Faculty Bibliography

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination.

Parathyroid carcinoma is a rare endocrine malignancy. The reported incidence is from 0.5 to 5% of primary hyperparathyroidism cases in various series. The cause is unknown, but clinical correlations with different genetic syndromes exist. Mutations in the HPRT2 gene seem to play a significant role in the pathogenesis of this disease. Men and women are equally affected, usually in the fourth or fifth decade of life. Most patients will present with signs and symptoms of hypercalcaemia. Cases of non-functioning carcinoma are exceedingly rare. Surgical resection is the most effective method of treatment and palliation. A significant proportion of patients will experience recurrence, and will need further surgical and, eventually, medical management of hypercalcaemia. The disease is progressive but slow growing. Most patients will require multiple operations to resect recurrent disease. The main cause of morbidity and mortality is the sequela of uncontrolled chronic hypercalcaemia rather than tumour burden. The current paper will review the epidemiology, pathogenesis, clinical presentation and diagnostic work-up of this disease. Surgical management in different scenarios is reviewed in detail, followed by other types of treatment and management of incurable disease.

OBJECTIVE: Endoscopic balloon dilation is increasingly popular as primary therapy for infants with subglottic stenosis. We aim to determine the maximum balloon diameter and pressure where no fracture of the cricoid would occur, minimum balloon size and pressures where a gross fracture of the cricoid occurs, and location of these fractures. We tested these objectives by performing balloon dilation in laryngotracheal complexes of eight euthanized adult male New Zealand white rabbits, with airway characteristics similar to a 3- to 9-month-old infant. METHODS: Subglottic airway diameter of each specimen was determined using endotracheal tubes (Cotton-Myer grading system). Preexistent subglottic disease was excluded by rigid endoscopy. Serial dilation with balloon catheters was performed, employing incremental balloon sizes and pressures, to determine balloon size and pressure, which resulted in a cricoid fracture. Locations of gross fractures were validated by two independent observers. RESULTS: Airway diameter of all specimens was 5.4 mm (size 4.0 endotracheal tube). Four of the seven cricoid cartilages exhibited gross fractures. Dilation with balloon diameters less than 6.0 mm failed to induce a fracture despite maximal inflation to 16.0 atmospheres. The minimum balloon size required to create a fracture was 7.0 mm, at a pressure of 6.0 atmospheres. All fractures occurred at the anterior lamina of cricoid ring. CONCLUSIONS: No fractures occurred when balloon dilation was performed with a balloon 0.6 mm or smaller than the measured subglottic diameter. Fractures of the cricoid occurred when balloon dilation was performed with a balloon 1.6 mm or larger than the subglottic diameter.

The source of ultrasonic vocalizations (USVs) produced by rats is thought to be within the larynx. The purpose of this investigation was to determine if the rat larynx is capable of producing ultrasounds with the full range of frequencies reported in vivo. Acoustic output of excised rat larynges with and without vocal fold constriction was measured. At biologically-reasonable airflow rates and pressures, only larynges with a constriction produced the full range of ultrasounds reported in vivo, providing support for the hypothesis that a constriction within the larynx is likely the source of rat USVs.

OBJECTIVES/HYPOTHESIS: Selective reinnervation for bilateral vocal fold paralysis has been successful in animal models and shows promise in humans, but detailed, surgically relevant measurements for performing this in the human larynx are not readily available. STUDY DESIGN: Anatomical study describing the anatomy and gender differences of the recurrent laryngeal nerve, with specific attention to the distance between the posterior cricoarytenoid (PCA) branch and the interarytenoid (IA) branch. METHODS: Dissection of 20 human cadaveric larynges. RESULTS: The mean distance between PCA and IA branches on the left side in male specimens was 4.9 +/- 2.7 mm; on the right side 5.4 +/- 2.5 mm. The mean distance between PCA and IA branches on the left side in female specimens was 4.9 +/- 2.0 mm; on the right side 5.5 +/- 2.6 mm. A thyroid cartilage notch was required to be able to achieve sufficient access for neurorrhaphy in 57.1% of male specimens on either side and in 69.2% of female specimens on either side. The mean size of the thyroid cartilage notch required in male specimens was 39.55 +/- 19.67 mm(2), and in female specimens 47.61 +/- 12.98 mm(2). CONCLUSIONS: This study provides new insight into laryngeal anatomy and further data for developing a reliable surgical approach.

CONCLUSION: Replacement of vestibular hair cells induced by atoh1 driven by the tissue-specific GFAP promoter was significantly more efficient than use of the cBA or hCMV promoter. OBJECTIVE: To test whether expression level, persistence, or selectivity from adenovirus vectors delivered in the inner ear can be altered by changing the adenovector backbone or by using different cellular and viral promoters. MATERIALS AND METHODS: Adenovector and promoter modifications were tested for differences in transgene expression in adult macular organs. The effect of using an E1/E3 deleted vector was compared to E1/E3/E4 deleted vectors. The effect of using viral and cellular promoters to modify transgene expression was tested in explanted adult mouse macular organs. Based on these results three different promoters were tested for efficacy of atonal gene. RESULTS: Use of adenovectors containing human CMV, the hybrid cBA and ubiquitin promoters driving transgene expression resulted in different types of transgene expression. While several viral and cellular promoters provided broad cell type expression, expression driven by the GFAP promoter was limited to vestibular supporting cells, demonstrating the specificity of this promoter.

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Gait dysfunction and falling are major sources of disability for patients with advanced Parkinson's disease (PD). It is presently thought that the fundamental defect is an inability to generate normal stride length. Our data suggest, however, that the basic problem in PD gait is an impaired ability to match step frequency to walking velocity. In this study, foot movements of PD and normal subjects were monitored with an OPTOTRAK motion-detection system while they walked on a treadmill at different velocities. PD subjects were also paced with auditory stimuli at different frequencies. PD gait was characterized by step frequencies that were faster and stride lengths that were shorter than those of normal controls. At low walking velocities, PD stepping had a reduced or absent terminal toe lift, which truncated swing phases, producing shortened steps. Auditory pacing was not able to normalize step frequency at these lower velocities. Peak forward toe velocities increased with walking velocity and PD subjects could initiate appropriate foot dynamics during initial phases of the swing. They could not control the foot appropriately in terminal phases, however. Increased treadmill velocity, which matched the natural PD step frequency, generated a second toe lift, normalizing step size. Levodopa increased the bandwidth of step frequencies, but was not as effective as increases in walking velocity in normalizing gait. We postulate that the inability to control step frequency and adjust swing phase dynamics to slower walking velocities are major causes for the gait impairment in PD.