Citations

Abstract Introduction: The data on outcomes comparing lung transplantation with ABO-identical versus ABO-compatible blood group is limited. Composite Allocation Score(CAS) was introduced on March 9th, 2023, and has considered additional points for the difficult-to-match blood group. We aimed to study the trend and outcomes of patients who underwent lung transplants with ABO identical versus compatible blood groups. Methods: We queried the United Network of Organ Sharing (UNOS) database of those who underwent lung transplantation between 10/1/1987 to 3/31/2024 and compared the outcomes between those who had ABO-identical vs ABO-compatible blood groups. Combined organ transplants and recipients age <18 were excluded. Results: A total of 50,406 patients were included in our study, out of which 4,111 (8.15%) were ABO-compatible and 47,347 (91.85%) were ABO-identical. Among the recipient demographics, the ABO-compatible group compared to the ABO-identical group showed a lesser lung allocation score (40 ± 16 vs 42 ± 16), but higher A-blood group (59% vs 38%), obstructive lung disease (38% vs 33%), CAS (49 ± 13 vs 47 ± 10), mechanical ventilator support pre-transplant (6.2% vs 5.2%), need for ex-vivo lung perfusion (9.6% vs 5.8%) and listing for single lung transplant (39% vs 34%), all p<0.05. The donors for the ABO-compatible group had a closer distance to the transplant center (205 ± 285 vs 226 ± 265 nautical miles), lesser white race (61% vs 64%), and gender mismatch (30% vs 32%) but higher male gender (64% vs 61%), O-blood group (81% vs 49%) and ethnicity mismatch (45% vs 41%), all p<0.05. The univariate analysis showed a higher 30-day (7.2% vs 5.8%), 1-year (22% vs 19%), and 5-year (54% vs 50%) mortality among patients with ABO-compatible compared to ABO-identical recipients, all p<0.001. However, the adjusted odds ratio of 30-day (0.76, 95% CI 0.36-1.47, p=0.4), 1-year (1.07, 95% CI 0.69-1.66, p=0.7) and 5-year (0.69, 95% CI 0.46-1.05, p=0.081) mortality were not statistically significant with ABO-identical when compared to ABO-compatible group on adjusting to the covariates in the multivariate analysis. The trend of ABO-compatible lung transplantation has been increasing with the introduction of CAS (figure 1). Conclusion: Patients who underwent lung transplantation with the ABO-compatible blood group donor organs had similar outcomes compared to the ABO-identical blood group. The findings of our study reinforce the importance of increasing the use of ABO-compatible organs to enhance the lung transplantation rate, aligning with the observed trend following the introduction of CAS.

Abstract RATIONALE: Airway remodeling, a key characteristic of severe asthma, leads to progressive loss of lung function and incomplete reversibility of airflow obstruction. We examined the effect of benralizumab on lung function in patients from the pooled SIROCCO (Bleecker ER, et al. Lancet 2016; PMID: 27609408) and CALIMA (FitzGerald JM, et al. Lancet 2016; PMID: 27609406) studies, utilizing a new analysis of spirometry to highlight important changes in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) throughout the studies. METHODS: This retrospective analysis pooled data from the randomized, placebo-controlled, double-blind Phase 3 SIROCCO and CALIMA studies. SIROCCO enrolled patients with severe asthma, while CALIMA enrolled patients with moderate-to-severe asthma, both with a planned 2:1 randomization for baseline blood eosinophils ≥300 cells/μL versus <300 cells/μL. All patients (aged 12-75 years) had ≥2 exacerbations in the previous year, despite use of medium- to high-dose inhaled corticosteroids plus additional controllers. Patients in this analysis received subcutaneous benralizumab 30 mg every 8 weeks (Q8W; first three doses given every 4 weeks) for 48 weeks in SIROCCO and 56 weeks in CALIMA. The changes in FEV1 and FVC following bronchodilator (BD) were measured at baseline and study end. Effects on FEV1 and FVC were further stratified by baseline eosinophil count (≥300 cells/μL or <300 cells/μL). Results are reported as mean (standard deviation). RESULTS: Overall, 839 patients received benralizumab Q8W; 557 had a baseline eosinophil count of ≥300 cells/μL and 282 had <300 cells/μL. At baseline, pre- and post-BD FEV1 were 1722 mL (615; n=837) and 2128 mL (755; n=813). At study end, pre- and post-BD FEV1 were 2029 mL (756; n=735) and 2225 mL (800; n=738). At baseline, pre- and post-BD FVC were 2865 mL (905; n=837) and 3285 mL (971; n=813). At study end, pre- and post-BD FVC were 3214 mL (1010; n=735) and 3379 mL (1021; n=738). Pre-BD FEV1 and FVC improved by 307 mL and 349 mL and post-BD FEV1 and FVC improved by 97 mL and 94 mL between baseline and study end, respectively. Stratified by baseline eosinophil count, findings were similar in both groups (Figure). CONCLUSIONS: Benralizumab treatment resulted in both improved FEV1 and FVC while maintaining BD response in patients with uncontrolled, moderate-to-severe asthma. Improvements were seen in patients with baseline eosinophil counts of both ≥300 cells/μL and <300 cells/μL. These results may reflect reduced hyperinflation, potentially due to improved airway inflammation and mucus plugging.

ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

EndMT has been reported to contribute to the pathogenesis of PAH. In this study, we aimed to determine the role of Ca 2+ signaling in the development of EndMT in human lung vascular endothelial cells. Our data suggest that TGF-β 1 requires store-operated Ca 2+ entry through STIM1/Orai channels to induce SNAI-mediated EndMT. For the first time, we demonstrated that TGF-β 1 -induced EndMT is a Ca 2+ -dependent event, whereas inhibition of STIM1/Orai interaction attenuated EndMT in response to TGF-β 1 .

Abstract Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. In this study, we reveal that lung mesenchymal Yap levels and fitness antagonize epithelial Yap levels and stemness during lung development and repair following bleomycin injury. Elevated mesenchymal Yap signaling and fitness antagonize epithelial Yap levels and stemness, accelerating alveolar epithelial differentiation while impairing branching during lung development or bronchiolization after bleomycin injury. Conversely, mesenchymal Snail/Slug sequesters Yap/Taz to direct an adipogenic differentiation program towards alveolar fibroblast 1 (AF1) during both lung development and the resolution of pulmonary fibrosis. On the other hand, Yap/Myc-Tead binding instructs a myogenic differentiation program. Through our experiments and modeling, we identify tissue-scale mechanical cooperation as a pivotal factor in orchestrating organ formation and regeneration.

Perioperative therapy has become a critical component in the management of resectable non–small cell lung cancer (NSCLC), particularly in the era of precision medicine. Although molecular testing is standard in metastatic NSCLC, its incorporation into early-stage disease remains essential for guiding treatment decisions. Reflex molecular testing pathways are necessary to optimize tissue utilization and ensure timely results. However, liquid biopsies, although valuable in advanced disease, have limited sensitivity in early-stage NSCLC, reinforcing the need for tissue-based next-generation sequencing. Targeted therapies have revolutionized treatment for oncogene-driven NSCLC, with adjuvant osimertinib now standard for EGFR-mutant disease and ongoing investigations into ALK tyrosine kinase inhibitors (TKIs). However, unanswered questions remain regarding the inclusion of perioperative TKI therapy, the role of molecular residual disease assessment, and whether specific TKIs offer greater benefit for high-risk subgroups. The role of immunotherapy (IO) in oncogene-driven NSCLC remains controversial. Although perioperative chemo-IO has demonstrated survival benefits in unselected NSCLC, its efficacy in EGFR, ALK, and other actionable alterations is unclear. Tumors harboring KRAS and BRAF mutations may respond better because of a more immune-inflamed microenvironment, and remains an active area of investigation. As the landscape of perioperative therapy continues to evolve, ongoing trials will help define the optimal integration of targeted therapies and IO in oncogene-driven NSCLC. Addressing these unanswered questions will be crucial in refining treatment strategies and improving patient outcomes.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534