Edell, Eric S.

ABSTRACTObjectiveWhile endoscopic laser wedge excision (LWE) for iSGS demonstrated lower surgical recurrence rates compared to endoscopic dilation (ED), ED remains the primary technique employed. Additionally, serial intralesional steroid injections (SILSIs) also demonstrate benefits in controlling disease. We aimed to compare surgical recurrence rates following ED, ED + SILSI, and LWE following a patient's first operation.MethodsThis was a two‐center retrospective analysis of iSGS patients who underwent either ED, ED + SILSI, or LWE. Patients were followed to their last follow‐up date or reoperation. Kaplan–Meier analysis and Cox proportional hazards were used to evaluate the recurrence times across the different surgical groups with additional stratification by age, compliance to medical adjuvant therapy, and percentage of stenosis rated at reoperation.ResultsA total of 126 patients from Institution 1 underwent LWE, while at Institution 2, ED and ED + SILSI were performed on 32 and 23 patients, respectively. One‐year recurrence estimates were 9%, 53%, and 0% for LWE, ED, and ED + SILSI, respectively, while 5‐year recurrence estimates were 45%, 90%, and 19%, respectively. Adjusted Cox‐proportional hazard ratios demonstrated a greater risk of surgical recurrence with ED compared to LWE (2.25; 95% confidence interval [CI]: 1.31–3.88) and no difference between ED + SILSI and LWE (0.84; 95% CI: 0.32–2.25).ConclusionLWE demonstrates reduced recurrence times compared to ED when controlling for surgery number, age, triple therapy compliance, and percentage of stenosis at reoperation. The application of postoperative SILSI appears to similarly reduce recurrence rates comparable to LWE and warrants further investigation.

AbstractObjectiveThis study aims to evaluate the impact of parity on the severity and recurrence rates of idiopathic subglottic stenosis (iSGS) in premenopausal females.Study DesignA retrospective cohort study.SettingTwo tertiary care centers from 2002 to 2024.MethodsWe analyzed premenopausal iSGS patients under 40 years who underwent balloon dilation or laser wedge excision. Clinical features, including demographics and pregnancy history, were examined. Recurrence rates between nulliparous and parous patients were compared using Poisson regression, adjusting for age and follow‐up duration. Linear regression assessed the relationship between pregnancy and iSGS recurrence.ResultsForty‐eight patients were included, with 36 parous and 12 nulliparous. Adjusting for age and follow‐up, the mean recurrence rate was 2.6 times higher in parous patients (95% confidence interval [CI]: [1.5, 4.8], P = .0008). Each additional pregnancy was associated with 0.81 additional recurrences (95% CI: [0.05, 1.57], P = .0375). No significant differences in surgery‐free time were observed between groups.ConclusionParity and pregnancy significantly increase the risk of iSGS recurrence, although they do not accelerate subsequent recurrences. Health care providers should counsel women of childbearing age about these risks in family planning discussions, emphasizing shared decision‐making regarding potential surgical interventions.Level of evidence3.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

Abstract Background: Tracheobronchomalacia (TBM) presents diagnostic challenges due to its nonspecific symptoms and variability in diagnostic methods. This study evaluates physician concordance in TBM diagnosis and phenotyping using chest computed tomography (CT) scans with dynamic expiratory views. Methods: We conducted a retrospective cross-sectional study at Mayo Clinic Rochester, analyzing 150 patients with dynamic expiratory CT scans. Three specialists—a thoracic radiologist, a bronchoscopist, and a pulmonologist—reviewed identical CT scans, blinded to prior interpretations. Inter-rater agreement was assessed using Fleiss's Kappa for TBM diagnosis and Cohen's Kappa for TBM phenotype classification into six categories: No TBM, Excessive Dynamic Airway Collapse (EDAC), Crescent Type, Circumferential Type, Saber-Sheath Type, and Mixed Type. Results: Among the 150 patients, 54 (36%) were diagnosed with TBM or EDAC. TBM was more prevalent in males, older individuals, and smokers. Agreement among specialists was substantial for TBM diagnosis (Fleiss’s Kappa = 0.61, p < 0.001) but moderate for phenotype classification (Fleiss’s Kappa = 0.52, p < 0.001). The highest concordance was between the thoracic radiologist and the pulmonologist (Cohen's Kappa = 0.68), while the lowest was between the bronchoscopist and other specialists. Conclusion: There is substantial agreement in TBM diagnosis using chest CT scans with dynamic expiratory views, but moderate variability in phenotyping. Standardizing criteria and integrating pulmonary function testing could enhance diagnostic consistency and clinical relevance.

ObjectiveTo evaluate the impact of age on disease recurrence in idiopathic subglottic stenosis (iSGS) patients.MethodsThis was a retrospective chart review of iSGS patients treated with laser wedge excision. Patients did not have prior surgery. Survival rates free of recurrence were estimated using the Kaplan–Meier methods, and associations were evaluated using Cox Proportional Hazards models.ResultsEighty‐five female patients were included in the study. Most patients (68%) were postmenopausal, had first period at or before 13 years of age, had at least one full‐term pregnancy (82%), were not undergoing hormone replacement therapy (93%), were not using hormonal birth control (88%), and were either partially or completely compliant with triple therapy regime (80%). There was a statistically significant average reduction in risk of recurrence of 5% for every additional year of age (p < 0.0001). When compared to patients older than 65 years of age, patients less than 35 were nearly 10 times more likely to recur (p = 0.002), and patients 55–65 and 45–55 years of age were 8 and 5 times more likely to recur, respectively (p = 0.003 and 0.009). Additionally, females on birth control showed decreased risk of recurrence of 74% compared with their counterparts (p = 0.04).ConclusionThis is the first study to demonstrate an inverse relationship between age and disease recurrence in patients with iSGS following surgery. Using age as a surrogate for menopausal status, these results suggest that increased age and/or birth control provide a protective effect through decreased recurrence rates, possibly mediated by decreased estrogen levels.Level of Evidence4 Laryngoscope, 2024

ObjectiveTo evaluate the impact of methotrexate and rituximab therapy on highly recurrent idiopathic subglottic stenosis (iSGS) patients with a negative antineutrophil cytoplasmic antibody titer cANCA(−).MethodsThis was a retrospective cohort study of highly recurrent iSGS patients who recurred within 1 year or less and were treated with methotrexate (MTX), and rituximab (RTX), or a combination of both at different time points (MTX/RTX). Average surgical durations before and after drug treatment were summarized, and the differences were calculated.ResultsA total of 21 female patients with median age of 62 years were included. Fifteen patients were treated with MTX, three were treated with RTX, and five treated with both. Patients treated with immunosuppressants showed a trend toward longer intervals between operations (mean pre‐drug interval: 338; mean post‐drug interval: 697 days) (p‐value = 0.25). Three patients did not recur following drug initiation with median follow‐up of 1265 days. All three treatment groups demonstrated a trend toward increased post‐drug recurrence intervals (MTX: 444 days, RTX: 374 days, MTX/RTX: 55 days), that was not statistically significant. Patients with prior dilations demonstrated longer post‐drug recurrence intervals (mean pre‐drug interval: 341 days, mean post‐drug interval 978 days) (p‐value = 0.17). Four patients in the cohort with the highest recurring disease improved from mean 129 days between operations to 509 days with drug therapy. The most common drug side effect was nausea (16%).ConclusionMTX and RTX may be treatment options for some highly recurrent iSGS patients. Initial results are variable and demonstrate a need for further research on drug candidacy.Level of Evidence3 Laryngoscope, 2024

Abstract Rationale Fibrosing mediastinitis (FM) is an uncommon fibroinflammatory condition without established or effective medical therapies. Infiltrating B lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures, including blood vessels and airways, resulting in significant morbidity and mortality. Objective To evaluate the benefits and side effects of rituximab in patients with progressive and symptomatic FM. Methods We treated 22 patients (median age, 35 yr; range, 15–68 yr; 45% female) with metabolically active, progressive FM with rituximab on an off-label basis. Additionally, patients were administered pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis, and time-to-event modeling was performed to estimate treatment response rates based on a &gt;30% reduction in pretreatment volume. The primary endpoints were lack of disease progression and change in mediastinal lesion volume on computed tomography (evaluated retrospectively). Results No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range, 7–94 mo) and imaging follow-up 21 months (range, 7–62 mo). A total of 82% of patients had confirmed histoplasmosis-associated FM. After rituximab treatment, a 49.6% (95% confidence interval, 17.5–64.4%) mean estimated decrease in pretreatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% confidence interval, 26.7–70.3%). Conclusions This observational study suggests that rituximab is a well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.

AbstractObjectiveAnalyze the duration of symptom‐free intervals following laser wedge excision (LWE) for recurrent idiopathic subglottic stenosis (iSGS). Secondary aim includes evaluating the influence of patient‐related or disease factors.Study DesignRetrospective review.SettingTertiary center.MethodsReview of iSGS patients who underwent LWE between 2002 and 2021. LWE patients without prior airway surgery were labeled LWE primary (LWEP) and those with prior history of dilation were labeled LWE secondary (LWES). A conditional frailty repeated events model was used to analyze the median time to recurrence (MTR) for each nth recurrence. Secondary analysis included stratification by use of medical therapy and initial preoperative characteristics of scar (Myer‐Cotton grade, distance between the glottis and superior‐most aspect of scar, DGS; length of scar, DL).ResultsTwo hundred and ten iSGS patients underwent LWE (131 LWEP, 79 LWES). The proportion of patients experiencing at least 1, 3, 6, and 12 recurrences, respectively, was 68.0% (n = 143), 40.7% (n = 85), 20.0% (n = 42), and 5.2% (n = 11). There was exponential time‐shortening from the 1st to 12th recurrence (P < .0001). While MTR was 4.1 years after the first LWE, this fell to 2.8, 1.7, 1.0, and 0.7 years for the 2nd, 3rd, 6th, and 12th recurrences. Furthermore, LWEP patients experienced longer MTR than LWES counterparts within the first 6 recurrences (P < .01). There was no significant relationship between intersurgical interval and medication adherence, DL, DGS, or grade for recurrences beyond the first (P = .207, P = .20, P = .43, P = .16).ConclusionSymptom‐free intervals in iSGS shorten with each subsequent recurrence and LWE. The difference in MTR between LWEP and LWES groups was significant within the first 6 recurrences with LWEP having longer MTR.Level of Evidence3.