Faculty Bibliography

There is currently a major paradigm shift from excision-based surgery to strictly volume enhancement. Because there is still no perfect facial filler, development of synthetic facial injectables continue to advance at a remarkable pace. Each type of filler carries a specific characteristic that makes it more suitable for a certain clinical application. The continuing change in facial fillers offers the possibility for volume augmentation procedures with less downtime and without the need for harvesting fat. We predict that volume enhancement will continue to play an increasing role as both a complementary and as a stand-alone procedure in facial rejuvenation.

BACKGROUND:Insulin resistance increases during adolescence in those with type 1 diabetes mellitus (T1DM), complicating glycemic control and potentially increasing cardiovascular disease (CVD) risk. Metformin, typically used in type 2 diabetes mellitus (T2DM), is a possible adjunct therapy in T1DM to help improve glycemic control and insulin sensitivity. OBJECTIVE:We hypothesized that metformin would improve metabolic parameters in adolescents with T1DM. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This randomized, double-blinded, placebo-controlled trial included 74 pubertal adolescents (ages: 13-20 yr) with T1DM. Participants were randomized to receive either metformin or placebo for 6 months. Glycated hemoglobin (HbA1c), insulin dose, waist circumference, body mass index (BMI), and blood pressure were measured at baseline, 3 and 6 months, with fasting lipids measured at baseline and 6 months. RESULTS:Total daily insulin dose, BMI z-score and waist circumference significantly decreased at 3 and 6 months compared to baseline within the metformin group, even among normal-weight participants. In the placebo group, total insulin dose and systolic blood pressure increased significantly at 3 months and total insulin dose increased significantly at 6 months. No significant change was observed in HbA1c at any time point between metformin and placebo groups or within either group. CONCLUSIONS:Low-dose metformin likely improves BMI as well as insulin sensitivity in T1DM adolescents, as indicated by a decrease in total daily insulin dose. The decrease in waist circumference indicates that fat distribution is also likely impacted by metformin in T1DM. Further studies with higher metformin doses and more detailed measurements are needed to confirm these results, their underlying mechanisms, and potential impact on CVD in T1DM youth.

ABSTRACT The purpose of this study was to evaluate the long-term outcome and patterns of failure in patients treated with primary radiotherapy (RT) for orbital lymphoma (OL). Seventy-nine patients diagnosed with Stage IE OL between 1995 and 2012 were included. Fifty-nine patients (75%) had mucosa-associated lymphoid tissue and 20 patients (25%) were of follicular lymphoma subtype. The median follow-up was 49.7 months. Major tumor sites were conjunctivas (29%), orbit (47%), and lacrimal glands (24%). After treatment to a median dose of 30.6Gy, there were a total of 0 local, 1 contralateral orbital, 2 regional, and 2 distant recurrences - all outside of the treatment fields. The 10-year local relapse-free, distant metastasis-free and overall rates were 100%, 94.2%, and 98.2%, respectively. Definitive RT to 30Gy was shown to be highly effective for indolent OL and this study represents one of the largest single institution studies using primary RT for Stage IE OL.

The first World Workshop on Oral Medicine (WWOM) was held in 1988. The portfolio has continued to expand in scope and impact over the past 26 years. Five World Workshops were conducted between 1988 and 2010, focusing on creation of systematic reviews in biomedicine and health care of importance to the international oral medicine community. WWOM VI was conducted in April 2014 and further extended this modeling. This most recent Workshop also fostered creation of the inaugural joint meeting between the American Academy of Oral Medicine and the European Association of Oral Medicine, together with The British Society for Oral Medicine and the Oral Medicine Academy of Australasia. The goal of the WWOM portfolio is to strategically enhance international oral medicine research, education, and clinical practice. To this end, this report summarizes subject areas for WWOM IV (2004) and research recommendations for WWOM V (2010), as well as citation metrics relative to publications from these two conferences. The information is designed to provide research and clinical context for key issues in oral medicine as delineated by the WWOM portfolio over the past 10 years, as well as for projected outcomes of WWOM VI over the next 12 months.

IMPORTANCE/OBJECTIVE:Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. OBJECTIVE:To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. INTERVENTION/METHODS:A brief course of erlotinib monotherapy followed by surgical resection. MAIN OUTCOMES AND MEASURES/METHODS:Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. RESULTS:No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Selective erlotinib use in HNSCC may be informed by precision oncology approaches.

OBJECTIVE:To compare post-cochlear implantation (CI) early speech perception (ESP) outcomes between a non-English speaking, ethnic minority study group and an English speaking, ethnic majority control group. STUDY DESIGN/METHODS/METHODS:We performed a retrospective case-control study at an academic tertiary care children's hospital. Records were reviewed of 49 children who underwent CI from February 2005 to September 2011. Children with abnormal cognitive function (n=12), post-surgical complications (n=1), or incomplete SP testing (n=24) were excluded. The remaining 12 cases (mean implant age 4.3 y) were reviewed for language, income, ethnicity, and ESP scores. Their scores were compared to a subset of patients (n=18; mean implant age 2.2 y) serving as control from the Childhood Development after Cochlear Implantation (CDaCI) study at 1 year follow up where standard ESP testing was performed. Briefly, CDaCI includes a demographically balanced and multicenter-based pediatric cohort from which publications are beginning to define normative post-CI SP outcomes. RESULTS:Of our 12 children, 7 were Hispanic, 2 Caucasian, 2 multi-ethnicity and 1 Russian. 4 were non-English speaking, 5 spoke English as a second language, and 7 were bilingual. Three received bilateral CI. Mean early speech perception (ESP) scores (reported on a scale of 1-4) collected at 6 and 12 months in the study group were 1.71 and 1.75, respectively; in the control group, 3.83 and 3.92. At both follow up intervals the study group performed significantly worse than the control group (6 mo P=0.048, 12 mo P=0.01). CONCLUSIONS:This study suggests that among pediatric CI recipients, those from predominantly non-English speaking, socioeconomically disadvantaged backgrounds develop SP at slower than normal rates. Future interventions should be directed at overcoming these obstacles.

More than half of all cancer patients have significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. We show that TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2 immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hind paw of wild-type mice but not PAR2-deficient mice. Coculture of human cancer cells with murine trigeminal neurons demonstrated colocalization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane-anchored mediator in cancer pain, as well as pain in general.

BACKGROUND:Hyperhomocysteinemia is associated with increased cardiovascular risk, but treatment with folic acid has no effect on outcome in unselected patient populations. OBJECTIVES/OBJECTIVE:To confirm previous observations on the association of homozygosity for the TT MTHFR genotype with B12 deficiency and endothelial dysfunction, and to investigate whether patients with B12 deficiency should be tested for 677MTHFR genotype. METHODS:We enrolled 100 individuals with B12 deficiency, tested them for the MTHFR C677T polymorphism and measured their homocysteine levels. Forearm endothelial function was checked in 23 B12-deficient individuals (13 with TT MTHFR genotype and 10 with CT or CC genotypes). Flow-mediated dilatation (FMD) was tested after short-term treatment with B12 and folic acid in 12 TT MTHFR homozygotes. RESULTS:Frequency of the TT MTHFR genotype was 28/100 (28%), compared with 47/313 (15%) in a previously published cohort of individuals with normal B12 levels (P = 0.005). Mean homocysteine level was 21.2 ± 16 μM among TT homozygotes as compared to 12.3 ± 5.6 μM in individuals with the CC or CT genotype (P = 0.008). FMD was abnormal ( 6%) in 9/13 TT individuals with B12 deficiency (69%), and was still abnormal in 7/12 of those tested 6 weeks after B12 and folic treatment (58%). CONCLUSIONS:Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid. Based on our findings we suggest that B12 deficiency be tested for MTHFR polymorphism in order to identify potential vascular abnormalities and increased cardiovascular risk.

The objective of this study is to establish normative waveform data for the external branch of the superior laryngeal nerve (SLN) utilizing laryngeal surface electrodes and intraoperative neurophysiological monitoring (IONM) in conjunction with a clinical neurophysiologist. A retrospective chart review of 91 consecutive at-risk SLN were identified in 51 patients in whom IONM using laryngeal surface electrodes was performed by a clinical neurophysiologist using Dragonfly (Neurovision Medical Products, Ventura, CA) recording electrodes and a Protektor (Natus Medical Inc., San Carlos, CA)16 channel- intraoperative nerve monitoring system. Inclusion criteria were met for 30 SLN. Data collected included preoperative diagnosis, surgical procedure, rates of nerve identification and stimulation, and waveform characteristics. Waveform analysis for 30 SLN yielded a peak latency of 4.0 ± 0.2 ms, onset latency 2.3 ± 0.1 ms, peak-to-peak amplitude of 220.4 ± 31.1 µV, onset-to-peak amplitude of 186.0 ± 25.0 µV, and stimulation current threshold of 0.55 ± 0.03 mA (data = mean ± SEM). Two patients had abnormal SLN function documented clinically on postoperative laryngoscopic examination. Laryngeal surface electrodes were successfully utilized to identify and monitor SLN function intraoperatively. IONM using laryngeal surface electrodes enables analysis of waveform morphology and latency in addition to threshold and amplitude data obtained with the traditional NIM system, potentially improving the performance of nerve monitoring during thyroid surgery.

Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.