Anca M. Barbu

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 their participation in the initial clinical trial with a single-site lower dose (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.

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.

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.

Bedside Injection Medialization Laryngoplasty in Immediate Postoperative Patients

Objectives The morbidity of glottic insufficiency resulting from unilateral vocal fold immobility may significantly compromise postoperative recovery in patients with decreased pulmonary reserve or inability to protect their airway. Injection medialization laryngoplasty is an effective means of treating glottic insufficiency due to unilateral vocal fold immobility. The purpose of this study is to present our experience with bedside transoral injection medialization laryngoplasty in the immediate postoperative period. Study Design Case series with chart review. Setting Academic tertiary care hospital. Subjects and Methods Patient demographics, clinical characteristics, procedural details, and short-term outcome measures of oral intake were recorded in a cohort of 68 patients over 5 years with unilateral vocal cord paralysis who underwent injection medialization as a bedside procedure in the immediate postoperative period. Results Mean time to injection was 8.2 days postoperatively. At the time of injection, 40 of 68 patients were nil per os. Seventy percent (28 of 40) had their diet advanced to adequate oral intake within 5 days of injection. Greater than half of the injections (36 of 68) were performed in the intensive care unit. No complications were noted, and all patients in this cohort were able to tolerate the bedside injection. Conclusion Bedside injection medialization laryngoplasty in the immediate postoperative period via the transoral approach can be performed in patients, even in the intensive care unit, while on anticoagulation, and may be of benefit for hospitalized patients with unilateral vocal fold immobility. Further studies quantifying improvement in voice and swallowing data are merited.

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.

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.

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

Abstract 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-2Db-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-2Db-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.

Revision Transcervical Medialization Laryngoplasty for Unilateral Vocal Fold Paralysis

Objective To identify patterns of failure following transcervical medialization laryngoplasty for unilateral vocal fold paralysis and describe indications and revision techniques for optimal vocal outcomes. Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods Thirty-nine consecutive patients between January 2005 and April 2014 undergoing transcervical revision of failed primary medialization laryngoplasty were identified. Demographics, etiology, stroboscopic assessment, and surgical techniques were recorded. Patient self-assessment using the Voice-Related Quality-of-Life (VRQOL) questionnaire and objective acoustic and aerodynamic assessments performed pre- and postoperatively were analyzed using t tests for paired comparisons. Results Thirty-nine patients underwent 48 transcervical revision surgeries. Median follow-up was 14.6 months from time of final revision surgery. Indications included anterior glottic incompetence (38/48, 79%), posterior glottic incompetence (20/48, 42%), glottic overclosure (8/48, 17%), and/or decreased phonatory pliability (12/48, 25%). A combination of findings was present in 21 (44%) surgeries. Revision techniques included either anterior augmentation, arytenopexy, and cricothyroid subluxation (alone or in combination) in 46 of 48 (96%) patients or partial implant removal alone in 2 patients. Seven patients (18%) required multiple revisions. A complete set of voice parameters was available for 22 patients, and statistically significant improvements included VRQOL scores, fundamental frequency in females, jitter, noise-to-harmonic ratio, and mean airflow rate. Conclusion Patterns of failure in patients with suboptimal phonatory function after transcervical medialization laryngoplasty included persistent glottic incompetence, glottic overclosure, and decreased vocal fold pliability. Revision transcervical medialization surgery, guided by individualized consideration of vocal fold position and surface pliability, can improve phonatory outcomes.

Laryngeal Exam Indications and Techniques

Postoperative voice changes are one of the most common and feared complications of thyroid surgery. In most cases, postoperative hoarseness is due to recurrent laryngeal nerve (RLN) injury, although injury to the external branch of the superior laryngeal nerve (EBSLN) can also result in significant vocal issues, including diminished vocal projection and inability to attain higher vocal registers. Voice complaints can also occur in the absence of neural dysfunction and may be present prior to any surgery being performed. Thus, timely and accurate evaluation of laryngeal function optimizes ongoing management efforts and provides important prognostic and outcome information.

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.