YM155 Induces DNA Damage and Cell Death in Anaplastic Thyroid Cancer Cells by Inhibiting DNA Topoisomerase IIα at the ATP-Binding Site.

Anaplastic thyroid cancer (ATC) is among the most aggressive of human cancers, and currently there are few effective treatments for most patients. YM155, first identified as a survivin inhibitor, was highlighted in a high-throughput screen performed by the National Cancer Institute, killing ATC cells in vitro and in vivo. However, there was no association between survivin expression and response to YM155 in clinical trials, and YM155 has been mostly abandoned for development despite favorable pharmacokinetic and toxicity profiles. Currently, alternative mechanisms are being explored for YM155 by a number of groups. In this study, ATC patient samples show overexpression of topoisomerase Top2α compared with benign thyroid samples and to differentiated thyroid cancers. ATC cell lines that overexpress Top2α are more sensitive to YM155. We created a YM155-resistant cell line, which shows decreased expression of Top2α and is resensitized with Top2α overexpression. Molecular modeling predicts binding for YM155 in the Top2α ATP-binding site and identifies key amino acids for YM155-Top2α interaction. A Top2α mutant abrogates the effect of YM155, confirming the contribution of Top2α to YM155 mechanism of action. Our results suggest a novel mechanism of action for YM155 and may represent a new therapeutic approach for the treatment of ATC.

Pilot Study: Pneumatic Compression Garment Therapy for Postradiotherapy Laryngopharyngeal Edema.

OBJECTIVES: Pneumatic compression garment therapy (PCGT) has been established as treatment for postradiotherapy lymphedema, and its use in head and neck patients is becoming more common. Although effects on interstitial edema of the cervical soft tissues have been studied, effects on internal laryngopharyngeal edema, as well as associated symptoms of dysphagia and dysphonia, have yet to be published. METHODS: We surveyed 7 patients treated with radiation for head and neck cancer (HNC) who had also been prescribed PCGT for cervical lymphedema. Patients were asked about subjective experience with the device, and also administered the Eating Assessment Tool-10 (EAT-10) and Voice Handicap Index-10 (VHI-10) surveys regarding their symptoms after using PCGT. Laryngoscopy videos from these same periods were also reviewed and scored using a validated tool for assessing laryngopharyngeal edema. RESULTS: 85% of patients reported at least some improvement in dysphagia and dysphonia following PCGT. Average EAT-10 score after PCGT was 11.4 and average VHI-10 score after PCGT was 8.7. These compare more favorably to historical scores for the same questionnaires in similar patient populations. Laryngeal edema scores on endoscopic examination were not significantly different after at least 3 months of therapy (pre: 20.15, post: 20.21, P = .975); however, the utility of this result is limited by a low inter-rater reliability (Krippendorff α = .513). CONCLUSIONS: While we are unable to show any difference in objective assessment of laryngopharyngeal edema on endoscopic examination in this small pilot study, patients report substantial subjective improvement in postradiotherapy dysphagia and dysphonia following cervical PCGT that warrants more formal investigation.

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphorylation of γ-H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA glycosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC.

R-Loop Physiology and Pathology: A Brief Review.

Physiological and pathological roles for R-loop structures continue to be discovered, and studies suggest that R-loops could contribute to human disease. R-loops are nucleic acid structures characterized by a DNA:RNA hybrid and displaced single-stranded DNA that occur in connection with transcription. R-loops form naturally and have been shown to be important for a number of physiological processes such as mitochondrial replication initiation, class switch recombination, DNA repair, modulating DNA topology, and regulation of gene expression. However, subsets of R-loops or persistent R-loops lead to DNA breaks, chromosome rearrangement, and genome instability. In addition, R-loops have been linked to human diseases, specifically neurological disorders and cancer. Of the large amount of research produced recently on R-loops, this review covers evidence for R-loop involvement in normal cellular physiology and pathophysiology, as well as describing factors that contribute to R-loop regulation.

Frequent HPV-independent p16/INK4A overexpression in head and neck cancer.

OBJECTIVES: p16INK4A (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven. MATERIALS AND METHODS: We integrated reverse phase protein array (RPPA) data for p16 with HPV status based on detection of viral transcripts by RNA-seq in a set of 210 HNSCCs profiled by The Cancer Genome Atlas project. Samples were queried for alterations in CDKN2A, and other pathway genes to investigate possible drivers of p16 expression. RESULTS: While p16 levels as measured by RPPA were significantly different by HPV status, there were multiple HPV (-) samples with similar expression levels of p16 to HPV (+) samples, particularly at non-oropharyngeal subsites. In many cases, p16 overexpression in HPV (-) tumors could not be explained by mutation or amplification of CDKN2A or by RB1 mutation. Instead, we observed enrichment for inactivating mutations in the histone H3 lysine 36 methyltransferase, NSD1 in HPV (-)/p16-high tumors. CONCLUSIONS: RPPA data suggest high p16 protein expression in many HPV (-) non-oropharyngeal HNSCCs, limiting its potential utility as an HPV biomarker outside of the oropharynx. HPV-independent overexpression of wild-type p16 in non-oropharyngeal HNSCC may be linked to global deregulation of chromatin state by inactivating mutations in NSD1.

Cytokeratin-8 in Anaplastic Thyroid Carcinoma: More Than a Simple Structural Cytoskeletal Protein.

Anaplastic thyroid carcinoma (ATC) is almost universally fatal. Elevated keratin-8 (KRT8) protein expression is an established diagnostic cancer biomarker in several epithelial cancers (but not ATC). Several keratins, including KRT8, have been suggested to have a role in cell biology beyond that of structural cytoskeletal proteins. Here, we provide evidence that KRT8 plays a direct role in the growth of ATCs. Genomic and transcriptomic analysis of >5000 patients demonstrates that KRT8 mutation and copy number amplification are frequently evident in epithelial-derived cancers. Carcinomas arising from diverse tissues exhibit KRT8 mRNA and protein overexpression when compared to normal tissue levels. Similarly, in a panel of patient-derived ATC cell lines and patient tumors, KRT8 expression shows a similar pattern. sh-RNA-mediated KRT8 knockdown in these cell lines increases apoptosis, whereas forced overexpression of KRT8 confers resistance to apoptosis under peroxide-induced cell stress conditions. We further show that KRT8 protein binds to annexin A2, a protein known to mediate apoptosis as well as the redox pathway.

The feasibility of gamma radiation sterilization for decellularized tracheal grafts.

OBJECTIVES/HYPOTHESIS: The most promising stem cell-derived tracheal transplantation approach is dependent upon the use of decellularized tracheal grafts. It has been assumed that a sterilization step, such as gamma radiation, would damage the delicate extracellular matrix of the graft, thus rendering it less viable for cellular repopulation, although this has not been thoroughly investigated. STUDY DESIGN: Laboratory-based comparative analysis. METHODS: Fifteen murine tracheas of strain C57/B-6 mice were obtained. Thirteen were subjected to a detergent-enzymatic decellularization process. Of these decellularized tracheas (DT), eight were irradiated, exposing five tracheas to a radiation level of 25 kGy (DT25) and three to 5 kGy (DT5). Two were left untreated. The two untreated tracheas, two DTs, and two DT25s were prepared and examined using both scanning and transmission electron microscopy. Bioburden calculations were obtained from three DTs, three DT25s, and three DT5s by homogenization, serial dilution, and streak plating. RESULTS: Electron microscopy of untreated fresh tracheas and DTs showed a slight qualitative degradation of cartilage ultrastructure due to the decellularization process. In contrast, examination of DT25 shows significant degradation including poor overall preservation of cartilage architecture with disorganized collagen fibers. The nonirradiated DTs had a calculated bacterial bioburden of 7.8 × 107 to 3.4 × 108 colony-forming units per gram. Both the DT25 and DT5 specimens were found to have a bioburden of zero. CONCLUSIONS: Gamma radiation at 25 kGy degrades the architecture of decellularized tracheal grafts. These ultrastructural changes may prove detrimental to graft viability; however, bioburden calculations suggest that a 5 kGy radiation dose may be sufficient for sterilization. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E258-E264, 2017.

In vitro characterization of design and compressive properties of 3D-biofabricated/decellularized hybrid grafts for tracheal tissue engineering.

Infection or damage to the trachea, a thin walled and cartilage reinforced conduit that connects the pharynx and larynx to the lungs, leads to serious respiratory medical conditions which can often prove fatal. Current clinical strategies for complex tracheal reconstruction are of limited availability and efficacy, but tissue engineering and regenerative medicine approaches may provide viable alternatives. In this study, we have developed a new "hybrid graft" approach that utilizes decellularized tracheal tissue along with a resorbable polymer scaffold, and holds promise for potential clinical applications. First, we evaluated the effect of our decellularization process on the compression properties of porcine tracheal segments, and noted approximately 63% decrease in resistance to compression following decellularization. Next we developed four C-shape scaffold designs by varying the base geometry and thickness, and fabricated polycaprolactone scaffolds using a combination of 3D-Bioplotting and thermally-assisted forming. All scaffolds designs were evaluated in vitro under three different environmental testing conditions to determine the design that offered the best resistance to compression. These were further studied to determine the effect of gamma radiation sterilization and cyclic compression loading. Finally, hybrid grafts were developed by securing these optimal design scaffolds to decellularized tracheal segments and evaluated in vitro under physiological testing conditions. Results show that the resistance to compression offered by the hybrid grafts created using gamma radiation sterilized scaffolds was comparable to that of fresh tracheal segments. Given that current clinical attempts at tracheal transplantation using decellularized tissue have been fraught with luminal collapse and complications, our data support the possibility that future embodiments using a hybrid graft approach may reduce the need for intraluminal stenting in tracheal transplant recipients.

Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility.

BACKGROUND: Transgelin is an actin-binding protein that promotes motility in normal cells. Although the role of transgelin in cancer is controversial, a number of studies have shown that elevated levels correlate with aggressive tumor behavior, advanced stage, and poor prognosis. Here we sought to determine the role of transgelin more directly by determining whether experimental manipulation of transgelin levels in colorectal cancer (CRC) cells led to changes in metastatic potential in vivo. METHODS: Isogenic CRC cell lines that differ in transgelin expression were characterized using in vitro assays of growth and invasiveness and a mouse tail vein assay of experimental metastasis. Downstream effects of transgelin overexpression were investigated by gene expression profiling and quantitative PCR. RESULTS: Stable overexpression of transgelin in RKO cells, which have low endogenous levels, led to increased invasiveness, growth at low density, and growth in soft agar. Overexpression also led to an increase in the number and size of lung metastases in the mouse tail vein injection model. Similarly, attenuation of transgelin expression in HCT116 cells, which have high endogenous levels, decreased metastases in the same model. Investigation of mRNA expression patterns showed that transgelin overexpression altered the levels of approximately 250 other transcripts, with over-representation of genes that affect function of actin or other cytoskeletal proteins. Changes included increases in HOOK1, SDCCAG8, ENAH/Mena, and TNS1 and decreases in EMB, BCL11B, and PTPRD. CONCLUSIONS: Increases or decreases in transgelin levels have reciprocal effects on tumor cell behavior, with higher expression promoting metastasis. Chronic overexpression influences steady-state levels of mRNAs for metastasis-related genes.

Mechanical Modeling of the Human Cricoid Cartilage Using Computer-Aided Design: Applications in Airway Balloon Dilation Research.

OBJECTIVES: Balloon dilation is generally considered first-line treatment for airway stenosis. Some dilation systems utilize a compliant balloon that can conform around rigid structures. Others use a noncompliant balloon that does not conform, allowing for dilation of more rigid stenoses. We hypothesized that subglottic dilation with a noncompliant balloon increases the likelihood of fracture of the cricoid when compared to a compliant balloon. METHODS: Three fresh human cricoid cartilages were placed in a universal testing system to determine the expansile force necessary for cricoid fracture. Using these data, a 3D printer was used to construct a synthetic cricoid model possessing near identical physical characteristics to the human cricoid. Simulated dilation was then performed on the model using a compliant and a noncompliant balloon. RESULTS: Human cricoid fracture occurred at 97.25 N (SD = 8.34), and the synthetic cricoid model fractured at 100.10 N (SD = 7.32). Both balloons fractured the model in every replicate experiment. Mean balloon internal pressure at fracture was 7.67 ATM (SD = 1.21) for the compliant balloon and 11.34 ATM (SD = 1.29) for the noncompliant balloon. CONCLUSIONS: These data show that fracture of the cricoid is a valid concern in balloon dilation procedures where the balloon spans the subglottis. Furthermore, the hypothesis was rejected in that the compliant balloon system was at least as likely to fracture the cricoid model as the noncompliant.

Evaluating kinase ATP uptake and tyrosine phosphorylation using multiplexed quantification of chemically labeled and post-translationally modified peptides.

Cancer biologists and other healthcare researchers face an increasing challenge in addressing the molecular complexity of disease. Biomarker measurement tools and techniques now contribute to both basic science and translational research. In particular, liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) for multiplexed measurements of protein biomarkers has emerged as a versatile tool for systems biology. Assays can be developed for specific peptides that report on protein expression, mutation, or post-translational modification; discovery proteomics data rapidly translated into multiplexed quantitative approaches. Complementary advances in affinity purification enrich classes of enzymes or peptides representing post-translationally modified or chemically labeled substrates. Here, we illustrate the process for the relative quantification of hundreds of peptides in a single LC-MRM experiment. Desthiobiotinylated peptides produced by activity-based protein profiling (ABPP) using ATP probes and tyrosine-phosphorylated peptides are used as examples. These targeted quantification panels can be applied to further understand the biology of human disease.

Tracheal size variability is associated with sex: implications for endotracheal tube selection.

PURPOSE: Whereas selection of endotracheal tube (ETT) size in pediatric patients benefits from predictive nomograms, adult ETT sizing is relatively arbitrary. We sought to determine associations between cervical tracheal cross-sectional area (CTCSA) and clinical variables. METHODS: One hundred thirty-two consecutive patients undergoing noncontrasted chest computed tomography (CT) at a single tertiary care institution from January 2010 to June 2011 were reviewed. Patients with improper CT technique, endotracheal intubation, and pulmonary/tracheal pathology were excluded. Tracheal luminal diameters in anteroposterior (D1) and transverse (D2) were measured 2 cm inferior to the cricoid and used to determine CTCSA = π*D1*D2*». The demographic variables of age, height, weight, and body mass index (BMI) were tested for association with CTCSA by Spearman correlation. Wilcoxon rank-sum test was used to compare CTCSA by race and sex. Multivariate linear regression was performed including all clinical variables. RESULTS: There were 91 patients who met inclusion criteria. There was no correlation between age, weight, or BMI and CTCSA. There was a significant positive correlation between patient height and CTCSA (P = .001, R = 0.35); however, this was confounded by sex. Female patients had significantly smaller CTCSA (mean = 241 mm(2)) compared to male patients (mean = 349 mm(2), P < .001). Multivariate linear regression stratified by sex revealed that height is correlated with CTCSA only in males (P = .028). Males also had more variability in CTCSA (SD 118.6) compared to females (SD 65.5). CONCLUSION: Our data suggest that selection of ETT size in male patients should include height as a predictive factor. For female patients, it may be appropriate to select a uniformly smaller diameter ETT size.

Biomechanical changes from long-term freezer storage and cellular reduction of tracheal scaffoldings.

OBJECTIVES/HYPOTHESIS: To determine structural biomechanical changes in tracheal scaffolds resulting from cellular reduction and storage at -80(o) C. STUDY DESIGN: Laboratory-based study. METHODS: Forty-four rabbit tracheal segments were separated into four treatment groups: untreated (group A, control), cellular-reduced (group B), storage at -80(o) C followed by cellular reduction (group C), and cellular-reduced followed by storage at -80(o) C (group D). Tracheal segments were subjected to uniaxial tension (n = 21) or compression (n = 23) using a universal testing machine to determine sutured tensile yield load and radial compressive strengths at 50% lumen occlusion. Mean differences among groups for tension and compression were compared by analysis of variance with post-hoc Tukey-Kramer test. RESULTS: The untreated trachea (group A) demonstrated mean yield strength of 5.93 (± 1.65) N and compressive strength of 2.10 (± 0.51) N. Following treatment/storage, the tensile yield strength was not impaired (group B = 6.79 [± 1.58] N, C = 6.21 [± 1.40] N, D = 6.26 [± 1.18]; P > 0.10 each). Following cellular reduction, there was a significant reduction in compressive strength (group B = 0.44 N [± 0.13], P < 0.0001), but no further reduction due to storage (group C = 0.39 N [± 0.10]; P = 0.97 compared to group B). CONCLUSION: The data suggest cellular reduction leads to loss of compressive strength. Freezing at -80°C (either before, or subsequent to cellular reduction) may be a viable storage method for tracheal grafts.

Comparison of tensile strength of fibrin glue and suture in microflap closure.

OBJECTIVES/HYPOTHESIS: Suture closure and fibrin glue placement have been advocated as alternatives to healing by secondary intention. The aim of this study was to examine the tensile strength of these microflap closure techniques. STUDY DESIGN: Basic research. METHODS: Three pairs of excised bovine true vocal folds underwent microflap creation and closure by either single 6-0 polyglactin suture or fibrin glue. Vocal folds were distracted to failure on a universal testing system. Excised porcine true vocal folds underwent microflap creation and were closed with either single 6-0 polyglactin suture or fibrin glue, or were left without closure. Tensile strength testing was performed with a universal testing system measuring load at 1 mm, 5 mm, and 10 mm of distraction. RESULTS: The bovine vocal fold model failed after an average extension of 22.6 mm (range, 21.4-23.9 mm) corresponding to 11.61 N (range, 8.04-13.47 N), with no failure of the suture prior to model failure. Fibrin glue did not demonstrate any measureable resistance to tension application. In the porcine vocal fold model, there was a significant difference between the median tensile load of suture closure (2.91 N) and no closure (1.16 N) at 10 mm of distraction (P = .01). There was no significant difference in median load of vocal folds undergoing fibrin glue closure or no closure. CONCLUSIONS: There is no significant difference in tensile strength of a microflap closed with fibrin glue or not closed. Suture closure of a microflap provides a significantly stronger mechanical closure than no closure. This suggests that use of fibrin glue is of little benefit on the vocal folds.

Synergistic effect of high charge and energy particle radiation and chronological age on biomarkers of oxidative stress and tissue degeneration: a ground-based study using the vertebrate laboratory model organism Oryzias latipes.

High charge and energy (HZE) particles are a main hazard of the space radiation environment. Uncertainty regarding their health effects is a limiting factor in the design of human exploration-class space missions, that is, missions beyond low earth orbit. Previous work has shown that HZE exposure increases cancer risk and elicits other aging-like phenomena in animal models. Here, we investigate how a single exposure to HZE particle radiation, early in life, influences the subsequent age-dependent evolution of oxidative stress and appearance of degenerative tissue changes. Embryos of the laboratory model organism, Oryzias latipes (Japanese medaka fish), were exposed to HZE particle radiation at doses overlapping the range of anticipated human exposure. A separate cohort was exposed to reference γ-radiation. Survival was monitored for 750 days, well beyond the median lifespan. The population was also sampled at intervals and liver tissue was subjected to histological and molecular analysis. HZE particle radiation dose and aging contributed synergistically to accumulation of lipid peroxidation products, which are a marker of chronic oxidative stress. This was mirrored by a decline in PPARGC1A mRNA, which encodes a transcriptional co-activator required for expression of oxidative stress defense genes and for mitochondrial maintenance. Consistent with chronic oxidative stress, mitochondria had an elongated and enlarged ultrastructure. Livers also had distinctive, cystic lesions. Depending on the endpoint, effects of γ-rays in the same dose range were either lesser or not detected. Results provide a quantitative and qualitative framework for understanding relative contributions of HZE particle radiation exposure and aging to chronic oxidative stress and tissue degeneration.

Microdebrider complications in laryngologic and airway surgery.

OBJECTIVES/HYPOTHESIS: There is a paucity of experience in the published literature documenting complications of powered surgical instruments in laryngologic surgery. Our objective was to ascertain the nature of these complications from expert opinion and review of the literature, and to recommend strategies to decrease major complications. STUDY DESIGN: Review of the literature and an e-mail survey. METHODS: A literature review of microdebrider complications in laryngologic surgery was conducted using PubMed and Ovid (1985 to 2013), along with an analysis of a confidential e-mail survey of various surgeons in selected high-volume laryngologic centers. RESULTS: Powered instrumentation is frequently used in the operating room for larynx and airway surgery. The microdebrider can improve efficiency, lower costs, and shorten operative times. However, use of the microdebrider has the potential for serious complications in the larynx and airway. Great care must be taken when utilizing the microdebrider in laryngologic surgery. Significant complications including major vocal fold scar, airway compromise, severe hemorrhage, and unintentional tissue loss have occurred. CONCLUSIONS: The microdebrider is a popular and valuable tool for the otolaryngologist. A thorough knowledge of the instrument and its potential complications will improve surgical outcomes and may prevent complications. Awareness of the risks and surgeon experience with use of the microdebrider will allow the surgeon to successfully utilize this device in a safe and effective manner. LEVEL OF EVIDENCE: 5.

Thyroid ala perichondrial flaps for subglottic reconstruction.

OBJECTIVES/HYPOTHESIS: Techniques available for reconstruction of the cricotracheal region in adults are currently suboptimal. We sought to 1) understand the anatomic basis for the thyroid ala perichondrial flap, 2) describe the technique of harvesting and intraluminal placement, and 3) learn the limitations of defects for which it can be used. STUDY DESIGN: Cadaveric anatomical study. METHODS: In fresh cadaveric specimens, the perichondrium of the outer layer of the thyroid cartilage was elevated by tracing the superior, medial, and lateral borders of each thyroid cartilage ala. The inferiorly based flap was then placed into the airway through the cricothyroid membrane. The extent of coverage was measured. RESULTS: A total of 10 flaps were performed (6 male and 4 female). The average length of thyroid perichondrial flaps obtained was 1.67 cm. All flaps were able to completely cover the cricoid cartilage and extended to but did not cover the first tracheal ring. Once placed intraluminally, the flaps extended 2.4 cm below the vocal cords. Using both flaps enabled coverage of the entire anterior 180 degrees of the airway lumen in all specimens. There were no significant differences in male/female or right-sided/left-sided flaps. CONCLUSIONS: The thyroid ala perichondrial flap is technically feasible and can provide coverage of anterior airway defects up to approximately 2.4 cm below the true vocal cords. This flap could enable transfer of vascularized tissue to aid in cricotracheal reconstruction.

Defining the biomechanical properties of the rabbit trachea.

OBJECTIVES/HYPOTHESIS: Surgical advancements rely heavily on validated animal models. The New Zealand White (NZW) rabbit is a widely used model for airway research, including regenerative medicine applications. Currently, the biomechanical properties of the normal rabbit trachea are not known. Our objective was to define these properties to assist in the standardization and understanding of future airway research using this model. STUDY DESIGN: Laboratory-based study. METHODS: Fresh tracheas from four adult NZW rabbits were dissected into 20 segments. To examine the biomechanical properties, segments were subjected to uniaxial tension (n = 9) and compression (n = 11) testing. Yield and maximum load (tension) and force at 50% displacement (compression) were recorded, and differences between segments were examined using analysis of covariance. RESULTS: Normative data for native rabbit trachea show mean maximum load = 6.44 newtons (N), yield load = 5.93 N, and compressive strength = 2.10 N. In addition to establishing the baseline measurements, statistically significant differences in tensile measures based on location along the trachea and diameter were identified. Proximal segments had significantly higher maximum load (P = .0029) and yield load (P = .0062) than distal segments. Association between diameter and both maximum load (P = .0139) and yield load (P = .0082) was observed. CONCLUSIONS: The adult NZW rabbit trachea is intrinsically less able to withstand tensile and compressive forces, compared to other airway models such as sheep or cadaveric human. Establishment of normative values will enable future research into changes in tracheal biomechanical properties during regenerative medicine manipulation and processing.

Ethical issues in laryngology: tracheal stenting as palliative care.

OBJECTIVES/HYPOTHESIS: To improve understanding of aspects of end-of-life care that may not be intuitive to the otolaryngology community. DATA SOURCES AND REVIEW METHODS: A comprehensive review of the literature was performed by searching Medline, Embase, and Google Scholar databases. Primary manuscripts' bibliographies were reviewed to identify any nonindexed references. Prospective consultation by means of one-on-one interviews was sought from nonotolaryngology key stakeholders in the areas of hospice nursing care and patient advocacy in order to identify pertinent issues. RESULTS: We identified over 1,000 articles published from 1965 to 2013 on the topic of tracheal stents, as well as over 40,000 on hospice/end-of-life care. Three articles focusing specifically on palliative care and airway stenting were identified, of which three were case reports and none were definitive reviews. There are a number of significant issues and concepts unique to hospice care. These are likely unfamiliar to all except for head and neck oncology-specialized otolaryngologists. An example is that hospice care focuses on quality of life rather than prolongation of life (such as curative surgery). Patients with nonoperable tracheal obstruction from malignancy face an unpleasant demise from suffocation. For those patients, stenting can relieve suffering by restoring airway patency. CONCLUSIONS: Airway stenting can be a valid palliative care option, even for terminal patients receiving hospice care, when performed to relieve airway obstruction and improve quality of life. End-of-life ethics is an underdeveloped area of otolaryngology that should be explored.