Faculty Bibliography

Vocal communication is negatively affected by neurodegenerative diseases, such as Parkinson disease, and by aging. The neurological and sensorimotor mechanisms underlying voice deficits in Parkinson disease and aging are not well-understood. Rat ultrasonic vocalizations provide a unique behavioral model for studying communication deficits and the mechanisms underlying these deficits in these conditions. The purpose of this review was to examine the existing literature for methods using rat ultrasonic vocalization with regard to the primary disease pathology of Parkinson disease, dopamine denervation, and aging. Although only a small amount of papers were found for each of these topics, results suggest that both shared and unique acoustic deficits in ultrasonic vocalizations exist across conditions and that these acoustic deficits are due to changes in either dopamine signaling or denervation and in aging models changes to the nucleus ambiguus, at the level of the neuromuscular junction, and the composition of the vocal folds in the larynx. We conclude that ultrasonic vocalizations are a useful tool for studying biologic mechanisms underlying vocal communication deficits in neurodegenerative diseases and aging.

INTRODUCTION/BACKGROUND:Transoral resection of pharyngeal tumors with acceptable oncological and functional results can be challenging due to their location in a narrow anatomic space. CASE PRESENTATION/METHODS:In this case report, we demonstrate successful visualization and resection of a squamous cell carcinoma of the oropharynx using the novel Medrobotics(®) Flex(®) System. The Medrobotics(®) Flex(®) System (Medrobotics Corp., Raynham, MA, USA) is an operator controlled flexible endoscope system that includes a rigid endoscope and computer-assisted controllers, with two external channels for the use of compatible, 3.5mm flexible instruments. DISCUSSION/CONCLUSIONS:In a 74-year old female patient a T1 squamous cell carcinoma of the oropharynx was visualized and completely resected using this system. The Medrobotics(®) Flex(®) System is a promising device for transoral approaches in resection of tumors within the pharynx. CONCLUSION/CONCLUSIONS:Good visualization, access, and flexibility of the endoscope and instruments are hereby clear advantages of the system compared to commonly used systems.

INTRODUCTION: We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM). MATERIALS AND METHODS: All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined. Analyses were performed associating clinical variables with LR and DF. Salvage approaches and toxicity of treatment for each patient were also assessed. RESULTS: Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. LR-free survival was 91.4%, DF-free survival was 68.4%, and OS was 77.7% at 12 months. No variables were associated with increased LR; however, melanoma histopathology and infratentorial location were associated with DF on multivariate analysis. LRs were salvaged in 5/8 patients, and DFs were salvaged in 24/29 patients. Two patients developed radionecrosis. CONCLUSION: Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single BM. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up.

Background: Gene expression profiling studies have demonstrated aberrant expression of inflammatory response genes in myeloproliferative neoplasm (MPN) granulocytes and/or CD34+ cells. Our understanding of the immune response to primary myelofibrosis (PMF) hematopoietic stem cells and tissue-specific microenvironments is not complete due to a limited availability of bone marrow (BM) aspirates and fresh spleen samples from PMF patients. In order to overcome this obstacle, we utilized a novel approach with mRNA enrichment analysis which utilizes formalin fixed, paraffin embedded (FFPE) specimens of BM and spleen from PMF patients to identify immune and other microenvironment cell types and to construct pathway activation patterns. Methods: We applied enzyme-free NanoString nCounter PanCancer Immune Profiling Panel system (NanoString Technologies, Inc., Seattle, WA) consisting of 770 standard gene panel and 20 custom gene panel for identification of immune cells and assessing immunological milieus in the microenvironement of matched, archival FFPE spleen and BM samples from MPN patients. Up to 500ng of RNA (at 100ng/ul) isolated from FFPE BM and/or spleen specimens from PMF patients was used for digital expression profiling in accordance with the manufacturer's protocol. The panel included 109 genes that define 24 immune cell types and populations, and 40 housekeeping genes that facilitate sample-to-sample normalization. Data analysis was performed using nSolver software 2.5 and the PanCancer Immune Profiling Advanced Analysis Module (v.1.0.22). Findings identified from the digital expression profiles on cells types were confirmed via immunohistochemical evaluation. Results: Twenty-six archival FFPE tissue samples (13 BM and 13 spleen) obtained from PMF patients who had undergone therapeutic splenectomy and BM biopsy at the same time, and normal tissue controls, were analyzed as described previously (Liew et al 2015). Following data normalization, genes were selected based on P < 0.05 (unpaired t -test) and fold change > 2.0 differentially expressed mRNA levels in the BM (n=208) and spleen (n=108). These genes were distributed across several functional categories including: TNF superfamily (e.g. TNFRS13C, CD70, LTB), signal ligands (cytokine, chemokine) (e.g. JAK3, IFI16, SPP1), B and T cell functions (TIGIT, CXCR5, CXCL14), and cell adhesion (e.g. ITGB3). In supervised clustering of the significantly expressed genes, the first bifurcation of the dendrogram separated controls from PMF samples in both BM and spleen. Twenty-seven genes were significantly differentially expressed by both PMF BM and spleen, compared to control specimens. Interestingly, the PMF BM samples were further separated in a second bifurcation of the dendrogram into 3 subgroups, indicating immune transcriptional diversity within PMF samples (Figure 1). Further characterization of these subgroups and potential clinical relevance are being studied in a larger number of specimens in order to achieve statistical power. Cell type analysis indicated a significant (P =<0.05) difference in activated CD4 T-cells, T helper-1 cells, CD8 T-cells, and B-cells across all BM and spleen samples. Macrophages (P =<0.001) were increased in the spleen, and neutrophils (P =0.01) were increased only in BM samples. A decrease in CD8-positive T-cells in PMF samples (p =0.009) was confirmed using immunohistochemistry with computer assisted image analysis. Heterogeneity of Tregs in PMF spleen samples (n=10) was further confirmed by immunohistochemistry (n-3). Conclusions: Digital immune expression profiling coupled with immunohistochemistry is a novel approach for characterization of tumor microenvironment in fibrotic PMF marrow and spleen. Our preliminary findings indicate a consistent decrease in cytotoxic CD8 T-cells but varying expression of Tregs. In addition, we identified several genes in various immune functional categories within PMF patients that could potentially serve as therapy targets

Cochlear implant (CI) users have difficulty understanding speech in noisy listening conditions and perceiving music. Aided residual acoustic hearing in the contralateral ear can mitigate these limitations. The present study examined contributions of electric and acoustic hearing to speech understanding in noise and melodic pitch perception. Data was collected with the CI only, the hearing aid (HA) only, and both devices together (CI+HA). Speech reception thresholds (SRTs) were adaptively measured for simple sentences in speech babble. Melodic contour identification (MCI) was measured with and without a masker instrument; the fundamental frequency of the masker was varied to be overlapping or non-overlapping with the target contour. Results showed that the CI contributes primarily to bimodal speech perception and that the HA contributes primarily to bimodal melodic pitch perception. In general, CI+HA performance was slightly improved relative to the better ear alone (CI-only) for SRTs but not for MCI, with some subjects experiencing a decrease in bimodal MCI performance relative to the better ear alone (HA-only). Individual performance was highly variable, and the contribution of either device to bimodal perception was both subject- and task-dependent. The results suggest that individualized mapping of CIs and HAs may further improve bimodal speech and music perception.

BACKGROUND/AIMS: The purpose of this study was to correlate imaging and sialendoscopic findings to therapeutic response in patients with idiopathic chronic parotitis. METHODS: We retrospectively reviewed 122 consecutive sialendoscopies performed in an academic medical center by two surgeons between 2008 and 2013. Forty-one (34%) and 54 (44%) patients were excluded on the basis of having parotid or submandibular sialolith, respectively. Nineteen cases were included in the study with idiopathic chronic parotitis. There was a median follow-up of 5 months. RESULTS: Computed tomography (CT) imaging had a sensitivity and specificity of 80.0 and 71.4%, respectively, for predicting abnormal findings on sialendoscopy, while magnetic resonance imaging (MRI) had 100% accuracy in a small set of cases. In glands with noticeable pathology present on preoperative imaging or sialendoscopy, 11 out of 12 glands (92%) treated experienced symptomatic improvement, while 3 out of 7 glands (43%) without pathology on imaging or endoscopy experienced symptomatic improvement (p = 0.038). CONCLUSIONS: Sialendoscopy for the treatment of idiopathic chronic parotid disease can improve pain and swelling with a higher frequency of success in patients with abnormalities noted on endoscopy. CT and MRI have a moderate degree of accuracy in predicting which patients will benefit from therapeutic sialendoscopy.

The inhibitory effects of metformin have been observed in many types of cancer. However, its effect on human salivary gland carcinoma is unknown. The effect of metformin alone or in combination with pp242 (an mTOR inhibitor) on salivary adenocarcinoma cells growth were determined in vitro and in vivo. We found that metformin suppressed HSY cell growth in vitro in a time and dose dependent manner associated with a reduced expression of MYC onco-protein, and the same inhibitory effect of metformin was also confirmed in HSG cells. In association with the reduction of MYC onco-protein, metformin significantly restored p53 tumor suppressor gene expression. The distinctive effects of metformin and PP242 on MYC reduction and P53 restoration suggested that metformin inhibited cell growth through a different pathway from PP242 in salivary carcinoma cells. Furthermore, the anti-tumor efficacy of metformin was confirmed in vivo as indicated by the increases of tumor necrosis and reduced proliferation in xenograft tumors from metformin treated group. For the first time, the inhibitory effect of metformin on human salivary gland tumor cells was documented. Moreover, metformin inhibitory effects were enhanced by mTOR inhibitor suggesting that metformin and mTOR inhibitor utilize distinctive signaling pathways to suppress salivary tumor growth.