Faculty Bibliography

OBJECTIVES/HYPOTHESIS: The potassium titanyl phosphate (KTP) laser is emerging as a potentially effective treatment for various vocal fold pathologies. To date, the precise mechanism(s) of action of this wavelength on the layered microarchitecture of the vocal fold remains unknown. The purpose of this study is to develop an in vivo model for the use of the KTP laser in the rat vocal fold and to characterize the potential of this model for future studies. STUDY DESIGN: In vivo survival surgery. METHODS: A model for videoendoscopic visualization and injury to the rat vocal fold was established using a microlaryngoscope and rigid telescope. Unilateral vocal fold injury was induced with the KTP laser at 10 Watts (W) 20 milliseconds (ms) pulse width. Animals were euthanized at 1 day post-treatment. Larynges were subjected to gross visual analysis and histological analyses via hematoxylin and eosin and trichrome staining. RESULTS: Consistent endoscopic visualization and injury was obtained without significant operative morbidity or mortality. The KTP laser caused superficial blanching and minor edema in the vocal fold, which resolved grossly by 24 hours postinjury. A modest inflammatory cell infiltrate was observed 1 day following injury. However, no remarkable alterations to the vocal fold microarchitecture were observed in the acute period. CONCLUSIONS: We propose that this novel model simulates the clinical scenario of laser use for the vocal folds. Use of this model will allow us to further characterize effects, mechanisms, and therapeutic efficacy of this wavelength

OBJECTIVE/HYPOTHESIS: Oxidative damage mediates the lower airway response to cigarette smoke (CS). In the vocal folds, the tissue phenotype is both distinct and largely uncharacterized. We sought to investigate the effects of CS on the oxidative status and fibroblast phenotype in the vocal folds. Specifically, we hypothesized that CS would induce a hypermetabolic fibroblast phenotype and altered oxidative metabolism potentially providing insight into the relationship among CS, Reinke's edema (RE), and malignancy. STUDY DESIGN: In vivo/in vitro. METHODS: Heme oxygenase (HO)-1 gene expression was examined in human tissue. In vitro, the effects of cigarette smoke condensate (CSC) on HO-1 gene expression and secretion was assayed. In addition, CS-mediated intracellular reactive oxygen species synthesis was quantified, and compared to the response in pulmonary fibroblasts (HFL). We then examined the effects of CSC on migration and proliferation in human vocal fold fibroblasts (HVOX). RESULTS:: HO-1 expression was approximately 4-fold higher in RE samples versus vocal fold polyps. CSC induced HO-1 gene expression and secretion in a time- and dose-dependent fashion in vitro. CSC also increased intracellular ROS in both HVOX and HFL. CSC decreased HVOX proliferation and migration in a dose-dependent manner. CONCLUSIONS: These data suggest that the fibroblast phenotype is influenced by smoke. Our data suggest that the antioxidant response in the vocal fold tissue may be one mechanism of chemoprotection, a putative explanation for the observation that RE rarely transforms to malignancy. In addition, CSC does not appear to induce a hypermetabolic fibroblast phenotype as expected

The objectives of this study are to describe central nervous system modulation associated with voice improvement following Type I thyroplasty in a patient with glottic insufficiency secondary to unilateral vocal fold paralysis. Serial functional magnetic resonance imaging scans were performed before as well as one and six months after thyroplasty. Paradigms consisting of four voice production tasks and a motor control task were completed. Volumes of activation within regions activated during each task were measured. Acoustic and aerodynamic measures were also obtained. A widespread network of neural activations was shown for all tasks. Differences in volumes of activation 1-month postsurgery positively correlated with acoustic and aerodynamic improvements. Sixth months following medialization, lesser volumes of activation were observed in all regions. Prior to this session, however, the patient's mediastinal disease progressed, leading to a significant deterioration in voice. Functional differences between patient brain maps yield new information about the central nervous system's ability to reorganize sensorimotor representations associated with voice improvement following Type I thyroplasty in a patient with glottic insufficiency secondary to unilateral vocal fold paralysis (UVFP)

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