Acute Effects of Systemic Glucocorticoids on the Vocal Folds in a Pre-Clinical Model.

OBJECTIVES/HYPOTHESIS: Systemic glucocorticoids (GC)s are employed to treat various voice disorders. However, GCs have varying pharmacodynamic properties with adverse effects ranging from changes in epithelial integrity, skeletal muscle catabolism, and altered body weight. We sought to characterize the acute temporal effects of systemic dexamethasone and methylprednisolone on vocal fold (VF) epithelial glucocorticoid receptor (GR) nuclear translocation, epithelial tight junction (ZO-1) expression, thyroarytenoid (TA) muscle fiber morphology, and body weight using an established pre-clinical model. We hypothesized dexamethasone and methylprednisolone will elicit changes in VF epithelial GR nuclear translocation, epithelial ZO-1 expression, TA muscle morphology, and body weight compared to placebo-treated controls. METHODS: Forty-five New Zealand white rabbits received intramuscular injections of methylprednisolone (4.5 mg; n = 15), dexamethasone (450 µg; n = 15), or volume matched saline (n = 15) into the iliocostalis/longissimus muscle for 6 consecutive days. Vocal folds from 5 rabbits from each treatment group were harvested at 1-, 3-, or 7 days following the final injection and subjected to immunohistochemistry for ZO-1 and GR as well as TA muscle fiber cross-sectional area (CSA) measures. RESULTS: Dexamethasone increased epithelial GR nuclear translocation and ZO-1 expression 1-day following injections compared to methylprednisolone (P = .024; P = .012). Dexamethasone and methylprednisolone increased TA CSA 1-day following injections (P = .011). Methylprednisolone decreased body weight 7 days following injections compared to controls (P = .004). CONCLUSIONS: Systemic dexamethasone may more efficiently activate GR in the VF epithelium with a lower risk of body weight loss, suggesting a role for more refined approaches to GC selection for laryngeal pathology.

Duration of Clinical Response After In-Office Steroid Injection for Vocal Fold Scar.

OBJECTIVE: To assess the duration of clinical response after in-office vocal fold steroid injection (VFSI) for vocal fold (VF) scar. METHODS: Demographic and clinical data for in-office VFSI occurring from 2017 to 2020 were collected. Two Speech-Language Pathologists (SLPs) used perceptual evaluation of voice and functional scales to evaluate blinded voice and laryngovideostroboscopy (LVS) samples collected pre- and post-injection across multiple timepoints. RESULTS: Blinded SLP ratings were used for 30 individual VFs undergoing initial injection in 18 patients. Persistent improvement in voice past 6 months was seen in 57% of patients after VFSI. Multiple measures of voice and amplitude, percent vibrating tissue, and closed phase predominance significantly improved at various follow-up timepoints on average. CONCLUSION: Accounting for patient heterogeneity and disease progression, in-office VFSI for VF scar is associated with sustained improvement in a subset of patients. Approximately half of patients can expect to experience a lasting improvement in voice. Future studies of larger scale are required to identify patient factors associated with long-term benefit. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2333-2339, 2023.

Tamoxifen Alters TGF-ß1/Smad Signaling in Vocal Fold Injury.

OBJECTIVES: Effective treatments for vocal fold fibrosis remain elusive. Tamoxifen (TAM) is a selective estrogen receptor modulator and was recently reported to have antifibrotic actions. We hypothesized that TAM inhibits vocal fold fibrosis via altered transforming growth factor beta 1 (TGF-ß1) signaling. Both in vitro and in vivo approaches were employed to address this hypothesis. METHODS: In vitro, vocal fold fibroblasts were treated with TAM (10-8 or 10-9 M) ± TGF-ß1 (10 ng/ml) to quantify cell proliferation. The effects of TAM on genes related to fibrosis were quantified via quantitative real-time polymerase chain reaction. In vivo, rat vocal folds were unilaterally injured, and TAM was administered by oral gavage from pre-injury day 5 to post-injury day 7. The rats were randomized into two groups: 0 mg/kg/day (sham) and 50 mg/kg/day (TAM). Histological changes were examined on day 56 to assess tissue architecture. RESULTS: TAM (10-8 M) did not affect Smad3, Smad7, Acta2, or genes related to extracellular matrix metabolism. TAM (10-8 or 10-9 M) + TGF-ß1, however, significantly increased Smad7 and Has3 expression and decreased Col1a1 and Acta2 expression compared to TGF-ß1 alone. In vivo, TAM significantly increased lamina propria area, hyaluronic acid concentration, and reduced collagen deposition compared to sham treatment. CONCLUSIONS: TAM has antifibrotic potential via the regulation of TGF-ß1/Smad signaling in vocal fold injury. These findings provide foundational data to develop innovative therapeutic options for vocal fold fibrosis. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2248-2254, 2023.

Concurrent Chemoradiotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil for T3 N0 Glottic Carcinoma Without Vocal Cord Fixation.

BACKGROUND/AIM: We retrospectively evaluated the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) for T3 N0 glottic carcinoma without vocal cord fixation. PATIENTS AND METHODS: Twenty-five patients underwent TPF-CCRT without elective nodal irradiaion (ENI). After the RT of 40 Gy, five patients (20%) without tumor regression underwent surgery. Others underwent RT with a median total dose of 66 Gy. RESULTS: Of the five patients who underwent surgery after the RT of 40 Gy, two showed residual carcinoma pathologically and the other three were confirmed to have complete pathological response to the treatment. The 5-year local control rate was 87%. No patients exhibited regional failure. No acute toxicities of grade 5 or late toxicities ≥grade 3 were observed. CONCLUSION: TPF-CCRT provides excellent tumor control with acceptable toxicities. CCRT while omitting ENI is a reasonable approach for T3 N0 glottic carcinoma without vocal cord fixation.

Vocal fold injection material does not preclude interpretation of laryngeal electromyography.

INTRODUCTION/AIMS: Temporary vocal fold injection (VFI) is a common treatment for acute and subacute vocal fold paralysis (VFP). Laryngeal electromyography (LEMG) is useful for diagnosing neurogenic causes of VFP. This study evaluated whether the presence of VFI material prevents interpretation of LEMG in patients with acute and subacute VFP. METHODS: Patients with acute and subacute unilateral VFP (onset ≤6 mo) who underwent temporary VFI within 3 mo preceding LEMG were evaluated. A matched control group that did not undergo VFI was also studied. The LEMG team (laryngologist and electromyographer) performed and interpreted LEMG using a pre-specified protocol, including qualitative and quantitative motor unit analysis. RESULTS: Eighteen patients with VFI underwent LEMG successfully with interpretation of spontaneous activity and motor unit recruitment. Fourteen patients were seen in follow-up to determine accuracy of established LEMG prognosis. Seven of seven subjects with poor LEMG prognosis did not recover vocal fold motion. Five of seven subjects with fair LEMG prognosis recovered vocal fold motion. Findings were similar for the control group. DISCUSSION: VFI augmentation material did not prevent interpretation of meaningful LEMG data in patients with acute and subacute VFP, and accurate prognoses of vocal fold motion recovery were established.

Mainstream Cigarette Smoke Impacts the Mouse Vocal Fold Epithelium and Mucus Barrier.

OBJECTIVES/HYPOTHESIS: Cigarette smoke (CS) is a primary risk factor for the development of numerous benign and malignant laryngeal diseases. The epithelium and mucus lining the vocal folds (VF) are the first barriers against CS. The primary objective of this study was to investigate epithelial and mucus barrier changes in the mouse laryngeal mucosa upon exposure to subacute CS. The secondary objective was to compare mucus barrier changes in mice and human smokers and nonsmokers. Study Design Animal model. METHODS: Mice were exposed to CS for 4 weeks for 4 hours (N = 12, high dose [HD]) or 1 hour (N = 12, low dose [LD]) per day. Air-exposed mice were used as a control group (N = 10). Larynges were harvested and VF epithelial barrier integrity was evaluated including cellular proliferation and expression of cell junctions. We also investigated mucus production by examining mucus cell area and mucin expression in mice and human smokers and nonsmokers. RESULTS: HD CS increased VF epithelial cellular proliferation but did not alter the expression of cell junctions. HD CS also induced hypertrophy of the mucus-producing submucosal glands. However, only LD CS increased MUC5AC gene expression. MUC5AC staining appeared elevated in laryngeal specimens from smokers, but this was not significant as compared to nonsmokers. CONCLUSIONS: These findings help us identify potential adaptive mechanisms to CS exposure as well as set the foundation for further study of key aspects of epithelial and mucus barrier integrity that may be implicated in laryngeal disease development following prolonged smoking. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2530-2539, 2021.

Prospective Evaluation of Safety of Singing on Steroids: Testing the Truth of Received Wisdom.

OBJECTIVES/HYPOTHESIS: Performing while on steroids is widely considered to increase risk of vocal injury. This study aims to determine incidence and type of injury, and changes in performers' voices after treatment of vocal fold edema (VFE) with glucocorticoids. STUDY DESIGN: Prospective Cohort. METHODS: Fifty-five performers (34 female; 21 male) treated for acute VFE with short-course oral glucocorticoids were prospectively evaluated pre- and post-treatment. Subjects underwent videostroboscopy, acoustic/aerodynamic assessment, and functional assessment with the Singing Voice Handicap Index-10 (SVHI-10) and Evaluation of the Ability to Sing Easily (EASE). Blinded reviewers rated videostroboscopic examinations and performed audio-perceptual assessment. Chi-square tests and Wilcoxon signed rank tests were applied for analyses of treatment changes. RESULTS: Following glucocorticoid treatment, two instances of vocal fold hemorrhage (3.6%) and three instances of glottic thrush (5.5%) were observed. These resolved without consequence. Mucosal wave dynamics and edema improved. Nearly all subjects completed scheduled performances, and significant improvement was noted on the EASE, reflecting improved function after treatment. These were further supported by statistically significant improvements in CAPE-V and some acoustic and aerodynamic outcomes (semitone pitch range for females, airflow measures for males). CONCLUSIONS: Oral glucocorticoids appear to be generally safe for performers presenting with acute VFE. The incidence of adverse effects, specifically hemorrhage and thrush, was low and the effects transient. Vocal fold examination should be considered obligatory before prescribing glucorticoids to working performers. A treatment strategy for acute VF edema incorporating glucocorticoids when appropriate appears to result in significant improvements in measures of glottal function including videostroboscopic appearance, subject perception, and auditory perception. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2298-2304, 2021.

Intracordal Injection of Basic Fibroblast Growth Factor in 100 Cases of Vocal Fold Atrophy and Scar.

OBJECTIVES/HYPOTHESIS: Vocal fold atrophy, scar, and sulcus reduce the vibratory function of the vocal fold mucosa, which causes severe refractory dysphonia. We have reported encouraging preliminary results using an intracordal injection of basic fibroblast growth factor (bFGF) and showed improvement in phonatory parameters and voice. The present study summarizes our experience with 100 cases of stiffened vocal folds that were treated with bFGF injections. STUDY DESIGN: Retrospective chart review with Interstitial Review Board (IRB) approval. METHODS: Local injection of bFGF was performed in 100 cases of vocal fold pathology, which included 43 cases of vocal fold atrophy, 41 cases with scar, and 16 cases with sulcus. Ten micrograms of bFGF were injected into the vocal folds under topical anesthesia 4 times in each patient. Therapeutic outcomes were examined with maximum phonation time (MPT), voice handicap index-10 (VHI-10), and GRBAS scale. RESULTS: MPT, VHI-10, and GRBAS scores significantly improved in all pathology groups. An improvement on the VHI-10 greater than five points was observed in 82% of atrophy cases, 78% of scar cases, and 67% of sulcus cases. Improvement on the VHI-10 was significantly better in the atrophy group than the scar or sulcus groups. The mild/moderate cases of scar and sulcus showed better improvement than severe cases. CONCLUSIONS: The current large case series indicates positive effects of intracordal injection of bFGF for improvement of voice with no severe adverse events. The effects appeared best for cases of atrophy, while the treatment of severe scar and sulcus requires further improvement. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2059-2064, 2021.

Regenerative efficacy of fibroblast growth factor for the treatment of aged vocal fold: From animal model to clinical application.

OBJECTIVES: We assessed fibroblast growth factor (FGF) regenerative efficacy in an aged vocal fold rat model and confirmed it in a prospective clinical trial. DESIGN, SETTING, AND PARTICIPANTS: For animal experiments, 48 Sprague-Dawley rats were divided into two groups: 24 six-month-olds (young group) and 24 twenty-four-month-olds (old group). FGF was injected once a week thrice into the left vocal fold of the old group, dividing them into two sub-groups (injected [left] and uninjected [right]). Additionally, we conducted a prospective clinical trial for 38 patients with aged atrophic vocal fold. MAIN OUTCOME MEASURES: A month post-injection, excised larynx from the three groups was subjected to comparative histopathological (ratio of relative lamina propria to total vocal fold) and mRNA expression analysis (of procollagen I, hyaluronic acid synthase (HAS)-2 and matrix metalloproteinase (MMP)-2) by real-time PCR. We performed perceptual, stroboscopic, acoustic aerodynamic test and Voice Handicap Index survey prior to and 1, 6 and 12 months after FGF injection. RESULTS: In rats, the relative lamina propria ratio increased after FGF injection. Procollagen I mRNA level decreased, whereas that of HAS-2 and MMP-2 increased significantly in the injected compared to the uninjected old group. Enrolled patients showed improved subjective and objective voice parameters after FGF injection, and these were maintained for a year. Potential side effects were not observed. CONCLUSIONS: Animal experiments and prospective clinical trial suggest that FGF injection to vocal fold can significantly improve voice quality until one year, without complications, and is effective for aged atrophic vocal fold treatment.

Exploring the Pathophysiology of Reinke's Edema: The Cellular Impact of Cigarette Smoke and Vibration.

OBJECTIVES: To explore the isolated or combined effects of cigarette smoke extract (CSE) and vibration on human vocal fold fibroblasts (hVFF) in an in vitro setting in order to elucidate their influence in the pathophysiology of Reinke's edema (RE). STUDY DESIGN: Immortalized hVFF were exposed to CSE or control medium under static or vibrational conditions. A phonomimetic bioreactor was used to deliver vibrational patterns to hVFF over a period of 5 days. METHODS: Cytotoxicity was quantified using a lactate dehydrogenase assay. We employed reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Magnetic Luminex(R) assays (R&D Systems, Minneapolis, MN) to assess the influence on extracellular matrix production, fibrogenesis, inflammation, and angiogenesis. RESULTS: We observed significant changes induced by CSE alone (hyaluronic acid, matrix metalloproteinase 1, Interleukin-8, cyclooxygenase [COX]1, COX2, vascular endothelial growth factor [VEGF]D), as well as settings in which only the combination of CSE and vibration led to significant changes (transforming growth factor beta 1, VEGFA, VEGFC). Also, CSE-induced levels of COX2 were only significantly reduced when vibration was applied. CONCLUSION: We were able to explore the cellular effects of CSE and vibration on hVFF by employing a phonomimetic bioreactor. Whereas cigarette smoke is generally accepted as a risk factor for RE, the role of vibration remained unclear as it is difficult to study in humans. Our data showed that some genes and proteins in the pathophysiological context of RE were only affected when CSE in combination with vibration was applied. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E547-E554, 2021.

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.

Hyaluronic Acid Injection Laryngoplasty for Unilateral Vocal Fold Paralysis-A Systematic Review and Meta-Analysis.

Unilateral vocal fold paralysis (UVFP) is a common disorder that may cause glottal closure insufficiency and then hoarseness of voice and aspiration during swallowing. We conducted a systematic review and meta-analysis to evaluate whether hyaluronic acid (HA) injection laryngoplasty (IL) is an effective treatment for patients with UVFP. Comprehensive systematic searches were undertaken using PubMed, EBSCO Medline, and Cochrane Library databases. We appraised the quality of studies according to preset inclusion and exclusion criteria. The lengths of follow-up were divided into "short-term" (3 months or shorter), "medium-term" (6 months), and "long-term" (12 months or longer). We performed random-effect meta-analysis to estimate the changes in voice-related quality of life, perceptual evaluation by grading systems, voice lab analysis of maximal phonation time, and normalized glottal gap area, before and after HA IL. Fourteen studies were eligible for the final analysis. The results showed that patients' glottal closure insufficiency could be improved; maximal phonation time could be prolonged; perceptual evaluations of the voice and quality of life were better after HA IL, but the duration of treatment effect varied among different studies. In conclusion, HA IL is an effective treatment for UVFP, which may achieve a long-term effect and therefore reduce the likelihood of requiring permanent medialization thyroplasty.

Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds.

Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-ß as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-ß and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling. Human VF fibroblasts (HVOX) were treated with three commonly-employed GCs+ /-TGF-ß1. Phosphorylation of the glucocorticoid receptor (GR:NR3C1) and activation of NR4A1 was analyzed by western blotting. Genes involved in the fibrotic response, including ACTA2, TGFBR1, and TGFBR2 were analyzed by qPCR. RNA-seq was performed to identify global changes in gene expression induced by dexamethasone. GCs enhanced phosphorylation of GR at Ser211 and TGF-ß-induced ACTA2 expression. Dexamethasone upregulated TGFBR1, and TGFBR2 in the presence of TGF-ß1 and increased active NR4A1. RNA-seq results confirmed numerous pathways, including TGF-ß signaling, affected by dexamethasone. Synergistic pro-fibrotic effects of TGF-ß were observed across GCs and appeared to be mediated, at least partially, via upregulation of TGF-ß receptors. Dexamethasone exhibited diverse regulation of gene expression including NR4A1 upregulation consistent with the anti-fibrotic potential of GCs.

In vitro mechanical vibration down-regulates pro-inflammatory and pro-fibrotic signaling in human vocal fold fibroblasts.

INTRODUCTION: Voice rest following phonotrauma or phonosurgery has a considerable clinical impact, but clinical recommendations are inconsistent due to inconclusive data. As biopsies of the vocal folds (VF) for molecular biology studies in humans are unethical, we established a new in vitro model to explore the effects of vibration on human vocal fold fibroblasts (hVFF) in an inflammatory and normal state, which is based on previously published models. METHODS: By using a phonomimetic bioreactor we were able to apply predefined vibrational stress patterns on hVFF cultured under inflammatory or normal conditions. Inflammatory and pro-fibrotic stimuli were induced by interleukin (IL)1ß and transforming growth factor (TGF)ß1, respectively. Mechanical stimulation was applied four hours daily, over a period of 72 hours. Outcome measurements comprised assessment of extracellular matrix (ECM)-related components, angiogenic factors, and inflammatory and fibrogenic markers on gene expression and protein levels. RESULTS: Under inflammatory conditions, the inflammatory cytokine IL11, as well as the myofibroblast marker alpha smooth muscle actin (α-SMA) were significantly reduced when additional vibration was applied. The desirable anti-fibrotic ECM component hyaluronic acid was increased following cytokine treatment, but was not diminished following vibration. CONCLUSION: Our experiments revealed the effect of vibrational stress on hVFF in an inflammatory state. Elevated levels of certain pro-inflammatory/pro-fibrotic factors could be mitigated by additional vibrational excitation in an in vitro setting. These findings corroborate clinical studies which recommend early voice activation following an acute event.

TrkA inhibitor promotes motor functional regeneration of recurrent laryngeal nerve by suppression of sensory nerve regeneration.

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.

Effect of Urban Particulate Matter on Vocal Fold Fibrosis through the MAPK/NF-κB Signaling Pathway.

Particulate matter (PM) is an environmental exposure factor that adversely affects human health. PM is a risk factor for various diseases. However, the mechanism by which PM affects the vocal folds (VF) has not yet been evaluated. Thus, we investigated the cytotoxic effects of PM on human vocal fold fibroblasts (hVFF) and the underlying signaling pathways. hVFF were isolated from human VF. The effect of PM on hVFF, and the underlying mechanism, were analyzed using Western blot, quantitative real-time polymerase chain reaction, and flow cytometry. In addition, a histological evaluation was performed in animal experiments. Cell proliferation decreased after the PM treatment. PM increased the expression of interleukin (IL)-6 and IL-1ß. The generation of reactive oxygen species (ROS) in PM-treated hVFF and subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were confirmed. Furthermore, PM increased the expression of fibrosis-related markers and induced the accumulation of collagen in the extracellular matrix. As a result, PM exposure significantly enhances the inflammatory response on VF through the ROS-mediated activation of the MAPK and NF-κB signaling pathways. In addition, PM promotes differentiation into myofibroblasts and induces fibrosis. These results suggest that PM triggers an inflammatory reaction through ROS production and causes VF fibrosis.

Comparison of Fundamental Frequency in Postmenopausal Women Who Are Treated With Hormone Replacement Therapy vs Those Who Are Not: A Systematic Review and Meta-analysis.

Importance: Hormonal changes during menopause have been associated with significant changes in voice. Although hormone replacement therapy (HRT) is used primarily to manage systemic symptoms of menopause, its association with voice in postmenopausal women has not been adequately investigated by large-scale studies. Objective: To compare fundamental frequency between postmenopausal women who used HRT and those who did not use HRT. Data Sources: PubMed, Ovid MEDLINE, CINAHL, Cochrane EBM Reviews, and Embase were searched from 1946 to February 19, 2020. Study Selection: Studies included in the final review were those in English that compared voice outcomes in postmenopausal women who were or were not receiving HRT for treatment of climacteric symptoms associated with menopause. Data Extraction and Synthesis: The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction was performed by 2 independent investigators. Study quality was assessed using a validated quality tool. Whenever possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures: The primary outcome was the difference in speaking fundamental frequency (F0) between HRT users and nonusers. Subgroup analysis of the primary outcome was based on body mass index (BMI) using a cutoff value of 25. A BMI of 18.5 to 24.9 is considered normal, and a BMI of at least 25 is considered overweight. Secondary outcomes included other objective measurements of voice, including jitter and shimmer. Results: A total of 937 records were screened, 18 full texts were assessed, and 11 studies were included in the final review. All 11 studies were case-control studies and were rated from fair to good quality based on the Newcastle-Ottawa Scale. A total of 5 studies including 154 participants who received HRT and 154 controls were used for meta-analysis. The mean (SD) F0 was 185.9 (8.6) Hz for HRT users compared with 174.6 (6.6) Hz for nonusers. Hormone replacement therapy was associated with a higher mean F0 by a difference of 11.85 Hz (95% CI, 7.35-16.36 Hz). Subgroup analysis showed that the change in F0 was significant in postmenopausal women with a normal body mass index (mean difference, 13.47 Hz; 95% CI, 8.48-18.46 Hz) but not in those with a high body mass index. Conclusions and Relevance: Existing evidence suggests that HRT is associated with a higher F0 in postmenopausal women. The effectiveness of the treatment appeared to be more pronounced in women with a normal body mass index.

The role of steroid injection for vocal folds lesions in professional voice users.

BACKGROUND: Benign vocal fold lesions identified in professional voice users, frequently require further treatment after failure of conservative measures. The role of vocal fold steroid injection as a treatment option for select benign lesions is the focus of this study. Steroid injection may avoid phonosurgery in some individuals thereby reducing the potential for adverse side effects associated with surgery. OBJECTIVE: The purpose of the study is to review the effect of steroid injection on vocal function in professional voice users associated with a benign lesion(s) using the Voice Handicap Index-10. METHOD: This study is a retrospective review of patients (professional voice users) that underwent 1 or more steroid injection(s) between July 2014-December 2018. The Voice Handicap Index-10 was compared from pre to post treatment. Patients were identified using billing code data for laryngeal injection. Patient demographics (age, gender, profession), previous phonosurgery, date of steroid injection and follow up dates as well as VHI-10 scores were collected from the electronic medical record. RESULTS: Twenty four patients were identified. The mean Voice HandicapIndex-10 score decreased from 23.5 pre injection to 17.8 post injection which represented a reduction of 24.3%. Vocal fold steroid injection procedure in our series was associated with one complication. CONCLUSION: Vocal fold steroid injection for benign lesions is a safe, well-tolerated procedure with an improvement in vocal function without surgical intervention. Steroid injection should be considered as a treatment option to avoid surgery in patients with select vocal fold lesions.

The Antiproliferative and Antifibrotic Effects of Cisplatin on Primary Human Vocal Fold Fibroblasts.

OBJECTIVE: Vocal fold scarring and laryngeal stenosis are major clinical challenges. Current drugs do not efficiently reduce scarring. We examined the antiproliferative and antifibrotic effects of cisplatin on primary human vocal fold fibroblasts (HVFFs). METHODS: HVFFs were cultured in vitro and identified by immunocytochemistry. The relative viability of HVFFs was analyzed by Cell Counting Kit-8 assays (CCK-8). The fibrogenic phenotype was induced by transforming growth factor-ß1 (TGF-ß1) and reversed by cisplatin as shown by immunocytochemistry. Real-time PCR and Western blotting assessed collagen III and I. Western blotting for Smad2, p-Smad2, Smad-3, p-Smad3 and caspase-3 were performed. RESULTS: CCK-8 results showed that cisplatin decreased the relative viability of HVFFs, and Western blots revealed elevation of the apoptosis-related protein caspase-3 in HVFFs. Cisplatin treatment reduced α-smooth muscle actin staining intensity in the presence of TGF-ß1. Real-time PCR revealed the downregulation of collagen III and I in cisplatin-treated HVFFs. The TGF-ß1-induced increased fibrogenic protein levels were decreased by cisplatin. Reduced levels were detected at late time points. CONCLUSIONS: Cisplatin induces antiproliferative and antifibrotic alterations in HVFFs. Cisplatin may prevent postoperative vocal fold scarring and laryngeal stenosis in patients treated with CO2 laser microsurgery and undergoing delayed wound healing.

Therapeutic Efficacy of Basic Fibroblast Growth Factor in Patients With Vocal Fold Atrophy.

OBJECTIVES/HYPOTHESIS: In recent years, basic fibroblast growth factor (bFGF) injection has been used in the treatment of aging-related vocal fold atrophy. This injection not only improves closure by increasing the mass of the vocal fold but also improves its viscoelasticity. However, it has been reported that fibroblasts targeted by bFGF treatment decrease in number with age. The purpose of this study was to examine the effects of local injection of bFGF on age-related vocal atrophy as well as the influence of age on phonological outcomes. STUDY DESIGN: Retrospective chart review. METHODS: Fifty-three patients with age-related vocal fold atrophy underwent single injections of bFGF in their vocal folds. Phonological outcomes were evaluated 3 and 6 months after injection by acoustic and aerodynamic measurements. RESULTS: Voice Handicap Index (VHI), maximum phonation time (MPT), jitter, shimmer, and pitch range improved after injection, and the effects continued for 6 months. In those over 70 years of age, VHI and MPT showed improvement at 3 and 6 months after injection. In addition, the degree of improvement in VHI and MPT did not differ significantly between those older than 70 years and those younger than 70 years. CONCLUSIONS: Regenerative treatments dependent on bFGF single injection was safe and effective for both early and late elderly patients suffering of vocal fold atrophy. LEVEL OF EVIDENCE: 2c Laryngoscope, 2020.