Daily Respiratory Research Analysis
Analyzed 199 papers and selected 3 impactful papers.
Summary
Analyzed 199 papers and selected 3 impactful articles.
Selected Articles
1. Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8
Translational analyses across patients and syngeneic models show that NSCLC brain metastases are immune-excluded with reduced CTLs and TLSs, explaining resistance to anti-PD-1 monotherapy. Dual checkpoint blockade (anti-PD-1 plus anti-CTLA-4) restores CTL infiltration/effector function and improves intracranial control and survival in preclinical models, with supportive clinical signals.
Impact: Defines an immune-excluded phenotype in NSCLC brain metastases and demonstrates a mechanistic basis for superior activity of dual checkpoint blockade over anti-PD-1 alone.
Clinical Implications: Supports prioritizing or prospectively testing anti-PD-1 plus anti-CTLA-4 for NSCLC brain metastases and motivates biomarker-driven trials (e.g., CTL/TLS metrics) to overcome intracranial immune exclusion.
Key Findings
- Brain metastases showed fewer CTLs and TLSs than matched primary tumors, indicating an immune-excluded phenotype.
- Clinical analyses suggested improved intracranial disease control with nivolumab plus ipilimumab versus nivolumab alone.
- In a syngeneic brain metastasis model, anti-PD-1 monotherapy failed, whereas dual anti-PD-1/anti-CTLA-4 suppressed tumor growth and extended survival.
- Single-cell RNA-seq, flow cytometry, and immunofluorescence demonstrated increased CTL infiltration and effector function after combination therapy.
Methodological Strengths
- Integration of paired human tissue profiling with syngeneic mouse models for mechanistic validation
- Use of single-cell RNA-seq and multimodal immune profiling to dissect T-cell effector responses
Limitations
- Non-randomized clinical comparisons may be confounded
- Human tissue sample sizes and heterogeneity may limit generalizability
Future Directions: Prospective randomized trials of dual checkpoint blockade in NSCLC brain metastases with biomarker stratification (CTL/TLS density) and exploration of strategies to induce TLS formation.
Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) respond poorly to anti-PD-1 monotherapy, but the underlying immune resistance remains incompletely defined. Here we integrate clinical outcome analyses, paired human tissue profiling and syngeneic mouse models to characterize the BrM immune microenvironment. Clinical analyses suggest improved intracranial disease control with nivolumab plus ipilimumab compared with nivolumab alone. Paired human specimens show that BrMs contain fewer cytotoxic T lymphocytes (CTLs) and tertiary lymphoid structures (TLSs) than primary tumors, defining an immune-excluded phenotype. A syngeneic BrM model recapitulates this phenotype and resists anti-PD-1 monotherapy, whereas combined anti-PD-1 and anti-CTLA-4 blockade suppresses tumor growth and prolongs survival. Single-cell RNA sequencing, flow cytometry and immunofluorescence show increased CTL infiltration and effector function after combination therapy. CD8
2. Cost-Effectiveness of Universal Low-Dose Computed Tomographic Lung Cancer Screening in Singapore.
Using a national Markov cohort model, biennial universal LDCT screening of adults aged 50–75 in Singapore was cost-effective relative to conventional thresholds and captured cancers missed by smoking-based criteria. Risk modeling indicated that if never-smoker risk tools achieve AUROC ≥0.82 (men) or ≥0.81 (women), targeted screening of never-smokers would be as cost-effective as smoking-based eligibility.
Impact: Addresses a critical gap in Asian populations with high proportions of never-smoker lung cancer and provides quantitative thresholds to operationalize risk-based screening beyond smoking history.
Clinical Implications: Health systems should consider pilots of biennial LDCT including never-smokers and invest in validation of never-smoker risk models meeting AUROC thresholds to guide targeted expansion.
Key Findings
- Biennial universal LDCT (50–75 years) was below SGD 100,000/QALY and most likely cost-effective at standard willingness-to-pay.
- USPSTF 2021 criteria were cost-effective but screened only ~8% of males and ~2% of females, leaving ~37% of lung cancers unaddressed.
- Targeted never-smoker screening becomes as cost-effective as smoking-based eligibility if AUROC ≥0.82 (males) or ≥0.81 (females).
Methodological Strengths
- Robust 9-state Markov model parameterized with contemporary national life tables, cancer registry, and smoking prevalence.
- Extensive probabilistic sensitivity analysis (1,000,000 iterations) and explicit AUROC threshold analysis for never-smoker targeting.
Limitations
- Model-based evaluation subject to structural and parameter uncertainty; real-world implementation factors (uptake, capacity) not tested.
- Generalizability to non-Singapore settings and to varying prevalence contexts requires adaptation.
Future Directions: Externally validate never-smoker risk models in Asian populations, implement pilot universal or risk-based screening programs, and assess real-world outcomes, equity, and capacity impacts.
IMPORTANCE: Lung cancer is the leading cause of cancer death in Singapore, with approximately 48% of cases occurring in individuals who have never smoked (never smokers) and 82% diagnosed at late stages (stage III or IV). Current screening guidelines exclude never smokers entirely. OBJECTIVE: To determine whether low-dose computed tomography (LDCT) lung cancer screening including never smokers is cost-effective in Singapore and to identify the minimum risk model performance for targeted never smoker screening. DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation from the perspective of the Singapore health care system used a 9-state Markov cohort model with annual cycles. The model was parameterized with 2023-2024 national life tables, cancer registry incidence from 2019 to 2023, and 2024 smoking prevalence data, simulating adults from 30 to 100 years of age stratified by sex and smoking status. EXPOSURES: Four LDCT screening strategies included no screening, US Preventive Services Task Force (USPSTF) 2021 (annual screening of eligible ever smokers aged 50-80 years), a universal program (annual screening of all adults aged 50-74 years), and Singapore expanded (biennial screening of all adults aged 50-75 years). MAIN OUTCOMES AND MEASURES: Quality-adjusted life-years (QALYs), lifetime costs in 2024 Singapore dollars (SGD), and incremental cost-effectiveness ratios (ICERs). Probabilistic sensitivity analysis used 1 000 000 iterations. Risk threshold analysis identified the minimum area under the receiver operating characteristics curve (AUROC) for targeted never smoker screening. RESULTS: The model reproduced registry-reported late-stage diagnosis (79% modeled vs 82% observed). The USPSTF strategy achieved the lowest ICER (SGD 8741/QALY [US $6523/QALY] for males and SGD 6480/QALY [US $4836/QALY] for females) but screened approximately 8% of males and 2% of females only. Sequential ICERs for extending from the USPSTF strategy to Singapore expanded biennial screening were SGD 86 312/QALY (US $64 412/QALY) for males and SGD 80 881/QALY (US $60 359/QALY) for females, below the SGD 100 000 (US $74 627) benchmark. At SGD 100 000/QALY (US $74 627/QALY) willingness to pay, the Singapore expanded strategy had the highest probability of being cost-effective (61.1% for males and 72.1% for females). A risk prediction model with AUROC of 0.82 or higher for males or 0.81 or higher for females would make targeted never smoker screening as cost-effective as smoking-based criteria. CONCLUSIONS AND RELEVANCE: In this economic evaluation of LDCT lung cancer screening including never smokers in Singapore, targeted ever smoker screening was highly cost-effective but left approximately 37% of lung cancers unaddressed. Universal biennial screening fell below conventional cost-effectiveness thresholds. Extending screening to never smokers warrants consideration as risk prediction models are validated for Asian populations of never smokers.
3. Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16.
Across discovery and two validation cohorts, higher serum CC16 consistently associated with fibrosis-like CT abnormalities up to 3 years after COVID-19 and correlated with airway-to-lung ratio. scRNA-seq and tissue analyses localized expansion of CC16+MUC5B+ epithelial progenitors to small airways, linking a serum biomarker to airway-centered remodeling in post-COVID fibrosis.
Impact: Integrates longitudinal biomarker data with airway imaging metrics and single-cell/tissue validation, offering mechanistic insight and a feasible serum marker (CC16) for prognostic enrichment in post-COVID fibrotic lung disease.
Clinical Implications: CC16 could stratify risk and guide follow-up intensity or trial enrollment for post-COVID fibrosis; emphasis on small-airway pathology suggests targets for future airway-focused therapies.
Key Findings
- Elevated serum CC16 at discharge, 4 months, 15 months, and 3 years associated with CT fibrosis-like abnormalities in discovery and two external validation cohorts.
- CC16 levels showed a linear relationship with increased airway-to-lung ratio, linking biomarker to airway structural changes.
- scRNA-seq and immunofluorescence localized increased SCGB1A1 and CC16/MUC5B coexpressing epithelial cells to small airways and respiratory bronchioles.
Methodological Strengths
- Discovery and external validation across independent cohorts with longitudinal sampling up to 3 years.
- Mechanistic triangulation via scRNA-seq and tissue immunofluorescence linking serum biomarker to small-airway cellular remodeling.
Limitations
- Observational design limits causal inference; biomarker thresholds for clinical decision-making are not established.
- Cohort composition and referral patterns may affect generalizability; intercurrent therapies not fully controlled.
Future Directions: Prospective validation of CC16 thresholds for risk stratification, integration into trial enrichment strategies, and interventional studies targeting small-airway progenitor dysregulation.
BACKGROUNDThere are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post-COVID-19 pulmonary fibrosis.METHODSWe tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTSAmong 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATIONNot applicable.FUNDINGDepartment of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.