prognosis in patients with NSCLC receiving first-line chemotherapy. OBJECTIVES: To investigate whether severe-to-very severe COPD impacted survival of patients with NSCLC receiving first-line chemotherapy. METHODS: A retrospective review was performed on 513 consecutive NSCLC patients receiving first-line chemotherapy between February 2014 and May 2018. Prognostic impact of severe-to-very severe COPD was analysed using regression analyses. RESULTS: Totally 258 NSCLC patients (118 non-COPD, 96 mild-to-moderate COPD and 44 severe-to-very severe COPD) were evaluated retrospectively. Kaplan-Meier analysis showed that the median overall survival times in the severe-to-very severe COPD, mild-to-moderate COPD and non-COPD groups were 14.0 months [95% confidence interval (CI): 11.0-17.0], 18 months (95% CI: 14.8-21.2) and 19 months (95% CI: 15.3-22.7), respectively. The difference was significant between patients with severe-to-very severe COPD and those without COPD (χ2  = 6.8, P = 0.009) and between patients with severe-to-very severe COPD and those with mild-to-moderate COPD (χ2  = 4.0, P = 0.045). Multivariate analysis showed that survival time was significantly shorter in the severe-to-very severe COPD group than in the non-COPD group (adjusted hazard ratio: 1.876, 95% CI: 1.161-3.030, P = 0.01) and mild-to-moderate COPD group (adjusted hazard ratio: 1.782, 95% CI: 1.046-3.034, P = 0.033). CONCLUSION: Severe-to-very severe COPD may worsen the prognosis of NSCLC patients who received first-line chemotherapy.

Association between features of COPD and risk of venous thromboembolism.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with risk of venous thromboembolism (VTE) events. A detailed understanding of which clinical features of COPD increase risk of VTE events is needed. OBJECTIVES: To investigate the association between features of COPD and risk of venous thromboembolism. METHODS: A retrospective observational clinical study was conducted on 551 consecutive COPD patients visiting the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital between February 2014 and April 2018. Finally, 151 patients were eligible for inclusion. Of these, 29 patients had COPD with VTE and 121 patients had COPD without VTE. Patient informations regarding age, gender, BMI, smoking history, smoking status (package/year), COPD-related symptoms, lung function, number of acute exacerbations and imaging visual emphysema were gathered. RESULTS: Among the 29 VTE patients, 18 patients had PE and five had DVT, while 6 patients had simultaneous PE and DVT. There were statistically significant differences in GOLD grade, Imaging visual emphysema, and frequent acute exacerbations between the two groups. Multivariate logistic regression analysis showed that after adjustment for gender, age, BMI and smoking history, there were statistically significant for visible emphysema (OR = 3.54, 95% CI: 1.13-11.08; P = 0.03) and GOLD grade (OR = 1.77, 95% CI: 1.04-3.01; P = 0.035), but not for frequent acute exacerbations (OR = 1.65, 95% CI: 0.62-4.38; P = 0.31). CONCLUSIONS: Visual emphysema is an independent risk factor for VTE events and the risk of VTE in COPD patients increases with the degree of airway obstruction. However, there is no evidence of an association between exacerbation frequency and VTE events.

Impact of chemotherapy in the prognosis of non-small-cell lung cancer patients with severe to very severe COPD.

BACKGROUND: The aim of the study was to investigate if first-line chemotherapy improves total survival time in non-small-cell lung cancer (NSCLC) patients complicated with severe to very severe COPD. MATERIALS AND METHODS: This retrospective observational clinical study included 267 consecutive NSCLC patients with COPD complications at the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital between January 2009 and January 2018. Sixty-nine evaluable patients were included. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients receiving and those not receiving chemotherapy. RESULTS: Forty-five and 24 patients received first-line chemotherapy plus supportive care and supportive care alone, respectively. Kaplan-Meier curves showed that patients receiving chemotherapy had a statistically significant 6-month longer median overall survival (OS) than that of patients receiving supportive care alone (14.0, 95% CI: 8.5-19.5 vs 8.0, 95% CI: 6.4-9.6, respectively) (chi2=8.857, P=0.003). In the multivariate Cox proportional hazard model adjusted for the most relevant variables, the adjusted hazard ratio (HRadj) differed significantly for the receipt of chemotherapy (HRadj=0.4464, 95% CI: 0.2495-0.7988; P=0.0066) but not for gender (HRadj=0.8527, 95% CI: 0.4461-1.6298; P=0.6297), age (HRadj=1.0021, 95% CI: 0.9609-1.0451; P=0.9214), histology (HRadj=1.4422, 95% CI: 0.6959-2.9889; P=0.3247), cancer stage (HRadj=1.9098, 95% CI: 0.8607-4.2375; P=0.1116), performance status score (HRadj=1.5155, 95% CI: 0.7523-3.0529; P=0.2446), lung function (HRadj=1.3856, 95% CI: 0.7149-2.6857; P=0.3341), or respiratory symptoms (HRadj=1.0518, 95% CI: 0.6032-1.8342; P=0.8586). Patients with grade 3/4 adverse reactions accounted for 29% (13/45) of the chemotherapy group. CONCLUSION: The results indicated that chemotherapy may improve the OS of NSCLC patients with severe to very severe COPD.

[Relationship between nasal inverted papilloma and human papillomavirus subtypes].

OBJECTIVE: To study the distribution of human papillomavirus (HPV) subtypes in nasal inverted papilloma (NIP), and to evaluate the relationship between HPV and NIP. METHODS: Twenty-one HPV subtypes were detected in paraffin-embedded tissues of 101 cases of NIP by flow through hybridization and gene chip (HybriMax), 24 cases of normal nasal mucosa were used as controls. RESULTS: HPV positive rates of NIP were 64.36% (65/101). Benign NIP group, NIP with atypical hyperplasia group, NIP with cancerous group of HPV positive rates were 59.7% (46/77), 81.8% (18/22) and 50% (1/2) respectively. The control group was negative (0/24). The comparison between NIP group and control group was statistically significant (chi(2) = 32.178, P < 0.05). Benign NIP group and NIP with atypical hyperplasia group were compared, but no statistically significance (chi(2) = 3.649, P = 0.056) was found. The constituent ratio of benign NIP group and NIP with atypical hyperplasia group in high, low-risk HPV subtypes infections was compared, a statistically significance (chi(2) = 10.412, P < 0.05) was found. CONCLUSIONS: The occurrence of NIP was related with HPV infection. High-risk HPV subtype infections or multiple infections will prompt benign NIP to NIP with atypical hyperplasia. Understanding the distribution of HPV subtypes in the NIP is helpful to predict the clinical behavior.