Faculty Bibliography
Searched for:
Department/Unit:Otolaryngology
Total Results:
7801
First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy
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.
PMID: 22719020
ISSN: 2159-8290
CID: 5481072
Robot-assisted oropharyngeal reconstruction with free tissue transfer
The surgical robot has been demonstrated to have useful applications in urologic, gynecologic, cardiac, general, and endocrine surgery. The development of robotic surgery has enhanced the precision and control of the surgeon in minimally invasive surgical situations specific to these specialties and, more recently, has been applied to the treatment of oropharyngeal tumors in the form of transoral robotic surgery (TORS). The elimination of the need for lip- and mandible-splitting approaches has allowed a reassessment of surgical options for the treatment of tumors that have until recently been primarily addressed nonoperatively with chemoradiation. The TORS approach has created the need to adapt current reconstructive options to robotic technology to manage the resultant tissue defects and to assess and compare the effectiveness of these procedures. This report details our early experience with the use of robot-assisted free tissue transfer for management of soft tissue defects of the oropharynx.
PMID: 22638875
ISSN: 1098-8947
CID: 5481062
TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression
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.
PMCID:3694774
PMID: 22564524
ISSN: 1538-7445
CID: 5481052
DOG1: a novel marker of salivary acinar and intercalated duct differentiation
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.
PMID: 22460810
ISSN: 1530-0285
CID: 5481042
A transoral highly flexible robot: Novel technology and application
OBJECTIVES/HYPOTHESIS/OBJECTIVE:Organ preservation surgery is a major focus in head and neck oncology. Current approaches are aimed toward improving quality of life and decreasing treatment-related morbidity. Transoral robotic surgery was developed to overcome the limitations of traditional surgical approaches. The most widely used robotic system is the da Vinci Surgical System. Although the da Vinci offers clear surgical advantages over traditional approaches, its rigid operative arms prevent complex maneuverability in three-dimensional space. The ideal surgical robot would configure to the anatomy of the patient and maneuver in narrow spaces. We present the first cadaveric trials of the use of a highly flexible robot able to traverse the nonlinear upper aerodigestive tract and gain physical and visual access to important anatomical landmarks without laryngeal suspension. STUDY DESIGN/METHODS:Feasibility. METHODS:Using human cadavers, we investigated the feasibility of visualizing the endolarynx transorally with a highly flexible robot without performing suspension of the larynx. Two fresh and four preserved human specimens were used. RESULTS:Unhampered visualization of the endolarynx was achieved in all specimens without performing laryngeal suspension. Standard mouth retractors facilitated the delivery of the robot into the endolarynx. CONCLUSIONS:The flexible robot technology mitigates laryngeal suspension and the limitations of current robotic surgery with rigid line-of-sight-directed instruments. Having demonstrated the feasibility of physical and visual access to the endolarynx, future work will study the feasibility of using the highly flexible robot in transoral robotic procedures with flexible instrumentation placed in the robot's available working ports.
PMID: 22447466
ISSN: 1531-4995
CID: 5481032
Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis
BACKGROUND:BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS:In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS:At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS:In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
PMID: 22992072
ISSN: 1533-4406
CID: 5347972
Radiation impairs perineural invasion by modulating the nerve microenvironment
PURPOSE/OBJECTIVE:Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined. EXPERIMENTAL DESIGN/METHODS:An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer. RESULTS:Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function. CONCLUSIONS:Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.
PMCID:3386941
PMID: 22768171
ISSN: 1932-6203
CID: 5241782
First bite syndrome: incidence, risk factors, treatment, and outcomes
OBJECTIVES/HYPOTHESIS/OBJECTIVE:First bite syndrome (FBS) refers to facial pain characterized by a severe cramping or spasm in the parotid region with the first bite of each meal that diminishes over the next several bites.1, 2 It is a potential sequela of surgery involving the infratemporal fossa (ITF), parapharyngeal space (PPS), and/or deep lobe of the parotid gland. The incidence, risk factors, treatment options, and outcomes of FBS are poorly understood. We hypothesized that certain clinical and tumor variables independently predict the development of FBS. STUDY DESIGN/METHODS:Retrospective cohort study. METHODS:We reviewed the records of 499 patients (mean age, 50 years; range, 12-81 years) undergoing surgery of the deep lobe of the parotid gland, PPS, and/or ITF between 1992 and 2010. Minimum follow-up time was 3 months (median, 39 months). Patient, tumor, and FBS characteristics were analyzed. Incidence was calculated using the Kaplan-Meier method. Univariate analyses and multivariate logistic regression were used to identify independent risk factors for FBS. Patients developing FBS were interviewed to assess the efficacy of various treatment modalities. RESULTS:FBS developed in 45 patients (incidence, 9.6%), at a mean time of 97 (range, 6-877) days from surgery. On multivariate analysis, three variables were significant independent risk factors for FBS: sympathetic chain sacrifice (odds ratio [OR], 4.7; P = .008), PPS dissection (OR, 8.7; P = .001), and resection of only the deep lobe of the parotid gland (OR, 4.2; P = .002). FBS developed in 48.6% of patients undergoing sympathetic chain sacrifice, 22.4% of patients undergoing PPS dissection, 38.4% of patients undergoing isolated deep lobe parotid resection, and 0.8% of patients undergoing total parotidectomy. Partial resolution of FBS symptoms occurred in 69% and complete resolution in 12%. Of 45 FBS patients, 15 (33%) underwent at least one type of treatment for symptomatic relief. No treatment consistently provided effective symptomatic relief. CONCLUSIONS:The strongest independent risk factors for FBS are PPS dissection, deep lobe of parotid resection, and sympathetic chain sacrifice. Patients undergoing surgery with dissection and/or manipulation in these anatomical sites and structures should be thoroughly counseled about the risk of developing FBS.
PMID: 22573579
ISSN: 1531-4995
CID: 5241772
Sinonasal manifestations in cystic fibrosis
Cystic fibrosis is a genetic disease, characterized by accumulation of thickened mucous secretions in exocrine glands. Although the major clinical manifestations of the disease are pancreatic and pulmonary disease, the majority of cystic fibrosis patients will develop sinonasal manifestations as well. This paper outlines the etiology, evaluation, and management of the nasal and sinus manifestations in patients with cystic fibrosis.
PMCID:3420104
PMID: 22919396
ISSN: 1687-921x
CID: 4587512
Endoscopic Sphenopalatine Artery Ligation-a Four Year Experience at One Institution [Meeting Abstract]
ISI:000312261500014
ISSN: 0021-1265
CID: 4581742
