Faculty Bibliography

The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.

OBJECTIVE: This pilot study examined speech recognition, localization, temporal and spectral discrimination, and subjective reports of cochlear implant (CI) recipients with unilateral deafness. STUDY DESIGN: Three adult male participants with short-term unilateral deafness (<5 yr) participated. All had sudden onset of severe-to-profound hearing loss in 1 ear, which then received a CI, and normal or near normal hearing in the other ear. Speech recognition in quiet and noise, localization, discrimination of temporal and spectral cues, and a subjective questionnaire were obtained over several days. Listening conditions were CI, normal hearing (NH) ear, and bilaterally (CI and NH). RESULTS: All participants had open-set speech recognition and excellent audibility (250-6,000 Hz) with the CI. Localization improved bilaterally compared with the NH ear alone. Word recognition in noise was significantly better bilaterally than with the NH ear for 2 participants. Sentence recognition in various noise conditions did not show significant bilateral improvement; however, the CI did not hinder performance in noise even when noise was toward the CI side. The addition of the CI improved temporal difference discrimination for 2 participants and spectral difference discrimination for all participants. Participants wore the CI full time, and subjective reports were positive. CONCLUSION: Overall, the CI recipients with unilateral deafness obtained open-set speech recognition, improved localization, improved word recognition in noise, and improved perception of their ability to hear in everyday life. A larger study is warranted to further quantify the benefits and limitations of cochlear implantation in individuals with unilateral deafness.

PURPOSE: Assessment of donor site morbidity and recipient site complications following free radial forearm osteocutaneous flap (FRFOCF) harvest and evaluation of patient perceived upper limb disability for free radial forearm osteocutaneous versus fasciocutaneous flaps (FRFF). METHODS: First a case series was undertaken of 218 patients who underwent an FRFOCF at two tertiary referral centers between February 1998 and November 2010. Outcomes included forearm donor site morbidity and recipient site complications. Second, the disability of the arm, shoulder, and hand (DASH) questionnaire assessing patient perceived arm disability was administered by phone to 60 consecutive patients who underwent an FRFOCF or FRFF. RESULTS: Mean patient age was 63 years with male predominance (62.8%). Median bone length harvested was 8 cm (range, 3-12 cm) with prophylactic plating of the radius following harvest. Donor site morbidity included fracture (1 patient, 0.5%) and sensory neuropathy (5 patients, 2.3%). Mean DASH scores were comparative between groups and to established normative values. Mandibular malunion rate was 3.2% and hardware extrusion at the recipient site occurred in 15.6%. CONCLUSION: Reluctance to perform FRFOCF by surgeons usually centers on concerns regarding potential donor site morbidity and adequacy of available bone stock; however, we identified minimal objective or patient perceived donor site morbidity or recipient site complications following harvest of FRFOCFs. Mild wrist weakness and stiffness are common but do not impede ability to perform activities of daily living. Data from this and other reports suggest this flap is particularly useful for midfacial and short segment mandibular reconstruction.

Objective. The optimal type of neck dissection in head and neck squamous cell carcinoma (SCC) with clinical cervical metastases has not been determined. The following study was performed to determine the rate of regional control with selective neck dissection (SND) in these patients.Study Design. Case series with planned data collection.Settings. Single institution, cancer center.Methods and Subjects. Patients with cervical lymph node metastases from mucosal cancers of the head and neck who were treated with SND from 2000 to 2010 were selected. Demographics, tumor characteristics, extent of neck dissection, adjuvant treatments, locoregional control, and survival were recorded. Recurrence in the neck and disease-specific survival (DSS) were primary and secondary end points.Results. One hundred eight patients underwent SND. Sixty-nine (64%) were male. Median age was 62 (20-89) years. The most common primary site was the oral cavity (71.3%). Ninety-five (88%) received adjuvant treatment. Median follow-up was 21 months. Six patients (5.5%) had isolated recurrence in the dissected neck. Patients with N2C disease had poorer neck recurrence-free survival. At the end of study, 64 (59.3%) patients had no evidence of disease, and 23 (21.3%) had died of disease. Two-year DSS was 76.9%. Number of positive nodes (P = .026) and positive surgical margins (P = .001), among others, were predictors of poorer DSS.Conclusion. In a highly selected group of patients with cervical lymph node metastases from head and neck SCC, selective neck dissection is effective in controlling the disease in the neck when performed in the setting of a multimodality treatment, including adjuvant radiotherapy or radiochemotherapy.

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as >/=15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%-47%), with median time to response of 4.5 months (range, 3-12). In responders, reduction in VS volumes ranged from -15.7% to -23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%-58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%-82.1%) and 70.6% (95% CI, 43.1%-86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.

OBJECTIVE: To report the pretreatment and posttreatment population characteristics and the overall stability of the audiologic outcomes found during the Sudden Hearing Loss Clinical Trial (ClinicalTrials.gov: Identifier NCT00097448). STUDY DESIGN: Multicenter, prospective randomized noninferiority trial of oral versus intratympanic (IT) steroid treatment of sudden sensorineural hearing loss (SSNHL). SETTING: Fifteen academically based otology practices. PATIENTS: Two hundred fifty patients with unilateral SSNHL presenting within 14 days of onset with 50 dBHL or greater pure tone average hearing threshold in the affected ear. INTERVENTION: Either 60 mg/d oral prednisone for 14 days with a 5-day taper (121 patients) or 4 IT doses for 14 days of 40 mg/ml methylprednisolone (129 patients). MAIN OUTCOME MEASURE: Primary end point was change in hearing [dB PTA] at 2 months after treatment. Noninferiority was defined as less than 10 dB difference in hearing outcome between treatments. In this article, pretreatment and posttreatment hearing findings will be reported in detail. RESULTS: A general (and stable) effect of treatment and a specific effect of greater improvement at low frequencies were found in both treatment groups. CONCLUSION: Hearing improvements are stable, and a significantly greater improvement occurs with lower frequency after either oral or IT steroid treatment of SSNHL.

BACKGROUND: Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. RESULTS: Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex. CONCLUSIONS: We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.