D Bradley Welling

The Ohio State University, Columbus, Ohio, United States

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Publications (93)191.76 Total impact

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    ABSTRACT: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.
    Oncotarget 12/2014; · 6.63 Impact Factor
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    ABSTRACT: To compare long-term quality-of-life outcomes in vestibular schwannoma patients managed with observation, microsurgery, or stereotactic radiation. ross-sectional survey with retrospective chart review. Tertiary care center. The Penn Acoustic Neuroma Quality of Life (PANQOL) survey was mailed to 600 patients treated for vestibular schwannoma. Patients were separated by treatment and subsequently subdivided by years of follow-up (0-5, 6-10, and >10 years). Composite quality-of-life (cQOL) scores and subscores for hearing, balance, facial nerve, pain, anxiety, energy, and general health were calculated. Scores were compared among treatment groups as a whole, among treatment groups at each time interval, and within treatment groups over time using a 2-tailed analysis of variance and paired t test. The survey return rate was 49%, and the mean follow-up was 7.9 years. The only significant difference in cQOL occurred at 0 to 5 years, where stereotactic radiation scores were better than both microsurgery and observation (P = .009). No significant differences were detected in cQOL after 5 years. Within the radiation group, cQOL was significantly lower at 6 to 10 years than at 0 to 5 years (P = .013). At no point was cQOL for stereotactic radiation less than that for observation or microsurgery. Long-term (>5 years) quality-of-life outcomes measured by the PANQOL in vestibular schwannoma patients show no significant differences between stereotactic radiation, observation, and microsurgical intervention. Studies are needed to fully evaluate very-long-term QOL for patients with vestibular schwannoma.
    Otolaryngology Head and Neck Surgery 03/2014; 149(2 Suppl). DOI:10.1177/0194599814524531 · 1.72 Impact Factor
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    ABSTRACT: Listeners assign different weights to spectral dynamics, such as formant rise time (FRT), and temporal dynamics, such as amplitude rise time (ART), during phonetic judgments. We examined the neurophysiological basis of FRT and ART weighting in the /ba/–/wa/ contrast. Electroencephalography was recorded for thirteen adult English speakers during a mismatch negativity (MMN) design using synthetic stimuli: a /ba/ with /ba/-like FRT and ART; a /wa/ with /wa/-like FRT and ART; and a /ba/wa with /ba/-like FRT and /wa/-like ART. We hypothesized that because of stronger reliance on FRT, subjects would encode a stronger memory trace and exhibit larger MMN during the FRT than the ART contrast. Results supported this hypothesis. The effect was most robust in the later portion of MMN. Findings suggest that MMN is generated by multiple sources, differentially reflecting acoustic change detection (earlier MMN, bottom-up process) and perceptual weighting of ART and FRT (later MMN, top-down process).
    Brain and Language 03/2014; 130:42–49. DOI:10.1016/j.bandl.2014.01.007 · 3.31 Impact Factor
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    ABSTRACT: PURPOSE Several acoustic cues specify any single phonemic contrast. Nonetheless, adult, native speakers of a language share weighting strategies, showing preferential attention to some properties over others. Cochlear implant (CI) signal processing disrupts the salience of some cues: in general, amplitude structure remains readily available, but spectral structure less so. This study asked how well speech recognition is supported if CI users shift attention to salient cues not weighted strongly by native speakers. METHOD 20 adults with CIs participated. The /bɑ/-/wɑ/ contrast was used because spectral and amplitude structure varies in correlated fashion for this contrast. Normal-hearing adults weight the spectral cue strongly, but the amplitude cue negligibly. Three measurements were made: labeling decisions, spectral and amplitude discrimination, and word recognition. RESULTS Outcomes varied across listeners: some weighted the spectral cue strongly, some weighted the amplitude cue, and some weighted neither. Spectral discrimination predicted spectral weighting. Spectral weighting explained the most variance in word recognition. Age of onset of hearing loss predicted spectral weighting, but not unique variance in word recognition. CONCLUSIONS The weighting strategies of listeners with normal hearing likely support speech recognition best, so efforts in implant design, fitting, and training should focus on developing those strategies.
    Journal of Speech Language and Hearing Research 02/2014; DOI:10.1044/2014_JSLHR-H-12-0323 · 1.97 Impact Factor
  • Aaron C Moberly, Benjamin C Tweel, D Bradley Welling
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    ABSTRACT: Wound complications after middle cranial fossa craniotomy are rare. We describe a patient who underwent a left middle fossa craniotomy for resection of a small internal auditory canal tumor with subsequent development of wound breakdown and infection 1 week postoperatively. Prompting of the patient elicited a history of bilateral rhytidectomies. Wound debridement, hyperbaric oxygen therapy, dermal regeneration template placement, and prolonged antibiotic treatment were performed. Complete secondary intention healing occurred with an acceptable cosmetic outcome. Prior rhytidectomy scars must be identified and incorporated into the surgical planning prior to performing middle fossa craniotomy incisions. Laryngoscope, 2013.
    The Laryngoscope 10/2013; 124(2). DOI:10.1002/lary.24078 · 2.03 Impact Factor
  • Aaron C Moberly, D Bradley Welling, Susan Nittrouer
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    ABSTRACT: Undesirable behaviors in young children with cochlear implants suggest device soft failure. Cochlear implant soft failure refers to nonoptimal performance not detectable with routine hardware checks. Pediatric failures may delay language development, but failure detection is difficult. A 2005 soft failure consensus statement recommended a checklist for suspected device malfunctions. That checklist included the appearance of "bad" behaviors and aggression (externalizing behaviors) or self-injury and inattentiveness (internalizing behaviors) as indicators of soft failure. Accordingly, these behaviors should predict slowed language growth, and the analyses reported here sought evidence of that predictive power. Data from a longitudinal study of 80 children with cochlear implants collected at 6 times between 18 and 48 months were reexamined. Language measures included auditory comprehension, expressive vocabulary, and unstructured language. A parent questionnaire, the Child Behavior Checklist, examined externalizing and internalizing behaviors. Behavior measures were correlated with language measures in a series of analyses. Externalizing and internalizing behaviors did not consistently correlate with language at the ages tested. Additionally, early behaviors did not predict later language abilities. Individual language measures correlated best with overall language development 12 months later. This study fails to support the hypothesis that externalizing and internalizing behaviors in pediatric cochlear implant users correlate with slowed language advance. These behaviors should not be seen as evidence of declining language performance as may be seen with device soft failure. Instead clinical assessments of language abilities are necessary.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 10/2013; DOI:10.1097/MAO.0b013e3182a0036c · 1.44 Impact Factor
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene that encodes a tumor-suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss-of-function is associated with increased activity of Rac and p21-activated kinases (PAKs) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates the actin severing and depolymerizing activity of cofilin. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2(Delta Ex2)) exhibited increased levels of LIMK1, LIMK2 and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared with wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared with normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2(Delta Ex2) MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5 decreased the viability of Nf2(Delta Ex2) MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2(Delta Ex2) MSCs. The decreased viability of Nf2(Delta Ex2) MSCs was not due to caspase-dependent or -independent apoptosis, but rather due to inhibition of cell cycle progression as evidenced by accumulation of cells in G(2)/M phase. Inhibition of LIMKs arrests cells in early mitosis by decreasing aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency.
    Oncogene 08/2013; 33(27). DOI:10.1038/onc.2013.320 · 8.56 Impact Factor
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    ABSTRACT: Cucurbitacin D and goyazensolide, 2 plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells. Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin D and goyazensolide, may be developed as potential treatments for these tumors. The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signaling molecules related to the cell cycle and the AKT pathway. Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ∼ 0.75 μM) and Ben-Men-1 cells (IC50 ∼0.2 μM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ∼0.9 μM) and Ben-Men-1 cells (IC50 ∼1 μM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFκB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells. Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2-deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 08/2013; DOI:10.1097/MAO.0b013e3182956169 · 1.44 Impact Factor
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    ABSTRACT: Meningiomas constitute ~34% of primary intracranial tumors and are associated with increased mortality in NF2 patients. To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also demonstrated that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A, p21CIP1/WAF1, and p27KIP1. Also, AR-42 increased pro-apoptotic Bim expression and decreased anti-apoptotic BclXL levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G2/M, while inducing cell-cycle arrest at G1 in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and PCNA in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G2, in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth.
    Cancer Research 11/2012; 73(2). DOI:10.1158/0008-5472.CAN-12-1888 · 9.28 Impact Factor
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    ABSTRACT: Objective To compare 3-D segmented volumetric analysis of vestibular schwannomas (VS) with traditional linear tumor measurement on serial magnetic resonance imaging (MRI) studies to assess volume and growth rates. Study Design Case series with retrospective chart review. Setting Tertiary care medical center. Methods This analysis identified 24 VS patients clinically followed with serial gadolinium enhanced images. Maximum linear dimensions (MLD) were obtained from gadolinium-contrasted T1 sequences from 3 serial MRI scans per RECIST guidelines. MLD was cubed (MLD(3)) and orthogonal analysis (OA) was carried out to provide volumetric estimates for comparison with segmented data. Segmented volumetric analysis (SVA) was performed with semi-automated 3-D conformal procedure. Tumor volume, percentage change in volume, and interval percentage change were compared using paired 2-tailed t tests. Results The average interval between MRIs was 2.6 years. Volume estimates differed significantly between SVA and OA and MLD(3) at all intervals. Linear growth measurements averaged 0.5 mm/y (5.4%). Volumetric growth was 50 mm(3)/y (22.8%) with SVA, 110 mm(3)/y (19.6%) with OA, and 210 mm(3)/y (14.4%) with MLD(3) estimates. Differences between MLD and both MLD(3) and SVA were significant, but significance between MLD(3) and SVA was only identified in interval analysis. Progression was identified in 75% more patients with SVA than OA, MLD(3), or MLD. Conclusions VS assume complex configurations. Linear measurements inaccurately estimate tumor volume and growth compared with segmented analysis. SVA is a useful clinical tool that accurately assesses tumor volume. Use of outcomes such as tumor volume and percentage of volume change may be more sensitive in assessing tumor progression compared with linear measurements.
    Otolaryngology Head and Neck Surgery 05/2012; 147(4):737-43. DOI:10.1177/0194599812447766 · 1.72 Impact Factor
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    ABSTRACT: The objective of this project was to develop a virtual temporal bone dissection system that would provide an enhanced educational experience for the training of otologic surgeons. A randomized, controlled, multi-institutional, single-blinded validation study. The project encompassed four areas of emphasis: structural data acquisition, integration of the system, dissemination of the system, and validation. Structural acquisition was performed on multiple imaging platforms. Integration achieved a cost-effective system. Dissemination was achieved on different levels including casual interest, downloading of software, and full involvement in development and validation studies. A validation study was performed at eight different training institutions across the country using a two-arm randomized trial where study subjects were randomized to a 2-week practice session using either the virtual temporal bone or standard cadaveric temporal bones. Eighty subjects were enrolled and randomized to one of the two treatment arms; 65 completed the study. There was no difference between the two groups using a blinded rating tool to assess performance after training. A virtual temporal bone dissection system has been developed and compared to cadaveric temporal bones for practice using a multicenter trial. There was no statistical difference between practice on the current simulator compared to practice on human cadaveric temporal bones. Further refinements in structural acquisition and interface design have been identified, which can be implemented prior to full incorporation into training programs and used for objective skills assessment.
    The Laryngoscope 03/2012; 122 Suppl 1:S1-12. DOI:10.1002/lary.22499 · 2.03 Impact Factor
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    ABSTRACT: Aberrant phosphorylation of ErbB family receptor tyrosine kinases (RTK) in human vestibular schwannomas (VSs) renders them susceptible to growth suppression by RTK inhibitors. Recent evidence has implicated increased ErbB family receptor tyrosine kinase signaling in VS tumorigenesis; however, the characterization of ErbB receptor activity and the chemotherapeutic potential of RTK inhibitors in VS treatment have not been fully explored. To confirm phosphorylation of ErbB receptors in VS, protein extracts from paired VS tumor-vestibular nerve samples were examined using phospho-RTK arrays. ErbB receptor phosphorylation was similarly examined in cultured schwannoma cells, normal Schwann cells, and VS tumor tissues using Western blotting. Also, VS tumor sections were immunostained for members of the ErbB receptor family. The effects of RTK inhibitors on ErbB phosphorylation and cell proliferation were assessed in schwannoma cells after epidermal growth factor receptor (EGFR) inhibitor (Erlotinib) and EGFR/ErbB2 inhibitor (Lapatinib) treatment. VS tumor tissues consistently demonstrated higher levels of phosphorylated ErbB3 compared with paired vestibular nerves. However, cultured VS, malignant schwannoma, and normal Schwann cells demonstrated EGFR phosphorylation. Immunohistochemistry confirmed high expression of ErbB3 in a series of VS tumor sections. Erlotinib inhibited schwannoma cell proliferation with an IC50 value of 2.5 µmol/L, whereas Lapatinib was less potent for growth inhibition. Erlotinib treatment resulted in a decrease of multiple phospho-ErbB receptors in schwannoma cells. VS variably express activated ErbB receptors with consistently higher levels of phospho-ErbB3 expression relative to paired vestibular nerve samples. Chemotherapeutic targeting of ErbB3 may be a novel means of inhibiting VS growth.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 02/2012; 33(2):244-57. DOI:10.1097/MAO.0b013e31823e287f · 1.44 Impact Factor
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    ABSTRACT: Bimodal stimulation may offer improved auditory function following cochlear implantation. Modification of technique during cochleostomy may minimize trauma and maximize residual hearing. We hypothesize that CO(2) laser use during cochleostomy is useful and may decrease intracochlear trauma. This study examines the utility of CO(2) laser to perform cochleostomy and compares intracochlear sound and temperature levels during laser and drill usage. Experimental (30 cadaveric temporal bones). A CO(2) laser at 3 W (four bones) and 6 W (four bones) and otologic drill (six bones) were utilized to perform a cochleostomy while recording operative time. Subsequently, 16 bones were used to simultaneously record intracochlear sound (in decibels) and temperature (in degrees Fahrenheit) during CO(2) laser (eight bones) and drill cochleostomies (eight bones). Average cochleostomy time for CO(2) laser was 15.5 minutes (3 W) and 7.75 minutes (6 W); it was 8 minutes for the drill. Average intracochlear sound level was 54.9 dB during laser use and 89.9 dB during drill use (P < .001), whereas maximal levels were 75 to 118 dB during laser use and 95 to 136 dB during drill use (P = .018). Average temperature was 63.4°F during laser use and 61.5°F during drill use (P = .151), whereas maximum temperatures ranged from 66 to 120°F during laser use and 62 to 70°F during drill use (P = .045). CO(2) laser can create cochleostomies comparable in operative time and intracochlear temperature to drilling while decreasing intracochlear sound levels. Further investigation is warranted to minimize trauma and maximize auditory function during cochleostomy.
    The Laryngoscope 02/2012; 122(5):1142-7. DOI:10.1002/lary.23231 · 2.03 Impact Factor
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    ABSTRACT: Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42. In vivo mouse studies. AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity. Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities. AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.
    The Laryngoscope 01/2012; 122(1):174-89. DOI:10.1002/lary.22392 · 2.03 Impact Factor
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas, and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors. © 2011 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 12/2011; DOI:10.1002/ajmg.a.34359 · 2.30 Impact Factor
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    ABSTRACT: Objective: Compare 3D conformal volumetric analysis (3DCVA) versus traditional linear measurements on serial MRI imaging of vestibular schwannomas (VS) for determination and assessment of accurate tumor volume and growth rates.
    Otolaryngology Head and Neck Surgery 09/2011; 145(2 Suppl):P202-P202. DOI:10.1177/0194599811415823a221 · 1.72 Impact Factor
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.
    Neuro-Oncology 09/2011; 13(9):983-99. DOI:10.1093/neuonc/nor072 · 5.29 Impact Factor
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    ABSTRACT: We sought to report the efficacy of oral melatonin as treatment for chronic tinnitus and to determine whether particular subsets of tinnitus patients have greater benefit from melatonin therapy than others. This was a prospective, randomized, double-blind, crossover clinical trial in an ambulatory tertiary referral otology and neurotology practice. Adults with chronic tinnitus were randomized to 3 mg melatonin or placebo nightly for 30 days followed by a 1-month washout period. Each group then crossed into the opposite treatment arm for 30 days. The tests audiometric tinnitus matching (TM), Tinnitus Severity Index (TSI), Self Rated Tinnitus (SRT), Pittsburgh Sleep Quality Index (PSQI), and Beck Depression Inventory (BDI) were administered at the outset and every 30 days thereafter to assess the effects of each intervention. A total of 61 subjects completed the study. A significantly greater decrease in TM and SRT scores (p < 0.05) from baseline was observed after treatment with melatonin relative to the effect observed with placebo. Male gender, bilateral tinnitus, noise exposure, no prior tinnitus treatment, absence of depression and/or anxiety at baseline, and greater pretreatment TSI scores were associated with a positive response to melatonin. Absence of depression and/or anxiety at baseline, greater pretreatment TSI scores, and greater pretreatment SRT scores were found to be positively associated with greater likelihood of improvement in both tinnitus and sleep with use of melatonin (p<0.05). Melatonin is associated with a statistically significant decrease in tinnitus intensity and improved sleep quality in patients with chronic tinnitus. Melatonin is most effective in men, those without a history of depression, those who have not undergone prior tinnitus treatments, those with more severe and bilateral tinnitus, and those with a history of noise exposure.
    The Annals of otology, rhinology, and laryngology 07/2011; 120(7):433-40. DOI:10.1177/000348941112000703 · 1.05 Impact Factor
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    ABSTRACT: There is increasing interest in objective assessment of surgeon competence. In the field of otolaryngology, several surgical training programs, including The Ohio State University, the University of Toronto, and Stanford University, have pursued standardized criteria to rate their trainees' performance in the initial steps of temporal bone dissection (complete mastoidectomy with facial recess approach). Although these assessment metrics require the completion of similar basic components integral to successful temporal bone dissection, certain listed criteria are unique to each institution. Our aim was to establish a more standardized set of criteria that can be used across different institutions to objectively assess temporal bone dissection. We translated these new criteria into automated metrics in our temporal bone dissection simulator to achieve even more objective grading of temporal bone dissections. Cross-sectional study/survey. The temporal bone assessment criteria developed by each of the three aforementioned institutions were compiled into an all-encompassing scale. This compilation was sent out as an online survey to members of the American Neurotology Society and American Otological Society with instructions to rate the importance of each criterion. Criteria that were ranked by >70% of respondents as either "very important" or "important" were used to create the new, cross-institutional scale for the objective assessment of temporal bone dissection. The new assessment scale and its eventual incorporation into the temporal bone surgical simulator will enhance the objectivity of currently existing methods to evaluate surgical performance across different institutions.
    The Laryngoscope 07/2010; 120(7):1422-7. DOI:10.1002/lary.20957 · 2.03 Impact Factor
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    ABSTRACT: Methods for surgical education and training have changed little over the years. Recent calls to improve surgical efficiency and safety impose additional pressures that have an impact on surgical education and training. USE OF SIMULATION: Integration of data from advanced imaging technologies and computer technologies are creating simulation environments of unprecedented realism. Surgical education and training are poised to exploit low-cost simulation technologies to mitigate these pressures that are having an adverse impact on curricula. To become effective, simulation needs to undergo rigorous validation studies. With funding from that National Institute on Deafness and Other Communicative Disorders, we have embarked on a research design project to develop, disseminate, and validate a surgical system for use in otologic resident training and assessment and present key steps from this process. We discuss limiting factors related to technology and conducting multi-institutional studies, along with current developments to integrate curricula, as well as training and assessment capabilities in surgical education using simulation.
    09/2009; 1(1):61-6. DOI:10.4300/01.01.0010

Publication Stats

1k Citations
191.76 Total Impact Points

Institutions

  • 1992–2014
    • The Ohio State University
      • • Department of Otolaryngology - Head & Neck Surgery
      • • Department of Radiology
      Columbus, Ohio, United States
  • 2009–2013
    • Nationwide Children's Hospital
      Columbus, Ohio, United States
  • 2011
    • The University of Arizona
      • Department of Surgery
      Tucson, AZ, United States
  • 1989–2009
    • Vanderbilt University
      • Department of Otolaryngology
      Nashville, Michigan, United States
  • 2006
    • Riley Hospital for Children
      Indianapolis, Indiana, United States
  • 2005
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2001
    • Shea Ear Clinic
      Memphis, Tennessee, United States