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Abstract Introduction Pulmonary fibrosis is characterized by excessive fibroblast activation and alveolar remodeling, leading to progressive lung dysfunction. Osteoglycin (OGN), a small leucine-rich proteoglycan, and its functional fragment MC002 have been identified as regulators of alveolar epithelial regeneration, a process that is impaired in fibrotic lung disease. This study investigates the effects of OGN and MC002 on TGF-β-induced fibrotic responses in lung fibroblasts, organoids, and an in vivo fibrosis model. Methods Human lung fibroblasts (MRC5) were treated with OGN or MC002 for 48 hours, with or without transforming growth factor-beta (TGF-β; 2 ng/mL). Expression of the myofibroblast marker α-smooth muscle actin (ACTA2) and matrix markers collagen 1a1 (COL1A1) and fibronectin (FN1) was assessed by RT-PCR and Western blotting. Global transcriptomic changes were analyzed by RNA sequencing. Myofibroblast differentiation was evaluated by phalloidin staining and quantified using the phalloidin/DAPI ratio. Murine lung organoids were generated by co-culturing epithelial progenitor cells with fibroblasts and treated with TGF-β (2 ng/mL) in the presence or absence of OGN or MC002. Organoid number, size, and alveolar differentiation were quantified after 14 days. In vivo, pulmonary fibrosis was induced in mice using intratracheal bleomycin. MC002 was administered at different doses (6.75 µg or 20.25 µg) every other day starting from day 7 post-bleomycin, and lung weight and pressure-volume (PV) loops were assessed to evaluate fibrotic burden and lung mechanics. Osteoglycin expression in human lung tissue from 13 non-smokers, 11 ex-smokers, and 12 IPF patients was analyzed by immunostaining. Results TGF-β induced pro-fibrotic gene expression in fibroblasts, while OGN and MC002 alone had no pro-fibrotic effects. MC002 fully reversed TGF-β-induced ACTA2, COL1A1, and FN1 expression, whereas OGN selectively attenuated COL1A1. RNA-sequencing revealed broad suppression of fibrosis- and ECM-associated gene programs by MC002. At the protein level, TGF-β-induced ACTA2 expression was reversed by MC002 but not by OGN. Both compounds reduced TGF-β-induced stress fiber formation. In lung organoids, TGF-β impaired organoid formation and alveolar differentiation, effects that were restored by OGN and MC002 in a concentration-dependent manner. In the bleomycin model, MC002 significantly reduced lung weight and improved PV loop profiles, indicating attenuation of fibrotic stiffening and improved lung compliance. Osteoglycin protein expression was significantly diminished in IPF whole lung tissue and parenchyma compared to controls. Conclusion OGN, and particularly MC002, counteract TGF-β-driven fibroblast activation and myofibroblast differentiation while promoting alveolar preservation. The superior efficacy of MC002 supports its potential as a therapeutic candidate for pulmonary fibrosis. This abstract is funded by: Lung Foundation Netherlands 10.1.23.021PPS

PURPOSE Cancer survivors endure costly and time-intensive care throughout treatment and survivorship. Paid sick leave provides employment and financial stability while supporting time off for medical needs. We investigated whether paid sick leave is associated with financial hardship and overall and cancer-specific mortality risk in working adult cancer survivors. METHODS Working adults age 18-64 years with a cancer history were identified from the National Health Interview Survey (NHIS) between 2011 and 2023. Associations of paid sick leave and financial hardship (medical care delays, problems paying medical bills, worry about paying medical bills, and cost-related medication underuse) were examined with 2011-2018 and 2019-2023 data using separate multivariable logistic regressions because of survey redesign in 2019. Linked mortality files from the National Death Index were available for 2011-2018 respondents. The association of paid sick leave and mortality risk was examined with multivariable Cox proportional hazards models. RESULTS A total of 8,091 and 3,919 working cancer survivors were identified from the 2011-2018 and 2019-2023 NHIS, respectively. Paid sick leave was associated with decreased medical care delays because of cost (2011-2018 odds ratio [OR], 0.74 [95% CI, 0.60 to 0.93]; P = .008; 2019-2023 OR, 0.51 [95% CI, 0.35 to 0.74]; P < .001) but not consistently with other forms of financial hardship. In adjusted analyses, paid sick leave was associated with significant reductions in risk of overall mortality (hazard ratio [HR], 0.74 [95% CI, 0.61 to 0.9]; P = .003) and cancer mortality (HR, 0.74 [95% CI, 0.61 to 0.91]; P = .003). CONCLUSION In working cancer survivors, paid sick leave is associated with decreased care delays and lower overall and cancer-specific mortality risk, which may be due to maintained employment, household income, and health insurance coverage leading to improvements in treatment access, affordability, and overall survivorship care.

Abstract A low-cost, easy-to-adopt noninvasive imaging modality for differentiating bacterial infection from inflammation is desirable to accurately diagnose bacterial infections. Herein, a bacteria-specific PET probe, [68Ga]Ga-BP, was developed and evaluated in rat models of foreign body-associated osteomyelitis induced by methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae and was directly compared with sterile inflammation and uninstrumented uninfected controls. [68Ga]Ga-BP-based imaging of MRSA-infected tibiae was also compared to [68Ga]Ga-citrate and [18F]FDG. After iron depletion, dynamic PET/CT imaging was performed at 15–120 min postinjection of radiotracers, followed by assessment of ex vivo biodistribution. [68Ga]Ga-BP successfully detected tibial infection and demonstrated &gt;6-fold higher uptake in infected tibiae with all three bacterial species versus contralateral tibiae via PET imaging. [68Ga]Ga-BP outperformed [68Ga]Ga-citrate and [18F]FDG in identifying MRSA infection. [68Ga]Ga-BP represents a promising, noninvasive PET imaging agent for direct bacterial detection and bacterial infection treatment monitoring.

ABSTRACT Legionella species are important causes of community-acquired pneumonia. The diagnostic performance and clinical implications of a fluorescence resonance energy transfer (FRET)-based real-time PCR assay targeting the Legionella 5S rRNA gene were evaluated, with emphasis on melting temperature (Tm) analysis to differentiate detected species and associated clinical outcomes. A retrospective multicenter cohort study of adults with laboratory-confirmed Legionella infection between 2019 and 2025 was conducted. PCR crossing point (Cp) and Tm data were analyzed and compared with species identified in culture from respiratory specimens. Associations between Tm and clinical outcomes were assessed using multivariable logistic regression. Among 51,489 PCR tests performed, 823 (1.6%) were positive. Among 376 Legionella infections, PCR demonstrated the highest diagnostic yield. Among patients undergoing all three diagnostic tests, the addition of PCR increased detection from 49% with urine antigen and culture combined to 100% ( P < 0.001). Of 189 PCR-positive patient specimens with available Tm data, Tm showed a bimodal distribution, being either <66°C or ≥66°C. A Tm cutoff of ≥66°C discriminated L. pneumophila / L. longbeachae from other Legionella species with excellent performance (AUC, 1.00). Overall, 29.6% of infections had a Tm <66°C, consistent with non- pneumophila/ non- longbeachae Legionella species. Infections due to L. pneumophila / L. longbeachae , which correspond to high Tm values in the study assay, were independently associated with ICU admission (adjusted odds ratio, 2.85; 95% CI, 1.33–6.11; P = 0.007), but not 90-day mortality. Real-time PCR targeting the Legionella 5S rRNA gene provides superior detection compared to culture and/or urine antigen testing and enables higher-risk species discrimination through Tm analysis. IMPORTANCE Nearly one-third of Legionella infections in this cohort were attributable to non- pneumophila species, highlighting limitations of diagnostic strategies reliant on Legionella urine antigen testing or L. pneumophila PCR. The findings suggest that species-level inference can be derived from melting-temperature data generated during routine PCR testing. Incorporating validated melting-temperature interpretation into reporting workflows may improve epidemiologic surveillance and clinical understanding of characteristics of Legionella pneumonia.

We report the case of a woman with metastatic alveolar soft part sarcoma (ASPS) who experienced pregnancy-associated disease progression followed by unexpected postpartum regression. Pulmonary lesions increased in size after a miscarriage and during a subsequent pregnancy, prompting consideration for systemic treatment and potential enrolment in a clinical trial evaluating a tyrosine kinase inhibitor in combination with an immune checkpoint inhibitor. However, baseline staging CT performed a few weeks postpartum unexpectedly demonstrated marked spontaneous regression. Because trial enrolment required Response Evaluation Criteria in Solid Tumors-defined radiographic progression, she was deemed ineligible, and no systemic therapy was initiated. Surveillance imaging over the following 2 years confirmed sustained regression and stability of residual disease in the absence of treatment. This case highlights the potential influence of pregnancy-to-postpartum physiology on tumour behaviour through hormonal, immune and angiogenic mechanisms. It also emphasises the importance of short-interval reassessment after delivery before initiation of systemic therapy in reproductive-age patients with metastatic ASPS.

ABSTRACT Early identification of patients with treatment‐responsive rapidly progressive dementia (RPD) is important as early treatment improves outcomes. The STAM 3 P score identifies treatment‐responsive RPD using “high risk” presenting features. We optimized performance by adding a time component (i.e., dementia within 3 months) and validated the modified “STAM3 m P score” in two independent cohorts ( n = 302). A STAM3 m P score ≥ 1 identified 96% of patients with treatment‐responsive RPD; ≥ 3 features were highly specific (98%). These data suggest that ≥ 1 STAM3 m P features effectively identifies treatment‐responsive RPD and may be used to prioritize investigations, whereas ≥ 3 STAM3 m P features are highly specific and may inform early treatment decisions.

11502 Background: To report results from the open-label alveolar soft part sarcoma (ASPS) cohort of the phase III APROMISS trial (NCT03016819) evaluating Catequentinib hydrochloride (AL3818), an oral multitargeted receptor tyrosine kinase inhibitor, in adults with advanced or metastatic ASPS. Methods: Adult patients with pathologic and molecularly confirmed advanced ASPS, either treatment-naive or previously treated (excluding cediranib), were enrolled in the open-label, non-randomized ASPS cohort of the phase III APROMISS trial conducted across the United States, Asia, and Europe. Catequentinib hydrochloride was administered orally at 12 mg once daily in 21-day cycles (14 days on/7 days off) until disease progression, toxicity, or death. The primary endpoint was objective response rate (ORR) assessed per RECIST by Blinded Independent Central Review (BICR) (predefined threshold: 31%). Secondary endpoints included duration of response (DOR) with a predefined target of =/>6 months, progression free survival (PFS) and overall survival (OS). Results: From July 2017 to August 2022, a total of 56 patients entered the trial; 56 patients were evaluable for the primary endpoint. Median (m-) age was 29.5 years (range: 18 – 66), with 24 female and 32 male. Best overall response included 1/56 complete response (1.8%), 14/56 partial responses (25.0%), 36/56 stable disease (64.3%), and 3/56 (5.4%) progressive disease. RECIST ORR by BICR was 26.8% (95% CI, 15.8–40.3); m-DOR was 22.57 months (95%CI: 10.38-NE). The study data was collected close to 8 years for all patients. mPFS was 18.33 months (95% CI, 14.19–23.13), with 6- and 12-month progression-free rates of 88.77% (95% CI, 76.68–94.79) and 65.54% (95% CI, 50.42–77.06), respectively. mOS was 59.27 months (95% CI, 44.09–NE), with 6- and 12-month overall survival rates of 94.64% (95% CI, 84.30–98.24) and 90.81% (95% CI, 79.30–96.08), respectively. Overall, 27/56 (48.2%) patients experienced grade ≥3 treatment-related adverse events, most commonly diarrhea (50.0%), hypertension (44.6%), fatigue (37.5%), nausea (35.7%), and palmar-plantar erythrodysesthesia syndrome (30.4%); one patient (1.8%) had a grade 5 event (respiratory failure). Conclusions: Catequentinib hydrochloride demonstrated meaningful antitumor activity and durable responses in adults with advanced ASPS. Despite the ORR of 26.8% slightly below the predefined 31% threshold, disease control was prolonged, with a m-DOR exceeding 22 months. Favorable PFS and OS outcomes, together with a manageable safety profile, support its clinical benefit in this ultra-rare sarcoma. Clinical trial information: NCT03016819 .

11064 Background: Local and state paid sick leave (PSL) mandates have been associated with increased use of preventive services, including cancer screening, and reduced emergency care utilization. Little research has examined PSL policies and cancer after diagnosis. This study evaluates associations of PSL policies and timely treatment initiation among women with early-stage breast cancer. Methods: We identified patients aged 18-64 years newly diagnosed with stages 0-II breast cancer from the National Cancer Database in 2004-2023 and linked then to area-level policy implementation, measured as the month and year the state, county, or city required PSL. Primary outcomes were receipt of definitive surgery or neoadjuvant therapy within 30, 60, and 90 days of diagnosis. We compared changes in treatment initiation between patients residing in areas with and without PSL policies during and after the month and year of diagnosis. We used a staggered difference-in-differences design to account for differential timing of implementation, adjusting for patient demographics, clinical, and area-level characteristics. Random errors were clustered at the state level. Supplemental analyses stratified by county-level unemployment rates and individual insurance coverage. Results: The study included 1,891,411 patients, of whom 249,313 (13.2%) resided in an area with PSL policies at diagnosis. Patients in areas with PSL policies were more likely to have Medicaid, reside in higher-income and metropolitan areas. PSL policy implementation was significantly associated with a 3.4 percentage point (PPT) increase in the probability of treatment ≤30 days (95% CI: 1.1-5.7), 3.0 PPT increase ≤60 days (95% CI: 1.6-4.3), 1.3 PPT increase ≤90 days (95% CI: 0.5-2.1) (Table). Improvements in timely treatment were concentrated in low-unemployment areas; no significant improvements were observed in high-unemployment areas. The magnitude of associations between PSL policies and treatment initiation was stronger among patients without private insurance than with private insurance. Conclusions: Local and state PSL mandates were associated with earlier treatment initiation among working-age patients with early-stage breast cancer, especially in areas with low female unemployment rate. Findings suggest that PSL policies play an important role in timely cancer treatment for employed women who may not have PSL through their jobs. Association of paid sick leave policies and breast cancer treatment initiation. Time from diagnosis to surgery/neoadjuvant therapy (days) DID PPT Lower 95% CI Upper 95% CI P-value Overall ≤30 3.4 1.1 5.7 0.004 ≤60 3.0 1.6 4.3 0.000 ≤90 1.3 0.5 2.1 0.001 Low female unemployment ≤30 2.2 -0.7 5.0 0.136 ≤60 3.8 1.8 5.8 0.000 ≤90 1.2 0.3 2.2 0.012 High female unemployment ≤30 1.8 -0.6 4.2 0.145 ≤60 -1.2 -4.5 2.0 0.459 ≤90 -1.4 -3.7 0.9 0.232

ABSTRACT Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates ( n = 526) were more frequently susceptible to these agents than isolates from other countries ( n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases ( n = 157) were less frequently susceptible than isolates without carbapenemases ( n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%–52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.