Lions and brown bears colonized North America in multiple synchronous waves of dispersal across the Bering Land Bridge.

The Bering Land Bridge connecting North America and Eurasia was periodically exposed and inundated by oscillating sea levels during the Pleistocene glacial cycles. This land connection allowed the intermittent dispersal of animals, including humans, between Western Beringia (far northeast Asia) and Eastern Beringia (northwest North America), changing the faunal community composition of both continents. The Pleistocene glacial cycles also had profound impacts on temperature, precipitation and vegetation, impacting faunal community structure and demography. While these palaeoenvironmental impacts have been studied in many large herbivores from Beringia (e.g., bison, mammoths, horses), the Pleistocene population dynamics of the diverse guild of carnivorans present in the region are less well understood, due to their lower abundances. In this study, we analyse mitochondrial genome data from ancient brown bears (Ursus arctos; n = 103) and lions (Panthera spp.; n = 39), two megafaunal carnivorans that dispersed into North America during the Pleistocene. Our results reveal striking synchronicity in the population dynamics of Beringian lions and brown bears, with multiple waves of dispersal across the Bering Land Bridge coinciding with glacial periods of low sea levels, as well as synchronous local extinctions in Eastern Beringia during Marine Isotope Stage 3. The evolutionary histories of these two taxa underline the crucial biogeographical role of the Bering Land Bridge in the distribution, turnover and maintenance of megafaunal populations in North America.

Species-specific responses of Late Quaternary megafauna to climate and humans.

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.

Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes.

Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8+ T cell response that recognizes an H-2D(b)-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8+ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8+ T cells are able to efficiently kill target cells. Interestingly, the H-2D(b)-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8+ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.

Average Ambulatory Measures of Sound Pressure Level, Fundamental Frequency, and Vocal Dose Do Not Differ Between Adult Females With Phonotraumatic Lesions and Matched Control Subjects.

OBJECTIVES: Clinical management of phonotraumatic vocal fold lesions (nodules, polyps) is based largely on assumptions that abnormalities in habitual levels of sound pressure level (SPL), fundamental frequency (f0), and/or amount of voice use play a major role in lesion development and chronic persistence. This study used ambulatory voice monitoring to evaluate if significant differences in voice use exist between patients with phonotraumatic lesions and normal matched controls. METHODS: Subjects were 70 adult females: 35 with vocal fold nodules or polyps and 35 age-, sex-, and occupation-matched normal individuals. Weeklong summary statistics of voice use were computed from anterior neck surface acceleration recorded using a smartphone-based ambulatory voice monitor. RESULTS: Paired t tests and Kolmogorov-Smirnov tests resulted in no statistically significant differences between patients and matched controls regarding average measures of SPL, f0, vocal dose measures, and voicing/voice rest periods. Paired t tests comparing f0 variability between the groups resulted in statistically significant differences with moderate effect sizes. CONCLUSIONS: Individuals with phonotraumatic lesions did not exhibit differences in average ambulatory measures of vocal behavior when compared with matched controls. More refined characterizations of underlying phonatory mechanisms and other potentially contributing causes are warranted to better understand risk factors associated with phonotraumatic lesions.

Oncologic efficacy of angiolytic KTP laser treatment of early glottic cancer.

OBJECTIVE: Angiolytic laser removal of early glottic cancer with ultra-narrow margins was reported in a pilot study 5 years ago as an innovative surgical treatment strategy to better preserve vocal function. Subsequently, in a cohort of > 90 patients, enhanced voice outcomes were achieved and there was diminished need for post-treatment phonosurgical reconstruction. However, the initial pilot study examining oncologic efficacy had a limited number of patients and most did not have 3-year follow-up. Consequently, further analysis of the oncologic efficacy is valuable. METHOD: Retrospective review. RESULTS: One hundred seventeen patients (T1a-71, T1b-11, T2a-10, T2b-25) underwent potassium-titanyl-phosphate (KTP) laser treatment of early glottic cancer with a minimum 3-year follow-up (average = 53 months). The "b" designation delineated bilateral disease. Disease control for T1 and T2 lesions was 96% (79/82) and 80% (28/35), respectively. All 10 recurrences were treated with radiotherapy. Fifty percent (5/10) were controlled with radiotherapy, and the other 5 died of disease. Larynx preservation and survival were achieved in 99% (81/82) with T1 disease and 89% (31/35) with T2 disease. CONCLUSION: This investigation provides further evidence that angiolytic KTP laser removal of early glottic cancer with ultra-narrow margins is an effective oncologic treatment strategy. Radiotherapy was preserved for future use in more than 90% of patients. Since a majority of patients are referred by an otolaryngologist to undergo treatment of early glottic cancer with radiotherapy, this investigation provides compelling information to reappraise this paradigm.

Simulation model for transcervical laryngeal injection providing real-time feedback.

OBJECTIVE: This study aimed to develop and evaluate a model for teaching transcervical laryngeal injections. METHODS: A 3-dimensional printer was used to create a laryngotracheal framework based on de-identified computed tomography images of a human larynx. The arytenoid cartilages and intrinsic laryngeal musculature were created in silicone from clay casts and thermoplastic molds. The thyroarytenoid (TA) muscle was created with electrically conductive silicone using metallic filaments embedded in silicone. Wires connected TA muscles to an electrical circuit incorporating a cell phone and speaker. A needle electrode completed the circuit when inserted in the TA during simulated injection, providing real-time feedback of successful needle placement by producing an audible sound. Face validation by the senior author confirmed appropriate tactile feedback and anatomical realism. Otolaryngologists pilot tested the model and completed presimulation and postsimulation questionnaires. RESULTS: The high-fidelity simulation model provided tactile and audio feedback during needle placement, simulating transcervical vocal fold injections. Otolaryngology residents demonstrated higher comfort levels with transcervical thyroarytenoid injection on postsimulation questionnaires. CONCLUSION: This is the first study to describe a simulator for developing transcervical vocal fold injection skills. The model provides real-time tactile and auditory feedback that aids in skill acquisition. Otolaryngologists reported increased confidence with transcervical injection after using the simulator.

Effect of mandibular tori on glottic exposure during simulated suspension microlaryngoscopy.

OBJECTIVES: Mandibular tori have been identified as a contributing factor in difficult exposure during intubation. However, no investigation has measured the effect of mandibular tori on glottic exposure during suspension microlaryngoscopy (SML). The objective of this study was to measure how the size and location of mandibular tori affect glottic exposure during simulated SML at different thyromental distances. METHODS: Suspension microlaryngoscopy was modeled on an anatomically accurate skull and larynx with thyromental distances between 6 and 12 cm. Mandibular tori were simulated by protruding screws 5 to 15 mm from the lingual aspect of the mandible. The tori were positioned either 15 mm (anterior) or 25 mm (posterior) from the midline of the symphysis. The glottic exposure for the various-size tori in each location was measured by recording the displacement of the glottiscope tip relative to the most anterior exposure achievable without tori. The glottiscope angle relative to the horizontal plane was measured for each condition. RESULTS: Mandibular tori of more than 10 mm had a significant impact on glottic exposure. Displacement of the glottiscope tip ranged from 2 to 9 mm for anteriorly placed tori and from 7 to 29 mm for posteriorly placed tori, with larger tori causing greater displacement. Increasing the thyromental distance increased the posterior glottiscope tip displacement regardless of torus size or location. The glottiscope angle increased with larger tori (12º to 28º), but this angle did not change with increasing thyromental distance. CONCLUSIONS: Larger size and more-posterior location of mandibular tori more significantly reduce glottic exposure during SML. The inner table of the mandible is the most relevant anatomic constraint on glottic exposure, which varies with the presence or absence of mandibular tori independent of thyromental distance.

Voice outcomes for photoangiolytic KTP laser treatment of early glottic cancer.

OBJECTIVES: Surgery and radiotherapy routinely provide high cure rates in treating early glottic cancer. Therefore, key metrics for success are optimal voice outcome and preservation of future cancer treatment options. Remarkably, there is a paucity of pretreatment versus posttreatment voice outcome data. Angiolytic KTP (potassium titanyl phosphate) laser treatment of early glottic cancer with ultranarrow margins was initiated to better preserve vocal function. Given that effective oncological results have been achieved, it was hypothesized that this approach would also result in improved posttreatment measures of vocal function that more closely approximate historical norms than pretreatment values. METHODS: Pretreatment and posttreatment voice outcome data were obtained for 92 patients (64 with T1 cancer and 28 with T2 cancer) who underwent 532-nm KTP laser treatment of early glottic cancer in a study design in which each patient essentially served as his or her own control. The evaluations included objective measures (acoustic and aerodynamic) and patients' self-assessments of vocal function (Voice-Related Quality of Life; V-RQOL). A series of mixed analyses of variance were conducted for all vocal function measures, with tumor stage and depth of invasion as the between-subjects variables and time (presurgery versus postsurgery) as the within-subject variable. RESULTS: There were statistically significant (p < or = 0.05) postoperative improvements for acoustic (perturbation and noise-to-harmonics ratio) and aerodynamic (subglottic pressure and vocal efficiency) measures of vocal function, as well as for V-RQOL assessment. CONCLUSIONS: Comprehensive pretreatment and posttreatment voice measures in a large patient cohort demonstrated that the KTP laser significantly improved postoperative vocal function in patients with early glottic cancer. Furthermore, radiotherapy was preserved as an oncological treatment option.

Salvage endoscopic angiolytic KTP laser treatment of early glottic cancer after failed radiotherapy.

OBJECTIVES: Management of early glottic cancer subsequent to failed radiotherapy is challenging, especially in balancing oncological control and function preservation. Patients frequently have been incentivized against surgical management and thus have undergone radiotherapy as initial treatment. This history compounds the difficulty of discussions about surgical management after recurrence. Typically, endoscopic salvage has less morbidity than transcervical partial laryngectomy and is clearly desirable over total laryngectomy. However, there are appropriate concerns about the efficacy of endoscopic salvage and the overarching impact on larynx preservation and survival. Given our success with endoscopic angiolytic KTP laser treatment of previously nonirradiated T1 and T2 glottic cancers, we examined our results from treating similar-sized lesions after failed radiotherapy. METHODS: We performed a retrospective chart review of 20 patients from our cancer database who had undergone failed radiation therapy elsewhere for early glottic cancer and then underwent endoscopic angiolytic KTP laser treatment. RESULTS: Analysis of the geographic tumor recurrence of the 20 patients revealed T1a N0 M0 cancer in 4 patients, T1b N0 M0 cancer in 1 patient, T2a N0 M0 cancer in 1 patient, and T2b N0 M0 cancer in 14 patients. After KTP laser salvage treatment, 4 patients (20%) had local recurrence (all T2b) and required subsequent total laryngectomy, and 3 of these patients (15%) ultimately died of disease. The remaining 16 patients (80%) were free of disease at least 2 years after endoscopic salvage (average follow-up, 39 months). CONCLUSIONS: Our investigation provides preliminary evidence that angiolytic KTP laser salvage treatment of early glottic cancer is an effective treatment after failed irradiation. Studies with larger cohorts and longer follow-up will be necessary to establish incontrovertible evidence of its efficacy.

The Impact of Tonsillectomy on the Adult Singing Voice: Acoustic and Aerodynamic Measures.

OBJECTIVE: Singers undergoing tonsillectomy are understandably concerned about possible sequelae to their voice. The surgical risks of laryngeal damage from intubation and upper airway scarring are valid reasons for singers to carefully consider their options for treatment of tonsil-related symptoms. No prior studies have statistically assessed objective voice outcomes in a group of adult singers undergoing tonsillectomy. This study determined the impact of tonsillectomy on the adult singing voice by determining if there were statistically significant changes in preoperative versus postoperative acoustic, aerodynamic, and Voice-Related Quality of Life (VRQOL) measures. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary Referral Academic Hospital SUBJECTS: Thirty singers undergoing tonsillectomy from 2012 to 2019. METHODS: Acoustic recordings were obtained with Computerized Speech Lab (CSL) (Pentax CSL 4500) and analyzed with the Multidimensional Voice Program (MDVP) (Pentax MDVP) and Pratt Acoustic Analysis Software. Estimates of aerodynamic vocal efficiency were obtained and analyzed using the Phonatory Aerodynamic System (Pentax PAS 6600). Preoperative VRQOL scores were recorded, and singers were instructed to refrain from singing for 3 weeks following tonsillectomy. Repeat acoustic and aerodynamic measures as well as VRQOL scores were obtained at the first postoperative visit. RESULTS: Average postoperative acoustic (jitter, shimmer, HNR) and aerodynamic (sound pressure level divided by subglottal pressure) parameters related to laryngeal phonatory function did not differ significantly from preoperative measures. The only statistically significant change in postoperative measures of resonance was a decrease in the 3rd formant (F3) for the /a/ vowel. Average postoperative VRQOL scores (79.8, SD18.7) improved significantly from preoperative VRQOL scores (89, SD12.2) (P = 0.007). CONCLUSIONS: Tonsillectomy does not appear to alter laryngeal voice production in adult singers as measured by standard acoustic and aerodynamic parameters. The observed decrease in F3 for the /a/ vowel is hypothetically related to increasing the pharyngeal cross-sectional area by removing tonsillar tissue, but this would not be expected to appreciably impact the perceptual characteristics of the vowel. Singers' self-assessment (VRQOL) improved after tonsillectomy.

Minimizing Thermal Damage During Thulium Laser-Assisted Partial Arytenoidectomy: Pulsed Versus Continuous Cutting in an Ex-Vivo Calf Model.

OBJECTIVES: The 2 µm-wavelength thulium laser is an effective cutter during partial arytenoidectomy, but thermal trauma can damage adjacent laryngeal tissue. Pulsing laser energy may reduce trauma when compared to continuous-wave cutting. This study measured temperature changes, thermal trauma, and time to complete partial arytenoidectomy, with and without pulsing, in an ex-vivo calf model. METHODS: Tissue temperature and time to complete a trans-cartilaginous cut were measured during partial arytenoidectomy on ex-vivo calf vocal folds (N = 24) using a thulium laser in continuous-wave (CW, N = 12) and pulsed-wave (PW, N = 12) modes. Energy was 5 W for CW and PW cuts; pulse-widths were 250, 500, and 750 ms. Thermal damage was analyzed histologically by measuring the depth of lactate dehydrogenase (LDH) inactivation perpendicular to the laser-cut edge at the vocal process. Paired t-tests compared CW and PW modes. RESULTS: Change in temperature was lower using CW (6.5°C) compared to PW modes (250 ms = 18°; 500 ms = 16°; 750 = 19°; P < .05). Trans-cartilaginous cuts were completed faster using CW (37 seconds) compared to PW (250 ms = 136 seconds; 500 ms = 61 seconds; 750 = 44 seconds; P < .05), and both modes delivered the same total Joules. The average depth of LDH depletion (thermal damage) was similar for all cuts. CONCLUSIONS: 1. Thulium laser cuts in continuous-mode unexpectedly produced less tissue heating yet created similar thermal damage than pulsed-mode cuts during simulated partial arytenoidectomy. 2. Trans-cartilaginous cuts were completed significantly faster in continuous-mode as compared to pulsed-mode cutting. 3. Pulsing the thulium laser does not minimize thermal damage compared to continuous wave cutting during thulium laser-assisted partial arytenoidectomy.

High-force simulated intubation fails to dislocate cricoarytenoid joint in ex vivo human larynges.

OBJECTIVES: We assessed the likelihood of arytenoid dislocation during intubation through the application of controlled force. METHODS: Six cadaveric human larynges were mounted in an apparatus for simulating forcible collision with the arytenoid complexes. An endotracheal tube tip probe (ETTP) was used to push one arytenoid complex, and a non-slip probe (NSP) was tested on the other. Increasing pressure was applied until the probes either slipped or reached 5 kg of force. Dissection was then performed to assess the integrity of the cricoarytenoid ligament. The forces obtained by pushing an endotracheal tube against an electronic balance were measured to estimate the maximal possible intubating force. RESULTS: None of the ETTP or NSP trials disrupted the cricoarytenoid joint ligaments, and the joint never appeared to be dislocated. The mean maximal forces were 1.8 kg for the ETTP (after which, slippage consistently occurred) and 4.7 kg for the NSP. The mean maximal forces from an endotracheal tube pushed against a scale were 1.5 kg (without stylet) and 4.6 kg (with stylet). CONCLUSIONS: Arytenoid dislocation did not happen, and gross disruption of the joint capsule or ligament did not occur, even when the testing approximated the maximum force achievable under extreme conditions. Endotracheal tube insertion thus seems unlikely to cause arytenoid dislocation.

Novel device for tissue cooling during endoscopic laryngeal laser surgery: thermal damage study in an ex vivo calf model.

OBJECTIVES: Minimizing collateral thermal damage during endoscopic laryngeal laser surgery remains a priority, and tissue cooling is one way to achieve this goal. Cooling systems utilizing compressed air have been shown to reduce the extent of thermal trauma on the vocal folds, but these units are not ideal for endoscopic applications because cooling is inefficient at the low airflows needed. We examined whether a novel vortex cooling device that generates cooled air at low flow rates would provide a cooling benefit beyond that which could be obtained by using room-temperature air for cooling tissue or by using no cooling during simulated laryngeal laser surgery. METHODS: A continuous-wave thulium laser was used to incise glottic tissue in 12 calf vocal folds. Cooling was achieved with a prototype vortex cooler (9 degrees C air output; flow rate, 3 L/min), and tissue temperature measurements were compared to those with room-air cooling and no cooling. Thermal damage was analyzed histologically by measuring the depth of lactate dehydrogenase inactivation surrounding the mucosal incision. The cooling conditions were tested during time-constant cuts (8 seconds) and depth-constant cuts (into the thyroarytenoid muscle). RESULTS: During time-constant cuts, comparison between vortex cooling and room-air cooling revealed that vortex cooling resulted in a thermal damage zone that was 14% smaller (519 versus 603 microm; p < 0.05). During depth-constant cuts, vortex cooling created a thermal damage zone that was 32% smaller than that created with no cooling (p <0.01) and 9% smaller than that created with room-air cooling (p < 0.01). CONCLUSIONS: Vortex cooling reduces thermal damage more effectively than room-air cooling or no cooling during both time-constant and depth-constant thulium laser cuts.

Subepithelial vocal fold infusion: a useful diagnostic and therapeutic technique.

OBJECTIVES: Preservation of the maximum amount of subepithelial superficial lamina propria (SLP) remains an important goal during microlaryngoscopic surgery of phonatory mucosa. Volume expansion of the SLP (Reinke's space) with subepithelial infusion of saline solution has been widely adopted since its introduction in 1991. This technique has evolved so that it is currently used to assist with determining the depth of vocal fold disease, defining residual pliable SLP, enhancing microsurgical precision, and identifying unrecognized disease. The purpose of this investigation was to examine the indications, methods, and benefits of subepithelial infusion of saline solution as an adjunct technique during phonomicrosurgery. METHODS: In a prospective case series, we collected data on 280 consecutive microlaryngoscopy procedures performed over a 12-month period. Subepithelial infusion of saline solution was included in 178 procedures. RESULTS: New disease was identified in 20 of the 178 patients (scar in 15, sulcus in 4, and a mucosal bridge in 1). The depth of needle placement varied depending on the specific disease: 118 of the 178 infusions were done just below the epithelial basement membrane, and 60 infusions were performed deeper within the SLP, just superficial to the vocal ligament. The infusion technique provided surgical assistance in multiple ways, including identifying residual SLP (130 patients), defining the SLP-lesion interface (65 patients), lifting scar (60 patients),providing tension for cordotomy (47 patients), expanding the SLP volume to protect against laser damage (45 patients), and providing hydrostatic compression of vascular ectasias or varices for photoangiolysis (7 patients). The microlaryngoscopy procedures during which infusion was not performed (102 of 280 procedures) were primarily for nonglottic cancer (46 patients), stenosis (30 patients), or arytenoid granuloma (13 patients). CONCLUSIONS: Subepithelial infusion of the SLP with saline solution is a useful microsurgical adjunct during diagnosis and treatment of phonatory mucosal lesions.

Aortic homograft reconstruction of partial laryngectomy defects: a new technique.

OBJECTIVES: Wide-field transcervical partial laryngectomy often precludes tracheotomy decannulation. It is done infrequently today, primarily because of the popularity of chemotherapy-radiotherapy treatment regimens and limited enthusiasm for using transcervical partial laryngectomy after failed radiotherapy. We sought to identify a new reconstructive technique that would provide an alternative to total laryngectomy in as many patients as possible. METHODS: We performed a retrospective examination of 15 patients who underwent single-stage wide-field transcervical partial laryngectomy with cryopreserved aortic homograft reconstruction. Eight of the 15 patients had previously undergone failed radiotherapy. At least 40% of the cricoid circumference was resected in 8 patients. RESULTS: All 15 patients had their tracheotomy tube removed and have laryngeal phonation, and 14 of the 15 resumed oral intake. There were no major surgical complications. CONCLUSIONS: Use of aortic homografts is a new, reliable, and versatile reconstructive option for performing conservation laryngeal cancer surgery that allows for airway, swallowing, and voice preservation.

High-speed videoendoscopic analysis of relationships between cepstral-based acoustic measures and voice production mechanisms in patients undergoing phonomicrosurgery.

OBJECTIVES: There is increased interest in using cepstral-based acoustic measures for objective clinical voice assessment because of their apparent advantages over more time-honored methods, but there is a paucity of information about how these newer measures relate to underlying phonatory mechanisms. METHODS: We investigated the relationships between the acoustic cepstral peak magnitude (CPM) and high-speed videoendoscopy (HSV)-based measures of vocal fold phonatory function in 20 subjects who underwent phonomicrosurgery for vocal fold lesions. Acoustic and imaging data were acquired during sustained vowel phonation before and after surgery. RESULTS: The changes in the measures between presurgical and postsurgical assessments showed that the CPM correlated significantly with an HSV-based measure combining fundamental frequency deviation and average speed quotient (r = 0.70; p < 0.001) in a multiple linear regression, and that the variation in the CPM could also be attributed to trading relationships between the HSV-based measures of vibratory phase asymmetry and glottal closure. CONCLUSIONS: These initial results demonstrate that the clinical utility of cepstral-based measures can be enhanced by a better understanding of how these acoustic measures relate to underlying phonatory mechanisms. The CPM seems to integrate information about aperiodicity in vocal fold vibration, the relative speed of glottal closure, and estimates of glottal noise generation.

Safety and dosing of bevacizumab (avastin) for the treatment of recurrent respiratory papillomatosis.

OBJECTIVES: Increasing evidence supports the use of laryngeal injections of the antiangiogenic agent bevacizumab (Avastin) for the adjuvant treatment of recurrent respiratory papillomatosis (RRP). A recent prospective open-label investigation, approved by the US Food and Drug Administration, employing 12.5 mg of sublesional bevacizumab demonstrated single-site efficacy without complications; however, the safety of multiple-site injections and higher dosing has not yet been reported. The primary objective of this study was to report on the safety of increased doses of bevacizumab for the treatment of RRP. METHODS: Two cohorts of adult patients were evaluated. In the first group, a prospective analysis was performed on patients with a diagnosis of laryngeal RRP after t heir participation in th e initial clinical trial with a single-site lowerdose (7.5 to 12.5 mg). They received higher doses of sublesional laryngeal bevacizumab (15 to 50 mg total) with detailed physiologic, hematologic, and serum chemistry measurements performed before and after each bevacizumab injection. A second cohort of patients received sublesional laryngeal injections of bevacizumab (15 to 88 mg total) without physiologic measurements and underwent a retrospective analysis of reported complications. RESULTS: One hundred consecutive laryngeal injection sessions (office, 87; operating room, 13) with bevacizumab were performed in 43 patients, with a mean dose of 30 mg total per treatment (range, 15 to 88 mg). Sixty-three of the 100 sessions were accompanied by KTP laser photoangiolysis of the papilloma prior to bevacizumab injections. Eighteen patients (cohort 1) underwent detailed physiologic assessment, and no dysfunction was observed. There were no local or systemic complications of bevacizumab administration. The second group of 25 patients (cohort 2) also reported no significant local or systemic complications. Neither patient group was observed to have a local wound problem in the larynx. CONCLUSIONS: This investigation provides evidence that higher doses of bevacizumab are relatively safe in adult patients with laryngeal RRP. Further refinements in pharmacologic concentration and drug delivery will determine the optimal treatment regimens in the future.

Posterior glottic diastasis: mechanically deceptive and often overlooked.

Dysphonia secondary to posterior glottic aerodynamic incompetence can often be recognizable acoustically, but difficult to document visually. This mechanical impairment in posterior glottic closure is the result of injury caused by airway instrumentation. The difficulty of recognition of this entity is due to posterior supraglottic soft tissue that obscures the complete view during posterior glottic adduction, the lack of a structural organization of the cricoarytenoid region injury that leads to this disorder, and the lack of nomenclature. A retrospective assessment was done on 3 patients who underwent surgical reconstruction to correct posterior phonatory incompetence subsequent to laryngotracheal intubation. All 3 had sustained an injury to the cricoarytenoid joints, and 2 of the 3 had undergone paraglottic space medialization laryngoplasty that failed to solve the posterior glottic insufficiency. New procedures were designed and performed in these patients to correct the posterior glottic incompetence and are described: laryngofissure and partial posterior cricoid resection, endoscopic pharyngoepiglottic-aryepiglottic fold advancement-rotation flap with interarytenoid interposition, and interarytenoid submucosal implant augmentation. Although the academic literature is replete with reports describing stenosis resulting from impaired cricoarytenoid joint abduction, the term glottic diastasis provides nomenclature for the inability to normally adduct the arytenoid cartilages. The initial experience with surgical reconstruction is preliminary, but encouraging.

Function preservation surgery in patients with chondrosarcoma of the cricoid cartilage.

Chondrosarcoma is a rare laryngeal neoplasm that is most commonly encountered in the cricoid cartilage and is optimally treated by surgical excision. It is typically a slow-growing malignancy with well-defined margins and a minimal risk of metastasis; however, radiographic imaging studies often appear ominous if the clinician correlates these findings to the biological behavior of epithelial cancer. Furthermore, the fact that the neoplasm's epicenter is usually under the cricoarytenoid joint can lead to airway and voice deficits before and after operation. Although many surgeons opt for function-sparing resection approaches, it is commonplace for some surgeons to injudiciously perform total laryngectomy as the initial treatment because of the rarity, large size, location, and appearance of these tumors on imaging studies. A retrospective review was done on 10 cases of cricoid chondrosarcoma to gain insight into the treatment strategies designed to preserve laryngeal function while minimizing the risk of local recurrence. We performed surgical resection in 8 of the 10 patients; 2 underwent endoscopic removal and 6 underwent transcervical partial laryngectomy. All are free of disease with good voice and swallowing function. One patient developed a limited recurrence and required a second transcervical partial laryngectomy. Function-sparing surgical treatment of chondrosarcomas of the cricoid cartilage can usually be achieved. Surgeons should carefully modify the core principles of epithelial cancer surgery techniques, adjusting to the different biological behavior of laryngeal chondrosarcomas.

Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study.

OBJECTIVES: Photoangiolytic laser treatment of recurrent respiratory papillomatosis (RRP) is effective, but does not reliably prevent recurrence. Therefore, sublesional injections of the antiangiogenic agent bevacizumab (Avastin) were given to assess the adjunctive effect on disease recurrence. Since bevacizumab is a new therapeutic modality for RRP, there were also primary safety objectives to determine whether there was a pegative impact on the voice and whether there were local or systemic complications. METHODS: A prospective open-label investigation was conducted in 20 adult patients with bilateral vocal fold RRP. The patients underwent planned 532-nm pulsed KTP laser photoangiolysis of bilateral glottal disease 4 times with an approximately 6-week interval between procedures. At each planned laser procedure, the vocal fold that on initial presentation had a greater volume of disease also underwent 4 serial sublesional bevacizumab injections (7.5 to 12.5 mg in 0.3 to 0.5 mL). A sham injection with saline solution was administered to the other vocal fold as a control. Disease resolution was compared between subjects' vocal folds, and objective measures of vocal function (acoustic, aerodynamic), as well as patients' self-assessments of vocal function (Voice-Related Quality of Life survey), were obtained. RESULTS: All 20 patients completed the study, and there were no local or systemic complications. After 4 injections, 3 of the 20 patients had no discernible disease in either vocal fold. Of the remaining 17 subjects, 16 had less disease in the bevacizumab-treated vocal fold despite starting with more disease. Only 1 of the 17 had more disease in the bevacizumab-treated vocal fold after 4 injections. Moreover, 7 of the 20 patients (35%) did not require a laser procedure in the vocal fold that had received 4 bevacizumab injections, as compared with 3 of the 20 vocal folds (15%) that were treated with laser alone. All of the vocal function measures displayed statistically significant posttreatment improvements, except for average fundamental frequency in the 3 female patients, in whom it fell below the normal range. CONCLUSIONS: This prospective investigation provided evidence that bevacizumab injections enhanced KTP laser treatment of glottal papillomatosis without systemic or local complications. Coupling the antiangiogenesis agent bevacizumab with KTP laser photoangiolysis is conceptually synergistic and scientifically promising since the mechanisms of action are complementary.