Faculty Bibliography

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.

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.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Parapharyngeal space (PS) tumors are surrounded by critical anatomical structures. Resection is often challenging due to limited surgical exposure. Herein, we report a novel transcervical, minimally invasive, video-assisted technique that facilitates the resection of PS lesions. STUDY DESIGN/METHODS:Case series and review of literature. METHODS:Description of surgical technique with analysis of four cases and literature review. RESULTS:The technique combines a transcervical approach to the PS and skull base with video-assisted and image-guided dissection of tumor. Four cases of benign PS tumors resected with this technique are reported. The size of the tumor excised varied between 0.9 cm and 5 cm. Estimated blood losses were minimal. The average length of hospital stay was 1.5 days. No permanent complications were encountered. CONCLUSIONS:Excision of PS tumor abutting the skull base using a novel minimally invasive, video-assisted, image-guided, transcervical approach is feasible and safe. The short hospitalization stay and low morbidity makes it well suited for the resection of benign PS lesions.

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.

BACKGROUND:Temporary remission of primary hyperparathyroidism (PHPT) following fine-needle aspiration (FNA)-induced hemorrhage of a parathyroid adenoma is extremely rare. The purpose of this report was to illustrate that parathyroid adenomas can masquerade as thyroid nodules and that these patients must be monitored closely following remission as their hyperparathyroidism may recur. PATIENT FINDINGS/METHODS:This report describes a patient who presented with a neck mass and was incidentally found to have PHPT. Ultrasound (US) evaluation revealed a lesion that was diagnosed as a thyroid nodule. After a nondiagnostic FNA, she developed a large neck hematoma and her PHPT went into remission. Soon thereafter, her hyperparathyroidism recurred, and she underwent parathyroidectomy and thyroid lobectomy, which confirmed a large parathyroid adenoma. SUMMARY/CONCLUSIONS:This report illustrates that remission of PHPT can occur because of FNA-induced hemorrhage leading to autoinfarction of a parathyroid adenoma. Following autoinfarction, the patient's parathyroid hormone and calcium levels must be monitored closely as the remission of PHPT may be temporary. Further, although US is a fast, inexpensive, often reliable modality for diagnosing neck masses, it does not always accurately identify parathyroid adenomas. CONCLUSION/CONCLUSIONS:Clinicians must be cognizant of the possibility that parathyroid adenomas can masquerade as thyroid nodules on US, especially as most patients with parathyroid adenomas are asymptomatic at presentation.

BACKGROUND:Currently described endoscopic techniques for subtotal resections of the maxilla include endoscopic medial maxillectomy and extended endoscopic medial maxillectomy; however, a complete resection of the maxilla is sometimes warranted. We describe a combined transoral and endoscopic technique for total and subtotal maxillectomy in an attempt to decrease the morbidity of traditional approaches. METHODS:Technical note, Feasibility, Human cadaveric dissection. RESULTS:Ten total and subtotal maxillectomies were performed in human specimens without the need of facial incisions or transfixion of the nasal septum. The pterygopalatine and infratemporal fossas were accessed and dissected in all cases. CONCLUSIONS:A combined transoral and endoscopic approach is feasible and can be used in selected patients when other minimally endoscopic techniques are not indicated. The benefits of no facial incisions and/or transfixion of the nasal septum, potential improvement in hemostasis, and visual magnification may help to decrease the morbidity of traditional open approaches.