Faculty Bibliography

Hearing impairment is a significant disability. According to the World Health Organization (WHO), more than 80% of the world's approximately 120 million people with hearing impairment live in developing countries. Cochlear implant is the only therapeutic intervention for those with severe-profound sensorineural hearing loss. We are reporting an interesting case of the very first cochlear implant operation carried out in Uganda. The patient was a 23 year old male whose presenting complaint was inability to hear in the left ear for three and a half years and in the right ear for one year. He had been treated for TB(Tuberculosis) mastoiditis. After the 8 months of treatment, the otorrhea persisted and he underwent a tympanomastoidectomy on the same ear. He reported no familial history of hearing loss. On examination, ENT examination revealed a small pars flaccida retration pocket of the right tympanic membrane with cholesteatoma. The left ear had an intact tympanic membrane. Pure tone audiometry revealed profound sensorineural hearing loss in both ears (see attached PTA results), CT scan of the temporal bone showed normal inner ear anatomy bilaterally and mild sclerotic changes in both mastoid bones. He then had surgery on his right ear which included cochlear implantation. The cochlear implant (CI) was activated on the first postoperative day remotely via internet with the help of the cochlear implant team at New York University Cochlear Implant Center and the patient was immediately able to appreciate some sounds. He received a pneumococcal vaccine on the first postoperative day and was discharged the following day.

A major impeding factor in designing effective therapies against glioblastoma (GBM) is its extensive molecular heterogeneity and the diversity of microenvironmental conditions within any given tumor. To test whether heterogeneity with the GBM stem cell (GSC) population is required to ensure tumor growth in such diverse microenvironments, we used human GBM biospecimens to examine the identity of cells marked by two established GSC markers: CD133 and activation of the Notch pathway. Using primary GBM cultures engineered to express GFP upon activation of Notch signaling, we observed only partial overlap between cells expressing cell surface CD133 and cells with Notch activation (n = 3 specimens), contrary to expectations based on prior literature. To further investigate this finding, we FACS-isolated these cell populations and characterized them. While both CD133+ (CD133 + /Notch-) and Notch+(CD133-/Notch+) cells fulfill GSC criteria, they differ vastly in their transcriptome, metabolic preferences and differentiation capacity, thus giving rise to histologically distinct tumors. CD133+ GSCs have increased expression of hypoxia-regulated and glycolytic genes, and are able to expand under hypoxia by activating anaerobic glycolysis. In contrast, Notch+ GSCs are unable to utilize anaerobic glycolysis under hypoxia, leading to decreased tumorsphere formation ability. While CD133+ GSCs give rise to histologically homogeneous tumors devoid of large tumor vessels, tumors initiated by Notch+ GSCs are marked by large perfusing vessels enveloped by pericytes. Using a lineage tracing system, we showed that pericytes are derived from Notch+ GSCs. In addition, Notch+ cells are able to give rise to all tumor lineages in vitro and in vivo, including CD133 + /Notch- cells, as opposed to Notch- populations, which have restricted differentiation capacity and do not generate Notch+ lineages. Our findings demonstrate that GSC heterogeneity is a mechanism used by tumors to sustain growth in diverse microenvironmental conditions

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.

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

BACKGROUND: Patients with established familial paraganglioma (PGL) syndrome may have multiple metachronous lesions. This article illustrates, via imaging and findings, the need for lifetime follow-up of patients with familial PGL syndromes. METHODS: Patients' medical charts and radiological images were reviewed in a retrospective analysis. RESULTS: Over the course of 18 years, this patient developed 2 simultaneous carotid PGLs, a cardiac PGL, and a biochemically active interaortocaval PGL. CONCLUSION: PGLs do not necessarily occur simultaneously in patients with familial PGL syndrome. Lifelong observation is needed to detect these lesions before they become large and symptomatic. Lack of biochemical activity is not a predictor of future lesions being inactive. Cardiac PGLs are rare and require resection. (c) 2015 Wiley Periodicals, Inc. Head Neck 37: E174-E178, 2015.

The incidence of thyroid cancer is increasing worldwide. Current standards in the diagnosis and management of thyroid cancer are limited by the uncertainty of fine-needle aspiration samples that are indeterminate in nature. Molecular markers have the potential to improve the accuracy of thyroid fine-needle aspiration and to aid the physician in giving a more accurate diagnosis and prognosis. This paper summarizes the various molecular markers currently available

Hypocalcemia is a well-known complication of total thyroidectomy. Patients who have previously undergone gastric bypass surgery may be at increased risk of hypocalcemia due to gastrointestinal malabsorption, secondary hyperparathyroidism, and an underlying vitamin D deficiency. We present the case of a 58-year-old woman who underwent a total thyroidectomy for the follicular variant of papillary thyroid carcinoma. Her history included Roux-en-Y gastric bypass surgery. Following the thyroid surgery, she developed postoperative hypocalcemia that required large doses of oral calcium carbonate (7.5 g/day), oral calcitriol (up to 4 mug/day), intravenous calcium gluconate (2.0 g/day), calcium citrate (2.0 g/day), and ergocalciferol (50,000 IU/day). Her serum calcium levels remained normal on this regimen after hospital discharge despite persistent hypoparathyroidism. Bariatric surgery patients who undergo thyroid surgery require aggressive supplementation to maintain normal serum calcium levels. Preoperative supplementation with calcium and vitamin D is strongly recommended.