Faculty Bibliography

Fibroblast growth factor (FGF) signaling is vital for many biological processes, beginning with development. The importance of FGF signaling for skeleton formation was first discovered by the analysis of genetic FGFR mutations which cause several bone morphogenetic disorders, including achondroplasia, the most common form of human dwarfism. The formation of the long bones is mediated through proliferation and differentiation of highly specialized cells - chondrocytes. Chondrocytes respond to FGF with growth inhibition, a unique response which differs from the proliferative response of the majority of cell types; however its molecular determinants are still unclear. Quantitative phosphoproteomic analysis was utilized to catalogue the proteins whose phosphorylation status is changed upon FGF1 treatment. The generated dataset consists of 756 proteins. We were able to localize the divergence between proliferative (canonical) and inhibitory (chondrocyte specific) FGF transduction pathways immediately upstream of AKT kinase. Gene Ontology (GO) analysis of the FGF1 regulated peptides revealed that many of the identified phosphorylated proteins are assigned to negative regulation clusters, in accordance with the observed inhibitory growth response. This is the first time a comprehensive subset of proteins involved in FGF inhibitory response is defined. We were able to identify a number of targets and specifically discover glycogen synthase kinase3beta (GSK3beta) as a novel key mediator of FGF inhibitory response in chondrocytes.

OBJECTIVE:To describe extracochlear extension of revision cochlear implant arrays into the Fallopian canal. PATIENTS:Two adult patients with extension of revision cochlear implant arrays into the Fallopian canal. INTERVENTIONS:Computed tomography (CT), selective deactivation of non-functional electrodes. MAIN OUTCOME MEASURES:Facial nerve function, facial nerve stimulation, cochlear implant electrode position, radiography, functional hearing. RESULTS:Two patients presented with failure of their long-standing cochlear implants (CIs). One patient with presumed postviral hearing loss presented with declining function and increasing facial stimulation from an implant placed 30 years previous. A second with postmeningitic hearing loss presented with a draining mastoid fistula from an implant placed 7 years before. Both patients were reimplanted with minimal insertion resistance via the established electrode tract, yet demonstrated facial nerve stimulation during intraoperative telemetry and on device activation. Postoperative CTs of each patient showed exit of the electrode from the cochlea into the tympanic or labyrinthine Fallopian canal. Both patients can use their devices effectively with selective electrode deactivation. CONCLUSIONS:Our cases illustrate the potential association of long-standing electrodes with otic capsule changes, allowing extracochlear malposition of subsequent arrays. This can occur despite apparently uneventful reinsertion of a flexible array without undue force. Previously reported histopathology confirms the potential for a reactive osteitis from arrays that may contribute to this phenomenon. Intraoperative facial stimulation with neural telemetry testing can raise suspicion of a malpositioned array involving the Fallopian canal. Such cases can be effectively managed with selective deactivation of malpositioned electrode contacts.

The existence of the adenoid first appears to have been noted by Conrad Victor Schneider in 1661. James Yearsley reported in 1842 one case in which he improved hearing by removal of a mucus membrane from behind the uvula, which indicates some appreciation of a relationship of the nasopharynx to ear disease. Hans Wilhelm Meyer, in 1868, was the first to demonstrate the relationship of the adenoid to ear disease and to develop an effective, although somewhat difficult, surgical operation to remove the adenoid. Removal of the adenoid became rapidly accepted worldwide as a treatment for many morbidities, including otitis, speech problems, cognitive problems, and sleep apnea. Until the 1920s, adenoidectomy often was performed as a staged procedure and without general anesthesia. Early tools and techniques included use of the bare fingernail, a finger ring knife, a curette, and electrical desiccation. From the mid-1930s to the early 1960s, radiation therapy of the adenoid was in extensive use, both for children and in caring for army aviators and navy submarine crews during WWII. The effectiveness of surgical adenoidectomy for hearing loss led to a belief that radiation, which had been found to ablate lymphoid tissue, would be equally effective, and led to the wide-spread use of radiation. Ultimately, 500 thousand to 2.5 million children and adults were estimated to have been treated with radiation, and follow-up studies found increased risk for cancer. Furthermore, a follow-up study by Stacey R. Guild (1890-1966), published in 1950, on a very large sample of children who previously were reported to have had their hearing loss diminished through radiation, found that irradiation had produced no effect on high-tone loss. Thus, irradiation was both useless and harmful. Acceptance of authority, which can lurk within medical culture, led to the development of a tragically misguided management of adenoid disease. Laryngoscope, 127:S13-S28, 2017.

BACKGROUND AND PURPOSE: Preoperative localization of the pituitary gland with imaging in patients with macroadenomas has been inadequately explored. The pituitary gland enhancing more avidly than a macroadenoma has been described in the literature. Taking advantage of this differential enhancement pattern, our aim was to evaluate the role of high-resolution dynamic MR imaging with golden-angle radial sparse parallel reconstruction in localizing the pituitary gland in patients undergoing trans-sphenoidal resection of a macroadenoma. MATERIALS AND METHODS: A retrospective study was performed in 17 patients who underwent trans-sphenoidal surgery for pituitary macroadenoma. Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were obtained. Using an ROI-based method to obtain signal-time curves and permeability measures, 3 separate readers identified the normal pituitary gland distinct from the macroadenoma. The readers' localizations were then compared with the intraoperative location of the gland. Statistical analyses were performed to assess the interobserver agreement and correlation with operative findings. RESULTS: The normal pituitary gland was found to have steeper enhancement-time curves as well as higher peak enhancement values compared with the macroadenoma (P < .001). Interobserver agreement was almost perfect in all 3 planes (kappa = 0.89). In the 14 cases in which the gland was clearly identified intraoperatively, the correlation between the readers' localization and the true location derived from surgery was also nearly perfect (kappa = 0.95). CONCLUSIONS: This study confirms our ability to consistently and accurately identify the normal pituitary gland in patients with macroadenomas with the golden-angle radial sparse parallel technique with quantitative permeability measurements and enhancement-time curves.

The potential for the misinterpretation of positron-emission tomography (PET) scans in the context of a possible malignancy has been confirmed in a case report showing increased 18F-fluorodeoxyglucose (FDG) uptake after unilateral vocal fold augmentation medialization. We sought to expand these findings by investigating FDG uptake in a larger cohort of patients via a retrospective chart review. We examined the records of 15 adults-8 men and 7 women-who had undergone vocal fold augmentation for unilateral vocal fold paralysis and at least one subsequent PET scan. The differences in PET standard uptake value (SUV) between the injected and noninjected vocal folds were assessed via the Wilcoxon signed-rank test. A Spearman rank correlation coefficient was then used to estimate the relationship between differences in PET uptake and the length of time between the injection and the follow-up PET scan. The mean SUV of the injected vocal folds was 3.70, and the mean in the noninjected folds was 2.97. The difference did not achieve statistical significance (p = 0.34). In addition, the rank correlation coefficient with regard to the association between the difference in PET uptake and the duration between injection and PET was -0.24, suggesting an inverse relationship. However, the correlation coefficient did not differ significantly from zero (p = 0.34). We conclude that PET uptake after vocal fold augmentation medialization is variable and that it can increase substantially. This information should be considered in the context of the diagnostic accuracy of malignancy on PET.

In this issue of Neuron, Chen et al. (2017) examine premotor activity representing motor planning, Allen et al. (2017) observe the global representation of goal-directed movement on the cortical network, and Makino et al. (2017) track changes in such dynamics throughout learning.

OBJECTIVE: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. METHODS: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. RESULTS: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1wt) patients and in 59%-74% of IDH1mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. CONCLUSIONS: The D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.

Objective Although thyroglossal duct cysts (TGDCs) are relatively common, malignancies within these lesions are infrequent. As a result, there are no large-scale series describing clinical characteristics. Our objectives were to perform a systematic review of the literature evaluating patient demographics, pathology, management, and prognosis of these patients. Data Sources PubMed, Embase, Cochrane reviews, and Google Scholar were searched for relevant articles. Articles meeting inclusion criteria were reviewed for data detailing epidemiology, treatment, and outcomes. Review Methods Inclusion criteria included English-language articles with original reports on human subjects. Two investigators independently reviewed all articles for the data collected, including epidemiology, treatment, and outcomes. Results Ninety-eight articles comprising 164 patients were included in the final analysis. The mean age at presentation was 39.5 years (9-83 years); 68.3% of patients were female. In total, 73.3% of cases were found on final pathologic analysis. The most common pathology was papillary cancer (92.1%). Of the patients, 98.9% underwent a Sistrunk procedure and 61.0% underwent total thyroidectomy. There was a 4.3% recurrence rate with a mean time to recurrence of 42.1 months from initial treatment. One patient died of TGDC carcinoma, while all other patients were disease free at the time of last follow-up (mean follow-up was 46.1 months). Conclusion TGDC carcinoma is typically diagnosed on final pathology. While management encompasses a Sistrunk procedure, further consideration should be given to thyroidectomy among patients ≥45 years of age and individuals with aggressive disease. TGDC carcinoma harbors an exceedingly low rate of mortality.

Background/Purpose: The reconstruction of the wide Tessier #4 cleft is classically limited by persistent lower lid ectropion/medical canthal disruption or the incorporation of unaesthetically located scars which violate the subunit border principle of facial reconstruction. We present a novel repair technique which: can be applied at infancy; does not require tissue expansion; restores stable lower eyelid and medial canthal position; and respects the subunit border principle of facial repair. Methods/Description: A neonate with a complete, wide, Tessier #4 facial cleft presents with an over 2/3rd lower eyelid loss. Presurgical tape therapy was applied to lengthen the lateral tissues transversely and vertically. A Tenzel flap extended to a Schrudde cervicofacial flap was planned to radically mobilize the lower eyelid to the medial canthus in a tension-free manner. A robust vascular supply was maintained to this large flap using a deep plane dissection. Results: Surgical repair was performed at 3 months of age. No tissue expansion was used. A Tenzel pattern flap was mobilized in the subcutaneous plane. This flap was raised in continuity with a Schrudde cervicofacial flap raised in the deep plane. Facial nerves were directly visualized and preserved during the operation. A conjunctival flap was raised from the floor of the orbit was used to reconstruct the posterior lamella of the lower eyelid. The Tenzel/Schrudde flap was rotated, without tension over the defect and to the nose/cheek junction. At the time of inset, there was redundant flap skin superiorly at the level of the lower eyelid and medially at the area of the medial canthus. This redundancy was incorporated into the reconstruction to prevent ectropion and medial canthus disruption. Suspensory sutures were applied to the infraorbital rim and pyriform aperture to prevent sagging of the flap. A Millard repair was used to reconstruct the lip at the level of the philtrum. The flap demonstrated 100% take despite radical mobilization. The final scar followed the philtral line, the nasal/cheek junction, the subcilliary line and the anterior auricular/retro auricular border. Lower eyelid and medial canthal position was stable after 6 months. Facial nerve function was preserved with this approach. Conclusions: A Tenzel/Schrudde deep-plane cervicofacial flap can be safely applied to infants with a wide Tessier #4 facial cleft. No tissue expansion is needed. This is the first repair technique which places final scars perfectly along the subunit borders of the face while preserving lower eyelid and medial canthal position, even in the patient with significant lower eyelid loss