Mechanisms Underlying the Antifibrotic Potential of Estradiol for Vocal Fold Fibrosis.

OBJECTIVES/HYPOTHESIS: Vocal fold fibrosis remains a significant clinical challenge. Estrogens, steroid hormones predominantly responsible for secondary sexual characteristics in women, have been shown to alter wound healing and limit fibrosis, but the effects on vocal fold fibrosis are unknown. We sought to elucidate the expression of estrogen receptors and the effects of estrogens on TGF-ß1 signaling in rat vocal fold fibroblasts (VFFs). STUDY DESIGN: In vitro. METHODS: VFFs were isolated from 10-week-old, male Sprague-Dawley rats, and estrogen receptor alpha (ERα) and G protein-coupled receptor 30 (GPR30) were examined via immunostaining and quantitative polymerase chain reaction (qPCR). VFFs were treated with estradiol (E2, 10-7 , 10-8 or 10-9 M) ± transforming growth factor beta 1 (TGF-ß1, 10 ng/mL). ICI 182,780 (ICI, 10-7 M) or G36 (10-7 M) were employed as antagonists of ERα or GPR30, respectively. qPCR was employed to determine estrogen receptor-mediated effects of E2 on genes related to fibrosis. RESULTS: ERα and GPR30 were expressed in VFFs at both the protein and the mRNA levels. E2 (10-7 M) did not alter Smad3, Smad7, Acta2 mRNA, or extracellular matrix related genes. However, the combination of E2 (10-8 M) and TGF-ß1 significantly increased Smad7 (P = .03) and decreased Col1a1 (P = .04) compared to TGF-ß1 alone; this response was negated by the combination of ICI and G36 (P = .009). CONCLUSIONS: E2 regulated TGF-ß1/Smad signaling via estrogen receptors in VFFs. These findings provide insight into potential mechanisms of estrogens on vocal fold injury with the goal of enhanced therapeutics for vocal fold fibrosis. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2285-2291, 2021.

Systematic Review of Voice Outcomes for Injection Laryngoplasty Performed under Local vs General Anesthesia.

Objective To assist otolaryngologists in counseling patients with hoarseness who would benefit from injection laryngoplasty on whether or not to perform the procedure in the office vs the operating room. Data Sources Cochrane library, CINAHL, PubMed, and EMBASE. Review Methods Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting standards of English-language articles that compared voice outcomes for in-office and in the operating room injection laryngoplasty. Two independent investigators assessed study eligibility, rated the quality using Methodological Index for Non-Randomized Studies (MINORS), and abstracted data for comparative analysis. Results Of 689 initial studies, 4 observational, comparative studies met inclusion criteria, with follow-up of 2 weeks to 12 months postinjection. Laryngoplasty was most commonly performed for vocal fold immobility with varied injectable materials (micronized dermis, hyaluronic acid, and calcium hydroxyapatite). Follow-up ranged from 2 weeks to 12 months. Voice outcomes improved in all studies, with comparable improvement for patients injected in the office vs the operating room ( P = .42 to P = .88). Meta-analysis of 3 studies showed no difference in Voice Handicap Index-10 voice outcomes by treatment setting (standardized mean difference -0.11, P = .441), with the 95% confidence interval (-0.405 to 0.176), making it unlikely that anything larger than a small or trivial difference was missed. Conclusion Our systematic review makes it unlikely that meaningful clinical differences exist in postprocedure voice outcomes for injection laryngoplasty in the office vs the operating room.

Office-Based Procedures for the Diagnosis and Treatment of Laryngeal Pathology.

INTRODUCTION: Since the development of distal chip endoscopes with a working channel, diagnostic and therapeutic possibilities in the outpatient clinic in the management of laryngeal pathology have increased. Which of these office-based procedures are currently available, and their clinical indications and possible advantages, remains unclear. MATERIAL AND METHODS: Review of literature on office-based procedures in laryngology and head and neck oncology. RESULTS: Flexible endoscopic biopsy (FEB), vocal cord injection, and laser surgery are well-established office-based procedures that can be performed under topical anesthesia. These procedures demonstrate good patient tolerability and multiple advantages. CONCLUSION: Office-based procedures under topical anesthesia are currently an established method in the management of laryngeal pathology. These procedures offer medical and economic advantages compared with operating room-performed procedures. Furthermore, office-based procedures enhance the speed and timing of the diagnostic and therapeutic process.

Failed Vocalis Muscle Monitoring During Thyroid Surgery Resulting From Residual Muscle Relaxation.

Postoperative paralysis of the vocal cords resulting from intraoperative surgical injury of the recurrent laryngeal nerve is one of the most serious complications of elective thyroid surgery. The chance of injury is reduced by using intraoperative neuromonitoring (IONM). This educational report describes a case of IONM failure resulting from residual muscle relaxation that was restored by administration of sugammadex. It discusses possible pharmacology explanations and provides recommendations for how to prevent this situation in daily practice.

Utility and safety of commercially available injection laryngoplasty materials in a rabbit model.

OBJECTIVE: To demonstrate foreign body and chronic inflammatory reaction of commercially available injection materials using the rabbit vocal fold paralysis model. STUDY DESIGN: Animal study. METHODS: The left recurrent laryngeal nerve was identified and divided at the tracheoesophageal groove. Amounts (100 µL) of phosphate-buffered saline (PBS), polyacrylamide hydrogel (Aquamid; Ferrosan A/S, Søborg, Denmark), calcium hydroxyapatite (Radiesse; BioForm Medical Inc., San Mateo, CA), or hyaluronic acid derivative (Rofilan; Rofil Medical International, Breda, Netherlands) were injected into the left vocalis muscle. Six months later, the larynx was harvested. Hematoxylin/eosin and Masson trichrome staining were performed to compare inflammatory and foreign body reactions, granuloma development, and relative vocal fold areas among groups. RESULTS: Compared with the PBS (control) group, the Aquamid, Radiesse, and Rofilan groups exhibited only mild chronic inflammatory reactions that did not significantly differ among groups, or from controls (P > 0.05). However, the Aquamid and Radiesse groups exhibited moderate foreign body reactions that were significantly greater than those of controls (P < 0.05). No foreign body granuloma formed in any group. All test groups exhibited significant increases in vocal fold areas at 6 months (P < 0.05). CONCLUSIONS: Although commercially available injection materials induced more foreign body reactions than a control injection of PBS, no foreign body granuloma developed and the augmented vocal fold area was maintained until 6 months after injection.

Effect of vocal fold injection of cidofovir and bevacizumab in a porcine model.

IMPORTANCE: Recurrent respiratory papillomatosis (RRP) is a common and often chronic disorder. Intralaryngeal bevacizumab has gained recent interest as an adjuvant therapy for RRP. However, no histologic model has been published describing the effects of bevacizumab on the vocal fold. OBJECTIVE: To investigate the histologic effects of bevacizumab injections into the vocal fold and compare these findings with those for cidofovir and saline control injections. DESIGN AND SETTING: In vivo animal study involving eighteen 1-year-old Yorkshire crossbreed pigs, with a blinded review of pathologic findings conducted in a veterinary research laboratory. INTERVENTIONS: The pigs were randomly divided into six study groups receiving 2.5 or 5.0 mg of cidofovir or bevacizumab alone or in combination. Each pig received an injection of 0.5 mL of the test drug in the right vocal fold and 0.5 mL of saline in the left vocal fold. These injections were performed 4 times during the course of 8 weeks. One pig from each group was killed humanely and the larynges harvested 2 weeks after the last injection. The remaining pigs were killed 4 months after the last injection on the remaining pigs. The vocal folds were fixed and stained with hematoxylin-eosin and trichrome and reviewed for histologic changes by 3 blinded pathologists. MAIN OUTCOMES AND MEASURES: Histologic changes to the vocal folds. RESULTS: Minimal inflammation, edema, and atypia were found in all treatment groups. No appreciable histologic differences were found among the 3 treatment groups and their controls. No difference was seen in the vocal folds that were harvested late (4 months) vs early (2 weeks) after last injection. No fibrosis was found in any of the specimens. CONCLUSIONS AND RELEVANCE: No histologic evidence suggests that intralaryngeal cidofovir or bevacizumab alone or in combination resulted in significant changes to the porcine vocal fold. Future studies may build on this model to test higher dosages and/or may combine injections with potassium titanyl phosphate laser therapy.

Experience-dependent modulation of feedback integration during singing: role of the right anterior insula.

Somatosensation plays an important role in the motor control of vocal functions, yet its neural correlate and relation to vocal learning is not well understood. We used fMRI in 17 trained singers and 12 nonsingers to study the effects of vocal-fold anesthesia on the vocal-motor singing network as a function of singing expertise. Tasks required participants to sing musical target intervals under normal conditions and after anesthesia. At the behavioral level, anesthesia altered pitch accuracy in both groups, but singers were less affected than nonsingers, indicating an experience-dependent effect of the intervention. At the neural level, this difference was accompanied by distinct patterns of decreased activation in singers (cortical and subcortical sensory and motor areas) and nonsingers (subcortical motor areas only) respectively, suggesting that anesthesia affected the higher-level voluntary (explicit) motor and sensorimotor integration network more in experienced singers, and the lower-level (implicit) subcortical motor loops in nonsingers. The right anterior insular cortex (AIC) was identified as the principal area dissociating the effect of expertise as a function of anesthesia by three separate sources of evidence. First, it responded differently to anesthesia in singers (decreased activation) and nonsingers (increased activation). Second, functional connectivity between AIC and bilateral A1, M1, and S1 was reduced in singers but augmented in nonsingers. Third, increased BOLD activity in right AIC in singers was correlated with larger pitch deviation under anesthesia. We conclude that the right AIC and sensory-motor areas play a role in experience-dependent modulation of feedback integration for vocal motor control during singing.

Larynx preservation for patients with locally advanced laryngeal cancer.

A 53-year-old man presented with a 6-month history of mild hoarseness, with no associated pain, dysphagia, or stridor. At nasoendoscopy, a lesion was detected involving the whole length of the left vocal cord, with abnormal mucosa also seen in the right ventricle (Fig 1). The left vocal cord movement was impaired. There were no palpable neck nodes. Biopsy under anesthesia revealed moderately differentiated squamous cell carcinoma. He was a current smoker of 30 cigarettes per day (45 pack-year smoking history), and he consumed four standard drinks of alcohol per day. His Eastern Cooperative Oncology Group performance status was 1, and he had no significant comorbidities. Radiologic review of his outside computed tomography scan noted that it was of poor quality, and a magnetic resonance imaging scan was recommended, which showed low-volume T4a disease based on focal thyroid cartilage penetration (Fig 2). A positron emission tomography (PET) scan revealed no evidence of nodal or distant metastasis.

Comparative study in swines' vocal cords healing after excision of fragment with CO2 laser with mitomycin and 5-fluorouracil postoperative topical application / Estudo comparado da cicatrização da prega vocal de suínos após exérese de fragmento com laser de CO2 e aplicação tópica pós-operatória de mitomicina e 5-fluorouracil

PURPOSE: To evaluate the deposition of collagen fibers at pig's vocal folds after topical use of mitomycin or 5-fluorouracil, when partial exeresis of mucosa layer had been promoted by CO2 laser. METHODS: There were used 18 Larger white pigs which were anesthetized and submitted to mucosa fragment's exeresis, bilaterally, at its free border. The animals were divided into 3 groups, each one with 6 animals: control group, without topical drug application; mitomycin group; and 5-fluorouracil group. After 30 days, the animals were subjected to euthanasia, and samples of the vocal folds were collected and stained by picrosirius red technique with polarization for quantification of total collagen deposition. RESULTS: In control group, the mean rate of right vocal fold's collagen deposition at submucosa consisted in a 3428.66 micrometers area. There was found an area whose size had, in average, 2196.36 micrometers, in mitomycin group, and 2269.19 micrometers, in 5-fluorouracil group. CONCLUSION: Mitomycin and 5-fluorouracil had promoted beneficial change in vocal fold's cicatrization with less collagen deposition, but there was no significant statistically difference when they were compared between themselves.

OBJETIVO: Avaliar a deposição das fibras de colágeno total em pregas vocais suínas após o uso tópico de mitomicina ou 5-fluorouracil nas exéreses parciais de mucosa com laser de CO2. MÉTODOS: Foram utilizados 18 porcos da raça Larger white anestesiados e submetidos à exérese de fragmento de mucosa de borda livre da prega vocal direita e prega vocal esquerda. Os animais foram divididos em 3 grupos com 6 animais cada: grupo controle, sem aplicação de medicação tópica; grupo mitomicina, com uso tópico dessa substância; grupo 5-fluorouracil, uso tópico. Após 30 dias do experimento os animais foram submetidos à eutanásia, coletadas amostras das pregas vocais e coradas pela técnica do picrosirius red com polarização para a quantificação computadorizada da deposição do colágeno total. RESULTADOS: No grupo controle, a média da área do colágeno depositado na submucosa da prega vocal direita foi de 3428,66 micrômetros. No grupo mitomicina a média foi de 2196,36 micrômetros. No grupo 5-fluorouracil, a média foi de 2269,19 micrômetros. CONCLUSÃO: A mitomicina e o 5-fluorouracil promoveram mudança benéfica na cicatrização da prega vocal, com menor deposição de colágeno, porém, quando comparados entre si, eles não apresentaram diferença estatisticamente significante.

Comparative study in swines' vocal cords healing after excision of fragment with CO2 laser with mitomycin and 5-fluorouracil postoperative topical application.

PURPOSE: To evaluate the deposition of collagen fibers at pig's vocal folds after topical use of mitomycin or 5-fluorouracil, when partial exeresis of mucosa layer had been promoted by CO2 laser. METHODS: There were used 18 Larger white pigs which were anesthetized and submitted to mucosa fragment's exeresis, bilaterally, at its free border. The animals were divided into 3 groups, each one with 6 animals: control group, without topical drug application; mitomycin group; and 5-fluorouracil group. After 30 days, the animals were subjected to euthanasia, and samples of the vocal folds were collected and stained by picrosirius red technique with polarization for quantification of total collagen deposition. RESULTS: In control group, the mean rate of right vocal fold's collagen deposition at submucosa consisted in a 3428.66 micrometers area. There was found an area whose size had, in average, 2196.36 micrometers, in mitomycin group, and 2269.19 micrometers, in 5-fluorouracil group. CONCLUSION: Mitomycin and 5-fluorouracil had promoted beneficial change in vocal fold's cicatrization with less collagen deposition, but there was no significant statistically difference when they were compared between themselves.

Retrospective analysis: concurrent chemoradiotherapy using protracted continuous infusion of low-dose cisplatin and 5-fluorouracil for T2N0 glottic cancer.

PURPOSE: Treatment with conventional radiotherapy alone for local control of T2 glottic cancer (T2GC) is insufficient. To improve local control of T2GC, we have simultaneously administered continuous intravenous infusions of low-dose cisplatin and 5-fluorouracil (5-FU) in combination with irradiation. MATERIALS AND METHODS: We performed this combination therapy in a total of 11 consecutive patients with previously untreated invasive squamous cell carcinoma (T2GC). Cisplatin was administered at 4 mg/m2/day and 5-FU at 200 mg/m2/day for 120 h, except during weekends, beginning on the day irradiation with a once-daily fraction at 2 Gy was started. RESULTS: An initial local control rate of the primary tumor was achieved in 10 of the 11 patients (91%), and ultimate laryngeal preservation by cordectomy was achieved in all cases. Regarding adverse reactions, grade 3 or 4 hemotoxicity did not develop in any of the patients. Grade 3 laryngitis was observed in four patients (36%), but none of these patients required interruption of treatment owing to acute laryngeal reactions. CONCLUSION: Instead of radiotherapy alone, this combination chemoradiotherapy is suggested with the possibility of improving local control of T2GCs.

Impact of topical anesthesia on acoustic characteristics of voice during laryngeal telescopic examination.

OBJECTIVE: The purposes of this study are to investigate the impact of topical anesthetic alone and with concurrent laryngeal telescopic examination on acoustic characteristics of vocal fold function. Comparison with phonation in controlled conditions may imply diagnostic information from the examination. STUDY DESIGN: Thirty males evaluated as having a normal voice were included in the study. The subjects were asked to phonate sustained /i/ with a naturally comfortable pitch and loudness in three consecutive experimental sequences as "control condition," "anesthetic condition," and "telescopic condition." Acoustic analysis of fundamental frequency, jitter, shimmer, and harmonic to noise ratio in the three different conditions were executed. RESULTS: The mean and standard deviation of Fo in control condition, anesthetic condition, and telescopic condition were 130.1 +/- 18.5 Hz, 125.7 +/- 19.7 Hz, and 173.2 +/- 35.1 Hz, respectively. The telescopic condition showed more negative change than that in control condition and anesthetic condition in other parameters. There was a significant difference (P < 0.001) between control condition and telescopic condition in all four parameters. CONCLUSIONS: This study showed that anesthesia has little effect on voice performance for subjects with a normal voice. On the other hand, the acoustic characteristics changed significantly during telescopic performance. When doing interpretation of acoustic data, the abnormality of the acoustic characteristics might be the result of the procedures and not reflect vocal pathology. Laryngeal variations due to manipulation of telescope should be ruled out.

Steroid injection to vocal nodules using fiberoptic laryngeal surgery under topical anesthesia.

Since 1990, we have performed steroid injection into the vocal fold by fiberoptic laryngeal surgery (FLS) under local anesthesia. In this study, the usefulness of this method was evaluated in 28 patients with vocal nodules. Under monitoring using a fiberoptic laryngoscope, a curved injection needle was inserted via the oral cavity and steroid was injected. Endoscopic findings showed that the vocal nodule had disappeared in 17 patients of the 27 patients and decreased in 10 after injection. The maximum phonation time was 10.9 s before operation and 13.9 s after operation, showing a significant increase (P<0.05), and the mean flow rate also showed a significant improvement (P<0.05). The patients self-rating concerning hoarseness demonstrated great improvement after injection. This technique can be performed under local anesthesia in combination with voice therapy on an outpatient basis, and it is considered to be useful for treating vocal nodules.

Physiologic assessment of botulinum toxin effects in the rat larynx.

OBJECTIVE: Botulinum toxin (BT) is a currently used treatment for spasmodic dysphonia (SD) and other related focal dystonias. The goal of this study is to provide a basis for using the rat larynx to objectively assess physiological and histological effects of BT. STUDY DESIGN: Dosages and volumes of BT injection were varied and three physiological parameters were measured. These measures included: optical density of PAS-stained laryngeal muscle after electrical stimulation, which is an indirect measure of denervation, spontaneous laryngeal muscle activity, and laryngeal movement. METHODS: A new microlaryngoscopic technique was developed, which made it possible to observe and manipulate the rat larynx endoscopically. Laryngeal movement and electromyographic (EMG) measures were made prior to injection and 3 days following BT injections of various dosages and volumes. Optical density measures were made 3 days after injection. RESULTS: Significant reductions in vocal fold motion and spontaneous laryngeal muscle activity as a function of increased BT dosage were observed. In addition, the optical density of PAS-stained laryngeal muscle after electrical stimulation was increased following BT injection. Significant volume effects in optical density were observed in the lateral thyroarytenoid and lateral cricoarytenoid muscles on the contralateral side. CONCLUSIONS: The rat laryngeal model is suitable for assessing BT effects. In addition, the three physiological variables provided useful and reliable measures of laryngeal function. It is the authors' intention to use the rat laryngeal model to further examine the physiological and histological effects of BT with the goal of developing new methods for the treatment of patients with SD and other focal dystonias.

Effect of topical anaesthesia on the motor performance of vocal cords as assessed by tussometry.

Tussometry involves a continuous measurement of airflow produced by a cough manoeuvre displayed as an airflow-time wave. There is a rapid rise to its peak (cough peak flow rate) and the time taken to reach the peak (peak velocity time) is determined by the laryngeal opening at the onset of cough. Cough peak flow and peak velocity time were measured in 10 healthy volunteers before and after topical anaesthesia of the larynx with lignocaine 100 mg sprayed under indirect laryngoscopy. Adequacy of anaesthesia was established by touching the cords deliberately with a fibreoptic laryngoscope. All subjects had excellent anaesthesia of the larynx. However, cough peak flow rate and peak velocity time remained unchanged following topical anaesthesia. We conclude that topical anaesthesia of the larynx does not impair the motor performance of the vocal cords during a voluntary cough.

Radioiodine-131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer.

131I continues to be one of the safest and most effective methods of diagnosing and treating metastatic well differentiated thyroid cancer. It is not without risk, however, and must be judiciously applied to carefully prepared and selected patients.

A method of rapid-sequence induction using high-dose narcotics with vecuronium or vecuronium and pancuronium in patients with coronary artery disease.

A method of rapid-sequence induction was studied in 18 patients undergoing coronary artery bypass grafting (CABG) to assess the adequacy of relaxation for endotracheal intubation without resulting in major changes in heart rate (HR). Ten patients received vercuronium, 0.2 mg/kg (V); and eight patients received vecuronium, 0.1 mg/kg, and pancuronium, 0.1 mg/kg (V + P). All patients then received fentanyl, 50 to 70 microg/kg, or sufentanil, 5 to 7 microg/kg, followed 60 seconds later by intubation. Patients were assessed for ulnar and mandibular nerve response to train-of-four (TOF) and tetanic (T) stimulation at 60 seconds; presence or absence of coughing or bucking; degree of vocal cord relaxation (1=none, 2=some, 3=complete relaxation); ability to intubate at 60 seconds; and changes in HR. At the time of intubation, 17 patients had four twitches to TOF and a positive response to T stimulation of the ulnar nerve, while all 18 patients had zero or one twitch to TOF and only four had a positive response to T stimulation of the mandibular nerve (P < .0001 for T and TOF, ulnar v mandibular). Coughing and bucking were not observed in any patient. Vocal cord position was "3" in 14 patients and "2" in four patients. All patients were intubated without difficulty. The mean change in HR was -4.1 beats/min for patients receiving V and +16.4 beats/min for those receiving V + P (P < .002 for change in HR), with two V + P patients developing tachycardia. It is concluded that the onset of neuromuscular blockade is more rapid in the distribution of the mandibular nerve than at the ulnar nerve; mandibular nerve stimulation is a better predictor of adequate intubating conditions; good intubating conditions can be attained with either V or V + P; and, rapid-sequence induction with V is safe from a cardiac standpoint as measured by changes in HR, but the addition of pancuronium is unnecessary.