Myofibroblast differentiation is a pivotal event in idiopathic pulmonary fibrosis (IPF) and is driven by TGF-β1-dependent PTEN destabilization; however, the intermediate regulators remain incompletely defined. We tested three lung fibroblast cell lines (one normal and two IPF-derived) and identified the phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (PREX2)-membrane-associated guanylate kinase inverted 2 (MAGI2) as a critical regulator of myofibroblast differentiation. Loss-of-function analysis of MAGI2 in normal human lung fibroblasts revealed a shift toward a myofibroblast phenotype characterized by abundant α-SMA expression. In vitro experiments revealed increased PREX2 expression and decreased MAGI2 expression in IPF-derived lung fibroblasts compared with those in normal lung fibroblasts. Consistent with this finding, in vivo experiments using bleomycin-induced murine pulmonary fibrosis revealed PREX2 upregulation in contrast to MAGI2 downregulation with the progression of lesions. Notably, PREX2 depletion in IPF-derived cells enhanced MAGI2 expression, mitigating TGF-β1-induced α-SMA expression. Conversely, PREX2 overexpression promoted myofibroblast differentiation, as evidenced by MAGI2 downregulation followed by marked α-SMA expression. The PREX2-targeting suppressive miR-338-3p upregulated MAGI2 expression in vitro and ameliorated bleomycin-induced murine pulmonary fibrosis in vivo. Immunohistochemical staining of PREX2 on lung samples obtained from patients with IPF delineated that PREX2 was exclusively expressed in the fibroblastic foci of IPF-affected lungs. Fluorescence immunostaining revealed PREX2 colocalization with α-SMA in myofibroblasts within fibroblastic foci, corroborating our hypothesis. These findings suggest that MAGI2 acts as a negative regulator of myofibroblast differentiation by stabilizing PTEN, whereas PREX2 is aberrantly expressed in the fibrotic milieu, negatively modulating MAGI2, thereby accelerating pulmonary fibrosis.

Introduction: Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. Methods: We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Results: Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. Conclusions: This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.

Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk of lung cancer, with cumulative incidence rates of 3.3

Background:The combination of an anti-programmed death-ligand 1 (PD-L1) antibody with etoposide and either carboplatin or cisplatin (platinum-etoposide) has become the first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Although previous studies have examined the relationship between geriatric assessments and treatment efficacy, the association with treatment tolerability in elderly patients with ES-SCLC remains insufficiently understood. We aimed to evaluate the association between low body mass index (BMI)-a component of geriatric assessment-and treatment tolerability. Methods:We conducted a retrospective analysis of patients aged ≥65 years with ES-SCLC who received anti-PD-L1 antibody plus platinum-etoposide at a single center between August 2019 and April 2024. Tolerability was defined as the completion of four cycles of anti-PD-L1 antibody combined with platinum-etoposide. We also assessed treatment efficacy and safety profiles. Results:A total of 71 patients were included, with a median age of 73 years (range: 65-91 years). Of these, 51 patients (72%) were male, and 54 (76%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Sixteen patients (23%) showed a low BMI (<19 kg/m2), whereas 55 (77%) showed a non-low BMI. Tolerability was achieved in 8 patients (50%) with low BMI compared with 44 patients (80%) with non-low BMI. There were no significant differences in overall survival, progression-free survival, or the incidence of grade ≥3 adverse events among the two groups. In multivariate analysis, low BMI and ECOG-PS ≥2 were independently associated with reduced treatment tolerability [odds ratio (OR): 0.24, 95% confidence interval (CI): 0.06-0.88, P=0.03; OR: 0.13, 95% CI: 0.04-0.48, P<0.01, respectively]. Conclusions:Low BMI and poor performance status were independently associated with decreased tolerability to anti-PD-L1 antibody combined with platinum-etoposide in elderly patients with ES-SCLC. These findings underscore the importance of incorporating geriatric assessments into treatment decision-making for this population.

Septic pulmonary embolism (SPE) is a severe condition often linked to infective endocarditis (IE) or intravascular catheter infections, with Staphylococcus aureus being a common pathogen. However, SPE originating from a gastrointestinal malignancy, particularly when caused by a non-enteric pathogen like methicillin-resistant Staphylococcus aureus (MRSA) via a malignancy-associated fistula, is rarely reported. We report the case of a 49-year-old man undergoing preoperative chemotherapy for anal canal cancer who developed MRSA-induced SPE complicated by multiple lung abscesses. Initial investigations revealed multiple bilateral pulmonary nodules with cavitation on chest computed tomography, and blood and sputum cultures subsequently grew MRSA. No evidence of IE was found on transthoracic echocardiography, and other common sources of SPE were not identified. A cutaneous fistula adjacent to the anal canal cancer, without overt signs of local infection, suggested that the cutaneous fistula was a plausible portal of entry for MRSA. The patient was successfully treated with an extended course of anti-MRSA therapy, including linezolid, and supportive care, leading to clinical and radiological improvement. This case highlights that anal canal cancer with an associated cutaneous fistula may serve as an occult portal of entry for MRSA, leading to SPE. Clinicians should consider this atypical mechanism in patients with malignancy presenting with SPE, especially when common sources are absent. Prompt recognition and targeted antimicrobial therapy are crucial for managing such complex infections.

BACKGROUND:Early intolerance to nintedanib may shorten time spent on treatment. Whether initiating treatment at 100 mg vs 150 mg twice daily improves treatment persistence for 12 months without compromising lung function is uncertain. OBJECTIVES:To estimate the effects of 100 mg vs 150 mg at initiation on 12-month time on treatment and ∼1-year lung function. METHODS:An observational emulation of an individually randomized target trial in a single-center new-user cohort was conducted. Baseline confounding was addressed using stabilized inverse probability of treatment weighting (IPTW) with 1st to 99th percentile trimming. The primary estimand was the difference in the restricted mean time on treatment (RMST) over 12 months. Key secondary estimands were the IPTW-adjusted absolute risk difference (RD) in 12-month treatment discontinuation (accounting for competing death) and the mean difference in change in forced vital capacity (ΔFVC) %predicted at ∼12 months among survivors. Uncertainty was quantified by patient-level bootstrapping. RESULTS:Among 172 initiators (100 mg, n = 94; 150 mg, n = 78), 100-mg initiation extended the 12-month RMST by 52.9 days (95% CI, 11.8-97.1 days) and decreased the 12-month discontinuation risk (cumulative incidence function, 0.135 vs 0.281; RD, 0.146). The ΔFVC %predicted was broadly similar among survivors, but the estimates were imprecise. CONCLUSIONS:In this target-trial emulation, starting at 100 mg twice daily improved 12-month treatment persistence. One-year FVC %predicted estimates among survivors were broadly similar but imprecise and should be interpreted with caution; a start-low, escalate-as-tolerated policy warrants prospective evaluation.

Background Neoadjuvant nivolumab plus chemotherapy improved event-free survival (EFS) and pathological complete response (pCR) in Japanese patients with non-small cell lung cancer (NSCLC) compared with chemotherapy alone in the CheckMate 816 study (NCT02998528). Overall survival (OS) and updated EFS data from the Japanese subpopulation in this study are needed. Methods The phase 3 open-label study randomized patients with stage IB–IIIA resectable NSCLC to receive three cycles of nivolumab plus chemotherapy or chemotherapy alone before undergoing definitive surgery. Primary endpoints were EFS and pCR. OS and safety were secondary and exploratory endpoints, respectively. Results Sixty-eight Japanese patients were concurrently assigned to receive nivolumab plus chemotherapy (n = 33) or chemotherapy alone (n = 35). Baseline characteristics were generally balanced between treatment arms. In this final analysis, 75.0% of patients in the nivolumab-plus-chemotherapy arm were still alive, and 43.3% were alive without disease progression or recurrence, compared with 64.7% and 37.4%, respectively, in the chemotherapy-alone arm. Median OS at 5 years was not reached in patients treated with nivolumab plus chemotherapy and 76.8 months in patients treated with chemotherapy alone. Most subgroup analyses of OS showed similar results to the overall Japanese subpopulation. At final data cutoff, eight patients in the nivolumab-plus-chemotherapy arm had died due to lung cancer, compared with 12 patients in the chemotherapy-alone arm. No new safety signals were identified. Conclusion Neoadjuvant nivolumab plus chemotherapy prolonged OS compared with chemotherapy alone in the Japanese subpopulation with resectable NSCLC, similar to the global population.

We investigated immunologic biomarkers that predict outcomes of patients with previously treated metastatic non-small cell lung cancer who were enrolled in the J-TAIL study, a prospective, observational study of atezolizumab monotherapy. Of 262 patients participating in the J-TAIL exploratory study, peripheral blood mononuclear cells were obtained from 51 patients and analyzed by T-cell fractionation analysis using Helios mass cytometry and serum proteomics analysis. Following treatment with atezolizumab, an increase in programmed cell death-1 (PD-1)-expressing CD8 and CD4 T-cell populations was observed. A more pronounced increase in PD-1 expression was seen in T cells from patients whose progression-free survival (PFS) was 100 days or longer compared with those with shorter PFS. The proximity extension assay, which is highly sensitive multiplex analysis technology that combines antibody-based affinity assays with next-generation sequencing, showed a significant increase in FOXO1, possibly in response to precursor-exhausted T-cell population activation. Immune-related adverse events were associated with a high percentage of PD-1-positive cells on effector memory CD8 T cells, which was thought to be accompanied by extremely high CD8 T-cell activation. Further analysis distinguished poor prognosis populations with significant differences in CD62Lhigh Th7R and CXCR3+ component of Th7R (CXCR3+ Th7R) within the population with PFS < 50 days. Patients with low Th7R or CXCR3+ Th7R percentages prior to atezolizumab treatment had significantly poorer overall survival. These findings provide valuable insights regarding T-cell kinetics and biomarkers in atezolizumab therapy and may offer promising directions for future research. Trial Registration: UMIN Clinical Trials Registry: UMIN000033133 and UMIN000035567; ClinicalTrials.gov: NCT03645330.

8528 Background: EGFR blockade enhances tumor antigen presentation and may potentiate PD-1 inhibition. This phase I/II study evaluated the safety and efficacy of adding necitumumab to pembrolizumab plus platinum-based chemotherapy in patients with previously untreated advanced squamous non–small cell lung cancer (NSCLC), a population with limited biomarker-driven treatment options. Methods: Patients received necitumumab (400–800 mg on days 1 and 8), pembrolizumab (200 mg on day 1), nab-paclitaxel (100 mg/m² on days 1, 8, and 15), and carboplatin (AUC 5 on day 1) every 3 weeks for four cycles, followed by necitumumab plus pembrolizumab maintenance. Phase I used a standard 3+3 dose-escalation design. Per protocol amendment, patients treated at the recommended dose (RD) in phase I (n = 6) and all phase II patients (n = 6) were pooled for efficacy analyses (n = 12). Tumor assessments were performed every 6 weeks per RECIST v1.1. Primary endpoints were safety and objective response rate (ORR). Data cutoff was September 14, 2025. Results: Twenty-one patients were enrolled, including 15 in phase I (400 mg, n = 6; 600 mg, n = 3; 800 mg, n = 6). One dose-limiting toxicity (DLT) occurred in the 800 mg cohort, which was determined as the RD and maximum tolerated dose (MTD). Among the 12 patients treated at the RD, the ORR was 75.0% (9/12; 95% CI, 42.8–94.5), with partial response in 9 patients, stable disease in 1 patient, and progressive disease in 2 patients. The disease control rate was 83.3%. The 24-week survival rate was 95.2%. Median progression-free survival and overall survival were not reached at the time of analysis. The most frequent adverse events (AEs) in 21 patients were hypomagnesemia (66.7%), acneiform dermatitis (66.7%), neutropenia (61.9%), decreased appetite (52.4%), anemia (52.4%), constipation (47.6%), stomatitis (42.9%), and leukopenia (42.9%). Grade 3 and 4 AEs occurred in 66.7% and 28.6% of patients, respectively, with no grade 5 events. Conclusions: The addition of necitumumab to pembrolizumab and platinum-based chemotherapy demonstrated manageable toxicity and resulted in a high ORR in patients with untreated squamous NSCLC. These findings support the potential activity of EGFR blockade–based immunochemotherapy and warrant further clinical investigation. Clinical trial information: 2031210387.

Background Antifibrotic therapies slow functional decline and improve survival in patients with idiopathic pulmonary fibrosis (IPF). Although early initiation is generally recommended, the optimal timing of treatment in real-world clinical practice remains uncertain. In particular, the relationship between the interval from diagnosis to treatment initiation and overall survival (OS), as well as the clinical implications of physician-judged deferred initiation, have not been fully clarified. Methods This multicenter retrospective cohort study included 150 patients diagnosed with IPF between April 2021 and March 2023 who received antifibrotic therapy. Treatment timing was evaluated using two definitions: 1) objectively defined intervals from diagnosis of IPF to treatment initiation (0–180, 181–364, and ≥ 365 days); and 2) physician-judged deferred initiation documented in medical records, defined as a clinician‑guided postponement based on clinical, patient‑related, or contextual considerations. The primary endpoint was OS. Landmark analyses were performed at 180 and 365 days to reduce immortal time bias. Survival outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazards regression models. Multivariable analyses were used to adjust for relevant clinical covariates. In addition, reasons for delayed treatment initiation were examined. Results Among the 150 patients, longer diagnosis-to-treatment intervals were associated with longer OS in the landmark analyses. In contrast, patients with physician-judged deferred initiation showed no significant difference in OS (log-rank p = 0.164), although physician-judged deferred initiation was independently associated with OS in the multivariable analysis. In the multivariable analysis, older age, lower percent predicted forced vital capacity (%forced vital capacity), and a longer interval from referral to IPF diagnosis were also independently associated with OS. The most common reasons for delayed initiation included minimal or stable symptoms, concerns regarding adverse effects, and diagnostic uncertainty. Conclusions Physician‑judged deferred initiation was independently associated with OS, likely reflecting underlying disease activity and clinical risk stratification rather than a direct causal effect of postponing therapy. These findings underscore the limitations of evaluating treatment timing solely by elapsed time and emphasize the importance of early diagnosis, timely referral to specialized centers, and individualized clinical decision-making in the management of IPF. Clinical trial registration Not applicable.

Evidence on mepolizumab soon after glucocorticoid initiation in newly diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) is limited. We compared nonrandomized initial treatment strategies defined by mepolizumab initiation within 30 days after glucocorticoid initiation with respect to post-landmark oral glucocorticoid exposure. We performed a single-center pilot retrospective cohort study of 30 patients with newly diagnosed EGPA who started systemic glucocorticoids. Primary analyses used a 30-day landmark cohort of 27 patients who remained under observation through day 30. Patients were classified into a mepolizumab-by-day-30 group and a no-mepolizumab-by-day-30 group; the latter comprised patients without initiation by day 30, regardless of later initiation. The primary outcome was cumulative oral prednisolone exposure from day 30 to 12 months. The landmark cohort included 6 patients in the mepolizumab-by-day-30 group and 21 in the no-mepolizumab-by-day-30 group. Cumulative oral prednisolone exposure from day 30 to 12 months was lower in the mepolizumab-by-day-30 group than in the no-mepolizumab-by-day-30 group (24.7 vs. 68.6 mg/kg). Similar differences were seen from day 30 to 6 months (17.6 vs. 43.6 mg/kg) and in oral prednisolone dose at 12 months (0.03 vs. 0.12 mg/kg/day). When intravenous methylprednisolone pulse therapy was added using observed dose and duration as prednisolone-equivalent systemic glucocorticoid exposure, the between-group difference was attenuated, especially over 0–6 months. By 3 months, the Birmingham Vasculitis Activity Score was 0 in all evaluable patients in both groups, and remission differences mainly reflected attainment of prednisolone ≤ 7.5 mg/day. In this single-center pilot cohort comparing nonrandomized initial treatment strategies, mepolizumab initiation within 30 days after glucocorticoid initiation was associated with lower post-landmark oral glucocorticoid exposure. These findings are hypothesis-generating and do not isolate the causal effect of mepolizumab from calendar-time, treatment-indication, or concomitant-treatment differences.

Prioritizing causal variants in a regulatory region of the genome remains challenging. Here we introduce the Expression Modifier Score (EMS) v2, allowing prioritization of regulatory variants with high precision. EMSv2 achieves higher prediction performance compared to alternative methods, especially in tissues with low sample size such as brains. We show that the power gain is attributed to implementation of (1) features accounting for long-range DNA sequence interaction, (2) customization of loss-function in training, and (3) multi-task learning framework. We then apply EMSv2 to an independent eQTL data from a Japanese population to demonstrate that EMSv2 outperforms alternative methods in regulatory variant prioritization and can be utilized for functionally-informed fine-mapping in a distinct population. We also show that EMSv2 can be utilized in combination with the gene-level polygenic prioritization score (PoPS) to prioritize complex trait-causal regulatory variants. Our work accelerates regulatory variant prioritization in the human genome. Expression Modifier Score v2 integrates Enformer-derived features and multi-task learning to prioritize regulatory variants and support interpretation of noncoding genetic associations.

Pivotal phase 3 trials leading to the approvals of atezolizumab─chemotherapy combinations for non-small cell and extensive-stage small cell lung cancer (NSCLC and ES-SCLC) had strict eligibility criteria. J-TAIL-2 was a prospective, observational study in Japan that evaluated atezolizumab regimens for advanced NSCLC/ES-SCLC, including patients ineligible for global trials. The primary endpoint was 12-month overall survival (OS); safety and efficacy in subgroups defined by age, ECOG PS and/or G8 score, and creatinine clearance were key secondary endpoints. As of February 3, 2023, 1217 patients were treated in clinical practice based on Japanese labeling/treatment guidelines. Patients received atezolizumab with either carboplatin and nab-paclitaxel (atezo + CnP), carboplatin/cisplatin and pemetrexed (atezo + PP), or bevacizumab and carboplatin and paclitaxel (atezo + bev + CP) in the NSCLC cohort (n = 814) or with carboplatin and etoposide (atezo + CE) in the ES-SCLC cohort (n = 403). Overall, 53.5% were ≥ 70 years old, and 11.8% had ECOG PS ≥ 2; median G8 scores were 13 (NSCLC cohort) and 12 (ES-SCLC). Patients < 70 and ≥ 70 years had similar median (m)OS and progression-free survival (mPFS) across treatment regimens. Patients with ECOG PS < 2 and G8 score ≥ median had the highest mOS/PFS vs. patients with ECOG PS ≥ 2 and G8 score<median. Patients ≥ 70 years had higher incidence of Grade ≥ 3 adverse events with atezo + CnP and atezo + PP than patients < 70 years; incidences were similar between groups for other regimens. Older vs. younger patients also had higher incidence of interstitial lung disease. Overall, these results suggest that atezolizumab-containing regimens remain effective in older patients, with no new safety signals. Trial Registration: ClinicalTrials.gov: NCT04501497.

Purpose:Preserved ratio impaired spirometry (PRISm) is heterogeneous, and its physiological relationship to early COPD remains unclear. We compared respiratory-mechanical patterns between non-restrictive PRISm (NrP) and GOLD stage 1 COPD (GOLD 1) using impulse oscillometry (IOS) and spirometry and explored longitudinal changes in a trackable subset. Patients and Methods:We retrospectively analyzed 1,139 adults who underwent post-bronchodilator spirometry in 2013; IOS was available for a subset. PRISm was defined by FEV1/FVC ≥ LLN with %FEV1 <80%. GOLD 1 was defined per GOLD criteria (FEV1/FVC <0.70; %FEV1 ≥80%). Longitudinal analyses were restricted to individuals with >10 pack-years, IgE <170 U/L, eosinophils <300/µL, and ≥2 examinations to minimize Th2-high asthma confounding. Results:Among PRISm cases, 18 met NrP criteria, and 127 met GOLD 1 criteria; IOS was available for all 18 NrP and for 39 GOLD 1 participants cross-sectionally. IOS indicated greater peripheral airway dysfunction in NrP than in GOLD 1, with higher R5-R20 and Fres and more negative X5, despite relatively preserved spirometric indices. In the longitudinal subset (39 GOLD 1; 8 NrP), annual changes in spirometry and IOS exhibited wide variability and did not differ meaningfully between groups. These analyses were limited by small NrP sample size and incomplete IOS availability. Conclusion:PRISm and GOLD 1 demonstrated distinct respiratory-mechanical patterns despite partially overlapping spirometric profiles. IOS identified peripheral airway abnormalities in PRISm that were not evident on spirometry, suggesting potential value for characterizing early or atypical airway dysfunction. However, sample-size limitations and major confounding factors-including age, smoking status, and bronchodilator exposure-preclude causal inference. Findings should be considered descriptive and hypothesis-generating. Larger prospective studies with balanced treatment exposure and comprehensive imaging and lung-volume assessment are needed to clarify the clinical relevance of IOS patterns in PRISm.

Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, induces near-complete eosinophil depletion and provides substantial benefit in severe eosinophilic asthma. We report an 80-year-old woman with severe eosinophilic asthma who was treated with benralizumab from August 2020. Peripheral blood eosinophils rapidly decreased to 0/μL, asthma exacerbations ceased, and lung function improved. Over the subsequent four years, while asthma remained well controlled, she developed a temporally ordered sequence of clinical events, including elderly-onset seronegative rheumatoid arthritis, biopsy-proven erythema nodosum, a radiologically characteristic pulmonary hamartoma, and early-stage hormone receptor-positive breast cancer. Erythema nodosum resolved completely after mastectomy without changes in immunosuppressive therapy, suggesting a possible paraneoplastic association. Among these events, inflammatory arthritis may represent the most biologically plausible finding potentially associated with prolonged eosinophil depletion, whereas the remaining findings are more appropriately interpreted descriptively and in the context of alternative explanations, including aging, background disease incidence, and coincidence. This case describes a rare temporal association in a single patient and does not establish causality. Rather than challenging the established favorable safety profile of benralizumab, it highlights the importance of careful long-term clinical follow-up and attention to newly emerging systemic manifestations during eosinophil-depleting biologic therapy, particularly in older adults.

Immunoglobulin light chain (AL) amyloidosis is characterized by the systemic deposition of light-chain-derived amyloids. Immunoglobulin M (IgM)-associated AL amyloidosis is extremely rare and clinically distinct. A 70-year-old man presented with dyspnea, bilateral pleural effusion, and mediastinal lymphadenopathy on computed tomography (CT). Amyloid was detected in a pleural effusion cell block and confirmed via an axillary lymph node biopsy. Serum studies and bone marrow findings supported IgM-λ AL amyloidosis associated with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. First-line therapy failed, but second-line therapy reduced pleural effusion, avoiding thoracentesis for one year. A pleural effusion cell block analysis enabled rapid diagnosis with minimally invasive exploration.

Background:Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and an independent determinant of prognosis. Increases in pulmonary vascular resistance often precede overt elevation of pulmonary arterial pressure, but early pulmonary vascular involvement remains difficult to detect noninvasively. Conventional echocardiographic assessment in COPD focuses mainly on right ventricular systolic indices, which may remain preserved despite increased pulmonary vascular load. Methods:We conducted a single-center retrospective observational study of 58 patients with stable COPD who underwent right heart catheterization and comprehensive transthoracic echocardiography during the same hospitalization. Right ventricular isovolumetric relaxation time (IRT), a Doppler-derived index of diastolic timing, was evaluated in relation to invasively measured pulmonary vascular resistance, dyspnea severity, exercise capacity, and pulmonary function. Results:A total of 58 patients were included. Patients meeting hemodynamic criteria for pulmonary hypertension exhibited lower diffusing capacity, more severe dyspnea, and reduced exercise capacity despite similar airflow limitation. Pulmonary vascular resistance was significantly higher, while cardiac index remained preserved. IRT was significantly prolonged in patients with pulmonary hypertension and showed a moderate correlation with pulmonary vascular resistance (ρ = 0.56, p < 0.001), six-minute walk distance (ρ = -0.46, p < 0.001), and dyspnea severity (ρ = 0.36, p = 0.006). In contrast, conventional right ventricular systolic indices showed no significant associations with pulmonary vascular resistance. Conclusion:Echocardiographic assessment of IRT may provide a physiologically grounded, noninvasive parameter associated with early right ventricular diastolic response to pulmonary vascular load.

Background:Previous studies have reported an association between expression of thyroid transcription factor 1 (TTF-1) and the efficacy of immune checkpoint inhibitors (ICIs), cytotoxic chemotherapy, and immunochemotherapy in patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC). However, the relationship between TTF-1 expression and the efficacy of cytotoxic chemotherapy in patients with NS-NSCLC with idiopathic interstitial pneumonias (IIPs) remains unclear. This study aimed to evaluate the relationship TTF-1 expression and the efficacy of platinum-doublet chemotherapy in patients with NS-NSCLC with coexisting IIPs. Methods:This retrospective study reviewed 120 patients with NSCLC complicated by IIPs who were treated at Nippon Medical School Hospital in Japan between January 2010 and December 2024. We analyzed the efficacy and safety of carboplatin and either paclitaxel or nanoparticle albumin-bound (nab-) paclitaxel for NS-NSCLC with IIPs. Results:In the total cohort, 51 patients were evaluated for TTF-1 expression status and administered carboplatin plus (nab-) paclitaxel as first-line therapy. TTF-1 expression was observed in 32 patients (63%). Twenty-five patients (49%) exhibited a usual interstitial pneumonia (UIP) pattern. The overall response rate (ORR) was significantly higher in the TTF-1-positive group compared to the TTF-1-negative group (62.4% vs. 31.6%, P=0.045). Median overall survival (OS) and progression-free survival (PFS) were also significantly longer in the TTF-1-positive group than in TTF-1-negative group (11.3 vs. 8.2 months, P=0.007; 8.4 vs. 4.4 months, P<0.001). TTF-1 negativity was identified as an independent prognostic factor associated with inferior OS and PFS in multivariate analysis. Furthermore, the TTF-1-negative group had a significantly higher incidence of lung cancer development in the setting of underlying interstitial pneumonia (IP) (P<0.001), suggesting that decreased TTF-1 expression may be involved in the pathogenesis of lung cancer arising from IIPs. Conclusions:TTF-1 expression is an independent prognostic factor in patients with NS-NSCLC complicated by IIPs who received carboplatin plus (nab-) paclitaxel. TTF-1 expression may represent a valuable biomarker for characterizing the disease subtypes and guiding therapeutic strategies in lung cancer with coexisting IIPs.

BACKGROUND:Non-invasive methods for detailed evaluation of airway pathology in asthma, including structural airway abnormalities, remain limited, and accurate assessment is still insufficient. The MostGraph, which utilizes the impulse oscillation system (IOS), allows non-invasive measurement of airway resistance and reactance. This study evaluated its utility in distinguishing airway pathology between bronchial asthma (BA) and cough variant asthma (CVA), with a focus on peripheral airway involvement. METHODS:In this cross-sectional study, 383 patients with stable respiratory symptoms for over three months were enrolled (203 BA, 180 CVA). All patients underwent spirometry, IOS assessment using the MostGraph, blood tests, and fractional exhaled nitric oxide (FeNO) measurement. RESULTS:Body composition was comparable between groups, although BA patients were older. BA showed significantly greater airway obstruction (%FEV1/predicted FEV1) and peripheral impairment (V50/V25, MMF). R5-R20 values were higher in BA than CVA before and after bronchodilator use. In BA, R5, R20, and R5-R20 correlated significantly with %FEV1; in CVA, only R5 and R20 did. R5-R20 showed no correlation (R = -0.11, P = 0.14). Inspiratory R5-R20 was not correlated in CVA (Pre-BD: R = -0.048, P = 0.53; Post-BD: R = -0.13, P = 0.091), while all parameters correlated in BA. Fres was significantly higher in BA both pre- and post-bronchodilator (P < 0.0001). CONCLUSION:MostGraph indices, when integrated with spirometry, may offer a valuable non-invasive approach for characterizing peripheral airway abnormalities that may reflect remodeling-related changes in BA and support airway monitoring in asthma management. TRIAL REGISTRATION:UMIN-CTR Clinical Trial (UMIN000054006). (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000061647).

e20712 Background: Molecular targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) with actionable genomic alterations. However, direct comparisons of treatment outcomes across different genomic subtypes within a single real-world cohort remain limited. We evaluated the relative efficacy and safety of targeted therapies across major actionable genomic alterations in a large Japanese real-world population. Methods: This multicenter retrospective study included 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy between 2017 and 2023. Patients were classified into three genomic groups: EGFR mutations (Group A, n = 659), fusion oncogenes involving ALK/ROS1/RET (Group B, n = 106), and other actionable alterations including MET exon 14 skipping, BRAF V600E, and KRAS G12C (Group C, n = 45). Treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety, were analyzed using Kaplan–Meier methods and multivariable Cox regression. Results: The median follow-up was 24.9 months overall (Group A 25.6, Group B 27.3, Group C 16.1). A total of 580 progression events and 398 deaths were observed. ORR differed significantly among groups (74.1% in Group A, 85.8% in Group B, and 68.9% in Group C; P = 0.014). Median PFS was 17.5 months in Group A, 42.5 months in Group B, and 9.2 months in Group C (P < 0.001). Median OS was not reached in Group B, compared with 39.3 months in Group A and 22.7 months in Group C (P < 0.001). In multivariable analyses adjusting for clinical covariates, genomic subgroup remained independently associated with both PFS and OS, with fusion-driven tumors demonstrating consistently superior outcomes. EGFR-mutated tumors showed intermediate outcomes, whereas Group C exhibited limited efficacy and higher treatment discontinuation due to adverse events. Conclusions: In this large Japanese real-world cohort, a clear hierarchy of therapeutic benefit across actionable genomic alterations was observed. Fusion oncogene–driven NSCLC derived exceptional and durable benefit from targeted therapy, EGFR-mutated tumors demonstrated intermediate outcomes, and MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations remained associated with limited efficacy and higher toxicity. These findings underscore the clinical importance of genomic subtype–based treatment strategies and highlight unmet needs in selected molecular subsets.