BACKGROUND:Osteoarthritis (OA) involves extracellular matrix (ECM) degradation, inflammation, oxidative stress, mitochondrial dysfunction, and chondrocyte loss. Methylnissolin (MN) is a natural isoflavonoid with anti-inflammatory and antioxidant properties, but its effects in OA remain unclear. PURPOSE:To evaluate the chondroprotective effects of MN in experimental OA and examine the involvement of PI3K-AKT-NF-κB signaling. METHODS:MN was investigated in interleukin-1β (IL-1β)-stimulated primary rat chondrocytes and a rat destabilization of the medial meniscus model. ECM metabolism, inflammation, oxidative stress, mitochondrial function, and apoptosis were assessed using molecular, cellular, and histological methods. Network pharmacology and molecular docking were used to identify candidate targets and pathways, and the PI3K activator 740Y-P was used for pharmacological reversal experiments. RESULTS:MN reduced IL-1β-induced ECM catabolism and inflammatory mediator production, decreased intracellular and mitochondrial reactive oxygen species, preserved mitochondrial membrane potential, and inhibited chondrocyte apoptosis. In vivo, MN alleviated cartilage degeneration and improved histological outcomes. Network analysis identified 39 overlapping MN- and OA-related targets and highlighted ECM remodeling and PI3K-AKT-related processes. MN reduced IL-1β-induced activation of PI3K-AKT-NF-κB signaling, whereas 740Y-P partially reversed several protective effects. CONCLUSION:MN protects against experimental OA by preserving ECM homeostasis and attenuating inflammatory, oxidative, mitochondrial, and apoptotic injury. These effects are associated, at least in part, with reduced PI3K-AKT-NF-κB pathway activation, while the computational findings remain hypothesis-generating.

Acute hypoxemic respiratory failure (AHRF) is a common critical condition in the intensive care unit (ICU). Accurate early prediction of the risk of death is of great significance for clinical decision-making. Although HACOR score was initially used to predict the failure of non-invasive ventilation in acute hypoxemic respiratory failure (AHRF) patients, the relationship between the HACOR score and the mortality remains unclear. Therefore, a retrospective cohort study was conducted to evaluate the ability of the HACOR score to predict mortality risk in patients with AHRF. Patients diagnosed with AHRF were extracted from the MIMIC-IV database and divided into two groups (low‑risk < 6 vs. high‑risk ≥ 6) based on the median HACOR score. The relationship between the HACOR score and all‑cause mortality at 28, 90, and 365 days was evaluated. To investigate the association between HACOR score and mortality in AHRF patients, restricted cubic spline (RCS) analysis and Cox proportional hazards regression were performed. This study included 2774 patients (median age 68 years, IQR 57–79; 56.1

This case report explores the role of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) monitoring in predicting tumor recurrence or metastasis after consolidative surgery in a patient with ALK-rearranged non-small cell lung cancer (NSCLC). We present a case of a 43-year-old female patient with stage IVA ALK-rearranged NSCLC who initially responded to six months of Alectinib targeted therapy, underwent consolidative surgery with postoperative pathology confirming complete response in the resected primary tumor and lymph nodes, and continued two years of maintenance therapy. During this period, three consecutive MRD tests showed negative results, leading to discontinuation of postoperative therapy. However, two months after stopping Alectinib, the patient developed new brain metastasis in the occipital lobe, necessitating re-initiation of targeted treatment. This case demonstrates the current limitations of ctDNA-based MRD monitoring in reliably predicting recurrence and determining optimal treatment duration in NSCLC. Although MRD monitoring represents an important advancement in NSCLC management, our findings emphasize the need for additional research to validate its clinical applications, particularly in guiding treatment decisions and predicting disease recurrence. The results suggest that larger prospective studies are required to establish evidence-based protocols for MRD monitoring in NSCLC patients.

Rationale: Thoracoscopy guidelines recommend inducing artificial pneumothorax before medical thoracoscopy in patients with minimal or absent pleural effusion. However, this procedure is complex and carries a higher risk; there is a lack of trials comparing the effectiveness and safety of performing artificial pneumothorax versus not performing it in these cases. Methods In this multicenter randomized non-inferiority trial, patients with minimal or absent pleural effusion requiring medical thoracoscopy were randomized 1:1 to either an artificial pneumothorax (AP) group or a non-artificial pneumothorax (non-AP) group. The primary outcome was pleural access success rate, with a non-inferiority margin of 10 percentage points. Secondary outcomes included pathological confirmation rates, complication rates, operation length, air leak duration, drain removal time, chest pain scores, and 90-day mortality. Results A total of 204 participants were equally allocated to the AP group (n=102) and the non-AP group (n=102). Pleural access success rate was 95.0% in the non-AP group and 78.4% in the AP group (difference: 16.6 percentage points; 95% CI, 7.6 to 25.7; P<0.0001 for non-inferiority). Complications occurred in 14.9% of non-AP and 17.6% of AP patients (difference, 2.7 percentage points; 95% CI, -12.9 to 7.3; P = 0.589). Conclusions In patients with minimal or absent pleural effusion, avoiding artificial pneumothorax induction prior to medical thoracoscopy demonstrated non-inferiority for successful pleural access compared to inducing artificial pneumothorax, while maintaining comparable complication rates. Keywords: Medical Thoracoscopy; interventional pulmonology (including bronchoscopy and thoracoscopy); pleural disease

Upon the activation of inflammasomes, inflammatory caspases cleave and activate gasdermin D (GSDMD), leading to pore formation that causes cell membrane rupture and amplifies downstream inflammatory responses. Dysregulated inflammasome activation and pyroptosis signaling pathways are implicated in numerous inflammatory diseases. In our work, a set of novel thiazole amide compounds with inhibitory activity against NLRP3 inflammasome-induced pyroptosis was identified. Of all the compounds tested, compound 21 demonstrated the most potent anti-pyroptotic effects. It suppressed GSDMD cleavage and decreased IL-1β and lactate dehydrogenase (LDH) release in a concentration-dependent manner. Compound 21 bound to NLRP3 protein and increased the thermal stability of NLRP3 concentration-dependently. The molecular docking and dynamics simulations revealed that compound 21 binds to the NLRP3 protein's active site, suppressing inflammasome activation. Further investigations showed that compound 21 also partially blocked upstream NF-κB signaling and downstream GSDMD N-terminal domain (GSDMD-NT) oligomerization, which explains its broad inhibitory effects on pyroptosis driven by multiple inflammasomes. Overall, this study presents a promising thiazole amide compound with inhibitory activity against inflammasome activation and subsequent pyroptosis, warranting further exploration.

Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR). For driver mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) is the standard treatment, but acquired resistance is inevitable. There is currently no standard treatment for first-line TKI-resistant NSCLC patients. In recent years, although immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for advanced NSCLC without driver gene mutations, the clinical efficacy of these agents in patients with advanced NSCLC harboring EGFR mutations remains limited. Whether ICIs are suitable for patients with EGFR-mutated advanced NSCLC still warrants further investigation. This review summarizes several clinically utilized ICIs, presents clinical evidence regarding the efficacy of immunotherapy in patients with EGFR-mutated advanced NSCLC, and identifies EGFR-mutated subpopulations that may benefit from ICI treatment. On this basis, we explored more effective therapeutic strategies to extend the benefits of immunotherapy to a larger cohort of patients with EGFR-mutated NSCLC.

Background This study aimed to compare the efficacy and safety of rezivertinib (BPI-7711) and gefitinib as first-line therapies in patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer (NSCLC). Methods This multicentre, double-blind, randomised, phase 3 study (REZOR) included eligible patients from 50 hospitals across China. Those who had been histologically or cytologically confirmed as having NSCLC with EGFR exon 19 deletion or exon 21 Leu858Arg mutation by central laboratory were randomly assigned (1:1) to receive once daily either rezivertinib 180 mg or gefitinib 250 mg, until unacceptable toxicity occurred, disease progression, or other treatment discontinuation criteria were met. Each cycle lasted for 21 days. The primary endpoint was progression-free survival evaluated by masked independent central review (MICR) in the intention-to-treat set. This trial is registered with ClinicalTrials.gov, NCT03866499 and follow-up is ongoing. Findings Between July 15, 2019, and Feb 14, 2022, 695 patients were screened. Among them, 369 eligible patients were randomly assigned to receive either rezivertinib 180 mg/day plus placebo (n=184) or gefitinib 250 mg/day plus placebo (n=185) in a 1:1 ratio; all of eligible participants were included in the intention-to-treat set. Median MICR-assessed progression-free survival was 193 months (95% CI 138-221) in the rezivertinib group and 96 months (84-113) in the gefitinib group (hazard ratio [HR] 048, 95% CI 036-063; p<00001) and the prespecified subgroup efficacy analysis showed consistent results. Median duration of exposure was 160 months (95% CI 00-297) in the rezivertinib group and 110 months (00-289) in the gefitinib group. Grade 3 or higher treatment-emergent adverse events (82 [45%] of 184 in the rezivertinib group; 80 [43%] of 185 in the gefitinib group) and treatment-related adverse events (TRAEs; 43 [23%] of 184 in the rezivertinib group; 43 [23%] of 185 in the gefitinib group) were similar in both groups. One patient died from a TRAE in the rezivertinib group, due to pneumonia and interstitial lung disease. Interpretation Our findings suggested that rezivertinib is a potential choice for patients with EGFR-mutated locally advanced or metastatic NSCLC as first-line therapy, owing to the superior overall efficacy and subgroup progression-free survival compared with gefitinib in targeted patients. No new safety signals were identified. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

e20547 Background: EGFR-TKIs is standard of care for treatment-naïve EGFR mutated ( EGFRm) advanced NSCLC (aNSCLC). The clinical outcome after 1L EGFR-TKI in clinical practice is not well studied prospectively. Herein, we reported the real-world clinical outcomes in Chinese EGFRm aNSCLC progressed from 1L EGFR-TKI. Methods: This prospective, observational study enrolled 300 Chinese patients (pts) from 16 sites between March, 2020 and August, 2021. At data cut-off date of August 27, 2023. 291 eligible pts were included into the full analysis set (FAS) and 225 pts in FAS received second-line EGFR-TKI or chemotherapy were included into outcome analysis set (OAS). The clinical outcome (PFS and OS, measured from 2nd line treatment) were presented. Results: The median age of 291 pts in FAS was 62 years, 57.0% was females and 29.3% pts with brain metastasis. EGFR mutation included 19del (143 pts, 49.1%), L858R (126 pts, 43.3%) and others (22 pts, 7.6%). 273 (93.8%) and 18 (6.2%) pts progressed from 1L 1G/2G EGFR-TKIs and 3G EGFR-TKIs, respectively. In OAS, overall mPFS and mOS in T790M + patients (90 pts) who received 2L 3G EGFR-TKIs were 14.7 (10.40-18.0) and 32 (25.20-NE) months, respectively. The mPFS and mOS by type of sample and T790M test results were presented in table. 85 pts with T790M- who progressed from 1L 1/2G EGFR-TKIs, including 51, 9 and 25 pts received 3G EGFR-TKIs, prior EGFR-TKIs plus local therapy, and chemotherapy as 2L therapy, respectively. The corresponding mPFS were 7.60 (95% CI, 4.70-10.40), 10.20 (2.30-14.90), and 4.90 (2.50-6.90) months, respectively. The corresponding mOS were 21.20 (12.10-NE), 16.60 (6.00-28.60), and 15.00 (9.40-NE) months, respectively. For T790M- patients with 19del (21 pts) and L858R (26 pts) mutation who received 2L 3G EGFR-TKIs, the mPFS was 21.00 (2.60-NE), and 8.00 (5.00-10.40) months, respectively. mOS was NE (21.00-NE) and 16.60 (8.20-24.60) months, respectively. 12 pts progressed from 1L 3G EGFR-TKIs, 10 and 2 pts received chemotherapy-based regimen and prior EGFR-TKIs plus local therapy as 2L therapy, respectively. The corresponding overall mPFS were 8.40 (95% CI: 1.20-11.80) months. The overall mOS was 14.20 (2.80-NE) months. Conclusions: The real-world treatment pattern and corresponding prognosis of EGFR-mutated NSCLC progressed from first-line EGFR-TKI were diverse, and among them those who received 3G EGFR-TKI at progression showed a better clinical outcome. These results supplemented the clinical evidence for the use of 3G EGFR-TKIs in EGFRm aNSCLC pts who progressed from 1L 1/2G EGFR-TKIs in the real-world setting. Clinical trial information: NCT04207775 . [Table: see text]

Abstract Chronic obstructive pulmonary disease (COPD) is characterised by persistent airway inflammation even after cigarette smoking cessation. Neutrophil extracellular traps (NETs) have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke (CS). However, whether and how NETs contribute to sustained airway inflammation in COPD remain unclear. This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD, employing human neutrophils, airway epithelial cells (AECs), dendritic cells (DCs), and a long-term CS-induced COPD mouse model, alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice (cGAS -−/− , TLR9 −/− ); Additionally, bronchoalveolar lavage fluid (BALF) of COPD patients was examined. Neutrophils from COPD patients released greater cigarette smoke extract (CSE)-induced NETs (CSE-NETs) due to mitochondrial respiratory chain dysfunction. These CSE-NETs, containing oxidatively-damaged DNA (NETs-DNA), promoted AECs proliferation, nuclear factor kappa B (NF-κB) activation, NF-κB-dependent cytokines and type-I interferons production, and DC maturation, which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9. In the COPD mouse model, blocking NETs-DNA-sensing via cGAS −/− and TLR9 −/− mice, inhibiting NETosis using mitoTEMPO, and degrading NETs-DNA with DNase-I, respectively, reduced NETs infiltrations, airway inflammation, NF-κB activation and NF-κB-dependent cytokines, but not type-I interferons due to IFN-α/β receptor degradation. Elevated NETs components (myeloperoxidase and neutrophil elastase activity) in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels, but not type-I interferon levels. In conclusion, NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD. Therefore, targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.

Drug exposure during pregnancy lacks global fetal safety data. The maternal drug exposure birth cohort (DEBC) study, a prospective longitudinal investigation, aims to explore the correlation of maternal drug exposure during pregnancy with pregnancy outcomes, and establish a human biospecimen biobank. Here we describe the process of establishing DEBC and show that the drug exposure rate in the first trimester of pregnant women in DEBC (n = 112,986) is 30.70%. Among the drugs used, dydrogesterone and progesterone have the highest exposure rates, which are 11.97% and 10.82%, respectively. The overall incidence of adverse pregnancy outcomes is 13.49%. Dydrogesterone exposure during the first trimester is correlated with higher incidences of stillbirth, preterm birth, low birth weight, and birth defects, along with a lower incidence of miscarriage/abortion. Due to the limitations of this cohort study, causative conclusions cannot be drawn. Further follow-up and in-depth data analysis are planned for future studies. Drug exposure during pregnancy lacks sufficient fetal safety information world-widely. Here, the authors report the establishment a multi-center birth cohort to explore the correlation of maternal drug exposure during pregnancy with pregnancy outcomes.

Background: Programmed Death 1 (PD-1) has a controversial role in the treatment of Tuberculosis (TB). Several clinical cases of TB development have been reported by administration of anti–PD-1 antibodies for patients with advanced unresectable cancers. Case presentation: In this article, we report an interesting case about a male patient with history of cured pulmonary tuberculosis and a 4-month history of repeated hemoptysis. Imaging showed one mass in the lower lobe of left lung and the other in the left upper lobe. The diagnosis of Non-Small-Ccell Lung Cancer (NSCLC) was determined by biopsy specimens in the lower lobe nodule and cured pulmonary tuberculosis determined by past medical history. He was given neoadjuvant treatment with an anti–PD-1 inhibitor and chemotherapy. He underwent surgery. Pathological examination revealed Mtb in left upper lobe nodule but previous imaging showed without reactivation and slight reduction in tubercular infection inflammation. The left lower lobe nodule was poorly differentiated carcinoma. Conclusions: Overall, the role of immune checkpoint inhibitors in patients with cancers and latent tuberculosis infection is inconclusive. Although we cannot establish whether patients with stage IIIA NSCLC and concurrent latent pulmonary tuberculosis after surgical evaluation can receive a PD-1 and chemotherapy as neoadjuvant therapy without the activation of pulmonary tuberculosis, our case endorses the need of further evaluation.

BACKGROUND:Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS:This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS:Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION:Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING:Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Background Zinc glycine chelate (Zn-Gly) has anti-inflammation and growth-promoting properties; however, the mechanism of Zn-Gly contribution to gut barrier function in Cherry Valley ducks during intestinal inflammation is unknown. Three-hundred 1-day-old ducks were divided into 5 groups (6 replicates and 10 ducks per replicate) in a completely randomized design: the control and dextran sulfate sodium (DSS) groups were fed a corn-soybean meal basal diet, and experimental groups received supplements of 70, 120 or 170 mg/kg Zn in form of Zn-Gly. The DSS and treatment groups were given 2 mL of 0.45 g/mL DSS daily during d 15–21, and the control group received normal saline. The experiment lasted 21 d. Results Compared with DSS group, 70, 120 and 170 mg/kg Zn significantly increased body weight (BW), villus height and the ratio of villus to crypt, and significantly decreased the crypt depth of jejunum at 21 d. The number of goblet cells in jejunal villi in the Zn-Gly group was significantly increased by periodic acid-Schiff staining. Compared with control, the content of intestinal permeability marker D-lactic acid (D-LA) and fluxes of fluorescein isothiocyanate (FITC-D) in plasma of DSS group significantly increased, and 170 mg/kg Zn supplementation significantly decreased the D-LA content and FITC-D fluxes. Compared with control, contents of plasma, jejunum endotoxin and jejunum pro-inflammatory factors IL-1β, IL-6 and TNF-α were significantly increased in DSS group, and were significantly decreased by 170 mg/kg Zn supplementation. Dietary Zn significantly increased the contents of anti-inflammatory factors IL-10, IL-22 and sIgA and IgG in jejunum. Real-time PCR and Western blot results showed that 170 mg/kg Zn supplementation significantly increased mRNA expression levels of CLDN-1 and expression of OCLN protein in jejunum, and decreased gene and protein expression of CLDN-2 compared with DSS group. The 120 mg/kg Zn significantly promoted the expressions of IL-22 and IgA . Dietary Zn-Gly supplementation significantly decreased pro-inflammatory genes IL-8 and TNF-α expression levels and TNF-α protein expression in jejunum. Additionally, Zn significantly reduced the gene and protein expression of TLR4, MYD88 and NF-κB p65. Conclusions Zn-Gly improved duck BW and alleviated intestinal injury by regulating intestinal morphology, barrier function and gut inflammation-related signal pathways TLR4/MYD88/NF-κB p65.

ABSTRACT Objectives Treatment guidelines have recommended tiotropium bromide inhalation (TBI), a long-acting muscarinic antagonist, for chronic obstructive pulmonary disease (COPD); however, its efficacy in symptomatic Chinese patients with COPD remains uninvestigated. Methods This multicenter, prospective, observational study enrolled patients with COPD assessment test (CAT) scores exceeding 10 points from 19 hospitals spread across China. All patients received TBI and underwent follow-up for 3 months. The demographic and clinical information were assessed. Results The final analysis included 378 patients. The forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) of all participants improved markedly after 3 months of treatment (FEV1: mean 1.33 L versus 1.61 L, P < 0.001; FEV1/FVC: mean 0.53 versus 0.62, P < 0.001). The mean CAT scores decreased from 26.56 to 16.28 (P < 0.001). Patients classified into group D based on the Global Initiative for COPD guidelines showed greater improvement in FEV1 and FEV1/FVC than that in patients in group B. The proportion of patients with acute exacerbations also declined from 28.6% in the first month to 4.2% in the third month. Conclusion TBI for 3 months could effectively and safely attenuate symptoms and airflow obstruction in symptomatic Chinese patients with COPD.

e14578 Background: According to studies in patients (pts) with solid tumors, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) plays an important role in tumor immunosurveillance. The preliminary results showed that IBI939 plus sintilimab demonstrated improved PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC pts with no prior systemic treatment (Ying Cheng et al. ESMO-IO, 2022). Here we report updated efficacy and safety data of this study. Methods: Eligible pts with systemic treatment-naïve, advanced or metastatic NSCLC, PD-L1 TPS ≥ 50%, and driver gene negative were enrolled and randomized 2:1 to IBI939 20 mg/kg plus sintilimab 200 mg IV Q3W (arm A) or sintilimab 200 mg monotherapy IV Q3W (arm B). The primary objective was to evaluate the ORR per RECIST v1.1. The secondary objectives include evaluation of PFS per RECIST v1.1, OS, and safety. Results: Of 42 pts enrolled, 28 pts (median age: 65; adenocarcinoma: n=19; brain metastasis: n=7) and 14 pts (median age: 58; adenocarcinoma: n=6; brain metastasis: n=1) were in arm A and arm B, respectively. As of Jan 1 st , 2023, with a median PFS follow-up of 12.2 months (95% CI, 11.1-13.9) in arm A and 11.3 months (95% CI, 10.8-13.6) in arm B. The median PFS per investigator was 13.2 months (95% CI, 6.7-16.5) in arm A vs 6.4 months (95% CI, 1.4-NA) in arm B (HR: 0.62; 95% CI, 0.26-1.43). All 42 pts were included for safety analysis. The overall safety profile was consistent with the latest previous report, with no new safety signals identified in each arm. The incidence of TRAEs was 96.4% vs 78.6% (5 pts in arm A and 6 pts in arm B experienced ≥ grade 3 events), respectively. Grade ≥ 3 immune-related AEs (determined by the investigator) were reported in 3 (10.7%) pts in arm A and 4 (28.6%) pts in arm B. All reported irAEs were manageable. One pt in each arm experienced TEAE leading to end of treatment. There was no TEAE leading to death happened in arm A. Two pts experienced grade 5 TEAE in arm B, which was unknown cause of death and respiratory failure. Conclusions: With longer follow-up time, IBI939 plus sintilimab demonstrated durable PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC patients with no prior systemic treatment. Clinical trial information: NCT04672369 .

9110 Background: SY-3505 is a potent, brain-penetrant, 3 rd -generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1 st and 2 nd -gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2 nd -gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2 nd -gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .

Although the treatment of aspergillosis has been studied for years, the optimal nonsurgical treatment of chronic cavitary pulmonary aspergillosis (CCPA) remains unsatisfactory, especially in lung cancer. We report two advanced non-small cell lung cancer (NSCLC) patients who recovered from CCPA following instillation of Amphotericin B (AmB) by bronchoscopy combined with systemic voriconazole. The first patient was diagnosed with lung adenocarcinoma after right upper lobe resection and was treated with anaplastic lymphoma kinase-targeted therapy. Chest computed tomography (CT) revealed a right pulmonary cavity containing solid materials. The second patient was diagnosed with squamous cell carcinoma and received immunotherapy following surgery, chemotherapy, and radiotherapy. Chest CT tomography revealed a mass in the right lung cavity. Both patients' cultures and next-generation sequencing of their bronchoalveolar lavage (BAL) samples revealed presence of Aspergillus fumigatus. In addition, the galactomannan test of both patients BAL samples was positive. Systemic voriconazole was prescribed based on in vitro susceptibility testing. The chest images and clinical symptoms of both patients did not improve after one month of voriconazole therapy within the therapeutic blood concentration. Considering the low local concentrations of antifungals against CCPA, AmB instillation by bronchoscopy combined with systemic voriconazole was utilized. The chest CT images and clinical symptoms of both patients markedly improved in the following third month. Instillation of AmB combined with systemic voriconazole may be a promising treatment option for NSCLC patients with CCPA who fail voriconazole monotherapy.

Chronic obstructive pulmonary disease (COPD) is an important public health challenge worldwide, and is usually caused by significant exposure to noxious agents, particularly cigarette smoke. Recent studies have revealed that excessive production of neutrophil extracellular traps (NETs) in the airways is associated with disease severity in COPD patients. NETs are extracellular neutrophil-derived structures composed of chromatin fibers decorated with histones and granule proteases including neutrophil elastase (NE). However, the effective prevention of NET formation in COPD remains elusive. Here, we demonstrated that treatment with GW311616A, a potent and selective inhibitor of NE, prevented cigarette smoke extract (CSE)-induced NET formation in human neutrophils by blocking NE nuclear translocation and subsequent chromatin decondensation. Inhibition of NE also abrogated CSE-induced ROS production and migration impairment of neutrophils. Administration of GW311616A in vivo substantially reduced pulmonary generation of NETs while attenuating the key pathological changes in COPD, including airway leukocyte infiltration, mucus-secreting goblet cell hyperplasia, and emphysema-like alveolar destruction in a mouse model of COPD induced by chronic cigarette smoke exposure. Mice treated with GW311616A also showed significant attenuation of neutrophil numbers and percentages and the levels of neutrophil chemotactic factors (LTB4, KC, and CXCL5) and proinflammatory cytokines (IL-1β, and TNF-α) in bronchoalveolar lavage fluid compared to mice treated with cigarette smoke exposure only. Furthermore, GW311616A treatment considerably improved lung function in the COPD mouse model, including preventing the decline of FEV100/FVC and delta PEF as well as inhibiting the increase in FRC, TLC, and FRC/TLC. Overall, our study suggests that NE plays a critical role in cigarette smoke-induced NET formation by neutrophils and that inhibition of NE is a promising strategy to suppress NET-mediated pathophysiological changes in COPD.