Faculty Bibliography

OBJECTIVES: X-linked deafness is a potential etiology of sensorineural hearing loss characterized by bulbous dilatation of the fundus of the internal auditory canal (IAC) and the absence of the bony plates separating the basal turn of the cochlea and IAC. These malformations predispose patients to IAC insertion during cochlear implantation (CI). Our objective is to describe the surgical technique, audiometric and speech performance outcomes in a group of patients with this unique cochlear malformation. METHODS: A retrospective chart review was performed of all patients at a tertiary care facility who underwent CI between January 2006 and July 2011. RESULTS: A total of five patients were identified with radiographic findings characteristic of X-linked deafness, specifically a deficient modiolous, absent lamina cribrosa and bulbous IAC. A modified cochleostomy was utilized to ensure electrode insertion within the scala tympani avoiding the IAC. In each case, fluoroscopy was utilized to visual electrode progression during insertion and complete insertion was accomplished. All patients demonstrated improved speech performance following implantation. CONCLUSIONS: Utilizing the techniques described, patients with these unique radiographic findings consistent with X-linked deafness may successfully undergo CI with excellent potential for auditory rehabilitation.

Background: The management of patients with atrial fibrillation (AF) on warfarin who need treatment interruption for surgery/procedure is a common clinical problem. Bridging with low-molecular-weight heparin (LMWH) has been used to minimize the time that patients are not anticoagulated to mitigate the risk for arterial thromboembolism (ATE). The efficacy of bridging has not been validated, and bridging may increase bleeding. Aims: We aimed to determine the efficacy and safety of bridging anticoagulation. Methods: BRIDGE is a randomized, double-blind, placebo-controlled trial comparing bridging vs. no bridging in adults with non-valvular/ valvular AF or atrial flutter who required warfarin interruption for elective surgery/procedure. Patients with a mechanical heart valve or creatinine clearance < 30 mL min^-1 were excluded. After stopping warfarin 5 days pre-procedure, patients received dalteparin, 100 IU kg^-1, or matching placebo, both subcutaneous twice daily, for 3 days pre- and 5-9 days post-procedure. Dalteparin/placebo was resumed 12-24 h after minor and 48-72 h after major surgery/procedure. Warfarin was resumed < 24 h post-procedure. Follow-up was for 30 +/- 7 days post-procedure. Primary outcomes were ATE and major bleeding; secondary outcomes were minor bleeding, death, myocardial infarction, and venous thromboembolism. Results: We enrolled 1884 patients: median age was 72.7 (IQR 65.8- 78.2) years; 73.4% were male; median CHADS2 score = 2.0 (IQR 2.0- 3.0); and 336 (17.7%) had prior stroke or transient ischemic attack. Protocol adherence occurred in pre- and post-procedure periods in 1432 (81.0%) and 1669 (94.5%) patients, respectively. We lost 5 (0.3%) patients to follow-up. Trial enrollment ended in Dec. 2014, with results to be presented at the Congress. Conclusion: BRIDGE is the first randomized trial comparing the efficacy and safety of LMWH bridging vs. no bridging in patients with AF who require warfarin interruption for an elective surgery/procedure

OBJECTIVE: Interobserver agreement in the context of oral epithelial dysplasia (OED) grading has been notoriously unreliable and can impose barriers for developing new molecular markers and diagnostic technologies. This paper aimed to report the details of a 3-stage histopathology review and adjudication process with the goal of achieving a consensus histopathologic diagnosis of each biopsy. STUDY DESIGN: Two adjacent serial histologic sections of oral lesions from 846 patients were independently scored by 2 different pathologists from a pool of 4. In instances where the original 2 pathologists disagreed, a third, independent adjudicating pathologist conducted a review of both sections. If a majority agreement was not achieved, the third stage involved a face-to-face consensus review. RESULTS: Individual pathologist pair kappa values ranged from 0.251 to 0.706 (fair-good) before the 3-stage review process. During the initial review phase, the 2 pathologists agreed on a diagnosis for 69.9% of the cases. After the adjudication review by a third pathologist, an additional 22.8% of cases were given a consensus diagnosis (agreement of 2 out of 3 pathologists). After the face-to-face review, the remaining 7.3% of cases had a consensus diagnosis. CONCLUSIONS: The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis.

Flexible laryngoscopes are common outpatient surveillance tools. Cleansing of these scopes between patients must be quick, effective, and safe. One sterilant that largely meets these criteria is ortho-phthalaldehyde (OPA); however, infrequently, patients may develop allergic reactions to it. We present three cases of patients who developed significant allergic reactions following repeated laryngoscopic examinations. Subsequent intradermal allergy testing confirmed sensitivity to OPA. In addition, we reviewed the current literature, which includes 17 similar reactions reported in nine patients across disciplines. Allergic reaction to OPA is uncommon, but a potentially under-reported severe complication of repeated endoscopy. LEVEL OF EVIDENCE: NA Laryngoscope, 2015.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate imaging correlates to the changes occurring during angiogenesis in gliomas. This was accomplished through in vivo assessment of vascular parameters (relative CBV and permeability surface-area product) and their changing relationship with increasing glioma grade. MATERIALS AND METHODS: Seventy-six patients with gliomas underwent preoperative perfusion CT and assessment of relative CBV and permeability surface-area product. Regression analyses were performed to assess the rate of change between relative CBV and permeability surface-area product and to test whether these differed for distinct glioma grades. The ratio of relative CBV to permeability surface-area product was also computed and compared among glioma grades by using analysis of variance methods. RESULTS: The rate of change in relative CBV with respect to permeability surface-area product was highest for grade II gliomas followed by grade III and then grade IV (1.64 versus 0.91 versus 0.27, respectively). The difference in the rate of change was significant between grade III and IV (P = .003) and showed a trend for grades II and IV (P = .098). Relative CBV/permeability surface-area product ratios were the highest for grade II and lowest for grade IV. The pair-wise difference among all 3 groups was significant (P < .001). CONCLUSIONS: There is an increase in relative CBV more than permeability surface-area product in lower grade gliomas, whereas in grade III and especially grade IV gliomas, permeability surface-area product increases much more than relative CBV. The rate of change of relative CBV with respect to permeability surface-area product and relative CBV/permeability surface-area product ratio can serve as an imaging correlate to changes occurring at the tumor microvasculature level.

Myelofibrosis (MF) is characterized by cytopenias constitutional symptoms, splenomegaly and marrow histopathological abnormalities (fibrosis, increased microvessel density and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2) were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > PV or ET) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species leading to increased DNA strand breaks and apoptosis of normal but not MF CD34+ cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts but not adipocytes. LCN2 priming of MSCs resulted in the upregulation of RUNX2 gene as well as other genes which are capable of further affecting osteoblastogenesis, angiogenesis and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine which likely contributes to the creation of a cascade of events that result not only in predominance of the MF clone but also a dysfunctional microenvironment.

We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. Dose-limiting toxicities were observed in three patients overall, at the 100 mg (n = 1) and 160 mg (n = 2) twice-daily dose levels. The maximum tolerated dose was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event. Sixteen patients were evaluable for response at 12 weeks. Seven patients had clinical improvement by International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria. Meaningful reductions in JAK2V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of signal transducer and activator of transcription 5 (STAT5): doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed (ClinicalTrials.gov identifier: NCT00668421).

Synapses are highly plastic and are modified by changes in patterns of neural activity or sensory experience. Plasticity of cortical excitatory synapses is thought to be important for learning and memory, leading to alterations in sensory representations and cognitive maps. However, these changes must be coordinated across other synapses within local circuits to preserve neural coding schemes and the organization of excitatory and inhibitory inputs, i.e., excitatory-inhibitory balance. Recent studies indicate that inhibitory synapses are also plastic and are controlled directly by a large number of neuromodulators, particularly during episodes of learning. Many modulators transiently alter excitatory-inhibitory balance by decreasing inhibition, and thus disinhibition has emerged as a major mechanism by which neuromodulation might enable long-term synaptic modifications naturally. This review examines the relationships between neuromodulation and synaptic plasticity, focusing on the induction of long-term changes that collectively enhance cortical excitatory-inhibitory balance for improving perception and behavior.

The relationship between the place of electrical stimulation from a cochlear implant and the corresponding perceived pitch remains uncertain. Previous studies have estimated what the pitch corresponding to a particular location should be. However, perceptual verification is difficult because a subject needs both a cochlear implant and sufficient residual hearing to reliably compare electric and acoustic pitches. Additional complications can arise from the possibility that the pitch corresponding to an electrode may change as the auditory system adapts to a sound processor. In the following experiment, five subjects with normal or near-to-normal hearing in one ear and a cochlear implant with a long electrode array in the other ear were studied. Pitch matches were made between single electrode pulse trains and acoustic tones before activation of the speech processor to gain an estimate of the pitch provided by electrical stimulation at a given insertion angle without the influence of exposure to a sound processor. The pitch matches were repeated after 1, 3, 6, and 12 months of experience with the sound processor to evaluate the effect of adaptation over time. Pre-activation pitch matches were lower than would be estimated by a spiral ganglion pitch map. Deviations were largest for stimulation below 240 degrees degrees and smallest above 480 degrees . With experience, pitch matches shifted towards the frequency-to-electrode allocation. However, no statistically significant pitch shifts were observed over time. The likely explanation for the lack of pitch change is that the frequency-to-electrode allocations for the long electrode arrays were already similar to the pre-activation pitch matches. Minimal place pitch shifts over time suggest a minimal amount of perceptual remapping needed for the integration of electric and acoustic stimuli, which may contribute to shorter times to asymptotic performance.

OBJECTIVE/HYPOTHESIS: To examine the short- and long-term histopathologic changes that occur in the subglottis in response to airway balloon dilation (ABD) with different balloon diameters and inflation pressures. STUDY DESIGN: Prospective animal study using forty-two 8-month old New Zealand white rabbits at an academic animal research facility. METHODS: Thirty-nine live New Zealand rabbits underwent a single ABD with diameters ranging from 6.0 mm to 10.0 mm and with pressures between 5.0 atmospheres (atm) to 15.0 atm. Animals were euthanized on postoperative days (POD) 1, 7, and 30, and the histopathological changes of the subglottis were examined. Three rabbits served as controls and underwent no ABD. RESULTS: The subglottic airway diameter of all specimens measured 5.4 mm. When examining the fracture rate by balloon diameter, we found the following: 0 of 6 (0%) at 6 mm, 0 of 9 (0%) at 7 mm, 6 of 9 (67%) at 8 mm, 8 of 9 (89%) at 9 mm, and 6 of 6 (100%) at 10 mm. There was a statistically significant relationship with the rate of cricoid fracture as balloon diameter increased (P < .0001). All fractures occurred at the anterior cricoid lamina. On POD 1, we found mild ulceration in 5 of 6 (83%) using a 6-mm or 7-mm balloon and in 0 of 6 (0%) using an 8-mm, 9-mm, or 10-mm balloon; and moderate/severe ulceration in 1 of 6 (16.67%) using a 6-mm or 7-mm balloon and in 11 of 11 (100%) using an 8-mm, 9-mm, or 10-mm balloon (P < .0001). Also on POD 1, we found mild edema in 6 of 6 (100%) using a 6-mm or 7-mm balloon and in 5 of 11 (45%) using an 8-mm, 9-mm, or 10-mm balloon; and moderate/severe edema in 0 of 6 (0%) using a 6-mm/7-mm balloon and in 6 of 11 (55%) using an 8-mm, 9-mm, or 10-mm balloon (P =.048). On POD 7, we found fibroplasia in 5 of 6 (83%) using a 6-mm or 7-mm balloon and in 1 of 7 (14%) using an 8-mm, 9-mm, or 10-mm balloon; and moderate/severe fibroplasia in 1 of 6 (17%) using a 6-mm or 7-mm balloon and in 6 of 7 (86%) using an 8-mm, 9-mm, or 10-mm balloon (P =.029). Also on POD7, we found granulation tissue in 0 of 6 (0%) using a 6-mm or 7-mm balloon and in 5 of 7 (71%) using an 8-mm, 9-mm, or 10-mm balloon (P = .021). On POD 30, we found no fibrosis in 0 of 3 (0%) using a 7-mm balloon, mild fibrosis in 1 of 6 (16.67%), and moderate/severe fibrosis in 5 of 6 (83%) using an 8-mm or 9-mm balloon (P = .048). Also on POD 30, we found the mean subglottic cross-sectional luminal area was 23.79 mm2 with a 7-mm balloon and 29.28 mm2 with an 8-mm or 9-mm balloon (P = .019). Inflation pressure alone had no correlation with mucosal injury or probability of cricoid fracture. CONCLUSIONS: Airway balloon dilation with balloon diameters that exceeded the airway diameter by 2.6 mm was associated with cricoid fractures. All cricoid fractures localized to the anterior cricoid lamina. Balloon diameters larger than the airway diameter by 2.6 mm resulted in a larger subglottic cross-sectional luminal area on POD 30. Airway balloon dilation with balloon diameters that could generate a cricoid fracture created more mucosal injury on POD 0, 1, and 7 than smaller balloon diameters. The histopathological effects of airway balloon dilation observed on POD 0, 1, and 7 resolved by POD 30. When balloon diameter is kept constant, inflation pressure alone had no correlation with mucosal injury or probability of cricoid fracture. LEVEL OF EVIDENCE: NA (animal study). Laryngoscope, 2015.