Faculty Bibliography

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

Importance:A method to optimize imaging of cholesteatoma by combining the strengths of available modalities will improve diagnostic accuracy and help to target treatment. Objective:To assess whether fusing Periodically Rotated Overlapping Parallel Lines With Enhanced Reconstruction (PROPELLER) diffusion-weighted magnetic resonance imaging (DW-MRI) with corresponding temporal bone computed tomography (CT) images could increase cholesteatoma diagnostic and localization accuracy across 6 distinct anatomical regions of the temporal bone. Design, Setting, and Participants:Case series and preliminary technology evaluation of adults with preoperative temporal bone CT and PROPELLER DW-MRI scans who underwent surgery for clinically suggested cholesteatoma at a tertiary academic hospital. When cholesteatoma was encountered surgically, the precise location was recorded in a diagram of the middle ear and mastoid. For each patient, the 3 image data sets (CT, PROPELLER DW-MRI, and CT-MRI fusion) were reviewed in random order for the presence or absence of cholesteatoma by an investigator blinded to operative findings. Main Outcomes and Measures:If cholesteatoma was deemed present on review of each imaging modality, the location of the lesion was mapped presumptively. Image analysis was then compared with surgical findings. Results:Twelve adults (5 women and 7 men; median [range] age, 45.5 [19-77] years) were included. The use of CT-MRI fusion had greater diagnostic sensitivity (0.88 vs 0.75), positive predictive value (0.88 vs 0.86), and negative predictive value (0.75 vs 0.60) than PROPELLER DW-MRI alone. Image fusion also showed increased overall localization accuracy when stratified across 6 distinct anatomical regions of the temporal bone (localization sensitivity and specificity, 0.76 and 0.98 for CT-MRI fusion vs 0.58 and 0.98 for PROPELLER DW-MRI). For PROPELLER DW-MRI, there were 15 true-positive, 45 true-negative, 1 false-positive, and 11 false-negative results; overall accuracy was 0.83. For CT-MRI fusion, there were 20 true-positive, 45 true-negative, 1 false-positive, and 6 false-negative results; overall accuracy was 0.90. Conclusions and Relevance:The poor anatomical spatial resolution of DW-MRI makes precise localization of cholesteatoma within the middle ear and mastoid a diagnostic challenge. This study suggests that the bony anatomic detail obtained via CT coupled with the excellent sensitivity and specificity of PROPELLER DW-MRI for cholesteatoma can improve both preoperative identification and localization of disease over DW-MRI alone.

PURPOSE: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses. RESULTS: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade >/=3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score. CONCLUSIONS: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.

An adolescent male presented to the office with a 3-month history of a small left ear mass located on the posterior helix. Although the patient was asymptomatic, the decision was made to remove the mass in the operating room and send for pathology. Following excision, the mass was stained and examined by the pathologist. Staining positive for Factor VIIIa and CD68, the lesion was also found to have a combination of histiocytes and fibroblastic spindle cells. The diagnosis of dermatofibroma, cellular type, was made and the patient required no further treatment. Seen in follow up several months after, there was complete resolution of the mass. <br /><br /> <em>J Drugs Dermatol.</em> 2016;15(10):1270-1272.

OBJECTIVE: To determine the prevalence and also accuracy of the laryngopharyngeal reflux (LPR) referring diagnosis and to determine the most useful clinical tool in arriving at the final diagnosis in a tertiary laryngology practice. STUDY DESIGN: Case series with planned data collection. SETTING: Six tertiary academic laryngology practices. SUBJECTS AND METHODS: We collected referring diagnosis and demographic information, including age, sex, ethnicity, referring physician, and whether or not patients had prior flexible laryngoscopy for 1077 patients presenting with laryngologic complaints from January 2010 and June 2013. Final diagnosis after the referred laryngologist's examination and the key diagnostic test used was then recorded. RESULTS: Of 1077 patients, 132 had a singular referring diagnosis of LPR. Only 47 of 132 patients (35.6%) had LPR confirmed on final primary diagnosis. Transnasal flexible laryngoscopy confirmed this in 27 of 47 (57.4%) patients. Eighty-five of 132 (64.4%) had a different final diagnosis than LPR. Sixty-five of 85 (76.5%) of these alternative pathologies were diagnosed with the aid of laryngeal stroboscopy. CONCLUSIONS: LPR appears to be an overused diagnosis for laryngologic complaints. For patients who have already had transnasal flexible laryngoscopic exams prior to their referral, laryngeal stroboscopy is the key diagnostic tool in arriving at the correct diagnosis.