Faculty Bibliography

OBJECTIVES: We studied the effect of transforming growth factor (TGF)-beta on immortalized human vocal fold fibroblasts. METHODS: Normal human vocal fold fibroblasts were subjected to sequential lentiviral transduction with genes for human telomerase (hTERT) and SV40 large T antigen in order to produce an 'immortalized' cell line of normal phenotype. After confirmation of vocal fold fibroblast transfection, these cells, referred to as HVOX, were treated with various concentrations of exogenous TGF-beta1 and assayed for collagen secretion, migration, and proliferation. In addition, components of the TGF-beta signaling pathway were examined in this cell line. RESULTS: TGF-beta stimulated collagen secretion and migration without altering proliferation of HVOX. HVOX constitutively expressed type I and II TGF-beta receptors, as well as messenger RNA for the Smad signaling proteins and for all TGF-beta isoforms. Exogenous TGF-beta1 induced temporally dependent alterations in Smad2 and Smad3 gene expression. TGF-beta increased Smad7 expression at both 4 and 24 hours. Prolonged exposure to TGF-beta decreased TGF-beta1 gene expression. CONCLUSIONS: Insight into the underlying pathophysiology of vocal fold fibrosis is likely to yield improved therapeutic strategies to mitigate vocal fold scarring. Our data suggest that TGF-beta signaling may be both paracrine and autocrine in this vocal fold fibroblast cell line, and we therefore propose that TGF-beta may be a reasonable target for therapies to prevent and/or treat vocal fold fibrosis, given its putative role in both acute and chronic vocal fold injury, as well as its effects on vocal fold fibroblasts

Voice production involves precise, coordinated movements of the intrinsic and extrinsic laryngeal musculature. A component of normal voice production is the modification of pitch. The underlying neural networks associated with these complex processes remains poorly characterized. However, several investigators are currently utilizing neuroimaging techniques to more clearly delineate these networks associated with phonation. The current study sought to identify the central cortical mechanism(s) associated with pitch variation during voice production using event-related functional MRI (fMRI). A single-trial design was employed consisting of three voice production tasks (low, comfortable, and high pitch) to contrast brain activity during the generation of varying frequencies. For whole brain analysis, volumes of activation within regions activated during each task were measured. Bilateral activations were shown in the cerebellum, superior temporal gyrus, insula, precentral gyrus, postcentral gyrus, inferior parietal lobe, and post-cingulate gyrus. In the left hemisphere, activations in the medial and middle frontal gyri were also observed. Regions active during high pitch production when compared to comfortable pitch were evident in the bilateral cerebellum, left inferior frontal gyrus, left cingulate gyrus, and left posterior cingulate. During low pitch generation, activations were present in the inferior frontal gyrus, insula, putamen, and cingulate gyrus in the left hemisphere. The inferior frontal gyrus in the right hemisphere produced greater activity than the area of the left hemisphere during high and low pitch generation. These results suggest that a single-trial design is sensitive enough to begin to delineate a widespread network of activations in both hemispheres associated with vocal pitch variation

Despite the fact that vocal folds are subjected to extensive mechanical forces, the role of mechanical strain in vocal fold wound healing has been overlooked. Recent studies on other tissues have demonstrated that low physiological levels of mechanical forces are beneficial to injured tissues, reduce inflammation, and induce synthesis of matrix-associated proteins essential for enhanced wound healing. In this study, we speculated that mechanical strain of low magnitudes also attenuates the production of inflammatory mediators and alters the extracellular matrix synthesis to augment wound healing in cultured vocal fold fibroblasts. To test this hypothesis, fibroblasts from rabbit vocal folds were isolated and exposed to various magnitudes of cyclic tensile strain (CTS) in the presence or absence of interleukin-1beta (IL-1beta). Results suggest that IL-1beta activates proinflammatory gene transcription in vocal fold fibroblasts. Furthermore, CTS abrogates the IL-1beta-induced proinflammatory gene induction in a magnitude-dependent manner. In addition, CTS blocks IL-1beta-mediated inhibition of collagen type I synthesis, and thereby upregulates collagen synthesis in the presence of IL-1beta. These findings are the first to reveal the potential utility of low levels of mechanical signals in vocal fold wound healing, and support the emerging on vivo data suggesting beneficial effects of vocal exercise on acute phonotrauma

OBJECTIVES: We describe the clinical features of granuloma of the membranous vocal fold (as opposed to granuloma of the vocal process, or 'contact granuloma'), a poorly recognized sequela of microlaryngoscopic surgery. Membranous vocal fold granuloma may mimic the initial lesion in appearance, and thus be mistaken for recurrence. METHODS: We performed a retrospective review of cases from 2 institutions. RESULTS: Fifteen cases of membranous vocal fold granuloma from 2 institutions were identified. In all but 1 case, granuloma developed in the early postoperative period, within 8 weeks. Of the 15 cases, 10 followed laser resection of carcinoma. Five were noted following cold steel resection of benign lesions (2 papillomas, 2 cysts, 1 Reinke's edema). Technical aspects of these cases suggest that membranous vocal fold granulomas result from surgical violation of deep tissue planes and/or epithelial defects. All patients were treated with proton pump inhibitors. In 12 cases, the granulomas proved self-limited, resolving over weeks to months following surgery. Three patients underwent surgical removal of the lesion, which confirmed the diagnosis. One of these cases recurred and was treated nonsurgically. CONCLUSIONS: Granuloma should be suspected when a mass lesion appears at the surgical site early in the postoperative course. Surgical excision is generally not necessary and may provoke further growth of granulation tissue

OBJECTIVE: To identify, summarize, and evaluate patient-reported outcome questionnaires for use in head and neck cancer surgery with the view to making recommendations for future research. DATA SOURCES: A systematic review of the English-language literature, with the use of head-and-neck-surgery-specific keywords, was performed in the following databases: Medline, Embase, HAPI, CINAHL, Science/Social Sciences Citation Index, and PsycINFO from 1966 to March 2006. DATA EXTRACTION AND STUDY SELECTION: All English-language instruments identified as patient-reported outcome questionnaires that measure quality of life and/or satisfaction that had undergone development and validation in a head and neck cancer surgery population were included. DATA SYNTHESIS: Twelve patient-reported outcome questionnaires fulfilled our inclusion criteria. Of these, four were developed from expert opinion alone or did not have a published development process and seven questionnaires lacked formal item reduction. Only three questionnaires (EORTC Head and Neck Module, University of Michigan Head and Neck Quality-of-life Questionnaire, and Head and Neck Cancer Inventory) fulfilled guidelines for instrument development and evaluation as outlined by the Medical Outcomes Trust. CONCLUSIONS: Rigorous instrument development is important for creating valid, reliable, and responsive disease-specific questionnaires. As a direction for future instrument development, an increased focus on qualitative research to ensure patient input may help to better conceptualize and operationalize the variables most relevant to head and neck cancer surgery patients. In addition, the use of alternative methods of psychometric data analysis, such as Rasch, may improve the value of health measurement in clinical practice for individual patients

OBJECTIVE: To investigate hepatocyte growth factor (HGF) primed fibroblasts and decorin application on skin and vocal fold fibroblasts in vitro and in vivo in rabbit vocal fold scar model. STUDY DESIGN AND SETTING: Vocal fold and skin fibroblasts underwent five in vitro treatment conditions: control, epidermal growth factor, HGF, both decorin and HGF, and decorin alone. Hyaluronic acid and collagen enzyme-linked immunosorbent assays were performed. In vivo, 12 rabbits underwent unilateral vocal fold stripping. Injured vocal folds were then injected with skin fibroblasts, HGF, HGF-primed fibroblasts and decorin, or decorin. Outcomes included histologic and lamina propria height analyses. RESULTS: In vitro, HGF increased hyaluronic acid synthesis in vocal fold fibroblasts (P<0.001). HGF and decorin treatment diminished collagen secretion (P<0.01). In vivo, histologic findings indicated minimal difference in collagen amount between treatment groups. CONCLUSION: HGF and decorin together may decrease collagen production by skin and vocal fold fibroblasts. Fibroblast transplantation into scarred vocal folds has equivocal benefit

SUMMARY: The basic science of wound healing is largely omitted from the curriculum of many voice clinicians. This fact is relatively disheartening as most therapeutic manipulation in the realm of laryngology and voice disorders deals with injured tissue. Therefore, the selection of therapeutic tasks for persons with vocal injury should ideally be informed by basic science in wound healing. Recently, several investigators have initiated lines of research to determine the course of vocal fold wound healing and the potential role of therapeutic agents, including behavioral agents. The current review seeks to provide a foundation of basic wound healing science and present the most current data regarding the wound healing process in the vocal folds

The application of topical anesthesia to the oropharynx is a common clinical practice during oral and nasal laryngoscopy. Clinically, questions have been raised about whether topical anesthesia alters laryngeal secretions, which distorts clinical impressions. A double-blind, placebo controlled design was employed to address this issue. Ten premenopausal women with healthy vocal folds and 10 premenopausal women with phonotraumatic lesions underwent oral videolaryngoscopic examinations on subsequent days under both anesthesia and placebo conditions, in counterbalanced order. Video segments were rated by three judges. Dependent variables were balling and pooling of secretions, as previously described in the literature. Statistical analyses failed to reveal any clear effect of topical anesthesia on either secretion balling or pooling for the collapsed data set, but one cannot exclude changes in individual cases. Moreover, there was no evidence that secretions were differentially affected by anesthesia across subject groups. Null results in this data set replicate and extend previously reported findings by other authors. An incidental but potentially interesting finding was that the order of treatment condition (anesthesia versus placebo first) seemed relevant for secretions: Subjects who received the anesthesia condition first tended to show more secretion balling in general, as compared with subjects who received the placebo condition first. Speculation is entertained regarding possible physiological pathways for these incidental findings, which could be relevant for some clinical practice

The current study retrospectively reviewed the cases of 68 patients who had undergone total laryngectomy and tracheoesophageal puncture (TEP) over a 16-year period. Fifty-one patients underwent primary TEP and 17 underwent secondary TEP. Nearly 80% of patients who received TEP at the time of laryngectomy achieved excellent voice quality perceptually. In contrast, only 50% of secondary TEP patients achieved excellent voice ratings. This difference was statistically robust (p = 0.03). Although both surgical and prosthesis-related complications occurred more frequently following primary TEP, statistically significant differences were not achieved. Neither pre- nor postoperative radiotherapy had any effect on voice restoration or complication rates. Based on these data, primary TEP may be preferable for several reasons, including a greater likelihood of successful voice restoration, a shorter duration of postoperative aphonia, and the elimination of the need for a second operation and interim tube feedings

This study seeks to determine the ability of enzyme-linked immunosorbent assays (ELISAs) of vocal fold secretions to detect and describe the acute tissue response to injury in a rabbit vocal fold model. Vocal fold secretions were collected before the induction of a unilateral surgical injury to the vocal fold and at 6 timepoints after injury (1, 5, 7, 10, 14, and 21 days). Secretions were then subjected to ELISAs to assess concentrations of interleukin-1 beta (IL-1beta) and prostaglandin-E2 (PGE-2). The results indicate that ELISAs may be useful in documenting fluctuations in these markers associated with the wound healing process in the rabbit model. The temporal expression of both IL-1beta and PGE-2 was consistent with their proposed roles in the wound healing cascade in other systems, pointing to the potential that surface secretions may be at least partial indicators of wound healing events within the tissue