Making minimally invasive procedures more sustainable: A systematic review comparing the environmental footprint of single-use versus multi-use instruments.

BACKGROUND: Healthcare systems contribute 5%-10% of the global carbon footprint. Given the detrimental impact of climate change on population health, health systems must seek to address this environmental responsibility. This is especially relevant in the modern era of minimally invasive procedures (MIP) where single-use instruments are increasingly popular. We compared the environmental footprint of single-use versus multi-use instruments in MIP. METHODS: We conducted a systematic review across five databases to identify relevant original studies, following the PRISMA guidelines. We extracted environmental impact data and performed a quality assessment of included studies. RESULTS: We included 13 studies published between 2005 and 2024. Eight employed Life Cycle Analysis (LCAs), which is the gold standard methodology for studies evaluating environmental impact. The instruments studied included laparoscopy systems, endoscopes, cystoscopes, bronchoscopes, duodenoscopes, and ureteroscopes. Six studies, including three high quality LCAs and one fair quality LCA, showed that single-use instruments have a significantly higher environmental footprint than their multi-use counterparts. Six studies suggested a lower environmental footprint for single-use instruments, and one study presented comparable results. However, these studies were of poor/fair quality. CONCLUSION: Although our systematic review yielded mixed results, all high quality LCAs suggested multi-use instruments may be more environmentally friendly than their single-use counterparts. Our findings are limited by inter-study heterogeneity and methodological quality. There is an urgent need for additional research employing gold standard methodologies to explore the interplay between environmental impact and operational factors such as workflow efficiency and cost-benefit ratio to allow health systems to make more informed decisions.

Editorial diversity correlates with journal impact factor and author diversity in cardiothoracic surgery.

INTRODUCTION: While there are no widely accepted diversity, equity, and inclusion (DEI) metrics for journals, geographic and sex diversity across a journal's editorial board may provide a surrogate measure of its commitment to DEI. We explored the association between journal quality and DEI metrics for cardiothoracic surgery (CTS) journals and investigated whether editorial diversity correlates with diversity across published articles. METHODS: We collected the following data for 30 CTS journals: country of publication (categorized by income level), journal quality metrics (citation-based metrics, e.g., impact factor (IF) or H-index), and sex and geographic representation across editorial boards and published articles. Bivariate correlations between numeric variables were assessed using Spearman's correlation. RESULTS: Female representation across editorial boards was 12.1%. Most editorial board members belonged to the United States (35.2%), with only 7.4% from the lower-middle-income countries and 0% from low-income countries. IF showed a strong positive correlation with female editorial representation (r = 0.70) but an inverse correlation with low- and middle-income countries (LMICs) editorial representation (r = -0.45). Female editorial representation demonstrated a significant positive correlation with female first authorship (r = 0.45), whereas LMIC editorial representation correlated strongly with LMIC corresponding authorship (r = 0.85). CONCLUSION: Women and researchers from LMICs are in the minority across editorial boards of CTS journals. However, a strong correlation between journal H-index and female editorial representation indicates that top-ranked journals are spearheading efforts to improve equitable sex-based and gender representations. Similar efforts are required to ensure more global geographic representation across editorial boards and top-ranked CTS journals are the best placed to lead by example.

From emissions to incisions and beyond: the repercussions of climate change on surgical disease in low- and-middle-income countries.

Climate change has far-reaching repercussions for surgical healthcare in low- and middle-income countries. Natural disasters cause injuries and infrastructural damage, while air pollution and global warming may increase surgical disease and predispose to worse outcomes. Socioeconomic ramifications further strain healthcare systems, highlighting the need for integrated climate and healthcare policies.

Surgical Advances in the Management of the Silent Sinus Syndrome: Our Experience and Review of the Literature.

Silent sinus syndrome is a rare disorder characterized by ipsilateral enophthalmos and hypoglobus caused by collapse of the orbital floor in the presence of asymptomatic long-term maxillary sinusitis. The basic principles in the management are to address the diseased sinus and reconstruct the orbit concurrently or separately. Failure to accurately restore the orbit volume can have significant consequences on the patient. In this article, we provide an update on current practices and highlight our experience of using computer-assisted planning and patient-specific implant in managing this syndrome.

Radiation therapy improves survival for unresectable postpneumonectomy lung tumors.

BACKGROUND: Additional resection for cancer in the single lung is often considered a prohibitive risk. The role of radiation therapy (RT) in this patient population is less clear with very limited available data. In this study, we sought to examine patients with postpneumonectomy lung cancer not amenable to surgery, identify factors associated with receiving RT, and determine the impact of RT on survival outcomes. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1988-2013) was queried for patients with inoperable contralateral lung cancer after pneumonectomy. Univariate and multivariate analyses were performed to identify factors associated with the receipt of RT. Survival outcomes were examined using the Kaplan-Meier method. RESULTS: In total, 191 patients with inoperable postpneumonectomy lung cancer were included. RT was delivered to 122 (63.9%) patients; 69 (36.1%) patients did not receive RT. On multivariate analysis, disease stage was identified as the only predictor associated with receipt of RT (P < 0.001). The median overall survival (OS) and disease-specific survival (DSS) for patients receiving RT were higher than those for patients who did not receive RT (25 versus 8 mo and 29 versus 10 mo, respectively; P < 0.001). Similarly, patients who received RT had a higher 3-y OS (34% versus 14%, P < 0.001) than those who did not receive RT. On subset analysis, survival benefit with RT was observed in patients with all tumor size groups, and there was a trend toward superior survival in patients with stage I/II disease, who received RT compared with those who did not. On multivariate Cox regression analysis, RT use was independently associated with decreased hazards of death after adjusting for other factors (HR, 0.539; P < 0.001). CONCLUSIONS: Based on our analysis of the Surveillance, Epidemiology, and End Results (SEER) database, RT is associated with improved outcomes in inoperable patients with a contralateral lung cancer after pneumonectomy compared with observation alone.

Primary appendiceal lymphoma: clinical characteristics and outcomes of 116 patients.

BACKGROUND: Primary appendiceal lymphoma (PAL) is extremely rare with limited data available in literature. In this study, we sought to describe clinical features and identify factors affecting survival in patients with PAL using a large population cohort. METHODS: Surveillance, Epidemiology, and End Results database was queried for patients with PAL between 1973 and 2012. Patient demographics, tumor characteristics, and outcomes were assessed. RESULTS: One hundred sixteen patients with PAL were included. The mean age (standard deviation) at diagnosis was 48 y (±22). PAL primarily afflicted males and white race. Diffuse large B-cell lymphoma was the most common histologic subtype (34.5%). Patients with Burkitt lymphoma presented at an earlier age compared with follicular lymphoma and diffuse large B-cell lymphoma (33 versus 59 and 53 y, respectively, [P < 0.001]). Mean overall survival (OS) for the whole cohort was 185 mo with a 5-y survival rate of 67%. No statistically significant survival difference was observed between gender, race and histologic subtypes. Right hemicolectomy conferred no survival benefit over appendectomy and/or partial colectomy (P = 0.501). In multivariate analysis, increasing age at diagnosis (P < 0.001) was associated with increased hazards of death while gender, race, tumor histology, disease stage, and nature of resection were not significantly associated with OS. CONCLUSIONS: This is the largest series of PALs. Our results demonstrate that age at diagnosis is an independent predictor of poor survival. Gender, race, histologic subtypes have no effect on OS, and hemicolectomy provides no survival benefit over appendectomy and/or partial colectomy. Additional prospective, multicenter studies including details about chemotherapy and immunotherapy are needed to guide management.

Racial disparities in esophageal cancer survival after surgery.

OBJECTIVES: Esophageal cancer (EC) black patients have higher mortality rates than Whites. The lower rate of surgery in Blacks may explain the survival difference. We explored the Surveillance Epidemiology and End Results database to determine the impact of surgery on mortality in Blacks and Whites EC. METHODS: All cases of pathologically proven local and locoregional adenocarcinoma and squamous cell carcinoma of the esophagus from 1973 to 2011 were identified (13,678 White, 2,894 Black patients). Cervical esophageal cancer was excluded. Age, sex, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed according to self-reported race. RESULTS: Blacks had higher 1-year mortality, adjusted for age, sex, stage, year of diagnosis, histology, and therapy [adjusted hazard ratio (HRadj ): 1.24 (95% CI 1.16-1.32)]. Undergoing surgery was an independent predictor of improved survival overall (HRadj 0.30, 95% CI 0.27-0.33). Black patients treated surgically experienced significantly lower survival than Whites, but the difference was not observed in those who did not undergo surgery. CONCLUSIONS: Although surgery appears to reduce mortality overall, early survival is worse for Blacks. Investigation into racial disparities in health care access and delivery, and to skilled esophageal surgeons is warranted to improve survival for all patients, particularly Blacks. J. Surg. Oncol. 2016;113:659-664. © 2016 Wiley Periodicals, Inc.

Oncological resection of lung cancer invading the aortic arch In full thickness using a non-fenestrated endograft.

T4 lung cancer invading the full thickness of the aortic arch was completely removed in a 78-year-old lady using a non-fenestrated endograft closing the left subclavian artery origin without performing surgical revascularization. Left thoracotomy and upper lobectomy with resection of superior segment of the lower lobe and full thickness of the infiltrated aorta was performed without covering the aortic defect. The margins of the specimen were free of tumor. The patient survived 32 months. J. Surg. Oncol. 2016;114:412-415. © 2016 Wiley Periodicals, Inc.

Antitumor activity of paclitaxel is significantly enhanced by a novel proapoptotic agent in non-small cell lung cancer.

BACKGROUND: Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced non-small cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of paclitaxel in combination with PAC-1. METHODS: Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1. RESULTS: PAC-1 significantly reduced the inhibitory concentration 50% of paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05). CONCLUSIONS: PAC-1 significantly enhances the antitumor activity of paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer.

Multilevel airway stenosis in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: To describe the presentation and clinical course of subglottic stenosis (SGS), in particular the development of concurrent airway lesions, in patients with Granulomatosis with Polyangiitis (Wegener's) (GPA). MATERIALS AND METHODS: Retrospective review of clinical data from all patients presenting to our institution from 2000 to 2012 with SGS and GPA. RESULTS: Thirty-five patients were identified. The average age at diagnosis was 33 years old. Eleven patients (31%) presented with SGS as part their initial manifestation of GPA. The remaining patients developed SGS later, at a median of 2.5 years from diagnosis (range 6 months to 14 years). Twelve patients (34%) were noted to have multilevel airway involvement. Seven patients (20%) had documentation of cricoarytenoid joint fixation and vocal cord immobility. This was typically progressive in nature and occurred at an average of two years following the diagnosis of SGS. Six patients (17%) had mid/distal tracheal stenosis and four (11%) had bronchial stenosis. The majority of patients (86%) had evidence of concurrent sinonasal involvement, ten patients (29%) had evidence of otologic involvement and eight (23%) had ocular involvement. CONCLUSIONS: Cricoarytenoid joint fixation and distal stenosis occur not infrequently in patients with GPA and SGS, resulting in progressive multilevel airway stenosis in about one third of patients. It is critical to identify multilevel stenosis when managing the airways of these patients.

The effect of metallic tracheal stents on radiation dose in the airway and surrounding tissues.

BACKGROUND: Metallic airway stents are often used in the management of central airway malignancies. The presence of a metallic foreign body may affect radiation dose in tissue. We studied the effect of a metallic airway stent on radiation dose delivery in a phantom and an in vivo porcine model. METHODS: A metallic tracheal stent was fitted onto a support in a water phantom. Point dosimeters were positioned in the phantom around the support and the stent. Irradiation was then performed on a linear accelerator with and without the stent. Metallic tracheal stents were deployed in the trachea of three pigs. Dosimeters were implanted in the tissues near (Group 1) and away (Group 2) from the stent. The pigs were then irradiated, and the dose perturbation factor was calculated by comparing the actual dose detected by the dosimeters versus the planned dose. RESULTS: The difference in the dose detected by the dosimeters and the planned dose ranged from 1.8% to 6.1% for the phantom with the stent and 0%-5.3% for the phantom without the stent. These values were largely within the manufacturer's specified error of 5%. No significant difference was observed in the dose perturbation factor for Group 1 and Group 2 dosimeters (0.836 ± 0.058 versus 0.877 ± 0.088, P = 0.220) in all the three pigs. CONCLUSIONS: Metallic airway stents do not significantly affect radiation dose in the airway and surrounding tissues in a phantom and porcine model. Radiation treatment planning systems can account for the presence of the stent. External beam radiation can be delivered without concern for significant dose perturbation.

Impact of facility type and volume in locally advanced esophageal cancer.

BACKGROUND: We hypothesized that academic facilities and high-volume facilities would be independently associated with improved survival and a greater propensity for performing surgery in locally advanced esophageal cancer. METHODS: We identified patients diagnosed with stage IB-III esophageal cancer during 2004-2016 from the National Cancer Database. Facility type was categorized as academic or community, and facility volume was based on the number of times a facility's unique identification code appeared in the dataset. Each facility type was dichotomized into high- and low-volume subgroups using the cutoff of 20 esophageal cancers treated/year. We fitted multivariable regression models in order to assess differences in surgery selection and survival between facilities according to type and volume. RESULTS: Compared to patients treated at high-volume community hospitals, those at high-volume academic facilities were more likely to undergo surgery (odds ratio: 1.865, p < 0.001) and were associated with lower odds of death (odds ratio: 0.784, p = 0.004). For both academic and community hospitals, patients at high-volume facilities were more likely to undergo surgery compared to those at low-volume facilities, p < 0.05. For patients treated at academic facilities, high-volume facilities were associated with lower odds of death (odds ratio: 0.858, p = 0.02) compared to low-volume facilities, while there was no significant difference in the odds of death between high- and low-volume community hospitals (odds ratio: 1.018, p = 0.87). CONCLUSIONS: Both facility type and case volume impact surgery selection and survival in locally advanced esophageal cancer. Compared to community hospitals, academic facilities were more likely to perform surgery and were associated with improved survival.

Gene expression profiles in COVID-19-associated tracheal stenosis indicate persistent anti-viral response and dysregulated retinol metabolism.

INTRODUCTION: Coronavirus disease 2019 (COVID-19)-associated tracheal stenosis (COATS) may occur as a result of prolonged intubation during COVID-19 infection. We aimed to investigate patterns of gene expression in the tracheal granulation tissue of patients with COATS, leverage gene expression data to identify dysregulated cellular pathways and processes, and discuss potential therapeutic options based on the identified gene expression profiles. METHODS: Adult patients (age ≥ 18 years) presenting to clinics for management of severe, recalcitrant COATS were included in this study. RNA sequencing and differential gene expression analysis was performed with transcriptomic data for normal tracheal tissue being used as a control. The top ten most highly upregulated and downregulated genes were identified. For each of these pathologically dysregulated genes, we identified key cellular pathways and processes they are involved in using Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) applied via Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS: Two women, aged 36 years and 37 years, were included. The profile of dysregulated genes indicated a cellular response consistent with viral infection (CXCL11, PI15, CCL8, DEFB103A, IFI6, ACOD1, and DEFB4A) and hyperproliferation/hypergranulation (MMP3, CASP14 and HAS1), while downregulated pathways included retinol metabolism (ALDH1A2, RBP1, RBP4, CRABP1 and CRABP2). CONCLUSION: Gene expression changes consistent with persistent viral infection and dysregulated retinol metabolism may promote tracheal hypergranulation and hyperproliferation leading to COATS. Given the presence of existing literature highlighting retinoic acid's ability to favorably regulate these genes, improve cell-cell adhesion, and decrease overall disease severity in COVID-19, future studies must evaluate its utility for adjunctive management of COATS in animal models and clinical settings.

Neoadjuvant vs Adjuvant Chemoimmunotherapy for Stage II-IIIB Non-Small Cell Lung Cancer.

BACKGROUND: In patients with resectable non-small cell lung cancer (NSCLC), recent trials demonstrate survival benefit of chemoimmunotherapy over chemotherapy alone in both the neoadjuvant and adjuvant settings. To date, there is no direct comparison between neoadjuvant and adjuvant protocols. We compared neoadjuvant vs adjuvant chemoimmunotherapy for resectable stage II-IIIB NSCLC. METHODS: We queried the National Cancer Database for patients who had undergone an operation for stage II-IIIB NSCLC and who had received neoadjuvant or adjuvant chemoimmunotherapy between 2015 and 2020. We used inverse probability weighting to adjust for confounding variables and used Kaplan-Meier survival curves and Cox regression to explore the relationship between treatment groups and overall survival (OS) at 3 years postoperatively. RESULTS: The inverse probability-weighted cohort represented 2119 weighted patient cases (neoadjuvant, 1034; adjuvant, 1085). Kaplan-Meier analysis demonstrated a significant OS benefit for neoadjuvant chemoimmunotherapy compared with adjuvant chemoimmunotherapy in the weighted cohort (3-year OS: 77% [95% CI, 71%-83%] vs 68% [95% CI, 64%-72%]; P = .035). On adjusted Cox regression, neoadjuvant chemoimmunotherapy was associated with a significant OS benefit (hazard ratio, 0.70; 95% CI, 0.50-0.96; P = .027). Among patients for whom pathologic stage data were available, 25% of patients receiving neoadjuvant chemoimmunotherapy had a pathologic complete response, with an additional 32.5% being downstaged. CONCLUSIONS: Neoadjuvant chemoimmunotherapy confers a significant OS benefit over adjuvant chemoimmunotherapy for patients with resectable stage II-IIIB NSCLC. Although randomized trials are needed to confirm our findings, strong consideration should be given to administering neoadjuvant chemoimmunotherapy to patients who are predetermined to receive systemic treatment.

Improved Composite Hydrogel for Bioengineered Tracheal Graft Demonstrates Effective Early Angiogenesis.

Background/Objectives: Collagen-agarose hydrogel blends currently used in tracheal graft bioengineering contain relatively high concentrations of collagen to withstand mechanical stresses associated with native trachea function (e.g., breathing). Unfortunately, the high collagen content restricts effective cell infiltration into the hydrogel. In this study, we created an improved hydrogel blend with lower concentrations of collagen (<5 mg/mL) and characterized its capacity for fibroblast invasion and angiogenesis. Methods: Four collagen-agarose hydrogel blends were created: 1 mg/mL type 1 collagen (T1C) and 0.25% agarose, 1 mg/mL T1C and 0.125% agarose, 2 mg/mL T1C and 0.25% agarose, and 2 mg/mL T1C and 0.125% agarose. The hydrogel surface was seeded with fibroblasts, while both endothelial cells and fibroblasts (3:1 ratio) were mixed within the hydrogel matrix. We assessed early angiogenesis by observing fibroblast migration and endothelial cell morphology (elongation and branching) at 7 days. In addition, we performed immunostaining for alpha-smooth muscle actin (aSMA) and explored the gene expression of various angiogenic markers (including vascular endothelial growth factor; VEGF). Results: Gels with lower agarose concentrations (0.125%) with 1 or 2 mg/mL T1C were more effective in allowing early attachment and migration of surface-applied fibroblasts compared to gels with higher (0.25%) agarose concentrations. The low-agarose gels also allowed cells to quickly adopt a spread morphology and self-assemble into elongated structures indicative of early angiogenesis, while demonstrating positive immunostaining for aSMA and increased gene expression of VEGF by day 7. Conclusions: Hydrogel blends with collagen and low agarose concentrations may be effective in allowing early cellular infiltration and angiogenesis, making such gels a suitable cell substrate for use in the development of composite bioengineered tracheal grafts. The collagen-agarose hydrogel blend is meant to be cast around a three-dimensional (3D) printed polycaprolactone support structure and wrapped in porcine small intestine submucosa ECM to create an off-the-shelf bioengineered tracheal implant.

Factors associated with safe and successful postoperative day 1 discharge after lung operations: a systematic review and meta-analysis.

BACKGROUND: A shorter length of stay (LOS) is associated with fewer hospital-acquired adverse conditions and decreased utilization of hospital resources. While modern perioperative care protocols have enabled some ambitious surgical teams to achieve discharge as early as within postoperative day 1 (POD1), most other teams remain cautious about such an approach due to the perceived risk of missing postoperative complications and increased readmission rates. We aimed to identify factors that would help guide surgical teams aiming for safe and successful POD1 discharge after lung resection. METHODS: We searched the PubMed, Embase, Scopus, Web of Science and CENTRAL databases for articles comparing perioperative characteristics in patients discharged within POD1 (DWPOD1) and after POD1 (DAPOD1) following lung resection. Meta-analysis was performed using a random-effects model. RESULTS: We included eight retrospective cohort studies with a total of 216,887 patients, of which 22,250 (10.3%) patients were DWPOD1. Our meta-analysis showed that younger patients, those without cardiovascular and respiratory comorbidities, and those with better preoperative pulmonary function are more likely to qualify for DWPOD1. Certain operative factors, such as a minimally invasive approach, shorter operations, and sublobar resections, also favor DWPOD1. DWPOD1 appears to be safe, with comparable 30-day mortality and readmission rates, and significantly less postoperative morbidity than DAPOD1. CONCLUSIONS: In select patients with a favorable preoperative profile, DWPOD1 after lung resection can be achieved successfully and without increased risk of adverse outcomes such as postoperative morbidity, mortality, or readmissions.

Novel Journal Metrics in Cardiothoracic Surgery: How Different Are Contemporary Metrics From the Impact Factor?

OBJECTIVE: Despite shortcomings, impact factor (IF) remains the "gold standard" metric for journal quality. However, novel metrics including the h-index, g-index, and Altmetric Attention Score (AAS; mentions in mainstream/social media) are gaining traction. We assessed correlations between these metrics among cardiothoracic surgery journals. METHODS: For all cardiothoracic surgery journals with a 2021 Clarivate IF (N = 20), the 2-year IF (2019 to 2020) and 5-year IF (2016 to 2020), h-index, and g-index were obtained. Two-year journal-level AAS (2019 to 2020) was also calculated. Journal Twitter presence and activity was sourced from Twitter and the Twitter application programming interface. Correlations were assessed using Spearman correlation, and coefficients of determination were calculated. RESULTS: IF demonstrated a moderate-strong positive correlation with the h-index (rs = 0.48 to 0.77) and g-index (rs = 0.49 to 0.79) and a moderate correlation with AAS (rs = 0.53 to 0.58). The 2-year IF accounted for 25% to 49% of variability in the h-index, 27% to 55% of variability in the g-index, and 32% of variability in the AAS. Among journals with a Twitter account (N = 10), IF was strongly correlated with Twitter following (rs = 0.81 to 0.86), which was in turn strongly correlated with journal AAS (rs = 0.79). Article-level AAS was moderately correlated with citation count (rs = 0.47). CONCLUSIONS: IF accounted for only between 25% and 55% of variability in the h-index and g-index, indicating that these newer metrics measure unique dimensions of citation-based impact. Thus, the academic community must familiarize itself with these newer journal metrics. Social media attention may be associated with scholarly impact, although further work is needed to understand these relationships.

Identifying Molecular Pathophysiology and Potential Therapeutic Options in Iatrogenic Tracheal Stenosis.

INTRODUCTION: While most patients with iatrogenic tracheal stenosis (ITS) respond to endoscopic ablative procedures, approximately 15% experience a recalcitrant, recurring disease course that is resistant to conventional management. We aimed to explore genetic profiles of patients with recalcitrant ITS to understand underlying pathophysiology and identify novel therapeutic options. METHODS: We collected 11 samples of granulation tissue from patients with ITS and performed RNA sequencing. We identified the top 10 most highly up- and down-regulated genes and cellular processes that these genes corresponded to. For the most highly dysregulated genes, we identified potential therapeutic options that favorably regulate their expression. RESULTS: The dysregulations in gene expression corresponded to hyperkeratinization (upregulation of genes involved in keratin production and keratinocyte differentiation) and cellular proliferation (downregulation of cell cycle regulating and pro-apoptotic genes). Genes involved in retinoic acid (RA) metabolism and signaling were dysregulated in a pattern suggesting local cellular RA deficiency. Consequently, RA also emerged as the most promising potential therapeutic option for ITS, as it favorably regulated seven of the ten most highly dysregulated genes. CONCLUSION: This is the first study to characterize the role of hyperkeratinization and dysregulations in RA metabolism and signaling in the disease pathophysiology. Given the ability of RA to favorably regulate key genes involved in ITS, future studies must explore its efficacy as a potential therapeutic option for patients with recalcitrant ITS.

Anastomotic stenosis of bioengineered trachea grafts is driven by transforming growth factor ß1-induced signaling, proinflammatory macrophages, and delayed epithelialization.

Objective: Anastomotic stenosis caused by hypertrophic granulation tissue often develops in response to orthotopically implanted bioengineered tracheal grafts. To determine mechanisms responsible for the development and persistence of this granulation tissue, we looked for changes in gene expression from tissue specimens from the graft-native interface. Methods: RNA was isolated from paraffin-embedded tissue samples of the anastomotic sites of orthotopically implanted bioengineered tracheal grafts of 9 animals. Tissue samples were binned into 3 groups based on degree of stenosis: no stenosis (<5%), mild stenosis (25%-50%), and moderate and severe stenosis (≥75%). Sections of healthy trachea tissue were used as control. The expression levels of ∼200 genes related to wound healing, plus several endogenous controls, were measured with a pathway-focused predesigned primer array. Results: Expression of ARG2, IL4, RPL13 A, TGFBR3, and EGFR decreased, whereas expression of RUNX2 was increased in stenotic wounds compared with nonstenotic tissue. Based on the cell types present in the trachea and wound healing, this expression profile indicates a lack of M2 anti-inflammatory macrophages, absent epithelial cells, and transforming growth factor ß1-induced signaling. Conclusions: These findings represent a significant step for tracheal tissue engineering by identifying several key mechanisms present in stenotic granulation tissue. Further research must be conducted to determine what modifications of the graft substrate and which coadministered therapeutics can be used to prevent the development of hypertrophic granulation tissue.