Faculty Bibliography

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

Chronic administration of colchicine remains a mainstay of therapy for patients with Familial Mediterranean Fever (FMF). As this medication is a strong CYP3A4 inhibitor, it has the potential to interact with many routinely used medications. One such medication is clarithromycin, itself a strong inhibitor of the same enzyme, and a typical choice for triple therapy eradication of H. pylori. Various sequelae of colchicine-clarithromycin interaction have been documented and can be expected by prescribing physicians, with rhabdomyolysis, though rare, being among the most serious. Review of cases from a tertiary academic medical center and full PubMed/MEDLINE literature review. Despite the prevalence of diseases treated with clarithromycin and the expected drug interaction with colchicine, only two cases in the literature document clinical rhabdomyolysis due to colchicine-clarithromycin interaction. In neither case, however, were patients undergoing treatment for FMF. Herein, we describe the first two cases in the literature of clinical rhabdomyolysis in FMF patients under colchicine therapy after administration of clarithromycin as part of therapy treating H. pylori infection.

BACKGROUND:Lepidopterism refers to the manifestations of contact from any number of moths, butterflies, and caterpillars. Various symptoms have been described, ranging from localized skin irritation to systemic anaphylactic reactions. CASE REPORT/METHODS:We present a case of airway edema in an 8-month-old child from oral exposure to Woolly Bear Caterpillar (Pyrrharctia Isabella). After prompt emergency department recognition, her symptoms necessitated urgent operating room management by a team of otolaryngologists and close monitoring in a pediatric intensive care unit. A similar presentation in this species has not been described previously in the English literature. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Leptidopterism is rare, but recognition by the emergency practitioner is necessary for prompt and appropriate treatment. Rapid identification by the emergency physician of oral exposure and careful spine removal can be lifesaving in cases of significant oropharyngeal edema.

PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross-sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one-way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states.

BACKGROUND: Aging of the face, neck, and decolletage is a multifactorial process involving epidermal photodamage and loss of soft tissue and bony volume. Multilevel rejuvenation of these areas can be obtained by enhancing volume restoration, neocollagenesis, and tissue contraction with combined efficacy of poly-L-lactic acid (PLLA) and microfocused ultrasound (MFU, Ultherapy) treatments. METHODS: The authors reviewed the use of PLLA and MFUs as collaborative modalities to improve the appearance of the face, neck, and decolletage. RESULTS: Experienced cosmetic dermatology centers deliver PLLA and MFU in a single session to target multiple tissue planes. CONCLUSIONS: Concurrent treatment with PLLA and MFUs can be performed efficiently and safely; however, additional research is needed to explore the synergistic effects of these treatments. Patients may also benefit from decreased overall downtime and necessary office visits.

In order to localize the neural circuits involved in generating behaviors, it is necessary to assign activity onto anatomical maps of the nervous system. Using brain registration across hundreds of larval zebrafish, we have built an expandable open-source atlas containing molecular labels and definitions of anatomical regions, the Z-Brain. Using this platform and immunohistochemical detection of phosphorylated extracellular signal-regulated kinase (ERK) as a readout of neural activity, we have developed a system to create and contextualize whole-brain maps of stimulus- and behavior-dependent neural activity. This mitogen-activated protein kinase (MAP)-mapping assay is technically simple, and data analysis is completely automated. Because MAP-mapping is performed on freely swimming fish, it is applicable to studies of nearly any stimulus or behavior. Here we demonstrate our high-throughput approach using pharmacological, visual and noxious stimuli, as well as hunting and feeding. The resultant maps outline hundreds of areas associated with behaviors.

PURPOSE: Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS: A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS: RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION: Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

INTRODUCTION/BACKGROUND:Ultrasonography-guided fine-needle aspiration (US-FNA) yields diagnostic material more often than palpation-guided FNA does. It is often performed by an interventional radiologist (IR) but rarely by a cytopathologist (CP). Herein we describe our method of performance and growing experience with this technique. MATERIALS AND METHODS/METHODS:Data from US-FNA of head and neck lesions performed over a 33-month period by both a CP and an IR were reviewed. Special attention was paid to cases for which histologic follow-up was available. Association in concordance between cytologic and histologic diagnoses was attempted using Fisher's exact test. Mean size of masses biopsied, number of passes performed, and passes needed to achieve adequacy were compared between groups using the Wilcoxon rank-sum test. Tests were 2-sided with P < 0.05 regarded as statistically significant. RESULTS:Of the 175 US-FNAs performed, 108 (62%) were done by the CP and 67 (38%) by the IR. Fifty-eight patients had histologic follow-up; 37 (64%) for the CP and 21 (36%) for the IR. Mean mass size was significantly smaller for the IR at 2.11 cm versus 2.9 cm for the CP (P = 0.021). Adequacy was achieved after 1 pass in 70% of cases (26 of 37) by the CP and 67% (14 of 21) by the IR. Number of passes performed did not vary significantly between groups. A variety of masses were biopsied; however, the small sample size precluded meaningful evaluation of cytologic concordance to final histology. CONCLUSIONS:CP-performed US-FNA has been successfully delivered to clinicians at our institution.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Adenosquamous carcinoma (ASC) is a rare variant of head-and-neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC. STUDY DESIGN/METHODS:Case-control retrospective study. METHODS:Forty-two primary tumors of the head and neck, treated with curative intent, were identified. Next, 2:1 matching of HNSCC was performed using the following matching criteria: gender, site, pathologic tumor stage, and pathologic node stage. Successful matching was performed for 32 of 42 tumors. Additionally, 20 samples were sent for break-apart FISH testing to evaluate for the presence of the CRTC1-MAML2 translocation. RESULTS:There was a 1.8:1 male to female ratio, with a mean age of 62 years (range 38-84). The layrnx was the most common site (26%), followed by oropharynx (24%), oral cavity (19%), and sinonasal (17%). Kaplan-Meier analysis of adenosquamous and matched HNSCC showed similar survival curves. Median survival times for ASC and HNSCC were 4 and 6 years, respectively. A random-effects Cox model with Gamma frailty revealed no statistical difference between the two groups (P=0.25). All cases of ASC were negative for the CRTC1-MAML2 translocation. CONCLUSION/CONCLUSIONS:This study directly compares primary ASC with HNSCC. No difference in overall survival was detected in contradistinction to the previously thought uniformly poor prognosis. We also highlight the importance of the CRTC1-MAML2 translocation in distinguishing ASC from mucoepidermoid carcinoma. LEVEL OF EVIDENCE/METHODS:3b.

OBJECTIVE:Congenital dermoid cysts of the skull and face frequently arise in embryonic fusion planes. They may follow these planes to extend intratemporally or intracranially. Advanced imaging and operative techniques are generally recommended for these lesions. Postauricular temporal bone dermoid cysts seem to form a distinct subgroup with a lesser tendency toward deep extension. They may be amenable to more conservative management strategies. METHODS:With IRB-approval, we queried a prospectively-accrued computerized patient-care database to find all postauricular temporal dermoid lesions surgically managed by a single pediatric otolaryngologist from 2001 to 2014. We reviewed the English-language literature to identify similar series of surgically treated pediatric temporal bone dermoid cysts. RESULTS:Ten postauricular temporal dermoid cysts with pathological confirmation were identified in our surgical series. The average size of the lesions was 1.5 cm (0.3-3 cm). The average age at time of surgery was 4 years (6 months-17 years). No intracranial extension was observed at surgery. There were no recurrences noted on last follow-up (mean 65 months, range 10-150 months). A computerized literature review found no examples of intracranial extension among typical postauricular dermoid cysts. CONCLUSION/CONCLUSIONS:There was no intracranial or temporal extension in our series or among postauricular lesions described in the literature. Given the low incidence of deep extension we advocate neither advanced imaging nor routine neurosurgical consultation for typical postauricular lesions. Dissection in continuity with cranial periosteum facilitates intact removal of adherent lesions. Surgery is curative if the dermoid is removed intact.