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Objectives: Animal models for laryngotracheal stenosis (LTS) are critical to understand underlying mechanisms and study new therapies. Current animal models for LTS are limited by small airway sizes compared to human. The objective of this study was to develop and validate a novel, large animal ovine model for LTS. Methods: Sheep underwent either bleomycin‐coated polypropylene brush injury to the subglottis (n = 6) or airway stent placement (n = 2) via suspension microlaryngoscopy. Laryngotracheal complexes were harvested 4 weeks following injury or stent placement. For the airway injury group, biopsies (n = 3 at each site) were collected of tracheal scar and distal normal regions, and analyzed for fibrotic gene expression. Lamina propria (LP) thickness was compared between injured and normal areas of trachea. Results: No mortality occurred in sheep undergoing airway injury or stent placement. There was no migration of tracheal stents. After protocol optimization, LP thickness was significantly increased in injured trachea (Sheep #3: 529.0 vs. 850.8 um; Sheep #4: 933.0 vs. 1693.2 um; Sheep #5: 743.7 vs. 1378.4 um; Sheep #6: 305.7 vs. 2257.6 um). A significant 62‐fold, 20‐fold, 16‐fold, 16‐fold, and 9‐fold change of COL1, COL3, COL5, FN1, and TGFB1 was observed in injured scar specimen relative to unaffected airway, respectively. Conclusion: An ovine LTS model produces histologic and transcriptional changes consistent with fibrosis seen in human LTS. Airway stent placement in this model is safe and feasible. This large airway model is a reliable and reproducible method to assess the efficacy of novel LTS therapies prior to clinical translation. Level of Evidence: N/A Laryngoscope, 134:4239–4245, 2024 [ABSTRACT FROM AUTHOR]

Objective: To present a comprehensive flow cytometry panel for idiopathic subglottic stenosis (iSGS). Study Design: Controlled ex vivo cohort study. Setting: Tertiary care academic hospital in a metropolitan area. Methods: Flow cytometry and single‐cell RNA sequencing were performed on 9 paired normal and scar tissue samples from iSGS patients. Flow cytometry was used to assess the presence of myeloid (CD11b, CD14, CD15, Siglec8), lymphoid (CD3, CD4, CD8, gamma delta [γδ], FOXP3), endothelial (CD31), fibroblast (CD90, SMA), and epithelial (CD326, CK5) markers. Results: On flow cytometry, iSGS scar is characterized by an increased presence of myeloid, lymphoid, endothelial, and fibroblast cell types, but a decreased presence of epithelial cells. In the myeloid lineage, iSGS scar samples demonstrated increased CD11b+ monocytes (P <.001), Siglec8+ eosinophils (P =.03), and CD14+ monocytes (P =.02). In the lymphoid lineage, iSGS scar demonstrated increased CD3+ T‐cells (P <.001), CD4+ helper T‐cells (P <.001), γδ+ T‐cells (P <.001), and FOXP3+ regulatory T‐cells (P =.002). iSGS scar exhibited specific increases in CD90+ (P =.04) and SMA+ (P <.001) fibroblasts but decreased CD326+ (E‐cadherin) epithelial cells (P =.01) relative to normal samples. Conclusion: We present a comprehensive flow cytometry panel for iSGS. This flow panel may serve as a common platform among airway scientists to elucidate the cellular mechanisms underpinning iSGS and other upper airway pathologies. Scar iSGS samples demonstrate a distinct cellular profile relative to normal iSGS specimens, exhibiting increased fibroblast, endothelial, and inflammatory cell types but decreased epithelium. [ABSTRACT FROM AUTHOR]

Objectives: Retrograde cricopharyngeal dysfunction (RCPD) is a newly described condition resulting from failure of cricopharyngeal sphincter relaxation during periods of esophageal distension that results in the inability to burp. Patients' perspectives on symptom experiences, barriers to care, and treatment benefits were investigated. Study Design: Qualitative semi‐structured interviews were conducted with patients diagnosed with RCPD who had been treated with botulinum toxin injection into the cricopharyngeus muscle. Interview questions centered on their experience living with RCPD. Conventional content analysis was performed on interview transcripts. Results: Thematic saturation was reached with 13 participants. All participants were diagnosed with RCPD by an otolaryngologist and underwent botulinum toxin injection into the cricopharyngeus muscle with or without dilation of the upper esophageal sphincter in the operating room. Participants described having no memories of ever being able to burp, and all started experiencing RCPD symptoms during adolescence. Patients with RCPD experienced increased social isolation, lost productivity, and worsened mental health. Unanimously, participants first learned about RCPD on social media. All patients were seen by physicians in non‐otolaryngology specialties regarding their symptoms prior to learning about their RCPD diagnosis and undergoing treatment by an otolaryngologist. Dilation and chemodenervation resulted in complete resolution of RCPD symptoms for 84.6% of participants. Participants emphasized a desire for more health providers to learn about RCPD and the impact it has on quality‐of‐life. Conclusion(s): The lived experience of patients with RCPD significantly impacts quality of life and is often met with diagnostic barriers in the medical community. Although social media plays a significant role in increasing awareness of RCPD, physician education about the impact of RCPD is essential to improve diagnosis and treatment. Level of Evidence: 4 Laryngoscope, 134:2136–2143, 2024 [ABSTRACT FROM AUTHOR]

Retrograde cricopharyngeal dysfunction (RCPD), also referred to as retrograde cricopharyngeus dysfunction, is a condition characterized by the inability to burp. The pathophysiology of this condition is thought to result from failure of cricopharyngeal sphincter relaxation during periods of esophageal distension, which leads to patients' bothersome symptoms. RCPD negatively impacts patients' quality of life and is associated with bloating, gurgling, avoidance of carbonation, self-imposed dietary and lifestyle changes designed to minimize discomfort, and flatulence. Complaints often start during adolescence, and many patients search for a diagnosis for years before obtaining treatment. A recent increase in awareness through patient-led social media discussion boards describing the 'no burp' syndrome is leading to an increasing incidence of presentations, often with patients making a self-diagnosis. The increased incidence of RCPD is fueling a larger case series investigating treatment options and outcomes. In this review, we discuss what is known about the pathophysiology of this condition, the otolaryngologic perspective on diagnosis and treatment, the patients' lived experience of this condition, and the influence of social media on RCPD. [ABSTRACT FROM AUTHOR]

Objectives: To aim of the study was to characterize the molecular profile and functional phenotype of idiopathic subglottic stenosis (iSGS)‐scar epithelium. Methods: Human tracheal biopsies from iSGS scar (n = 6) and matched non‐scar (n = 6) regions were analyzed using single‐cell RNA sequencing (scRNA‐seq). Separate specimens were used for epithelial cell expansion in vitro to assess average growth rate and functional capabilities using transepithelial‐electrical resistance (TEER), fluorescein isothiocyanate‐dextran flux permeability assay, ciliary coverage, and cilia beating frequency (CBF). Finally, epithelial tight junction protein expression of cultured cells was quantified using immunoblot assay (n = 4) and immunofluorescence (n = 6). Results: scRNA‐seq analysis revealed a decrease in goblet, ciliated, and basal epithelial cells in the scar iSGS cohort. Furthermore, mRNA expression of proteins E‐cadherin, claudin‐3, claudin‐10, occludin, TJP1, and TJP2 was also reduced (p < 0.001) in scar epithelium. Functional assays demonstrated a decrease in TEER (paired 95% confidence interval [CI], 195.68–890.83 Ω × cm2, p < 0.05), an increase in permeability (paired 95% CI, −6116.00 to −1401.99 RFU, p < 0.05), and reduced epithelial coverage (paired 95% CI, 0.1814–1.766, fold change p < 0.05) in iSGS‐scar epithelium relative to normal controls. No difference in growth rate (p < 0.05) or CBF was found (paired 95% CI, −2.118 to 3.820 Hz, p > 0.05). Immunoblot assay (paired 95% CI, 0.0367–0.605, p < 0.05) and immunofluorescence (paired 95% CI, 13.748–59.191 mean grey value, p < 0.05) revealed E‐cadherin reduction in iSGS‐scar epithelium. Conclusion: iSGS‐scar epithelium has a dysfunctional barrier and reduced structural protein expression. These results are consistent with dysfunctional epithelium seen in other airway pathology. Further studies are warranted to delineate the causality of epithelial dysfunction on the downstream fibroinflammatory cascade in iSGS. Level of Evidence: NA Laryngoscope, 134:374–381, 2024 [ABSTRACT FROM AUTHOR]

Objective(s): Tracheostomy‐associated granulation tissue is a common, recurrent problem occurring secondary to chronic mucosal irritation. Although granulation tissue is composed of predominantly innate immune cells, the phenotype of monocytes and macrophages in tracheostomy‐associated granulation tissue is unknown. This study aims to define the myeloid cell population in granulation tissue secondary to tracheostomy. Methods: Granulation tissue biopsies were obtained from 8 patients with tracheostomy secondary to laryngotracheal stenosis. Cell type analysis was performed by flow cytometry and gene expression was measured by quantitative real‐time polymerase chain reaction. These methods and immunohistochemistry were used to define the monocyte/macrophage population in granulation tissue and were compared to tracheal autopsy control specimens. Results: Flow cytometry demonstrated macrophages (CD45+CD11b+) and monocytes (CD45+FSClowSSClow) represent 23.2 ± 6% of the granulation tissue cell population. The M2 phenotype (CD206) is present in 77 ± 11% of the macrophage population and increased compared to the M1 phenotype (p = 0.012). Classical monocytes (CD45+CD14highCD16low) were increased in granulation tissue compared to controls (61.2 ± 7% and 30 ± 8.5%, p = 0.038). Eighty‐five percent of macrophages expressed pro‐inflammatory S100A8/A9 and 36 ± 4% of macrophages co‐localized CD169, associated with tissue‐resident macrophages. M2 gene expression (Arg1/CD206) was increased in granulation tissue (3.7 ± 0.4, p = 0.035 and 3.5 ± 0.5, p = 0.047) whereas M1 gene expression (CD80/CD86) was similar to controls (p = 0.64, p = 0.3). Immunohistochemistry of granulation tissue demonstrated increased cells co‐localizing CD11b and CD206. Conclusions: M2 macrophages are the dominant macrophage phenotype in tracheostomy‐associated granulation tissue. The role of this cell type in promoting ongoing inflammation warrants future investigation to identify potential treatments for granulation tissue secondary to tracheostomy. Level of Evidence: 3 Laryngoscope, 133:2346–2356, 2023 [ABSTRACT FROM AUTHOR]

Objectives: Idiopathic subglottic stenosis (iSGS) is characterized by progressive fibrosis and subglottic luminal narrowing. Currently, immune characterization has focused on T‐cells; however, macrophages remain largely unexplored. The goals of this study are to characterize the transcriptome of iSGS macrophages and the fibrogenic nature of identifed biomarkers. Study Design: Bioinformatics and in vitro. Methods: Human tracheal biopsies from iSGS scar (n = 4), and matched non‐scar (n = 4) regions were analyzed using single‐cell RNA‐seq (scRNA‐seq). Immunofluorescence (IF) was performed on rapidly processed autopsies (RPA) and iSGS tracheal resections (n = 4) to co‐localize S100A8/9 and CD11b. Collagen gene/protein expression was assessed in iSGS fibroblasts (n = 4) treated with protein S100A8/9 (1000 ng/ml). Macrophages were subclustered to identify distinct subpopulations. Results: scRNA‐seq analysis revealed S100A8/S100A9 (fold change (FC) = 4.1/1.88, p < 0.001) as top differentially expressed genes in iSGS macrophages. IF exhibited increased CD11b+/S100A8/9+ cells in tracheal samples of iSGS versus RPA (26.75% ± 7.08 vs. 0.594% ± 0.974, n = 4, p = 0.029). iSGS fibroblasts treated with S100A8/9 demonstrated increased gene expression of COL1A1 (FC = 2.30 ± 0.45, p = 0.03, n = 4) and COL3A1 (FC = 2.44 ± 0.40, p = 0.03, n = 4). COL1A1 protein assays revealed an increase in the experimental group, albeit not significant, (p = 0.12, n = 4). Finally, macrophage sub clustering revealed one subpopulation as a predominant source of S100A8/S100A9 expression (FC = 7.94/5.47, p < 0.001). Conclusions: S100A8/9 is a key biomarker in iSGS macrophages. Although S100A8/9 demonstrates profibrotic nature in vitro, the role of S100A8/9+ macrophages in vivo warrants further investigation. Level of Evidence: NA Laryngoscope, 133:2308–2316, 2023 [ABSTRACT FROM AUTHOR]

Objective: To report a case of a patient with idiopathic subglottic stenosis (iSGS) who no longer required surgical intervention for her disease following a chemotherapy regimen of carboplatin and doxorubicin for ovarian cancer. A brief review of the literature and discussion on the possible mechanism of action of chemotherapy agents affecting fibrosis is included. Methods: Case report and review of literature. Results: A 71-year-old Caucasian woman with iSGS was managed with serial endoscopic excision and dilation (n = 5) from 2013 to 2017 with an average dilation interval of 12.3 months. After a course of doxorubicin and carboplatin to treat her ovarian cancer, we observed that her airway stenosis surprisingly stabilized, and has no longer required a surgical dilation for 45 months, which signifies an increase of 33 months when compared to her averaged dilation interval (12.3 months) prior to her second course of chemotherapy. Conclusion: We present an iSGS patient whose fibrosis was arrested following carboplatin/doxorubicin treatment. While a single case, a possible mechanism is carboplatin/doxorubicin's inhibition of pathologic CD4 lymphocytes that propagate laryngotracheal fibrosis. Further investigation of like mechanisms may allow for translation of local agents with inhibitory effects on CD4+ cells and/or fibroblasts as a novel therapy for airway fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Characterize and quantify epithelium in multiple etiologies of laryngotracheal stenosis (LTS) to better understand its role in pathogenesis. Study Design: Controlled in vitro cohort study. Methods: Endoscopic brush biopsy samples of both normal (non‐scar) and scar were obtained in four patients with idiopathic subglottic stenosis (iSGS) and four patients with iatrogenic LTS (iLTS). mRNA expression of basal, ciliary, and secretory cell markers were evaluated using quantitative PCR. Cricotracheal resection tissue samples (n = 5 per group) were also collected, analyzed using quantitative immunohistochemistry, and compared with rapid autopsy tracheal samples. Results: Both iSGS and iLTS‐scar epithelium had reduced epithelial thickness compared with non‐scar control epithelium (P =.0009 and P =.0011, respectively). Basal cell gene and protein expression for cytokeratin 14 was increased in iSGS‐scar epithelium compared with iLTS or controls. Immunohistochemical expression of ciliary tubulin alpha 1, but not gene expression, was reduced in both iSGS and iLTS‐scar epithelium compared with controls (P =.0184 and P =.0125, respectively). Both iSGS and iLTS‐scar had reductions in Mucin 5AC gene expression (P =.0007 and P =.0035, respectively), an epithelial goblet cell marker, with reductions in secretory cells histologically (P <.0001). Conclusions: Compared with non‐scar epithelium, the epithelium within iSGS and iLTS is morphologically abnormal. Although both iSGS and iLTS have reduced epithelial thickness, ciliary cells, and secretory cells, only iSGS had significant increases in pathological basal cell expression. These data suggest that the epithelium in iSGS and iLTS play a common role in the pathogenesis of fibrosis in these two etiologies of laryngotracheal stenosis. Setting: Tertiary referral center (2017–2020). Level of Evidence: NA Laryngoscope, 132:2194–2201, 2022 [ABSTRACT FROM AUTHOR]

Objective: Tapered low-volume, low-pressure (LVLP) cuffs have been introduced to improve sealing and reduce injury from tracheostomy and endotracheal intubation compared to traditional cylindrical high-volume, low-pressure (HVLP) cuffs. The objective of this study is to develop a swine model of tracheostomy injury and to compare live tissue response following LVLP and HVLP tracheostomy placement.Study Design: In vivo animal study.Setting: Academic institution.Methods: Swine underwent tracheostomy followed by placement of LVLP and HVLP tracheostomy cuffs at 30 cm H2O. After 24 and 48 hours, tracheal specimens underwent histopathological analysis including cilia, lamina propria and epithelial thickness, and mucosal injury score.Results: In all cuff contact areas, mean epithelial thickness for both tracheostomy cohorts was decreased compared to control epithelium at 24 and 48 hours (P < .01). HVLP proximal epithelium thickness was decreased at 24 and 48 hours relative to LVLP sections (P < .05). Lamina propria thickness in proximal LVLP sections was less than HVLP sections at 24 hours and 48 hours (P < .05). Mucosal injury score at areas of cuff contact was increased in tracheostomy cohorts relative to controls (P < .001), with HVLP injury score greater than LVLP at the proximal cuff (P < .05).Conclusion: In a swine model, tracheostomy resulted in increased mucosal injury compared to normal tracheal mucosa. LVLP cuffs resulted in less injury than HVLP cuffs, with reduced mucosal inflammation and improved health of epithelium and lamina propria. The wider proximal LVLP cuff demonstrated improved mucosal health compared to the HVLP cylindrical cuff. [ABSTRACT FROM AUTHOR]

Objective: To describe technical aspects and surgical outcomes of endoscopic resection and mucosal reconstitution with epidermal grafting (ie, the Maddern procedure) in the treatment of idiopathic subglottic stenosis. Study Design: Medical record abstraction. Setting: Johns Hopkins Hospital. Methods: Retrospective series of 9 adults with idiopathic subglottic stenosis who underwent the Maddern procedure by a single surgeon over a 5-year period. Prespecified outcomes included (1) perioperative outcomes (Clavien-Dindo grade 4/5 complications, need for staged tracheostomy, hospital length of stay), (2) postoperative outcomes (peak expiratory flow rate [PEFR], need for subsequent airway surgery, tracheostomy at follow-up), and (3) patient-reported quality-of-life outcomes (Clinical COPD Questionnaire, Voice Handicap Index–10, Eating Assessment Tool–10, and 12-Item Short Form Version 2). Wilcoxon matched-pairs signed rank test and Kaplan-Meier analysis were performed. Results: There were no Clavien-Dindo grade 4/5 complications; 2 patients required unplanned staged tracheostomy; and the median length of stay was 3 days. Following endoscopic resection and stent removal, a median of 2 laser resurfacing procedures were required. Two patients developed recurrent stenosis requiring cricotracheal resection (CTR). There were significant improvements in PEFR, Clinical COPD Questionnaire, and Voice Handicap Index–10, without significant difference in Eating Assessment Tool–10. The 12-Item Short Form Version 2 approximated the population norm. Kaplan-Meier analysis demonstrated significant improvement in time to surgery after the final laser resurfacing. Conclusion: The Maddern procedure has a low complication rate and offers durable physiologic improvement in PEFR, limiting need for additional procedures. Risks included need for CTR salvage, temporary tracheostomy, phlegm accumulation, and laryngospasm. It is a surgical option for patients with short dilation intervals who prefer to avoid the risks of CTR. [ABSTRACT FROM AUTHOR]

Background/Aims: Laryngotracheal stenosis is a rare but devastating proximal airway fibrosis that restricts a patient's ability to breathe. Treatment is primarily surgical and to date, there has never been a multi-institutional, randomized, prospective, and interventional clinical trial for a medical therapy to treat laryngotracheal stenosis. Therefore, we aimed to obtain patient feedback to guide successful trial design, recruitment, retention, and for identifying potential barriers to study participation. Methods: Over 1000 members of an international laryngotracheal stenosis online support community (the Living with Idiopathic Subglottic Stenosis Facebook group) were sent two questionnaires for a proposed interventional double-blinded, randomized, placebo-controlled clinical trial. Results: A total of 317 and 558 participants responded to the first and second surveys, respectively. The majority of participants (77%) were willing to consider enrollment, regardless of having a 50% chance of receiving placebo versus treatment (78%). The majority (84%) of participants were willing to travel 200 miles to participate for up to six in-person visits over 50 days. Specific side effects, including anemia/thrombocytopenia (72%) or risk of infection (69.3%) had the greatest impact on clinical trial participation with other side effects (peripheral edema (53%), oral ulcers (51%), and gastrointestinal side effects (41%)) having less impact. Conclusion: Patients with laryngotracheal stenosis possess nuanced insight into their disease and treatment options. As a group, they are extremely motivated for better therapies. Future laryngotracheal stenosis clinical trials should focus on providing excellent side effect -related education and utilizing feedback from online advocacy groups to optimize recruitment and retention. [ABSTRACT FROM AUTHOR]

Objective: Iatrogenic laryngotracheal stenosis (iLTS) is the pathologic narrowing of the glottis, subglottis, and/or trachea secondary to intubation or tracheostomy related injury. Patients with type 2 diabetes mellitus (T2DM) are more likely to develop iLTS. To date, the metabolomics and phenotypic expression of cell markers in fibroblasts derived from patients with T2DM and iLTS are largely unknown. Study Design: Controlled in vitro cohort study. Setting: Tertiary referral center (2017-2020). Methods: This in vitro study assessed samples from 6 patients with iLTS who underwent surgery at a single institution. Fibroblasts were isolated from biopsy specimens of laryngotracheal scar and normal-appearing trachea and compared with controls obtained from the trachea of rapid autopsy specimens. Patients with iLTS were subcategorized into those with and without T2DM. Metabolic substrates were identified by mass spectrometry, and cell protein expression was measured by flow cytometry. Results: T2DM iLTS-scar fibroblasts had a metabolically distinct profile and clustered tightly on a Pearson correlation heat map as compared with non-T2DM iLTS-scar fibroblasts. Levels of itaconate were elevated in T2DM iLTS-scar fibroblasts. Flow cytometry demonstrated that T2DM iLTS-scar fibroblasts were associated with higher CD90 expression (Thy-1; mean, 95%) when compared with non-T2DM iLTS-scar (mean, 83.6%; P =.0109) or normal tracheal fibroblasts (mean, 81.1%; P =.0042). Conclusions: Scar-derived fibroblasts from patients with T2DM and iLTS have a metabolically distinct profile. These fibroblasts are characterized by an increase in itaconate, a metabolite related to immune-induced scar remodeling, and can be identified by elevated expression of CD90 (Thy-1) in vitro. [ABSTRACT FROM AUTHOR]

Diagnosing Parkinson's Disease (PD) necessitates monitoring symptom progression. Unfortunately, diagnostic confirmation often occurs years after disease onset. A more sensitive and objective approach is paramount to the expedient diagnosis and treatment of persons with PD (PwPDs). Recent studies have shown that we can train accurate models to detect signs of PD from audio recordings of confirmed PwPDs. However, disparities exist between studies and may be caused, in part, by differences in employed corpora or methodologies. Our hypothesis is that unaccounted covariates in methodology, experimental design, and data preparation resulted in overly optimistic results in studies of PD automatic detection employing sustained vowels. These issues include record-wise fold creation rather than subject-wise; an imbalance of age between the PwPD and control classes; using too small of a corpus compared to the sizes of feature vectors; performing cross-validation without including development data; and the absence of cross-corpora testing to confirm results. In this paper, we evaluate the influence of these methodological issues in the automatic detection of PD employing sustained vowels. We perform several experiments isolating each issue to measure its influence employing three different corpora. Moreover, we analyze if the perceived dysphonia of the speakers could be causing differences in results between the corpora. Results suggest that each independent methodological issue analyzed has an effect on classification accuracy. Consequently, we recommend a list of methodological steps to be considered in future experiments to avoid overoptimistic or misleading results. [ABSTRACT FROM AUTHOR]

Objective: Idiopathic subglottic stenosis (iSGS) is a rare disease, causing life‐threatening dyspnea secondary to scarring. Perhaps because it is rarely encountered, there is often a delay in diagnosing iSGS. The objective of this study is to characterize diagnostic delay of iSGS, factors that prolong delay, and its impact on iSGS patients. Study Design: Retrospective chart review. Methods: A retrospective chart review of 124 iSGS patients was performed. Times of symptom onset, presentation to otolaryngologist, diagnosis, imaging, pulmonary function testing (PFTs), surgeries, emergency department (ED) visits, and hospitalizations were recorded and univariate analyses were used to identify risk factors for delay. Results: The median total time to diagnosis from symptom onset was 24.5 months, with time to first presentation of 6.3 months and healthcare delay of 17.8 months. 54.8% of patients were diagnosed with asthma. Earlier presentation to otolaryngologist was associated with shorter healthcare delay and total time to diagnosis (rho = 0.75, rho = 0.99, P <.0001). Earlier CT imaging was correlated to shorter healthcare delay (rho = 0.84, P <.0001) and total time to diagnosis (rho = 0.74, P <.001), while earlier PFTs were correlated to shorter total time to diagnosis alone (rho = 0.71, P =.01). During evaluation, 10.5% (n = 17/124) of patients had ED visits and 13.7% (n = 13/124) patients were hospitalized. Before diagnosis, 7% (9/124) of patients underwent surgeries (including 3% (n = 4) undergoing tracheostomy) and 8% (n = 10) of patients required unplanned urgent endoscopic surgery that may have been avoided with earlier diagnosis. Conclusion: iSGS diagnosis is frequently delayed, resulting in additional surgeries (including tracheostomy), ED visits, and hospitalizations. Further, patients' symptoms are commonly attributed to asthma. Earlier otolaryngologist evaluation, PFTs, and CT imaging may expedite iSGS diagnosis. Level of Evidence: 4 Laryngoscope, 132:413–418, 2022 [ABSTRACT FROM AUTHOR]

Objective: Subglottic stenosis (SGS) is a known complication of granulomatosis with polyangiitis (GPA). We investigated the impact of medical and surgical interventions on the surgical dilation interval and characterized patients with glottic involvement. Study Design: A retrospective chart review of patients with GPA-associated SGS was performed from 2010 to 2019. Setting: Tertiary academic medical center. Methods: The impact of medical and surgical interventions on dilation interval was assessed. The prevalence of glottic involvement was assessed, and clinical characteristics and outcomes were compared with patients without glottic involvement. Results: A total of 39 patients with GPA-associated SGS were analyzed. Dilation intervals in patients receiving leflunomide (n = 4; median, 484 days; 95% CI, 405-1099) were greater than in those not receiving leflunomide (median, 155 days; 95% CI, 48-305; P =.033). The surgical technique used did not affect dilation interval. Patients with glottic involvement (n = 13) had a greater incidence of dysphonia (13/13 vs 15/26 [58%], P =.007) and a shorter dilation interval with involvement (median, 91 days; interquartile range, 70-277) versus without involvement (median, 377 days; interquartile range, 175-1148; hazard ratio, 3.38; 95% CI, 2.26-5.05; P <.001). Of 13 patients, 8 (62%) did not have glottic involvement on first presentation. Conclusion: Although GPA is classically thought to affect the subglottis, it also involves the glottis in a subset of patients. These patients have greater complaints of dysphonia and require more frequent surgery. Systemic therapy may increase dilation intervals. In this preliminary study, patients taking leflunomide demonstrated an improvement, highlighting the need for further study of immunosuppression regimens in the treatment of GPA-associated SGS. [ABSTRACT FROM AUTHOR]

Objective/Hypothesis: Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis‐associated gene expression in iLTS mice. Study Design: Prospective controlled animal study. Methods: iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin‐coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis‐associated gene expression. Results: The study demonstrated that DON treatment reduced lamina propria thickness (P =.025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis‐associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P <.0001), Col3a1 (P =.0046), Col5a1 (P <.0001), and Tgfβ (P =.023) expression. At day 14, DON reduced Co1a1 (P =.0076) and Tgfβ (P =.023) expression. Conclusions: Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the laryngotracheal stenosis. Level of Evidence: N/A Laryngoscope, 131:E2125–E2130, 2021 [ABSTRACT FROM AUTHOR]

Objectives: Iatrogenic laryngotracheal stenosis (iLTS) is the pathological narrowing of the glottis, subglottis, and/or trachea due to scar tissue. Patients with type 2 diabetes mellitus (T2DM) are over 8 times more likely to develop iLTS and represent 26% to 53% of all iLTS patients. In this investigation, we compared iLTS scar‐derived fibroblasts in patients with and without T2DM. Study Design: Controlled ex vivo study. Methods: iLTS scar fibroblasts were isolated and cultured from subglottic scar biopsies in iLTS patients diagnosed with or without type 2 diabetes (non‐T2DM). Fibroblast proliferation, fibrosis‐related gene expression, and metabolic utilization of oxidative phosphorylation (OXPHOS) and glycolysis were assessed. Contractility was measured using a collagen‐based assay. Metabolically targeted drugs (metformin, phenformin, amobarbital) were tested, and changes in fibrosis‐related gene expression, collagen protein, and contractility were evaluated. Results: Compared to non‐T2DM, T2DM iLTS scar fibroblasts had increased α‐smooth muscle actin (αSMA) expression (8.2× increased, P =.020), increased contractility (mean 71.4 ± 4.3% vs. 51.7 ± 16% Δ area × 90 minute−1, P =.016), and reduced proliferation (1.9× reduction at 5 days, P <.01). Collagen 1 (COL1) protein was significantly higher in the T2DM group (mean 2.06 ± 0.19 vs. 0.74 ±.44 COL1/total protein [pg/μg], P =.036). T2DM iLTS scar fibroblasts had increased measures of OXPHOS, including basal respiration (mean 86.7 vs. 31.5 pmol/minute/10 μg protein, P =.016) and adenosine triphosphate (ATP) generation (mean 97.5 vs. 25.7 pmol/minute/10 μg protein, P =.047) compared to non‐T2DM fibroblasts. Amobarbital reduced cellular contractility; decreased collagen protein; and decreased expression of αSMA, COL1, and fibronectin. Metformin and phenformin did not significantly affect fibrosis‐related gene expression. Conclusion: T2DM iLTS scar fibroblasts demonstrate a myofibroblast phenotype and greater contractility compared to non‐T2DM. Their bioenergetic preference for OXPHOS drives their increased contractility, which is selectively targeted by amobarbital. Level of Evidence: NA Laryngoscope, 131:1570–1577, 2021 [ABSTRACT FROM AUTHOR]

Objective: Iatrogenic laryngotracheal stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key role for CD4 T cells in its pathogenesis. The objective of this study is to validate emerging multiplex immunofluorescence (mIF) technology for use in the larynx and trachea while quantitatively characterizing the immune cell infiltrate in iLTS. In addition to analyzing previously unstudied immune cell subsets, this study aims to validate previously observed elevations in the immune checkpoint PD-1 and its ligand PD-L1 while exploring their spatial and cellular distributions in the iLTS microenvironment. Study Design: Controlled ex vivo cohort study. Setting: Tertiary care center. Methods: mIF staining was performed with formalin-fixed, paraffin-embedded slides from 10 patients with iLTS who underwent cricotracheal resection and 10 control specimens derived from rapid autopsy for CD4, CD8, CD20, FoxP3, PD-1, PD-L1, and cytokeratin. Results: There was greater infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, FoxP3+CD4+ Tregs, and FoxP3+CD8+ early effector T cells in the submucosa of iLTS specimens as compared with controls (P <.05 for all). PD-1 was primarily expressed on T cells and PD-L1 predominantly on CD4+ cells and "other" cells. Conclusion: This study leverages the power of mIF to quantify the iLTS immune infiltrate in greater detail. It confirms the highly inflammatory nature of iLTS, with CD4+ cells dominating the immune cell infiltrate; it further characterizes the cellular and spatial distribution of PD-1 and PD-L1; and it identifies novel immunologic targets in iLTS. [ABSTRACT FROM AUTHOR]

Objectives: Laryngotracheal stenosis (LTS) is a fibrotic condition of the upper airway. Recent evidence suggests dysregulated host immunity plays a role in LTS development and progression. The programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis, targeted by paradigm‐shifting immunotherapies for cancer treatment, has also recently been implicated in the pathogenesis of fibrotic pulmonary disease. However, a role for the PD‐1/PD‐L1 axis in the proximal airway fibrosis seen in LTS patients has not been explored. Study Design: Controlled ex vivo study. Methods: Expression of PD‐1, PD‐L1, CD4, and CD8 were evaluated using immunohistochemical staining of cricotracheal resection specimens from postintubation iatrogenic laryngotracheal stenosis (iLTS), idiopathic subglottic stenosis (iSGS) patients, and normal controls derived from rapid autopsy (n = 8 per group). Fibroblasts derived from iLTS scar were also treated with transforming growth factor beta 1 (TGFβ1) and analyzed for PD‐L1 expression by quantitative real‐time polymerase chain reaction (n = 6). Results: iLTS specimens exhibited increased expression of PD‐1, PD‐L1, and CD4 (all P <.0167) compared to controls, whereas iSGS specimens exhibited increased expression of PD‐1 and CD4 (P <.0167) compared to controls. PD‐1, PD‐L1, and CD4 showed periepithelial patterns of expression in both disease cohorts. TGFβ1 treatment of iLTS fibroblasts increased expression of PD‐L1 (the cognate ligand for PD‐1). Conclusion: Expression of both PD‐1 and its ligand PD‐L1 are significantly greater in patients with iLTS compared to controls, and PD‐1 expression is also elevated in patients with iSGS. Given published evidence implicating the PD‐1/PD‐L1 axis in pulmonary fibrosis, this suggests a possible role for checkpoint inhibitors targeting the PD‐1/PD‐L1 axis for the treatment of LTS. Level of Evidence: N/A Laryngoscope, 131:967–974, 2021 [ABSTRACT FROM AUTHOR]

Objective: Macrophages exhibit distinct phenotypes and are dysregulated in a model of iatrogenic laryngotracheal stenosis (iLTS). Increased populations of alternatively activated or M2 macrophages have been demonstrated. However, the role of these macrophages is unknown. The aims of this study are: 1) define the macrophage population in iLTS in the context of classically activated or M1 and M2 macrophage phenotypes, and 2) characterize the effect of monocyte‐derived M1 and M2 macrophages on normal airway and LTS‐derived fibroblasts (FBs) in vitro. Study Design: Comparative analysis; in vitro controlled study. Methods: Immunohistochemical analysis of human iLTS and control specimens was performed to define the macrophage population. In vitro, M1, and M2 macrophages were polarized using M‐CSF + Interferon‐gamma and lipopolysaccharide or Interleukin‐4, respectively. FBs isolated from laryngotracheal scar (LTS‐FBs) and normal tracheal airway (NA‐FBs) in eight patients with iLTS were cocultured with polarized macrophages. Fibrosis gene expression, soluble collagen production, and proliferation were assessed. Results: Immunohistochemical analysis revealed increased CD11b + cells (macrophage marker) in laryngotracheal scar specimens (18.3% vs. 8.5%, P =.03) and predominant CD206 (M2) costaining versus CD86 (M1) (51.5% vs. 9.8%, n = 10, P =.001). In vitro, NA‐FBs cultured with M2 macrophages demonstrated a 2.41‐fold increase in collagen‐1 expression (P =.05, n = 8) and an increase in soluble collagen (9.98 vs. 8.875, mean difference: 1.11 95%, confidence interval 0.024–2.192, n = 8, P =.015). Conclusion: Increased populations of CD11b cells are present in iLTS specimens and are predominantly CD206+, indicating an M2 phenotype. In vitro, M2 macrophages promoted collagen expression in airway FBs. Targeting macrophages may represent a therapeutic strategy for attenuating fibrosis in iLTS. Level of Evidence: NA Laryngoscope, 131:E346–E353, 2021 [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: Glutamine metabolism is a critical energy source for iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts, and glutaminase (GLS) is an essential enzyme converting glutamine to glutamate. We hypothesize that the GLS‐specific inhibitor BPTES will block glutaminolysis and reduce iLTS scar fibroblast proliferation, collagen deposition, and fibroblast metabolism in vitro. Study Design: Test‐tube Lab Research. Methods: Immunohistochemistry of a cricotracheal resection (n = 1) and a normal airway specimen (n = 1) were assessed for GLS expression. GLS expression was assessed in brush biopsies of subglottic/tracheal fibrosis and normal airway from patients with iLTS (n = 6). Fibroblasts were isolated and cultured from biopsies of subglottic/tracheal fibrosis (n = 6). Fibroblast were treated with BPTES and BPTES + dimethyl α‐ketoglutarate (DMK), an analogue of the downstream product of GLS. Fibroblast proliferation, gene expression, protein production, and metabolism were assessed in all treatment conditions and compared to control. Results: GLS was overexpressed in brush biopsies of iLTS scar specimens (P =.029) compared to normal controls. In vitro, BPTES inhibited iLTS scar fibroblast proliferation (P =.007), collagen I (Col I) (P <.0001), collagen III (P =.004), and α‐smooth muscle actin (P =.0025) gene expression and protein production (P =.031). Metabolic analysis demonstrated that BPTES reduced glycolytic reserve (P =.007) but had no effects on mitochondrial oxidative phosphorylation. DMK rescued BPTES inhibition of Col I gene expression (P =.0018) and protein production (P =.021). Conclusions: GLS is overexpressed in iLTS scar. Blockage of GLS with BPTES significantly inhibits iLTS scar fibroblasts proliferation and function, demonstrating a critical role for GLS in iLTS. Targeting GLS to inhibit glutaminolysis may be a successful strategy to reverse scar formation in the airway. Level of Evidence: NA Laryngoscope, 2020 [ABSTRACT FROM AUTHOR]

The article provides description of first 100 years of head and neck surgery at Johns Hopkins Hospital located in Baltimore, Maryland along with information on physicians, who worked at the hospital. Topics include opening of hospital in 1889, early Days of otolaryngology at Johns Hopkins, and surgical procedures performed in clinic examination rooms in early years. [ABSTRACT FROM AUTHOR]

Study Design. A posterolateral rabbit spinal fusion model was used to evaluate the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and teriparatide (PTH [1-34]) used individually and in combination on spinal fusion outcomes. Objective. To test the efficacy of parathyroid hormone on improving spinal fusion outcomes when used with BMP-2. Summary of Background Data. Of the more than 250,000 spinal fusion surgical procedures performed each year, 5% to 35% of these will result in pseudarthrosis. Growing controversy on the efficacy and cost of rhBMP-2 for improving spinal fusion outcomes has presented a challenge for clinicians. Research into PTH as an adjunct therapy to rhBMP-2 for spinal fusion has not yet been investigated. Methods. Forty-eight male New Zealand white rabbits underwent bilateral posterolateral intertransverse process arthrodesis surgery at the L5-L6 level. Animals were divided into 6 groups. Two groups were treated with autograft alone or autograft and PTH (1-34), whereas the other 4 groups were treated with low-dose rhBMP-2 alone, high-dose rhBMP-2 alone, or either dose combined with PTH (1-34). All animals were euthanized 6 weeks after surgery. The L4-L7 spinal segment was removed and assessed using manual palpation, computed tomography (CT), and biomechanical testing. Results. CT assessments revealed fusion in 50% of autograft controls, 75% of autograft PTH (1-34) animals, 87.5% in the 2 groups treated with low-dose rhBMP-2, and 100% in the 2 groups treated with high-dose rhBMP-2. CT volumetric analysis demonstrated that all groups treated with biologics had fusion masses that were on average significantly larger than those observed in the control group (P < 0.0001). Biomechanical data demonstrated no statistical difference between controls, PTH (1-34), and low-dose rhBMP-2 in any testing orientation. PTH (1-34) did not increase bending stiffness when used adjunctively with either low-dose or high-dose rhBMP-2. Conclusion. Although intermittent teriparatide administration results in increased fusion mass volume, it does not improve biomechnical stiffness over use of autograft alone. When delivered concurrently with high- and low-dose rhBMP-2, teriparatide provided no statistically significant improvement in biomechanical stiffness. [ABSTRACT FROM AUTHOR]

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

Importance: During respiratory disease outbreaks such as the COVID-19 pandemic, aerosol-generating procedures, including tracheostomy, are associated with the risk of viral transmission to health care workers., Objective: To quantify particle aerosolization during tracheostomy surgery and tracheostomy care and to evaluate interventions that minimize the risk of viral particle exposure., Design, Setting, and Participants: This comparative effectiveness study was conducted from August 2020 to January 2021 at a tertiary care academic institution. Aerosol generation was measured in real time with an optical particle counter during simulated (manikin) tracheostomy surgical and clinical conditions, including cough, airway nebulization, open suctioning, and electrocautery. Aerosol sampling was also performed during in vivo swine tracheostomy procedures (n = 4), with or without electrocautery. Fluorescent dye was used to visualize cough spread onto the surgical field during swine tracheostomy. Finally, 6 tracheostomy coverings were compared with no tracheostomy covering to quantify reduction in particle aerosolization., Main Outcomes and Measures: Respirable aerosolized particle concentration., Results: Cough, airway humidification, open suctioning, and electrocautery produced aerosol particles substantially above baseline. Compared with uncovered tracheostomy, decreased aerosolization was found with the use of tracheostomy coverings, including a cotton mask (73.8% [(95% CI, 63.0%-84.5%]; d = 3.8), polyester gaiter 79.5% [95% CI, 68.7%-90.3%]; d = 7.2), humidification mask (82.8% [95% CI, 72.0%-93.7%]; d = 8.6), heat moisture exchanger (HME) (91.0% [95% CI, 80.2%-101.7%]; d = 19.0), and surgical mask (89.9% [95% CI, 79.3%-100.6%]; d = 12.8). Simultaneous use of a surgical mask and HME decreased the particle concentration compared with either the HME (95% CI, 1.6%-12.3%; Cohen d = 1.2) or surgical mask (95% CI, 2.7%-13.2%; d = 1.9) used independently. Procedures performed with electrocautery increased total aerosolized particles by 1500 particles/m3 per 5-second interval (95% CI, 1380-1610 particles/m3 per 5-second interval; d = 1.8)., Conclusions and Relevance: The findings of this laboratory and animal comparative effectiveness study indicate that tracheostomy surgery and tracheostomy care are associated with significant aerosol generation, putting health care workers at risk for viral transmission of airborne diseases. Combined HME and surgical mask coverage of the tracheostomy was associated with decreased aerosolization, thereby reducing the risk of viral transmission to health care workers.

While several approaches have been suggested for performing a transthoracic corpectomy of the thoracolumbar spine, the steep learning curve and high risk of operative morbidity often dissuades its use clinically. As a result, posterior approaches have been more frequently used, though transthoracic approaches often allow for improved access for more complete decompression of the spinal cord. Additionally, the transthoracic approach allows for more complete removal of vertebral body lesions along with better access for reconstruction of the anterior column. Here we describe a distinct nine-step thoracolumbar corpectomy technique via a transthoracic approach. We include a description of one patient with one-year follow-up to further illustrate the surgical approach and relevant surgical anatomy. We have used this technique for maximal bi-pedicular decompression afforded by the lateral approach. We discuss key anatomical considerations, perioperative techniques and potential complications of the operation. The presented nine-step transthoracic corpectomy technique is a safe method for providing adequate neurological decompression and vertebral body tumor removal.

OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher.

Pedicle screw instrumentation has been used to stabilize the thoracolumbar spine for several decades. Although pedicle screws were originally placed via a free-hand technique, there has been a movement in favor of pedicle screw placement with the aid of imaging. Such assistive techniques include fluoroscopy guidance and stereotactic navigation. Imaging has the benefit of increased visualization of a pedicle's trajectory, but can result in increased morbidity associated with radiation exposure, increased time expenditure, and possible workflow interruption. Many institutions have reported high accuracies with each of these three core techniques. However, due to differing definitions of accuracy and varying radiographic analyses, it is extremely difficult to compare studies side-by-side to determine which techniques are superior. From the literature, it can be concluded that pedicles of vertebrae within the mid-thoracic spine and vertebrae that have altered morphology due to scoliosis or other deformities are the most difficult to cannulate. Thus, spine surgeons would benefit the most from using assistive technologies in these circumstances. All other pedicles in the thoracolumbar spine should theoretically be cannulated with ease via a free-hand technique, given appropriate training and experience. Despite these global recommendations, appropriate techniques must be chosen at the surgeon's discretion. Such determinations should be based on the surgeon's experience and the specific pathology that will be treated.