Charles N. Ford

Cidofovir efficacy in recurrent respiratory papillomatosis: a randomized, double-blind, placebo-controlled study.

Objectives: We performed a prospective, double-blind, placebo-controlled, longitudinal adjuvant therapy trial to determine the efficacy of cidofovir in the treatment of severe recurrent respiratory papillomatosis (RRP). Although results of case series suggest that cidofovir may decrease the frequency and rapidity of papilloma regrowth, no blinded placebo-controlled studies have demonstrated efficacy. Methods: Adults and children (n = 19) with aggressive RRP received either active drug (cidofovir) or placebo. When surgical intervention was needed, drug or placebo was injected into affected areas after surgical removal of disease. The following measures were made at baseline and at 2-month intervals for the course of 12 months: Derkay papilloma severity grading scale, Voice Handicap Index, Health-Related Quality of Life, and total number of procedures performed over 12 months. Results: At 2- and 12-month follow-ups, there was a significant (p < .05) improvement in the Derkay Severity Score within the cidofovir and placebo groups, but no difference between groups, and no difference between groups in the number of procedures performed. Significant improvement was found in Voice Handicap Index scores in the cidofovir group at the 12-month follow-up. No differences were seen in Health-Related Quality of Life. Conclusions: A randomized, blinded, placebo-controlled trial is necessary in the study of RRP, because the natural history of the disease can include remissions and reactivations. We found a significant improvement in the Derkay Severity Score 12 months after the baseline assessment in patients treated with cidofovir. This effect, however, was also seen in the placebo group. Accordingly, we were unable to provide proof of efficacy of cidofovir in the treatment of RRP.

Effect of growth factors on hyaluronan production by canine vocal fold fibroblasts

Hyaluronan (HYA) is considered to be a crucial factor in scarless wound healing and in maintaining tissue viscosity of the vocal fold lamina propria. In this study focusing on the effects of growth factors, we examined how HYA is produced and controlled in canine cultured vocal fold fibroblasts. Fibroblasts were taken from the lamina propria of the vocal folds of 8 dogs and cultured with and without growth factors. The production of HYA in the supernatant culture was quantitatively examined by enzyme-linked immunosorbent assay. Hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, and transforming growth factor β1 all stimulated HYA synthesis from vocal fold fibroblasts. These effects differed with the concentration of growth factors and the incubation period. We also examined how frequently the growth factors had to be administered in order to maintain appropriate levels of HYA. A single administration was sufficient to maintain appropriate HYA levels for at least 7 days. The present studies have demonstrated positive effects of growth factors in stimulating HYA production. Further in vivo study is needed to clarify the usefulness of these growth factors in the management of vocal fold scarring.

AN ANATOMIC STUDY OF THE RAT LARYNX : ESTABLISHING THE RAT MODEL FOR NEUROMUSCULAR FUNCTION

The gross and microscopic anatomy of the rat larynx was studied with particular attention to myology and neuromuscular structures to further validate it as a model to evaluate morphologic and functional changes induced by botulinum injection. A laryngeal alar cartilage (LAlC), alar cricoarytenoid (ACA) muscle, and a superior cricoarytenoid muscle (SCA) were identified as anatomic structures not previously described. Two portions (medial and lateral) of the thyroarytenoid muscle (TA) were distinguished. The function of the ACA was suggested to be similar to the aryepiglottis muscle in humans and the function of the SCA was suggested to be similar to the human interarytenoid muscle. The predominant pattern of motor endplate (MEP) distribution in rat laryngeal muscles (posterior cricoarytenoid, lateral cricoarytenoid, cricothyroid, and SCA) was to have MEPs concentrated mostly at the midbelly of muscle where they were distributed throughout the cross-sectional area of the midbelly. The TA and ACA differed from this pattern. The lateral TA had MEPs concentrated at the anterior third of its belly and those of the medial TA were located at the midbelly. Motor endplates in the ACA were located mostly at the posterior portion of muscle. Muscle fiber-typing showed subtle differences between the intrinsic laryngeal muscles. Fast fibers were predominant in the rat laryngeal muscles. This study supports the expanded use of rats in studies of laryngeal neuromuscular function and disease in humans.

Regeneration of Aged Vocal Folds with Basic Fibroblast Growth Factor in a Rat Model: A Preliminary Report

Aged vocal folds have been reported to have dense collagen deposition and decreased hyaluronic acid (HA) in the lamina propria. These characteristics are thought to contribute to vocal problems that occur with age (presbyphonia). To restore better viscoelasticity to aged vocal folds, an intervention that might increase HA and decrease collagen production from aged vocal fold fibroblasts would appear to be a potentially useful approach. Our previous in vitro study has revealed that basic fibroblast growth factor (bFGF) consistently stimulates HA production and decreases collagen production from aged rat vocal fold fibroblasts. The present in vivo study examined the effects of intracordal injection of bFGF into aged rats vocal folds in terms of restoration of HA and collagen distribution in the lamina propria. We injected bFGF transorally into the lamina propria of (unilateral) vocal folds. The injection was repeated 4 times weekly, and rats were painlessly sacrificed 1 week, 1 month, and 2 months after the final injection. Histologic examination revealed that bFGF significantly increased the HA content of the lamina propria up to 2 months, but showed no effect on collagen, even after 2 months. Because it might take longer for excessive collagen to be degraded, further studies are necessary to clarify the long-term effect on collagen. A drug delivery system for bFGF also needs to be developed to maximize its effect in the future. The present study suggested at least a positive effect of bFGF in restoring the HA content in the aged vocal fold lamina propria.

Age-related alterations in myosin heavy chain isoforms in rat intrinsic laryngeal muscles.

Deficits in voice and swallowing are found in the elderly, but the underlying neuromuscular mechanisms are unclear. A potential mechanism may be denervation-induced muscle fiber transformation to a slower-contracting type of muscle fiber. This study examined young, old, and denervated rat laryngeal muscles (lateral thyroarytenoid, lateral cricoarytenoid, and posterior cricoarytenoid) to examine differences in myosin heavy chain (MHC) composition. Results of sodium dodecyl sulfate–polyacrylamide gel electrophoresis analyses indicated that all muscles were composed predominately of type IIB MHC. With aging and denervation, type IIB was reduced and type IIX, a slower-contracting isoform, was increased in the lateral thyroarytenoid and lateral cricoarytenoid muscles. In the posterior cricoarytenoid muscle, the MHC composition was relatively unchanged. These findings suggest that aging may affect laryngeal adductory function by altering muscle fiber type composition to a slower-contracting isoform, in a manner similar to that observed with denervation.

Morphological and Functional Changes of Human Vocal Fold Fibroblasts with Hepatocyte Growth Factor

Fibroblasts produce extracellular matrix and play an important role in wound healing and scarring. Hepatocyte growth factor (HGF) has strong antifibrotic activity, and has been suggested to have therapeutic potential for treatment of fibrotic diseases. In the present in vitro study, morphological and functional changes of human vocal fold fibroblasts with HGF were examined by transmission electron microscopy and enzyme-linked immunosorbent assay to help clarify the potential use of HGF in the prevention or treatment of vocal fold scarring. The HGF stimulated the production of hyaluronic acid (HA) and decreased the production of collagen type I from the fibroblasts in Reinkes space (FbRS), whereas fibronectin production was not affected. The HGF also changed the shape of the FbRS from an oval shape toward a spindle and stellate shape, and developed Golgi apparatus (GA) and rough endoplasmic reticulum (rER) in the FbRS. The fibroblasts in the macula flava (FbMF) presented with much more production of HA and collagen type I than did FbRS, and were more frequently formed in a stellate shape with well-developed GA and rER. The HGF decreased the production of collagen type I from the FbMF, but barely affected the FbMF in terms of the shape of the cells, the development of GA and rER, or the production of HA. These results were interpreted to suggest that the FbMF are not as susceptible to HGF as are FbRS. On the contrary, HGF appeared to activate the FbRS and modify the function. The increased HA and decreased collagen type I production from the FbRS suggest that HGF may be useful in the prevention or treatment of fibrotic vocal fold scarring.

Laryngeal-Respiratory Kinematics are Impaired in Aged Rats

Fatigue and weakness in the elderly are the functional consequences of underlying neuromuscular decline. However, little is known about the manifestations of aging in the larynx. This study evaluated the manner in which laryngeal senescence affects laryngeal-respiratory kinematics by videorecording laryngeal motion in both young and old rats. Recorded images were digitized, and glottal displacement and movement rate were measured. The results indicated that the amplitude of change in glottal angle was significantly diminished, and laryngeal movement durations were prolonged in the old animals. These findings may be due to functional constraints on the respiratory system, impaired laryngeal-respiratory interactions, or decrements in vocal fold tension with age. Because of the serious and pervasive nature of dysphagia and communicative impairments in the elderly, research that specifically examines the manifestations and causes of these impairments is of great importance.

Dose intensification in curative head and neck cancer radiotherapy—Linear quadratic analysis and preliminary assessment of clinical results

PURPOSEnThe feasibility of reducing overall treatment time by 2 weeks in the curative radiotherapeutic management of head and neck cancer patients is reported in a pilot trial of Hyperfractionated, Accelerated Radiotherapy with Dose Escalation (HARDE). This regimen prescribes 76 Gy in 5 weeks to definitive head and neck cancer patients, and 65 Gy in 5 weeks to high-risk postoperative patients. The linear quadratic model is used to compare predicted tumor cell kill with HARDE versus that expected with conventional fractionation (CF).nnnMATERIALS AND METHODSnBetween January 1991 and March 1992, 40 head and neck cancer patients were treated with HARDE at the University of Wisconsin Comprehensive Cancer Center. Case-matched controls treated with CF were identified from patients treated at the same institution between 1980-1990, based on tumor site, stage, and extent of prior surgery. Individual patient treatment data (total dose, fraction size, overall time) rather than idealized schedule data from each group were analyzed using the linear quadratic model.nnnRESULTSnSeventy-nine case-matched controls were identified for comparison with HARDE patients. The predicted increase in log cell kill for HARDE patients over case-matched controls was 1.5 and 1.3 logs, respectively, in the definitive and postoperative settings. This difference in log cell kill projects an improvement in locoregional tumor control for HARDE patients of between 10-25%. HARDE patients experience very brisk acute mucosal reactions and moderately prolonged mucosal healing, however, 91% have completed therapy without a treatment break.nnnCONCLUSIONnA 2-week reduction in overall treatment time for curative head and neck cancer patients is feasible while maintaining doses > 70 Gy. Based on radiobiologic predictions, such treatment intensification may significantly improve rates of locoregional tumor control. However, intensified acute mucosal reactions accompany such accelerated therapy.

Influence of Computed Tomography on Pretherapeutic Tumor Staging in Head and Neck Cancer Patients

Refinements in radiographic techniques have resulted in increased use of radiographic studies in the evaluation of patients with head and neck cancer over the past 20 years. To assess the impact of such studies, we compared tumor clinical stages based solely on physical-examination findings with those obtained with the addition of CT findings. This study was accomplished through case review of 81 head and neck cancer patients who underwent CT after preliminary TNM-stage assignment as determined on the basis of physical examination alone. In this cohort, 44 patients (54%) had a change in assigned clinical stage. We reviewed individual anatomic sites to determine where CT was found to be most useful in modifying tumor stage. Changes in tumor and nodal stage were found across all major sites of the head and neck. Tumors of the hypopharynx were the most likely to change stage (90%) on the basis of CT findings, whereas tumors of the glottic larynx were least likely to undergo a change in stage (16%). The therapeutic implications of these findings are discussed in the context of the published literature.

Comparative study of vocal outcomes with silicone versus Gore-Tex thyroplasty.

Objectives We examined vocal outcomes of patients who underwent type I thyroplasty for unilateral vocal fold paralysis. Specifically, the vocal outcomes were compared between 15 patients whose thyroplasties were performed with silicone and 15 patients whose thyroplasties were performed with Gore-Tex. Methods The examined clinical characteristics did not differ significantly between the groups. The vocal outcomes were evaluated by aerodynamic and acoustic measurements. Results Aerodynamic examination indicated significant postoperative improvements in the maximum phonation time and mean flow rate in both groups. Shimmer was significantly improved only in the Gore-Tex group. A direct comparison between groups showed no significant difference in the degree of improvement of the vocal parameters, except for a significant improvement in the noise-to-harmonics ratio in the Gore-Tex group. The duration of surgery was significantly less in the Gore-Tex group than in the silicone group. Conclusions Gore-Tex thyroplasty is considered to be comparable to silicone thyroplasty in terms of postoperative vocal outcomes. Gore-Tex thyroplasty enables a less invasive procedure with a shorter surgical duration and easier adjustment of medialization due to its flexibility.