Faculty Bibliography

Most patients who die from cancer succumb to treatment-refractory advanced metastatic progression. Although the early stages of tumor metastasis result in the formation of clinically silent micrometastatic foci, its later stages primarily reflect the progressive, organ-destructive growth of already advanced metastases. Early-stage metastasis is regulated by multiple factors within tumor cells as well as by the tumor microenvironment (TME). In contrast, the molecular determinants that control advanced metastatic progression remain essentially uncharacterized, precluding the development of therapies targeted against it. Here we show that the TME, functioning in part through platelet endothelial cell adhesion molecule 1 (PECAM-1), drives advanced metastatic progression and is essential for progression through its preterminal end stage. PECAM-1-KO and chimeric mice revealed that its metastasis-promoting effects are mediated specifically through vascular endothelial cell (VEC) PECAM-1. Anti-PECAM-1 mAb therapy suppresses both end-stage metastatic progression and tumor-induced cachexia in tumor-bearing mice. It reduces proliferation, but not angiogenesis or apoptosis, within advanced tumor metastases. Because its antimetastatic effects are mediated by binding to VEC rather than to tumor cells, anti-PECAM-1 mAb appears to act independently of tumor type. A modified 3D coculture assay showed that anti-PECAM-1 mAb inhibits the proliferation of PECAM-1-negative tumor cells by altering the concentrations of secreted factors. Our studies indicate that a complex interplay between elements of the TME and advanced tumor metastases directs end-stage metastatic progression. They also suggest that some therapeutic interventions may target late-stage metastases specifically. mAb-based targeting of PECAM-1 represents a TME-targeted therapeutic approach that suppresses the end stages of metastatic progression, until now a refractory clinical entity

Herpes simplex virus-1 (HSV-1) establishes life-long latency in peripheral neurons where productive replication is suppressed. While periodic reactivation results in virus production, the molecular basis of neuronal latency remains incompletely understood. Using a primary neuronal culture system of HSV-1 latency and reactivation, we show that continuous signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway triggered by nerve growth factor (NGF)-binding to the TrkA receptor tyrosine kinase (RTK) is instrumental in maintaining latent HSV-1. The PI3-K p110alpha catalytic subunit, but not the beta or delta isoforms, is specifically required to activate 3-phosphoinositide-dependent protein kinase-1 (PDK1) and sustain latency. Disrupting this pathway leads to virus reactivation. EGF and GDNF, two other growth factors capable of activating PI3-K and PDK1 but that differ from NGF in their ability to persistently activate Akt, do not fully support HSV-1 latency. Thus, the nature of RTK signaling is a critical host parameter that regulates the HSV-1 latent-lytic switch

OBJECTIVE: To review our patient series who underwent revision cochlear implantation surgery, with special emphasis on the 'soft failure' group. STUDY DESIGN: Retrospective chart review of cochlear implant revision surgeries from 1979 to 2008. An extensive review of these patients' medical, audiologic, and radiographic histories was performed. SETTING: Two tertiary care hospitals and 1 academic cochlear implant center. INTERVENTION: Explantation and reimplantation of cochlear implant, explanted device analysis, speech perception testing. MAIN OUTCOME MEASURES: Postoperative speech performance. RESULTS: Approximately 1,500 cochlear implant surgeries were performed from 1979 to 2008. Of these, 113 (7.53%) procedures in 98 patients were revision cases. The underlying reason for revision surgery was divided into 4 categories: 26 hard failures (23%), 31 medical failures (27.4%), 14 soft failures (12.4%), and 42 (37.2%) not classified/ambiguous cases. The last group was not categorized because of lack of available medical documentation or because of an ambiguous device failure analysis. The top 3 most common causes of hard failure were loss of hermiticity (8 patients [30.8%]), Vendor B defects (7 patients [26.9%]), and cracked casing (4 patients [15.4%]). The most common cause of medical failure was device extrusion (11 patients [35.5%]) followed by head trauma to the site of implantation (11 patients [35.5%]), and wound infection (5 patients [16.1%]). Fourteen patients (14.2%) were categorized as soft failures. All soft failure patients demonstrated a deterioration in pure-tone average and speech perception. Of the soft failure group, time to revision surgery was 4.7 years in contrast to 4.2 years for the hard failure group and 4.3 years for all revisions. An extensive review of patients' medical histories showed that 4 (28.5%) of the 14 patients had a previous diagnosis of meningitis. Two patients (14.3%) had evidence of inner ear malformations, and 2 patients (14.3%) had history of asthma. CONCLUSION: Our cochlear revision series are comparable to what is reported in the literature. However, an unexpected relationship between meningitis was identified among our soft failure group. More than one-quarter carried a history of meningitis. Moreover, nearly one-half of all soft failures had some form of inflammatory derangement. We used the soft failure criteria established by the 2005 Consensus Development Conference for our population analysis. Although we agree that audiologic data often are essential for defining soft failure, multiple patients in our series experienced pain that was severe enough to prevent a complete audiometric evaluation, therefore not rigorously fulfilling the criteria set forth by the 2005 Consensus. However, because their symptoms resolved after reimplantation, and their speech performance restored, we propose modifications of the current definition of 'soft failure' to include these patients

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.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is commonly associated with adenotonsillar hypertrophy. We hypothesized that respiratory perturbations extend to other regions of the upper respiratory tract in such children, particularly to rhino-sinus regions. STUDY DESIGN: A prospective case control study using Magnetic Resonance Imaging (MRI) of the upper airway and surrounding tissues of OSAS and controls. Magnetic resonance imaging was used to evaluate radiographic changes within the: paranasal sinuses, middle ear and mastoid air cells, and the nasal passages. RESULTS: We studied 54 OSAS (age 5.7 +/- 3.0 years) and 54 controls (age 6.2 +/- 2.0 years, P = NS). Children with OSAS had significantly more opacification of: maxillary sinuses (P < 0.05), sphenoid sinuses (P < 0.01), and mastoid air cells (P < 0.01). They also had significantly more: middle ear effusions, (P < 0.001), prominence of inferior nasal turbinate(s) (P < 0.05), and deviation of the nasal septum (P < 0.05). CONCLUSIONS: Childhood OSAS is associated with a wide range of upper respiratory tract perturbations and is not limited to adenoid and tonsillar hypertrophy.

Meningitis after cochlear implantation continues to be a concern. Recent studies and anecdotal reports support the belief that intracochlear trauma, lack of appropriate immunizations, and a previously used dual-component electrode predispose patients to a higher rate of contracting meningitis. In addition, a history of meningitis, cochlear dysplasia, and certain variations of surgical technique such as the cochleostomy, very young age, immunocompromise, and the presence of neural prostheses such as shunts, are all potentially predisposing factors. Because many of these factors are beyond our control, there is likely to be an inevitable baseline incidence of meningitis, perhaps related to the underlying deafness, but by controlling other factors, we can hope to minimize the incidence. Despite the efforts of multiple individuals and organizations, there continue to be new cases of meningitis, including a small number of fatalities, each year. There is recent evidence that a sizeable percentage of children with implants have not been vaccinated as suggested by governmental agencies, otolaryngologic societies, implant manufacturers, and many cochlear implant centers. Clearly, efforts must be made to ensure age-appropriate vaccination for all cochlear implant recipients