Citations

Abstract Rationale Chronic bronchitis (CB), a common phenotype of chronic obstructive pulmonary disease (COPD), is characterized by pathologic mucus hypersecretion and is associated with substantial morbidity, impaired quality of life, and progressive functional decline, with prior studies demonstrating an average worsening of approximately one point/year on the COPD Assessment Test (CAT). Bronchial rheoplasty (BR) with RheOx® combines mechanical mucous plug disimpaction with pulsed electric field (PEF) energy to ablate and restore the airway mucosa. The RheSolve study was designed to provide evidence of safety and efficacy versus mechanical disimpaction alone. Primary endpoint results have been previously reported; final 2-year outcomes are reported here. Methods RheSolve was a prospective, randomized, double-blind study enrolling 273 patients with COPD and moderate-to-severe CB across 37 centers in the United States and Europe. Participants were randomized 2:1 to BR (n = 185) or a mechanical control procedure (n = 88). Following unblinding at 12 months, 75% of control patients crossed over to BR, precluding valid randomized comparisons beyond that time point; therefore, longer-term outcomes were evaluated using within-patient changes from baseline in the BR cohort. Outcomes included CAT, St George’s Respiratory Questionnaire (SGRQ), Cough and Sputum Assessment Questionnaire (CASA-Q), and pulmonary function tests (PFTs). Results Patients in the BR group represented a moderate to severe COPD CB phenotype at baseline (FEV1 60.9% predicted, emphysema (-950 HU) 11.0%, CAT 27.2 points, SGRQ 64.4) with most patients (93%) receiving a combination of ≥ 2 long-acting medications (LABA, LAMA, inhaled corticosteroids). The BR procedure was well-tolerated with no SAEs related to the device or procedure beyond 12 months. Both groups demonstrated clinically meaningful improvements in CAT, SGRQ, and CASA-Q at 12 months (P < 0.001), which were sustained in the BR group through 24 months. Follow-up was limited to 1 year in the mechanical control group, with outcomes demonstrating a modest regression towards baseline at 12 months (Figure). PFTs were also stable to improved in the BR group (changes from baseline to 24 months: FEV1 % Predicted 0.9 (±10.8) P = 0.319, FVC % Predicted 2.8% (±14.0) P = 0.02, FEV1/FVC -0.5% (±7.2) P = 0.449). Conclusions BR with RheOx® (e.g.,mechanical mucous plug disimpaction and PEF delivery) demonstrated clinically meaningful symptom improvement that was sustained through 24 months supporting BR as a therapeutic option for patients with persistent symptoms despite appropriate medical therapy. This abstract is funded by: Galvanize Therapeutics

e18026 Background: Immune checkpoint inhibitor (ICI) therapy is part of standard of care first-line therapy for recurrent or metastatic (R/M) HNSCC. However, less than 20% of patients (CPS ≥1) have an objective response to ICI monotherapy, and most tumors progress within ~3 months. We sought to improve the proportion of patients who benefit from a chemotherapy-free regimen by combining intratumoral (IT) VV1 oncolytic virus (VSV-IFNβ-NIS) injections with the anti-PD-1 antibody, cemiplimab. We report a pre-planned analysis of Simon's stage 1 results. Methods: We activated a phase 2 study testing the efficacy of first line IT VV1 plus cemiplimab in 1 st line patients with R/M HNSCC. A Simon's two-stage design was employed whereby 10 patients would be accrued in stage 1, and if 3 or more responses were observed, 12 additional patients would be accrued for stage 2. The primary endpoint was objective response rate (ORR) per investigator (RECIST 1.1). Eligible patients had untreated R/M HNSCC from primary oropharynx, oral cavity, hypopharynx, or larynx sites with CPS ≥1. Patients had to have at least one measurable lesion amenable to IT injection. Treatment comprised of IT injections to 1-5 lesions of oncolytic VV-1 virus and IV cemiplimab 350 mg on day 1, repeated every 21 days. Each lesion could be injected 3 times; a 4th injection was allowed if a partial response (PR) was achieved after 3 injections. Cemiplimab could be continued for up to 2 years until progression or unacceptable toxicity. Results: Patient and tumor characteristics, as well as efficacy and toxicity are summarized in the table below. Ten patients were treated at the time of Stage 1 analysis, with 3 showing a confirmed PR for ORR of 30%. Responder CPS scores were 45, 12 and 20%. Two of the responders subsequently showed progression after 6.2 and 9.9 months, the third has maintained PR at 7.7 months to date. Eight of 10 patients showed decrease in the sum of target lesion size (mean decrease of 16%; range -57 to 77%). One grade 2 event of ICI nephritis resolved with corticosteroid treatment. Conclusions: Three patients showed confirmed PR by RECIST 1.1 in Simon's stage 1, meeting criteria to proceed to Simon's stage 2. A total of 22 patients in the HNSCC will be enrolled. VV1 plus cemiplimab shows promise in first line R/M HNSCC based on these initial results. Clinical trial information: NCT04291105 . Patient demographics. N (treated) 10 Sex 20% female Median age (y) 60 (54 – 76) Oropharynx 7 HPV+ 7 Oral cavity 3 PD-L1 CPS median (range) 7.5 (1-45%) Locoregional injection 3 Distant injection 6 Local and distant injection 1 Best response (RECIST 1.1) PR 3 SD 5 PD 2 Adverse Events #pts any VV1/cemiplimab-related G3 AE 4 Lymphopenia 3 Elevated ALK 1

Abstract Introduction Custom stents are a fast-evolving and revolutionary therapy for use in patients who require therapeutic stenting options due to a variety of tracheal, bronchial, and parenchymal diseases. The combination of increasing high-resolution CT imaging with 3-D printing technology has allowed for even greater flexibility in therapeutic treatment. Returned mesh is a well-described phenomenon in the medical literature and can create a wide variety of difficult to manage complications. Description The patient is a 64-year-old male with a past medical history of tracheobronchomalacia status post tracheoplasty with prolene mesh placement in April 2011 which was complicated by erosion of mesh through the membranous airway in April 2017. He subsequently underwent a right thoracotomy with a muscle flap reconstruction of the membranous trachea in May 2017. This was then complicated by a diverticulum of the distal trachea that was non-communicative with the esophagus and chronic stenosis of the left mainstem bronchus with residual mesh retained in the posterior membranous left mainstem bronchus. He had a custom Y-stent placed for the first time in February 2022 due to persistent sensation of shortness of breath along with productive cough. He experienced immediate relief after placement of his custom stent and has since demonstrated remarkable stability, rarely requiring unscheduled bronchoscopy for mucous clearance. He has nonetheless derived immense benefit from stenting from a symptomatic standpoint since initial placement in 2022. Discussion Customized stents utilizing 3-D printing technology have allowed far more flexibility to the clinical approach of patients with complex airway pathology. As tracheal and bronchial reconstruction surgeries continue to involve more complicated management modalities, including the use of mesh, complications will continue to arise. Mesh erosion is a potentially devastating complication from tracheobronchoplasty. It will, therefore, be important to facilitate treatment of complications from these and other modalities. Therapeutic bronchoscopy with custom stent placement will almost certainly continue to evolve as an effective tool in the management of patients such as these. This abstract is funded by: None

Abstract Introduction Nuclear protein in testis (NUT) carcinoma, formerly known as NUT midline carcinoma, is a rare and highly aggressive subtype of squamous cell carcinoma characterized by NUTM1 gene rearrangements. It typically affects children and young adults and shows a predilection for midline structures of the head, neck, and thorax. We describe a rare case of NUT carcinoma in an elderly patient presenting with central airway obstruction treated with tumor debulking, devascularization, and pulsed electric field (PEF) ablation. Case An 89-year-old woman on chronic anticoagulation for atrial fibrillation presented with respiratory distress and hemoptysis requiring intubation and mechanical ventilation. Chest CT revealed a developing right lower lobe infiltrate and bronchoscopy demonstrated a non-obstructing right lower lobe endobronchial lesion. Pathology of the lesion confirmed NUT carcinoma but the patient was lost to follow-up. Two months later, she presented with altered mental status and respiratory failure. Imaging revealed a 4.6 x 2.6 cm mass at the level of the cricoid cartilage causing approximately 75% tracheal obstruction with tracheal wall invasion. She underwent rigid bronchoscopy with tumor debulking and devascularization, achieving >80% tracheal patency post-procedure. EBUS-guided PEF ablation was then performed to target residual bulky tumor found in the paratracheal area. Given her age, comorbidities, and poor performance status, palliative chemotherapy was deferred and palliative radiotherapy was offered to limit tumor progression. Discussion NUT carcinoma is a rare and aggressive malignancy with a poor prognosis. This case demonstrates rapid tumor progression leading to respiratory failure within two months of initial diagnosis. Management options for malignant central airway obstruction in non-surgical candidates may include endobronchial debulking and ablative therapies. In this case, EBUS-guided PEF ablation, a non-thermal technique that delivers brief electric pulses to induce tumor apoptosis while sparing adjacent structures, was successfully used to treat residual disease with the goal of reducing marginal regrowth and maintain airway patency. PEF ablation has been described in percutaneous and bronchoscopic management of early stage non-small cell lung cancer; however, its application in central airway obstruction represents an innovative therapeutic approach. Although chemoradiation may be considered when feasible, no standard regimen exists for NUT carcinoma. It typically responds poorly to conventional therapies, underscoring the importance of complementary local treatment strategies in select patients. This case highlights the rapidly progressive course of NUT carcinoma and demonstrates the potential role of PEF ablation as a novel adjunct in the palliative management of malignant central airway obstruction. This abstract is funded by: None

Abstract Background New insights into community-acquired pleural infection microbiology may enable development of more rapid and accessible diagnostics that can streamline treatment. This study systematically compared molecular approaches for pathogen detection in pleural fluid from patients with such infections. Considering the need for rapid results with minimum hands-on time and test complexity, off-label use of the cassette-based, random-access BIOFIRE Joint Infection Panel (BF-JIP, bioMérieux) with and without supplementary in-house polymerase chain reaction (PCR) assays was evaluated. Methods Pleural fluids from 162 subjects from the Mayo Clinic (Rochester, Minnesota) and Haukeland University Hospital (Bergen, Norway), where molecular tests are routinely used for analyzing pleural fluid, were studied. The performance of the BF-JIP was compared to 16S rRNA gene PCR followed by Sanger and/or next-generation sequencing (16S rRNA gene PCR/sequencing), an in-house PCR panel specifically designed for pleural space infections, and culture. Results The BF-JIP supplemented with 3 in-house PCR assays targeting Fusobacterium nucleatum group, Streptococcus intermedius/constellatus, and Aggregatibacter aphrophilus detected 96.8% of pleural infections, providing complete microbial profiles in 70.1%. In comparison, the detection rate of 16S rRNA gene PCR/sequencing was 92.2%, providing complete microbial profiles in 87.0%. Culture detected bacteria in only 31.9% of pleural fluids, providing complete microbial profiles in 15.3%. Conclusions These results underscore the importance of molecular approaches in diagnosing pleural space infections and demonstrate the feasibility of panel-based PCR-based diagnostics for these sometimes-complex infections. The BF-JIP, designed for testing synovial fluid, could be modified to provide a useful diagnostic for testing pleural fluid.

Abstract Background Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective The aim was to assess the frequency of dystonia‐linked pathogenic variants in PD. Methods We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership‐Parkinson's Disease (AMP‐PD) for variants in genes linked to isolated dystonia, dystonia‐parkinsonism, and myoclonus‐dystonia. Results Pathogenic variants were identified only in PD patients. Forty‐five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia‐linked genes, most frequently in GCH1 , followed by VPS16 . Conclusion Though rare, pathogenic variants in dystonia‐linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD‐relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract IntroductionFungal infections, particularly in the Midwest, can often be asymptomatic and may mimic primary lung cancer. This case illustrates pulmonary histoplasmosis in an 80-year-old woman with a history of lung cancer highlighting the diagnostic challenges presented when both conditions coexist.Case SummaryAn 80-year-old woman (prior smoking history of 47-pack-years) with synchronous lung cancers (poorly differentiated non-small cell carcinoma with squamous differentiation in the left lower lobe and squamous cell carcinoma in the right lower lobe) previously underwent radiation therapy to both lesions. She was admitted for shortness of breath and cough and was initially diagnosed with pneumonia based on CT findings. Despite multiple courses of antibiotics, her symptoms persisted over 2 months, improving only temporarily with a short course of prednisone. A follow-up CT revealed increasing confluent thick-walled cavitation in the posterior right upper lobe and superior segment of the right lower lobe concerning for cavitating/necrotizing pneumonia versus possible cancer progression. A PET-CT scan (Fig.1A) showed significant FDG uptake in the right upper lobe lesion and mild uptake in mediastinal lymph nodes complicating the differentiation between cancer and infection. Bronchoscopy with biopsy of an endobronchial lesion in the posterior segment of right lower lobe revealed necrotizing granulomatous inflammation (Fig.1B) with GMS stain showing the presence of fungal organisms suggestive of histoplasmosis. Histoplasma PCR from bronchoalveolar lavage was also positive. She was subsequently started on antifungal therapy for a planned one-year treatment course. DiscussionHigh positron emission tomography (PET) avidity in chest imaging is often linked to aggressive tumors but can also indicate benign conditions such as fungal infections. A “flip-flop sign” on PET imaging, where nodal activity surpasses that of a lung nodule, is typically seen in benign lung lesions, particularly fungal infections. However, infections and inflammatory conditions may also show high PET avidity mimicking malignancy. Endobronchial lesions, common in lung cancer, are less frequently associated with infections. In patients with a history of cancer, active lung infection, and PET-avid lesions without the flip-flop sign, invasive testing is usually required to differentiate between infection and malignancy. In this case, our patient with a history of lung cancer and a PET-avid lung lesion was found to have pulmonary histoplasmosis after invasive testing highlighting the need for comprehensive evaluation.ConclusionThis case emphasizes the importance of considering fungal infections in the differential diagnosis of PET-avid pulmonary lesions, particularly in patients with a history of malignancy.

Abstract Rational: Talc pleurodesis is an effective intervention for preventing recurrent pleural effusions and pneumothoraces, particularly in non-surgical candidates. Due to its efficacy and safety, it is recommended as the most effective sclerosant for pleurodesis. However, in some cases, the initial pleurodesis fails, necessitating a repeat procedure. The efficacy of repeat talc pleurodesis after an initial failure is an area that requires further exploration. This study explores the safety and efficacy of repeat talc pleurodesis among patients who did not respond to the initial intervention. Methods: This retrospective study analyzed hospitalized patients who underwent 4g talc slurry pleurodesis from 2019 to 2024, focusing on demographics, comorbidities, initial pleurodesis failure, and recurrence rates. Pleurodesis failure was identified by lung sliding, recurrent effusion, or pneumothorax during the same hospitalization. The primary outcome was recurrence post-discharge, assessed by pleural effusion or pneumothorax within 180 days post-repeat pleurodesis. Results: This study included 94 patients (52.1% male, 47.9% female) with a mean age of 67.6. Among them, 79 (84%) received a single 4g dose of talc, while 15 (16%) received multiple 4g talc doses for initial pleurodesis. Recurrence occurred in 20 (25.3%) of the single-dose group and 1 (6.7%) of the multiple-dose group within 180 days, though the difference was not statistically significant (p=0.112). Recurrence-free rates were 93.6% at 30 days, 85.1% at 90 days, and 77.7% at 180 days. Of the 20 patients with recurrence after a single 4g dose of talc, 8 (40%) underwent repeat pleurodesis, with only one recurrence requiring surgical intervention. Additionally, there was no recurrence after repeat talc pleurodesis in the one patient with recurrence after receiving multiple 4g talc doses for initial pleurodesis. No associations were found between recurrence rates and factors like gender (p=0.213) or comorbidities (emphysema, COPD, lung malignancy). Chest pain was a common complaint, but no cases of respiratory distress were reported post-pleurodesis. Conclusion: The efficacy of initial talc pleurodesis (77.7%-93.6%) in this cohort aligns with existing literature. Multiple-dose talc pleurodesis effectively prevented recurrence in 93.3% of patients, with no reported respiratory distress. Additionally, repeat talc pleurodesis was successful in 87.5% of those with recurrence after an initial single 4g dose. These findings support multiple-dose talc pleurodesis and repeat talc pleurodesis as safe and effective options for preventing recurrence post-initial failure and post-repeat talc pleurodesis, respectively. Although no significant recurrence predictors were identified, future research could focus on patient-specific factors to enhance treatment selection and optimize outcomes.