Citations

Background Bileaflet aortic valve prevalence in transcatheter aortic valve replacement (TAVR) patients is poorly defined. We evaluated a TAVR cohort to determine the bileaflet aortic valve prevalence and understand features which may improve detection. In addition, we related valvar morphology to the occurrence of permanent pacemaker implantation (PPI) following TAVR. Methods Aortic valvar morphology diagnosis was recorded from the pre-procedural cardiac CTA reports prior to TAVR. Commissural angles, comparison of commissural heights, and dynamic visual inspection of the aortic valve were subsequently evaluated on pre-procedural cardiac CTA by an expert cardiac anatomist and imager, methods previously validated in a surgical cohort, to determine aortic valvar morphology and compared to the historical diagnosis. Relationships between valvar morphological characteristics with the need for PPM within 30-days post-TAVR were determined. Results Four-hundred and thirty-three (mean age 81.3 ± 6.6 years, 53.8% female) underwent TAVR [corrected diagnosis: 393 (90.8%) trileaflet vs. 40 (9.2%) bileaflet valves]. Bileaflet valves were historically misdiagnosed in 80% of pre-procedural cardiac CTA reports. Thirty-four (85.0%) had intercoronary leaflet fusion [mean commissural angle = 148.1 (18.3) degrees]. A commissural angle threshold of 141.1 degrees had a sensitivity of 0.73 and specificity of 0.86 for identifying a bileaflet valve. PPI post-TAVR occurred in 38% bileaflet vs. 19% trileaflet patients ( p = 0.0114 ) [unadjusted OR for bileaflet valve requiring PPI = 2.54, 95% CI (1.25–5.01)]. Conclusions Bileaflet aortic valves are commonly misdiagnosed. Assessment of the commissural angle and comparison of commissural heights may improve CTA-based diagnostic accuracy prior to TAVR. Improved detection may guide improved outcomes in this higher risk population.

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-09.

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Context.— Distinguishing benign from malignant processes in small lung biopsy specimens is challenging, particularly in the presence of architectural distortion and crush artifacts. Mimics include reactive type II pneumocytes in peribronchiolar metaplasia or organizing pneumonia and benign mucinous elements, including goblet cells and submucosal glands, which can mimic adenocarcinoma with mucinous features. Objective.— To understand whether caudal-type homeobox 2 (CDX2) and cytokeratin 20 (CK20) immunoreactivity is specific to malignant epithelial processes and evaluate their expression in a range of benign, premalignant, and malignant pulmonary lesions. Design.— We assessed CDX2 and CK20 immunohistochemistry in 48 cases of interstitial lung disease with reactive type II pneumocytes, 13 foci of atypical adenomatous hyperplasia, 11 bronchiolar adenomas, 4 adenocarcinomas in situ, 25 minimally invasive adenocarcinomas, 39 pulmonary adenocarcinomas with mucinous features, 6 mucoepidermoid carcinomas, and 1 squamous papilloma with goblet cell hyperplasia. Results.— No expression of CDX2 or CK20 was observed in reactive processes, goblet cells, bronchial glands, atypical adenomatous hyperplasia, or bronchiolar adenomas. In adenocarcinomas with mucinous features (n = 39), 9 (23%) were CK20-reactive and 8 (20%) were CDX2-reactive. A minority of nonmucinous and mucinous minimally invasive adenocarcinomas (n = 25) showed immunoreactivity (3 [12%] for each marker), while all in situ adenocarcinomas were negative. Conclusions.— Our findings demonstrate that CDX2 and CK20 are not expressed in benign or reactive type II pneumocytes and are specific for malignancy, particularly adenocarcinomas with mucinous features. Immunoreactivity with either marker in small biopsy specimens can support a diagnosis of malignancy, especially in morphologically equivocal or limited samples. Absence of staining does not exclude malignancy, but immunoreactivity with CDX2 and/or CK20 provides strong supportive evidence for a malignant process.

Abstract This review aims to update recent advancements in the management and treatment of olfactory neuroblastoma (ONB) based on discussions and topics highlighted during the 2024 North American Skull Base Society session “Literature Review: What's New in Olfactory Neuroblastoma?” A systematic review was conducted using PubMed/MEDLINE, focusing on relevant studies published between January 2022 and June 2024. Data were organized into themes: prognostication and staging, surgical concepts, biomarkers/genomics, imaging, syndrome of inappropriate antidiuretic hormone release and hyponatremia, chemotherapy, and radiotherapy. Out of 289 initial records, 46 studies met eligibility criteria. Key findings include the proposed integration of Hyams grading and dural infiltration with traditional staging for better prognostic accuracy, a shift toward less invasive surgical techniques while maintaining clear resection margins, and the identification of biomarkers for improved diagnosis and targeted therapy. Advanced imaging modalities like DOTA-peptide tomography (positron emission tomography–computed tomography/magnetic resonance imaging) were highlighted for their diagnostic value. Variability in induction chemotherapy outcomes underscores the need for personalized treatment plans, and new radiotherapy techniques offer promising results with improving morbidity. Recent advancements in ONB management have enhanced prognostic accuracy, molecular diagnostics, imaging techniques, and treatment outcomes. Continuous research is necessary to optimize these strategies and further improve patient survival and quality of life.

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

Interstitial lung abnormalities (ILAs) are incidental nondependent radiologic findings that may portend early or future interstitial lung disease (ILD), but do not meet specific criteria at the time of presentation. They are subclinical by definition and found more commonly in older ever-smokers undergoing computed tomography (CT) imaging for other indications, including cardiac or lung cancer screening programs. As ILA prevalence increases, driven by an aging population and heightened awareness in younger patients, understanding risk factors for their development and progression has gained recent interest, particularly for optimizing subsequent ILD outcomes. This narrative review summarizes current ILA definitions, epidemiology, risk stratification, and management, while highlighting current challenges and knowledge gaps.

Background/Objectives: Individual and increasing numbers of comorbidities have been associated with worse outcomes in patients with fibrotic interstitial lung disease (f-ILD). The association and impact of medical comorbidities on patient-reported outcome measures (PROMs) in f-ILD have yet to be reported. Methods: Analysis was conducted using data from a single-center prospective cohort involving 199 patients with f-ILD. All f-ILD diagnoses and severities were screened and enrolled over a three-year study period. Baseline demographics, pulmonary function test (PFT) measures, and survival status were collected. PROMs, including the Chronic Respiratory Questionnaire (CRQ) and the Self-Management Ability Scale (SMAS-30), were assessed at baseline and serially. Thirteen medical comorbidities were evaluated for their prevalence and impact on PROMs and all-cause mortality. Results: Mean age was 69 years, with a female-to-male ratio of 61% vs. 39%. Dyslipidemia (74%) and gastroesophageal reflux disease (GERD) (71%) were the most prevalent comorbidities. Hypertension, diabetes, GERD, pulmonary hypertension (PH), depression, congestive heart failure (CHF), and obstructive sleep apnea (OSA), were independently associated with lower PROM scores along with increasing numbers of concomitant comorbidities. Increasing numbers of comorbidities, as well as specifically diabetes, PH, hypertension, CHF, and OSA, were associated with greater all-cause mortality. Conclusions: Medical comorbidities may independently impact respiratory-related PROMs in patients with f-ILD. These findings highlight the importance of comprehensive comorbidity management in improving quality of life and survival outcomes in patients with f-ILD.

Background The role of dose escalation of radiotherapy (RT) in unresectable stage III NSCLC followed by immunotherapy is unclear. The objective of the current study is to investigate if intermediate dose escalation (IDE) is beneficial in stage III NSCLC patients who receive definitive concurrent chemoradiation (dcCRT) followed by immunotherapy. Materials and methods The study used data from the National Cancer database. Multivariable Cox regression analysis was used to assess the all-cause mortality of patients who received standard RT dose (SD) (60 Gy ± 10%) and IDE (64–74 Gy). Results 47,315 patients were diagnosed in the era before immunotherapy and received dcCRT only, while 4,947 patients were treated with dcCRT and immunotherapy. In the cohort with dcCRT only, patients who received SD had statistically significant worse mortality but clinically minimal difference compared to patients with IDE (HR: 1.09, 95% CI: 1.07-1.12; p<0.0001). In the era of immunotherapy, SD was still associated with worse mortality compared to IDE (HR: 1.17, 95% CI: 1.03-1.33; p=0.02). However, the survival benefit associated with IDE was only restricted to patients who started immunotherapy within six weeks after RT completion (HR: 1.26, 95% CI: 1.05-1.6; p=0.01). There was no difference in mortality between SD and IDE among patients who started immunotherapy between 7–10 weeks (HR: 1.13, 95% CI: 0.88-1.45; p=0.35) or >10 weeks after RT completion (HR: 0.74, 95% CI: 0.51-1.07; p=0.11). Conclusion IDE of RT is not needed for patients diagnosed with stage III unresectable NSCLC who receive immunotherapy > six weeks after dcCRT.