Faculty Bibliography

OBJECTIVE: To investigate the hypothesis that prophylactic triamcinolone modulates acute vocal fold inflammatory and profibrotic signaling during acute phonotrauma. STUDY DESIGN: In vivo rabbit phonation model. SETTING: Academic medical center. SUBJECTS AND METHODS: Forty New Zealand white breeder rabbits were randomly assigned to 1 of 4 groups: control (no intervention), no treatment (30 minutes of raised intensity phonation), sham treatment (bilateral intralaryngeal triamcinolone acetonide injection at 0 microg/25 microL followed by 30 minutes of raised intensity phonation), or steroid treatment (bilateral intralaryngeal triamcinolone acetonide injection at 400 microg/25 microL followed by 30 minutes of raised intensity phonation). Quantitative polymerase chain reaction (qPCR) was used to investigate gene expression levels of cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, and transforming growth factor (TGF)-beta1. RESULTS: Results revealed a significant main effect for COX-2 (P = .002). Post hoc testing revealed that rabbits receiving no treatment (15.10) had higher COX-2 gene expression than control (5.90; P < .001). There were no significant differences in COX-2 expression between treatment groups. Results revealed a significant main effect for IL-1beta (P < .001). Post hoc testing revealed that rabbits receiving no treatment (14.70) had higher IL-1beta gene expression than control (6.30) (P = .001). There were no significant differences in IL-1beta gene expression between treatment groups. There were no significant differences in TGF-beta1 gene expression (P = .525) between treatment and control groups. CONCLUSION: Given conflicting evidence, further studies are necessary to investigate vocal fold steroid injections prior to and following the induction of phonotrauma. Prophylactic administration of triamcinolone immediately prior to acute phonotrauma resulted in no significant changes in COX-2, IL-1beta, and TGF-beta1 gene transcript levels.

OBJECTIVE: To report the pretreatment and posttreatment population characteristics and the overall stability of the audiologic outcomes found during the Sudden Hearing Loss Clinical Trial (ClinicalTrials.gov: Identifier NCT00097448). STUDY DESIGN: Multicenter, prospective randomized noninferiority trial of oral versus intratympanic (IT) steroid treatment of sudden sensorineural hearing loss (SSNHL). SETTING: Fifteen academically based otology practices. PATIENTS: Two hundred fifty patients with unilateral SSNHL presenting within 14 days of onset with 50 dBHL or greater pure tone average hearing threshold in the affected ear. INTERVENTION: Either 60 mg/d oral prednisone for 14 days with a 5-day taper (121 patients) or 4 IT doses for 14 days of 40 mg/ml methylprednisolone (129 patients). MAIN OUTCOME MEASURE: Primary end point was change in hearing [dB PTA] at 2 months after treatment. Noninferiority was defined as less than 10 dB difference in hearing outcome between treatments. In this article, pretreatment and posttreatment hearing findings will be reported in detail. RESULTS: A general (and stable) effect of treatment and a specific effect of greater improvement at low frequencies were found in both treatment groups. CONCLUSION: Hearing improvements are stable, and a significantly greater improvement occurs with lower frequency after either oral or IT steroid treatment of SSNHL.

OBJECTIVE: Nodal metastasis from oral tongue squamous cell carcinoma follows a predictable pattern. Isolated level IV involvement, termed skip metastases, is described. This study attempts to identify the incidence of skip metastasis. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic hospital. SUBJECTS: Fifty-two consecutive patients with T1 to T4 N0 stage who underwent excision of the primary tumor with neck dissection (levels I-IV). METHODS: Retrospective study. The incidence of isolated level III or IV involvement pathologically and isolated nodal recurrence in levels III and IV was analyzed. RESULTS: Pathologically, isolated level III involvement occurred in 2 (3.8%) patients. Isolated level IV occurred in 1 (1.9%) patient. Mean follow-up was 24 months. Two patients had recurrence in the primary site; 1 had recurrence in neck level II. None had recurrence in level III or IV. CONCLUSION: Skip metastasis is rare in T1 and T2 oral tongue squamous cell carcinoma. Inclusion of level IV is not mandatory in selective neck dissection for clinically and radiologically negative neck disease in early tumors (T1 and T2).

OBJECTIVES To assess the cross-sectional area and angle of the internal nasal valve more accurately by reformatting computed tomography (CT) scans of the nasal airway according to a more appropriate orientation than scans traditionally sectioned in the coronal plane and then to compare the results with clinical data on the nasal valve obtained from physical examination. METHODS We performed a retrospective review of the medical records of 24 rhinoplasty patients treated at a private practice facial plastic surgery office affiliated with a tertiary care university hospital. The patients had fine-cut (0.75-mm section) CT scans ordered for nasal airway obstruction or nasal valve compromise at the same institution. These patients were evaluated from January 1, 2000, through December 31, 2010. The previously acquired CT scans were reformatted to obtain sections through the internal nasal valve at a more appropriate orientation. The internal nasal valve cross-sectional area and valve angle were measured through a standardized section (1 cut immediately anterior to the head of the inferior turbinate) from the reformatted scans. The cross-sectional area was also measured through the same point on the traditionally oriented CT scan, and the values were compared. The results from each patient's scan were compared with data from the patient's medical record and analyzed against the patient's preoperative modified Cottle examination findings. RESULTS The CT scans oriented in the reformatted plane through the internal nasal valve provided a narrower valve angle than the traditionally oriented CT scans and more closely approximated the hypothesized true value of the internal nasal valve of 10 degrees to 15 degrees (P < .001). In a comparison of the same-side internal nasal valve angle and cross-sectional nasal valve area between the 2 different CT scan orientations, a statistically significant difference in the internal nasal valve angles between the 2 scan orientations was discovered, but this finding did not reach significance when distinguishing the nasal valve cross-sectional area. Finally, no correlation was found with regard to the preoperative modified Cottle maneuver scores for the internal nasal valve angle and cross-sectional valve area values in either scan orientation. CONCLUSIONS Precise preoperative evaluation of the internal nasal valve is critical to the workup for reconstruction or repair of problems that involve this area. Although tools such as acoustic rhinometry exist to evaluate the cross-sectional area of the nasal valve, many rhinoplasty surgeons do not have access to this expensive equipment. A CT scan with reformatting in the proper plane of the internal nasal valve can provide the surgeon with improved anatomical information to assess that region. With this in mind, however, the surgeon should always perform a thorough preoperative physical examination and treat the patient and his or her symptoms, not the imaging studies, when considering a candidate for a surgical intervention.

UNLABELLED:Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE/CONCLUSIONS:This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.

BACKGROUND: Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. RESULTS: Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex. CONCLUSIONS: We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.

PURPOSE: The negative attitudes of patients with cancer regarding clinical trials are an important contributor to low participation rates. This study evaluated whether a brief psychoeducational intervention was effective in improving patients' attitudes as well as their knowledge, self-efficacy for decision making, receptivity to receiving more information, and general willingness to participate in clinical trials. PATIENTS AND METHODS: A total of 472 adults with cancer who had not been asked previously to participate in a clinical trial were randomly assigned to receive printed educational information about clinical trials or a psychoeducational intervention that provided similar information and also addressed misperceptions and concerns about clinical trials. The primary (attitudes) and secondary outcomes (knowledge, self-efficacy, receptivity, and willingness) were assessed via patient self-report before random assignment and 7 to 28 days later. RESULTS: Patients who received the psychoeducational intervention showed more positive attitudes toward clinical trials (P = .016) and greater willingness to participate (P = .011) at follow-up than patients who received printed educational information. Evidence of an indirect effect of intervention assignment on willingness to participate (estimated at 0.168; 95% CI, 0.088 to 0.248) suggested that the benefits of psychoeducation on willingness to participate were explained by the positive impact of psychoeducation on attitudes toward clinical trials. CONCLUSION: A brief psychoeducational intervention can improve the attitudes of patients with cancer toward clinical trials and thereby increase their willingness to participate in clinical trials. Findings support conducting additional research to evaluate effects of this intervention on quality of decision making and rates of participation among patients asked to enroll onto therapeutic clinical trials.

Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN.

Anoctamin-1 (ANO1) (DOG1, TMEM16a) is a calcium-activated chloride channel initially described in gastrointestinal stromal tumors, but now known to be expressed in a variety of normal and tumor tissues including salivary tissue in murine models. We herein perform a comprehensive survey of DOG1 expression in 156 cases containing non-neoplastic human salivary tissues and tumors. ANO1 mRNA levels were significantly higher (8-fold increase, P<0.0001) in normal parotid tissue (n=6) as compared with squamous mucosa (n=15). By immunohistochemistry, DOG1 showed a diffuse moderate (2+) apical membranous staining pattern in normal serous acini, 1+ apical membranous pattern in mucous acini, and variable 1-2+ apical staining of distal intercalated ducts. Myoepithelial cells, striated and excretory ducts were invariably negative. All acinic cell carcinomas (n=28) were DOG1 positive demonstrating a complex mixture of intense (3+) apical membranous, cytoplasmic and complete membranous staining. Most ductal tumor types were negative or only showed a subset of positive cases. Within the biphasic tumor category, adenoid cystic carcinomas (18/24 cases) and epithelial-myoepithelial carcinomas (8/15 cases) were frequently positive, often showing a distinctive combined apical ductal and membranous/cytoplasmic myoepithelial staining profile. Thus, DOG1 staining is a marker of salivary acinar and to a lesser extent intercalated duct differentiation. Strong staining can be used to support the diagnosis of acinic cell carcinoma. DOG1 may also be a marker of a 'transformed' myoepithelial phenotype in a subset of biphasic salivary gland malignancies.