Faculty Bibliography

INTRODUCTION: Cancer pain creates a poor quality of life and decreases survival. The basic neurobiology of cancer pain is poorly understood. Adenosine triphosphate (ATP) and the ATP ionotropic receptor subunits, P2X2 and P2X3, mediate cancer pain in animal models; however, it is unknown whether this mechanism operates in human, and if so, what the relative contribution of P2X2- and P2X3-containing trimeric channels to cancer pain is. Here, we studied head and neck squamous cell carcinoma (HNSCC), which causes the highest level of function-induced pain relative to other types of cancer. RESULTS: We show that the human HNSCC tissues contain significantly increased levels of ATP compared to the matched normal tissues. The high levels of ATP are secreted by the cancer and positively correlate with self-reported function-induced pain in patients. The human HNSCC microenvironment is densely innervated by nerve fibers expressing both P2X2 and P2X3 subunits. In animal models of HNSCC we showed that ATP in the cancer microenvironment likely heightens pain perception through the P2X2/3 trimeric receptors. Nerve growth factor (NGF), another cancer-derived pain mediator found in both human and mouse HNSCC, induces P2X2 and P2X3 hypersensitivity and increases subunit expression in murine trigeminal ganglion (TG) neurons. CONCLUSIONS: These data identify a key peripheral mechanism in cancer pain and highlight the clinical potential of specifically targeting nociceptors expressing both P2X2 and P2X3 subunits (e.g., P2X2/3 heterotrimers) to alleviate cancer pain.

The present study aimed to characterize the mechanical response of beagle sartorius muscle fibers under strain rates that increase logarithmically (0.1mm/min, 1mm/min and 10mm/min), and provide an analysis of the fracture patterns of these tissues via scanning electron microscopy (SEM). Muscle tissue from dogs' sartorius was excised and test specimens were sectioned with a lancet into sections with nominal length, width, and thickness of 7, 2.5 and 0.6mm, respectively. Trimming of the tissue was done so that the loading would be parallel to the direction of the muscle fiber. Samples were immediately tested following excision and failures were observed under the SEM. No statistically significant difference was observed in strength between the 0.1mm/min (2.560+/-0.37MPa) and the 1mm/min (2.702+/-0.55MPa) groups. However, the 10mm/min group (1.545+/-0.50MPa) had a statistically significant lower strength than both the 1mm/min group and the 0.1mm/min group with p<0.01 in both cases. At the 0.1mm/min rate the primary fracture mechanism was that of a shear mode failure of the endomysium with a significant relative motion between fibers. At 1mm/min this continues to be the predominant failure mode. At the 10mm/min strain rate there is a significant change in the fracture pattern relative to other strain rates, where little to no evidence of endomysial shear failure nor of significant motion between fibers was detected.

Maxillectomy followed by radiotherapy and/or chemotherapy can result in lacrimal blockage and the need for subsequent dacryocystorhinostomy (DCR). Endonasal endoscopic DCR, as opposed to external DCR, allows better accuracy and leaves no scar. To date no report was published regarding the results of endoscopic DCR in these patients. The current study presents a retrospective review of all patients with paranasal and skull base tumors who developed nasolacrimal duct blockage after ablative maxillectomy with or without radiotherapy and/or chemotherapy and underwent endonasal endoscopic DCR between January 2006 and October 2012 in a tertiary reference medical center. According to our results, ten patients underwent 11 subsequent endonasal endoscopic DCR. There were 6 men and 4 women with a median age of 55 years (range, 19-81 years); four suffered from benign tumors and six had malignant tumors. All underwent maxillectomy. Six received high-dose radiotherapy. Time interval between primary ablative surgery and endonasal endoscopic DCR was 18 months (range, 7-118 months). Silicone stents were removed after median period of 11 weeks (range, 1-57 weeks). Nine out of ten patients experienced symptomatic improvement following one endonasal endoscopic DCR. One patient had recurrent epiphora and underwent a successful endonasal endoscopic revision DCR. In conclusion, endonasal endoscopic DCR in patients with paranasal and skull base tumors, who previously underwent maxillectomy, is generally successful and not associated with a high rate of complications or failure. Moreover, our findings may suggest that silicone stents can be removed shortly after the operation with high success rate.

BACKGROUND: Current augmentative and reconstructive rhinoplasties use auto logous tissue grafts or synthetic bioinert materials to repair nasal trauma or attain an aesthetic shape. Autologous grafts are associated with donor-site trauma and morbidity. Synthetic materials are widely used but often yield an unnatural appearance and are prone to infection or dislocation. There is an acute clinical need for the generation of native tissues to serve as rhinoplasty grafts without the undesirable features that are associated with autologous grafts or current synthetic materials. METHODS: Bioactive scaffolds were developed that not only recruited cells in the nasal dorsum in vivo, but also induced chondrogenesis of the recruited cells. Bilayered scaffolds were fabricated with alginate-containing gelatin microspheres encapsulating cytokines atop a porous poly(lactic-co-glycolic acid) base. Microspheres were fabricated to contain recombinant human transforming growth factor-beta3 at doses of 200, 500, or 1000 ng, with phosphate-buffered saline-loaded microspheres used as a control. A rat model of augmentation rhinoplasty was created by implanting scaffolds atop the native nasal cartilage surface that was scored to induce cell migration. Tissue formation and chondrogenesis in the scaffolds were evaluated by image analysis and histologic staining with hematoxylin and eosin, toluidine blue, Verhoeff elastic-van Geison, and aggrecan immunohistochemistry. RESULTS: Sustained release of increasing doses of transforming growth factor-beta3 for up to the tested 10 weeks promoted orthotopic cartilage-like tissue formation in a dose-dependent manner. CONCLUSIONS: These findings represent the first attempt to engineer cartilage tissue by cell homing for rhinoplasty, and could potentially serve as an alternative material for augmentative and reconstructive rhinoplasty.

OBJECTIVES/HYPOTHESIS: To characterize the videoendoscopic laryngeal findings in patients with a prior established diagnosis of laryngopharyngeal reflux disease (LPR) as the sole etiology for their chief complaint of hoarseness. We hypothesized that many, if not all, of these patients would present with discrete laryngeal pathology, divergent from LPR. STUDY DESIGN: Prospective, nonintervention. METHODS: Patients presenting to a tertiary laryngology practice with an established diagnosis of LPR as the sole etiology of their hoarseness were included. All subjects completed the Voice Handicap Index and Reflux Symptom Index, in addition to a questionnaire regarding their reflux diagnosis and prior treatment. Laryngoscopic examinations were reviewed by the laryngologist caring for the patients. Reliability of findings was assessed by interpretation of videoendoscopic findings by three outside laryngologists not involved in the care of the patients. RESULTS: Laryngeal pathology distinct from LPR was identified in all 21 patients felt to be causative of the chief complaint of dysphonia. Specifically, the most common findings were benign mucosal lesions and vocal fold paresis (29% each), followed by muscle tension dysphonia (14%). Two patients were found to have vocal fold leukoplakia, of which one was confirmed to be a microinvasive carcinoma upon removal. CONCLUSION: LPR may be overdiagnosed; other etiologies must be considered for patients with hoarseness who fail empiric LPR treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 2013.

A growing number of minimally invasive surgical and diagnostic procedures require the insertion of an optical, mechanical, or electronic device in narrow spaces inside a human body. In such procedures, precise motion control is essential to avoid damage to the patient's tissues and/or the device itself. A typical example is the insertion of a cochlear implant which should ideally be done with minimum physical contact between the moving device and the cochlear canal walls or the basilar membrane. Because optical monitoring is not possible, alternative techniques for sub millimeter-scale distance control can be very useful for such procedures. The first requirement for distance control is distance sensing. We developed a novel approach to distance sensing based on the principles of scanning electrochemical microscopy (SECM). The SECM signal, i.e., the diffusion current to a microelectrode, is very sensitive to the distance between the probe surface and any electrically insulating object present in its proximity. With several amperometric microprobes fabricated on the surface of an insertable device, one can monitor the distances between different parts of the moving implant and the surrounding tissues. Unlike typical SECM experiments, in which a disk-shaped tip approaches a relatively smooth sample, complex geometries of the mobile device and its surroundings make distance sensing challenging. Additional issues include the possibility of electrode surface contamination in biological fluids and the requirement for a biologically compatible redox mediator.

OBJECTIVES/HYPOTHESIS: Melanin is a pigmented polymer with a known role in dermal solar protection. In vertebrates, melanogenesis has been reported in leukocyte populations, suggesting a potential role in innate immunity. In this study, we report the novel finding of melanin associated with chronic inflammation and speculate on its potential role in the middle ear and mastoid. STUDY DESIGN: Retrospective review of case series. METHODS: Medical records of six patients who demonstrated melanin in the ear were reviewed. RESULTS: Six patients from 1 to 63 years of age were identified with extracellular melanin and melanin-laden histiocytes within the middle ear and/or mastoid air cells at time of surgery. Concurrent intraoperative findings included cholesteatoma (n = 3), chronic suppurative otitis media (n = 2), and coalescent mastoiditis (n = 1). Histologically, extracellular melanin and melanin-laden histiocytes were identified by Fontana-Masson stain; absence of melanocytes was confirmed by the absence of Melan-A staining. One patient had a positive stain for CD163 (a marker for macrophages). CONCLUSION: This case series is the first demonstration of melanin within middle ear mucosa without melanocytes in immediate proximity or metastatic melanocytic lesions. Melanin's presence in the setting of inflammation suggests that there may be a heretofore unreported link between the pigmentary and immune systems in the middle ear. LEVEL OF EVIDENCE: 4.