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Figure S1: Average MFI across all cancer and normal biopsy samples before (pre-contrast) and after (post-contrast) topical delivery with 2-NBDG (Black) and Alexa 647-pHLIP (White) Validating uniformity of illumination field. Figure S2: Validating uniformity of the illumination field using the widefield imaging system. (A) Shows the locations at which the model phantom was imaged using the widefield imaging system. (B) Quantification of the mean fluorescence intensity to characterize uniformity of the illumination field Representative images illustrating selection of the region of interest for quantification of the mean fluorescence intensity. Figure S3: Representative images showing the boundaries of the region of interest (ROI) for quantification of the mean fluorescence intensity using the fluorescence imaging data.

The overall objective of this study was to develop an optical imaging approach to simultaneously measure altered cell metabolism and changes in tissue extracellular pH with the progression of cancer using clinically isolated biopsies. In this study, 19 pairs of clinically normal and abnormal biopsies were obtained from consenting patients with head and neck cancer at University of California, Davis Medical Center. Fluorescence intensity of tissue biopsies before and after topical delivery of 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) and Alexa 647-pHLIP [pH (low) insertion peptide] was measured noninvasively by widefield imaging, and correlated with pathologic diagnosis. The results of widefield imaging of clinical biopsies demonstrated that 2-NBDG and pHLIP peptide can accurately distinguish the pathologically normal and abnormal biopsies. The results also demonstrated the potential of this approach to detect subepithelial lesions. Topical application of the contrast agents generated a significant increase in fluorescence contrast (3- to 4-fold) in the cancer biopsies as compared with the normal biopsies, irrespective of the patient and location of the biopsy within a head and neck cavity. This unpaired comparison across all the patients with cancer in this study highlights the specificity of the imaging approach. Furthermore, the results of this study indicated that changes in intracellular glucose metabolism and cancer acidosis are initiated in the early stages of cancer, and these changes are correlated with the progression of the disease. In conclusion, this novel optical molecular imaging approach to measure multiple biomarkers in cancer has a significant potential to be a useful tool for improving early detection and prognostic evaluation of oral neoplasia. Cancer Prev Res; 7(10); 1035–44. ©2014 AACR.

INTRODUCTION Malignant pleural mesothelioma (MPM) is a fatal disease lacking standardized treatment. We describe the use of fast neutron radiation therapy in MPM patients referred to the Department of Radiation Oncology at the University of Washington Medical Center. MATERIALS AND METHODS Retrospective chart review of MPM patients receiving neutron radiotherapy treatment from 1980 to 2012. RESULTS A total of 30 MPM patients received fast neutron radiotherapy as part of their treatment regimen. Median age at diagnosis was 59.6 years (range, 46.6 to 72.3 y). Eighteen patients received fast neutron radiotherapy as a component of trimodality treatment. Median overall survival was 20.3 months (range, 5.5 to 73.3 mo) with 1 patient censored at 34.8 months and all other patients with confirmed dates of death. One patient receiving radiotherapy alone as a palliative measure died during radiation treatment. One patient was unable to tolerate radiotherapy and stopped before completing prescribed treatment. On univariate analysis, Brigham Stage at presentation was a significant predictor of survival (P

Noninvasive localized measurement of extracellular pH in cancer tissues can have a significant impact on the management of cancer. Despite its significance, there are limited approaches for rapid and noninvasive measurement of local pH in a clinical environment. In this study, we demonstrate the potential of noninvasive topical delivery of Alexa-647 labeled pHLIP (pH responsive peptide conjugated with Alexa Fluor(®) 647) to image changes in extracellular pH associated with head and neck squamous cell carcinoma using widefield and high resolution imaging. We report a series of preclinical analyses to evaluate the optical contrast achieved after topical delivery of Alexa-647 labeled pHLIP in intact fresh human tissue specimens using widefield and high-resolution fluorescence imaging. Using topical delivery, Alexa-647 labeled pHLIP can be rapidly delivered throughout the epithelium of intact tissues with a depth exceeding 700 µm. Following labeling with Alexa-647 labeled pHLIP, the mean fluorescent contrast increased four to eight fold higher in clinically abnormal tissues as compared to paired clinically normal biopsies. Furthermore, the imaging approach showed significant differences in fluorescence contrast between the cancer and the normal biopsies across diverse patients and different anatomical sites (unpaired comparison). The fluorescence contrast differences between clinically abnormal and normal tissues were in agreement with the pathologic evaluation. Topical application of fluorescently labeled pHLIP can detect and differentiate normal from cancerous tissues using both widefield and high resolution imaging. This technology will provide an effective tool to assess tumor margins during surgery and improve detection and prognosis of head and neck cancer.

Classically, pterygoid plate fractures have been associated with fractures of the mid-face and skull base. When isolated pterygoid plate fractures are identified on imaging that only extends to the level of the skull base, other related facial fractures may be missed. We sought to evaluate isolated lateral pterygoid plate fractures on computed tomography (CT) scans in conjunction with mandible fractures and to propose a mechanism of fracture unrelated to the classic dissociating mid-face Le Fort fractures.In this retrospective case series, 7 patients who sustained facial trauma from 2006 to 2012 were found to have isolated lateral pterygoid plate fractures. All patients had an ipsilateral subcondylar fracture, 2 had symphyseal fracture, 2 had body fracture, and 1 had coronoid fracture.On the basis of these cases, isolated lateral pterygoid fractures noted on CT of the head may be suggestive of an unappreciated mandibular fracture. The suspected mechanism is due to force transduction through the medial and lateral pterygoid muscles when acute displacing force is placed on the mandible. In patients with identified isolated pterygoid plate factures, a dedicated CT of the mandible may be indicated to assess for associated mandibular fracture, even in patients whose clinical examinations have had negative results.

Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.

The overall objective of this study was to develop an optical imaging approach to simultaneously measure altered cell metabolism and changes in tissue extracellular pH with the progression of cancer using clinically isolated biopsies. In this study, 19 pairs of clinically normal and abnormal biopsies were obtained from consenting patients with head and neck cancer at University of California, Davis Medical Center. Fluorescence intensity of tissue biopsies before and after topical delivery of 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) and Alexa 647-pHLIP [pH (low) insertion peptide] was measured noninvasively by widefield imaging, and correlated with pathologic diagnosis. The results of widefield imaging of clinical biopsies demonstrated that 2-NBDG and pHLIP peptide can accurately distinguish the pathologically normal and abnormal biopsies. The results also demonstrated the potential of this approach to detect subepithelial lesions. Topical application of the contrast agents generated a significant increase in fluorescence contrast (3- to 4-fold) in the cancer biopsies as compared with the normal biopsies, irrespective of the patient and location of the biopsy within a head and neck cavity. This unpaired comparison across all the patients with cancer in this study highlights the specificity of the imaging approach. Furthermore, the results of this study indicated that changes in intracellular glucose metabolism and cancer acidosis are initiated in the early stages of cancer, and these changes are correlated with the progression of the disease. In conclusion, this novel optical molecular imaging approach to measure multiple biomarkers in cancer has a significant potential to be a useful tool for improving early detection and prognostic evaluation of oral neoplasia. Cancer Prev Res; 7(10); 1035–44. ©2014 AACR.

Purpose of review This review will consider the newly developed and emerging diagnostic techniques with real or potential clinical application to the diagnosis of Meniere's disease. Recent findings Several new diagnostic modalities have been introduced, which have the potential to help diagnose endolymphatic hydrops. These include cervical and ocular vestibular evoked myogenic potentials, cochlear hydrops analysis masking procedures, and three-dimensional fluid-attenuated inversion recovery MRI following intratympanic instillation of gadolinium. Summary Diagnosis of Meniere's disease has classically been of a clinical rather than a procedural nature. Despite the many recent advances in diagnostic testing which show potential applicability for aiding in diagnosis of Meniere's disease, each has limitations which prevent immediate utility. For now, Meniere's disease remains best diagnosed through the standard American Academy of Otolaryngology - Head and Neck Surgery clinical inclusionary and exclusionary criteria.

Objectives:1) Determine the patient characteristics, presentation, location, and rates of associated injury in pediatric foreign body ingestion and aspiration. 2) Analyze the types of intervention and rates of postoperative complications.Methods:Retrospective analysis of all patients under the age of 18 who were evaluated for foreign body (FB) ingestion and aspiration at a tertiary care center between January 1, 2003, and December 31, 2012.Results:We identified 315 patients. 61% were male and 39% female, with an average age of 3.9 years (SD 3.9). 55.6% of FBs were found to in the esophagus, 22.2% in the airway, and 22% in the oropharynx or GI tract. The most common signs and symptoms at presentation were emesis (30.9%), choking/gagging (27.4%), coughing (24.0%), drooling (23.4%), and dysphagia (23.4%) with an esophageal FB and increased work of breathing (50.0%), cough (48.6%), choking/gagging (44.3%), wheezing (40.0%), and stridor (20.0%) with an airway FB. The most common FBs were coins (88.6%) and nuts...

Objective: Isolated lateral pterygoid plate fractures on head CT imaging can serendipitously be associated with mandible fractures on subsequent maxillofacial imaging. Our objective is to understand the mechanism and to establish a protocol for the radiographic evaluation for this phenomenon.Method: We performed a retrospective case series of 7 maxillofacial trauma patients with evidence of isolated lateral pterygoid fractures noted on CT images between 2006 and 2012 at our tertiary care institution. Subsequent maxillofacial CT images with coronal, axial, and sagittal views allowed for complete evaluation of maxillofacial trauma.Results: Seven patients between 2006 and 2012 who sustained facial trauma were found to have isolated lateral pterygoid plate fractures. Subsequent evaluation via maxillofacial CT showed associated mandible fractures. All the patients were men with an average age of 37 years. Seven patients had an ipsilateral subcondylar fracture, 2 had a symphyseal fracture, 2 had a body fracture...

Osteopontin (OPN) is a potent inhibitor of ectopic calcification. Previous studies suggested that, in addition to blocking apatite crystal growth, OPN promoted regression of ectopic calcification by inducing the expression of acid-generating carbonic anhydrase II (CAR2) in monocyte-derived cells.To test this hypothesis, OPN and CAR2 expression and calcification of subcutaneously implanted glutaraldehyde-fixed bovine pericardium (GFBP) were studied in CAR2 mutant mice.Consistent with previous studies in Black Swiss mice, GFBP calcified to a greater extent in OPN-deficient mice compared to wild types on the C57Bl/6 background. GFBP implanted in CAR2-deficient mice (CAR2(-/-)) were significantly more calcified than those implanted into wild-type mice (CAR2(+/+)) [37+/-5 vs. 20+/-6.5 microg Ca/mg tissue, respectively, at 30 days (P.001), and 42+/-5 versus 20+/-4 microg Ca/mg tissue at 60 days, respectively (P.001)]. On the other hand, OPN levels within and surrounding the implants were similar in CAR2(+/+) and CAR2(-/-) mice, suggesting that OPN expression in the absence of CAR2 was not sufficient to mitigate ectopic calcification.These results indicate that CAR2 expression is an important regulator of ectopic calcification, potentially by facilitating OPN mediated mineral regression.

The phosphorylated glycoprotein osteopontin (OPN) is involved in the regulation of biomineralization under normal and pathological conditions. Its actions include inhibiting apatite crystal growth and promoting the formation and function of mineral resorbing cells, including osteoclasts (OCL). The purpose of this study was to develop stable apatitic mineral surfaces and determine their influence on OCL formation and mineral resorption from bone marrow macrophages derived from OPN wild-type (OPN +/+) and OPN deficient (OPN-/-) mice. We demonstrated that these mineral coatings were stable and supported bone marrow-derived macrophage differentiation to OCL under our culture conditions. Macrophages harvested from OPN-/- mice had a greater capacity to form OCL than macrophages from OPN+/+ mice when allowed to differentiate on tissue culture plastic. In contrast, when allowed to differentiate on a mineral surface, no difference in OCL formation was observed. Interestingly, OPN+/+ OCL were more efficient at mineral dissolution than OPN-/- OCL, and this difference was observed regardless of differentiating surface. Our results suggest that mineralized substrates as well as ability to synthesize OPN both control OCL function in our model system. The exact nature of these effects may be dependent on variables related to mineral substrate presentation.