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INTRODUCTION: Lung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. METHODS: This study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. RESULTS: Cox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase = 0.50, 95% confidence interval: 0.27-0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase = 0.36, confidence interval: 0.15-0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. CONCLUSIONS: Analysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set.

Abstract Background We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development. Methods EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically. Results EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO. Conclusions Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Objective: The American College of Radiology Thyroid Imaging Reporting and Data System (TI‐RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI‐RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. Methods: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI‐RADS. Management recommendations based on TI‐RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. Results: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI‐RADS for predicting malignancy was 0.78. Adult TI‐RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow‐up. Modifications to TI‐RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. Conclusions: TI‐RADS can risk‐stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children. [ABSTRACT FROM AUTHOR]

Objectives: A small number of Idiopathic subglottic stenosis (iSGS) patients are treated at institutions across the country. Divergence in operative techniques for endoscopic dilation (ED) of iSGS has been anecdotally recognized but not formally characterized. Additionally, the relationship between procedural variation and clinical outcome has not been studied. Methods: Secondary analysis of the NoAAC iSGS1000 cohort investigated variation in procedural techniques and treatment outcomes in patients treated with ED across high‐enrolling treatment centers (enrolled >10 patients in PR‐02 trial). Results: Thirteen NoAAC centers each enrolled >10 patients treated with ED for a total of 281 subjects. There was significant variation in procedural details and rate of recurrence among institutions. Hierarchal cluster analysis revealed significant heterogeneity among institutions and clusters in all procedural variables. However, analysis demonstrated a transient delay in disease recurrence in cluster 2 which disappeared with longer longitudinal follow‐up. Patient‐reported outcome and peak expiratory flow data supported the potential benefit of the technical variation in Cluster 2. Distinct to cluster 2, however, was routine use of adjuvant triple medical therapy (proton pump inhibitor (PPI), antibacterial agent, and steroid inhaler). Conclusions: Both outcome and procedural technique vary among centers employing ED to treat iSGS. A transient delay in recurrence was observed among centers that routinely prescribed adjuvant medical therapy (antibiotic, inhaled corticosteroid, and PPI) to iSGS patients after endoscopic dilation, which was further supported by patient‐reported data and peak expiratory flow data. Prospective studies are needed to understand the effects of adjuvant medical therapy on recurrence after endoscopic dilation. Level of Evidence: 4 Laryngoscope, 134:3260–3266, 2024 [ABSTRACT FROM AUTHOR]

Objective: Idiopathic subglottic stenosis (iSGS) is a rare, recurrent, fibroinflammatory disease affecting the larynx and proximal trachea. Given it occurs primarily in adult females, estrogen is speculated to play a central pathophysiological role. This study aimed to evaluate relationships between estrogen exposure, disease progression, and recurrence. Methods: North American Airway Collaborative (NoAAC) data of adults with iSGS obstructive airway lesions, who underwent index endoscopic airway dilation, were used to identify associations between estrogen exposure, disease characteristics, and time to recurrence (TTR), and interventions were analyzed using Kruskal–Wallis test and Pearson coefficient. Cox proportional hazards regression models compared hazard ratios by estrogen exposure. Kaplan–Meier curves were plotted for TTR based on menopausal status. Results: In all, 533 females had complete estrogen data (33% premenopausal, 17% perimenopausal, 50% postmenopausal). Median estrogen exposure was 28 years. Overall, there was no dose–response relationship between estrogen exposure and disease recurrence. Premenopausal patients had significantly shorter time from symptom manifestation to diagnosis (1.17 vs. 1.42 years perimenopausal vs. 2.08 years postmenopausal, p < 0.001), shorter time from diagnosis to index endoscopic airway dilation (1.90 vs. 2.50 vs. 3.76 years, p = 0.005), and higher number of procedures (1.73 vs. 1.20 vs. 1.08 procedures, p < 0.001). Conclusions: We demonstrate premenopausal patients may have a more aggressive disease variant than their peri‐ and postmenopausal counterparts. However, it is unclear as to whether this is related to reduced estrogen in the peri‐ and postmenopausal states or the age‐related physiology of wound healing and inflammation, regardless of estrogen. Level of Evidence: 3 Laryngoscope, 134:825–830, 2024 [ABSTRACT FROM AUTHOR]

Background: National survey data exploring the patient experience with lipedema are lacking. Methods: We conducted national surveys from 2016 to 2022 of women with lipedema as well as female controls. Surveys collected information on symptomatology, pain, and therapies. We performed logistic regression comparing symptoms among those with lipedema versus controls adjusting for age and BMI. Results: A total of 707 women with lipedema and 216 controls completed the surveys. Those with lipedema had a mean age of 48.6 years and mean BMI of 40.9 kg/m2. Lipedema symptom onset occurred frequently at puberty (48.0%) or pregnancy (41.2%). Compared to controls, women with lipedema were more likely to report leg swelling in heat (odds ratio [OR], 66.82; 95% CI, 33.04–135.12; p < 0.0001), easy bruising (OR, 26.23; 95% CI, 15.58–44.17; p < 0.0001), altered gait (OR, 15.54; 95% CI, 7.58–31.96; p < 0.0001), flu-like symptoms (OR, 12.99; 95% CI, 4.27–39.49; p < 0.0001), joint hypermobility (OR, 12.88; 95% CI, 6.68–24.81; p < 0.0001), cool skin (OR, 12.21; 95% CI, 5.20–28.69; p < 0.0001), varicose veins (OR, 11.29; 95% CI, 6.71–18.99; p < 0.0001), and fatigue (OR, 9.59; 95% CI, 6.10–15.09; p < 0.0001). Additionally, 70.3% had upper arm involvement, 21.2% reported foot swelling, and 16.6% reported foot pain. Most (52.2%) reported no symptom improvement with diet or exercise. Common therapies used included compression therapy (45.0%), gastric bypass (15.7%), and lower-extremity liposuction (14.0%). Conclusion: In a large, national, symptom survey, women with lipedema reported excess pain, swelling, and fat in the legs along with numerous symptoms beyond those classically described. Symptom responses to common therapies remain understudied. [ABSTRACT FROM AUTHOR]