Predicting Schwannoma Growth in a Tumor Model Using Targeted Imaging.

INTRODUCTION: Vestibular schwannoma (VS) is a common pathology encountered in neurotology clinics. Many patients are observed with a "wait and scan" approach. Previous efforts to determine radiographic indicators of future growth have been unsuccessful. Using a mouse subcutaneous tumor model, we seek to determine if fluorescent imaging with directed immunotargets could be used to predict schwannoma growth rate. METHODS: Anti-VEGFR2 and anti-Her2/Neu monoclonal antibodies were covalently linked to a near-infrared probe (IRDye800). Immunodeficient mice underwent subcutaneous injections with a rat-derived schwann (R3) cell line. When tumor growth was evident, either Anti-VEGFR2-IRDye800, anti-Her2/Neu-IRDye800, or Immunoglobulin G (IgG) Isotype-IRDye800 (control) were injected via tail vein. The mice were serially imaged in a closed field near-IR device. Fluorescent data were analyzed for tumor signal and correlated with tumor sie and growth rate. Heterogeneity of fluorescent tumor signal was also assessed. RESULTS: In both anti-VEGFR2 and anti-Her2/Neu groups, there were strong correlations between day 1 mean tumor fluorescence and eventual maximum tumor volume (p = 0.002, 0.001; r2 = 0.92, 0.86). There was also strong correlation with maximum tumor signal on day 1 and maximum tumor volume (p = 0.003, 0.008; r2 = 0.90, 0.91). There was no such correlation in the control group (p = 0.99, 0.75; r2 = 0.0002, 0.028). CONCLUSION: Given the potential morbidity in VS intervention, observation is an appropriate approach for patients with slow-growing or stagnant tumors. We seek to identify immunotargets in a murine model that show promise in predicting schwannoma growth with advanced imaging techniques. Both Her2/Neu and VEGFR2 correlated strongly wth tumor size and growth rates and are promising targets that merit further investigation.

Perioperative Pain Management Following Otologic Surgery.

Otologic surgery involves a broad range of procedures. In general, postoperative pain from most otologic surgeries can be managed with little to no opioids, and surgeons should make a concerted effort to minimize narcotic prescriptions in the midst of the opioid crisis. Many procedures, including transcanal surgeries and even postauricular surgeries, may performed with local anesthetic in selected patients. Multimodal pain regimens, local anesthesia, and alternative approaches have shown promise in minimizing narcotic use, and should be considered. Preoperative counseling to appropriately manage expectations and goals is imperative for patient satisfaction and safety.

Fluorescence Imaging of Nerves During Surgery.

OBJECTIVE: This review details the agents for fluorescence-guided nerve imaging in both preclinical and clinical use to identify factors important in selecting nerve-specific fluorescent agents for surgical procedures. BACKGROUND: Iatrogenic nerve injury remains a significant cause of morbidity in patients undergoing surgical procedures. Current real-time identification of nerves during surgery involves neurophysiologic nerve stimulation, which has practical limitations. Intraoperative fluorescence-guided imaging provides a complimentary means of differentiating tissue types and pathology. Recent advances in fluorescence-guided nerve imaging have shown promise, but the ideal agent remains elusive. METHODS: In February 2018, PubMed was searched for articles investigating peripheral nerve fluorescence. Key terms used in this search include: "intraoperative, nerve, fluorescence, peripheral nerve, visualization, near infrared, and myelin." Limits were set to exclude articles exclusively dealing with central nervous system targets or written in languages other than English. References were cross-checked for articles not otherwise identified. RESULTS: Of the nonspecific agents, tracers that rely on axonal transport showed the greatest tissue specificity; however, neurovascular dyes already enjoy wide clinical use. Fluorophores specific to nerve moieties result in excellent nerve to background ratios. Although noteworthy findings on tissue specificity, toxicity, and route of administration specific to each fluorescent agent were reported, significant data objectively quantifying nerve-specific fluorescence and toxicity are lacking. CONCLUSIONS: Fluorescence-based nerve enhancement has advanced rapidly over the past 10 years with potential for continued utilization and progression in translational research. An ideal agent would be easily administered perioperatively, would not cross the blood-brain barrier, and would fluoresce in the near-infrared spectrum. Agents administered systemically that target nerve-specific moieties have shown the greatest promise. Based on the heterogeneity of published studies and methods for reporting outcomes, it appears that the development of an optimal nerve imaging agent remains challenging.

Evolving Trends in Cochlear Implantation: A Critical Look at the Older Population.

OBJECTIVES/HYPOTHESIS: Cochlear implantation (CI) is a well-accepted surgical option for the treatment of moderate to profound deafness. The purpose of this study was to evaluate the temporal and geographic trends of this procedure nationwide in the Medicare population in an attempt to explore the impact of evolving technologies and changes in healthcare policy. METHODS: Medicare Part B national summary procedural datasets from 2007 to 2016 were obtained. Current Procedural Terminology codes for CI as well as auditory osseointegrated implantation were obtained. Centers for Medicare and Medicaid Services (CMS) datasets were evaluated to determine temporal trends. For geographic trends, specific carrier datasets from 2007 and 2016 were used. RESULTS: From 2007 through 2016, the number of CI procedures increased annually from 1603 to 3600 (124.6%). Other procedures to treat hearing loss including bone-anchored implantation exhibited comparatively modest increases (23%, 90%). CI procedures increased every year in contrast to bone-anchored implants. Controlling for Medicare population, the greatest number of CI procedures performed per capita in the United States was in the West North Central, with an average 1.05 CIs per 10,000 beneficiaries. CONCLUSION: The number of CI procedures performed in the elderly population has increased markedly over the past 10 years, far outpacing growth in other hearing surgeries. Potential reasons may relate to changes in criteria for CI candidacy over the past decade, although significant regional variability demonstrated suggests a lack of consensus. Further studies would be necessary to ascertain the true reason for geographic disparities.

Evaluation of optical imaging agents in a fluorescence-guided surgical model of head and neck cancer.

BACKGROUND: Tumor proliferation often occurs from pathologic receptor upregulation. These receptors provide unique targets for near-infrared (NIR) probes that have fluorescence-guided surgery (FGS) applications. We demonstrate the use of three smart-targeted probes in a model of head and neck squamous cell carcinoma. METHODS: A dose escalation study was performed using IntegriSense750, ProSense750EX, and ProSense750FAST in mice (n = 5) bearing luciferase-positive SCC-1 flank xenograft tumors. Whole body fluorescence imaging was performed serially after intravenous injection using commercially available open-field (LUNA, Novadaq, Canada) and closed-field NIR systems (Pearl, LI-COR, Lincoln, NE). An ex vivo, whole-body biodistribution was conducted. Lastly, FGS was performed with IntegriSense750 to demonstrate orthotopic and metastatic disease localization. RESULTS: Disease fluorescence delineation was assessed by tumor-to-background fluorescence ratios (TBR). Peak TBR values were 3.3 for 1 nmol ProSense750EX, 5.5 for 6 nmol ProSense750FAST, and 10.8 for 4 nmol IntegriSense750 at 5.5, 3, and 4 d post administration, respectively. Agent utility is unique: ProSense750FAST provides sufficient contrast quickly (TBR: 1.5, 3 h) while IntegriSense750 produces strong (TBR: 10.8) contrast with extended administration-to-resection time (96 h). IntegriSense750 correctly identified all diseased nodes in situ during exploratory surgeries. Ex vivo, whole-body biodistribution was assessed by tumor-to-tissue fluorescence ratios (TTR). Agents provided sufficient fluorescence contrast to discriminate disease from background, TTR>1. IntegriSense750 was most robust in neural tissue (TTR: 64) while ProSense750EX was superior localizing disease against lung tissue (TBR: 13). CONCLUSION: All three agents appear effective for FGS.

Characterizing the Utility and Limitations of Repurposing an Open-Field Optical Imaging Device for Fluorescence-Guided Surgery in Head and Neck Cancer Patients.

The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescence-guided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery. METHODS: Consenting patients (n = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast. RESULTS: In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P < 0.001). The repurposed device also successfully identified positive margins. CONCLUSION: The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery.

Fluorescence imaging to localize head and neck squamous cell carcinoma for enhanced pathological assessment.

Accurately identifying close or positive margins in real-time permits re-excision during surgical procedures. Intraoperative assessment of margins via gross examination and frozen section is a widely used tool to assist the surgeon in achieving complete resection. While this methodology permits diagnosis of freshly resected tissue, the process is fraught with misinterpretation and sampling errors. During fluorescence-guided surgery, an exogenous fluorescent agent specific for the target disease is imaged in order to navigate the surgical excision. As this technique quickly advances into the clinic, we hypothesize that the disease-specific fluorescence inherently contained within the resected tissues can be used to guide histopathological assessment. To evaluate the feasibility of fluorescence-guided pathology, we evaluated head and neck squamous cell carcinoma tumour specimens and margins resected from animals and patients after systemic injection of cetuximab-IRDye800CW. In a preclinical model of luciferase-positive tumour resection using bioluminescence as the gold standard, fluorescence assessment determined by closed-field fluorescence imaging of fresh resected margins accurately predicted the presence of disease in 33/39 positive margins yielding an overall sensitivity of 85%, specificity of 95%, positive predictive value (PPV) of 94%, and a negative predictive value (NPV) of 87%, which was superior to both surgical assessment (54%, 61%, 57%, and 58%) and pathological assessment (49%, 95%, 91%, and 66%), respectively. When the power of the technique was evaluated using human-derived tumour tissues, as little as 0.5mg (1mm(3)) of tumour tissue was identified (tumour-to-background-ratio:5.2). When the sensitivity/specificity of fluorescence-guided pathology was determined using traditional histological assessment as the gold standard in human tissues obtained during fluorescence-guided surgery, the technique was highly accurate with a sensitivity of 91%, specificity of 85%, PPV of 81%, and NPV of 93% for 90 human-derived samples. This approach can be used as a companion to the pathologist, eliminating confounding factors while impacting surgical intervention and patient management.

Psychological impact of breast asymmetry on adolescents: a prospective cohort study.

BACKGROUND: This study measures the impact of adolescent breast asymmetry compared with macromastia and female controls. METHODS: The following surveys were given to patients with breast asymmetry, macromastia, and controls aged 12 to 21 years: Short Form Health Survey, Version 2 (Short Form-36), the Rosenberg Self-Esteem Scale, and the Eating Attitudes Test. Demographics were compared, and linear regression models, adjusted for body mass index category and age, were fit to determine the effect of case status on survey score. RESULTS: Fifty-nine adolescents with asymmetry, 142 controls, and 160 macromastia patients participated. After controlling for differences in body mass index category, asymmetry patients scored lower on psychological Short Form-36 domains and the Rosenberg Self-Esteem Scale than controls (p < 0.05), but did not differ in physical health. When compared with macromastia adolescents, asymmetry patients scored significantly better on Short Form-36 physical health domains (p < 0.05), but had similar decrements in emotional functioning, mental health, self-esteem, and eating behaviors/attitudes, after accounting for differences in age. Age and asymmetry type and severity had no effect on survey scores, independent of body mass index category (p > 0.05). Asymmetry patients had a higher mean body mass index percentile than controls (83.36 versus 73.52) but did not differ from that of macromastia patients (83.39). CONCLUSIONS: Breast asymmetry may negatively impact the psychological quality of life of adolescents similar to macromastia. Breast asymmetry is not just a cosmetic issue. Providers should be aware of the psychological impairments associated with asymmetry and provide proper support.

Epidemiology and differential diagnosis of nasal polyps.

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic medical conditions, with a significant impact on patient quality of life. CRS is broadly classified into two groups: CRS with nasal polyposis (CRSwNP) and CRS without NP (CRSsNP). Clinically, the major subtypes of CRSwNP may be divided into eosinophilic chronic rhinosinusitis (e.g., allergic fungal rhinosinusitis and aspirin-exacerbated respiratory disease [AERD]) and nasal polyps associated with neutrophilic inflammation (e.g., cystic fibrosis [CF]). CF is characterized by mutation of the gene encoding the CF transmembrane conductance regulator. Functional endoscopic sinus surgery is usually required for most NP patients with increased frequency in patients with AERD. This study provides a review of the epidemiology and major classification of CRSwNP. METHODS: A review was performed of the literature regarding different subtypes of CRSwNP. RESULTS: Many definitions of CRSwNP exist and estimates of prevalence vary. CONCLUSION: CRSwNP is a clinical syndrome with a heterogeneous inflammatory profile. Of the subtypes associated with eosinophilic inflammation, AERD remains the most recalcitrant to medical and surgical therapeutic interventions.

Psychosocial impact of adolescent gynecomastia: a prospective case-control study.

BACKGROUND: The purpose of this study was to determine the physical and psychosocial impact of gynecomastia and its severity on adolescents seeking treatment as compared with healthy adolescent males. METHODS: The following surveys were administered to adolescents with gynecomastia and healthy male controls, aged 12 to 21 years: Short Form-36 Version 2, the Rosenberg Self-Esteem Scale, and the Eating Attitudes Test-26. Demographic variables were compared between the two groups, and controls were administered a short chest symptoms survey. Linear regression models, unadjusted and adjusted for body mass index category, were fit to determine the effect of case status and graded severity of gynecomastia on survey score. RESULTS: Forty-seven patients with gynecomastia and 92 male control subjects participated in this study. There was no difference in mean age between the groups, although patients with gynecomastia had a significantly higher body mass index. Gynecomastia subjects had three lower Short Form-36 domain and Rosenberg Self-Esteem Scale scores independent of body mass index category as compared with controls, although there was no difference in Eating Attitudes Test-26 scores between the groups. Graded gynecomastia severity had no effect on survey scores, all independent of body mass index category. CONCLUSIONS: Gynecomastia has a significant negative impact on primarily the psychosocial well-being of affected adolescent patients, specifically in regard to social functioning, mental health, and self-esteem. Psychosocial impact was not affected by graded severity of disease. Health care providers and patients should be aware of the psychosocial impairments associated with gynecomastia and consider early treatment for adolescents suffering from this condition, regardless of severity.