Faculty Bibliography

Objective To examine the prevalence of ultrarapid metabolizers of codeine among children in an ethnically diverse urban community. Study Design Cross-sectional study. Setting A tertiary care academic children's hospital in the Bronx, New York. Subjects and Methods In total, 256 children with nonsyndromic congenital sensorineural hearing loss were analyzed. DNA was assessed for 63 previously described single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) known to alter the function and expression of the CYP2D6 gene primarily responsible for codeine metabolism. The rate of CYP2D6 metabolism was predicted based on participants' haplotype. Results Ethnic distribution in the study subjects paralleled recent local census data, with the largest portion (115 children, 45.8%) identified as Hispanic or Latino. A total of 154 children (80.6%) had a haplotype that corresponds to extensive codeine metabolism, 18 children (9.42%) were identified as ultrarapid metabolizers (UMs), and 16 children (8.37%) were intermediate metabolizers. Only 3 children in our cohort (1.57%) were poor metabolizers. Patients identifying as Caucasian or Hispanic had an elevated incidence of UMs (11.3% and 11.2%, respectively) with extensive variability within subpopulations. Conclusions The clinically significant rate of ultrarapid metabolizers reinforces safety concerns regarding the use of codeine and related opiates. A patient-targeted approach using pharmacogenomics may mitigate adverse effects by individualizing the selection and dosing of these analgesics.

Oxytocin is an important neuromodulator in the mammalian brain that increases information salience and circuit plasticity, but its signaling mechanisms and circuit effect are not fully understood. Here we report robust oxytocinergic modulation of intrinsic properties and circuit operations in hippocampal area CA2, a region of emerging importance for hippocampal function and social behavior. Upon oxytocin receptor activation, CA2 pyramidal cells depolarize and fire bursts of action potentials, a consequence of phospholipase C signaling to modify two separate voltage-dependent ionic processes. A reduction of potassium current carried by KCNQ-based M channels depolarizes the cell; protein kinase C activity attenuates spike rate of rise and overshoot, dampening after-hyperpolarizations. These actions, in concert with activation of fast-spiking interneurons, promote repetitive firing and CA2 bursting; bursting then governs short-term plasticity of CA2 synaptic transmission onto CA1 and, thus, efficacy of information transfer in the hippocampal network.

BACKGROUND:This multicenter, retrospective review documents the initial experience using the Flex system for transoral surgery in 2 United States academic centers. METHODS:All patients who underwent transoral robotic surgery using the Medrobotics Flex Robotic System (Raynham, MA) between September 2015 and May 2017 were reviewed. Rates of successful surgery and complications were evaluated. RESULTS:Thirty-six men and 32 women were enrolled in the study. The average age was 55.6 years (range 17-82 years). The Flex system was used successfully in surgery of the tongue base, the palatine tonsils, the supraglottis, the glottis, the hypopharynx, the oral tongue, and the soft palate. Only 6 cases (7.6%) required readmission after discharge. There were no intraoperative or immediate postoperative complications, with no cases of intraoperative hemorrhage. CONCLUSION/CONCLUSIONS:To the best of our knowledge, this is the first study in the United States evaluating the use of the Flex system to safely resect lesions in the oral cavity, larynx, and pharynx.

OBJECTIVE:The clinical use of microsignals recorded over broad cortical regions is largely limited by the chronic reliability of the implanted interfaces. APPROACH/METHODS:We evaluated the chronic reliability of novel 61-channel micro-electrocorticographic (µECoG) arrays in rats chronically implanted for over one year and using accelerated aging. Devices were encapsulated with polyimide (PI) or liquid crystal polymer (LCP), and fabricated using commercial manufacturing processes. In vitro failure modes and predicted lifetimes were determined from accelerated soak testing. Successful designs were implanted epidurally over the rodent auditory cortex. Trends in baseline signal level, evoked responses and decoding performance were reported for over one year of implantation. MAIN RESULTS/RESULTS:Devices fabricated with LCP consistently had longer in vitro lifetimes than PI encapsulation. Our accelerated aging results predicted device integrity beyond 3.4 years. Five implanted arrays showed stable performance over the entire implantation period (247-435 days). Our regression analysis showed that impedance predicted signal quality and information content only in the first 31 days of recordings and had little predictive value in the chronic phase (> 31 days). In the chronic phase, site impedances slightly decreased yet decoding performance became statistically uncorrelated with impedance. We also employed an improved statistical model of spatial variation to measure sensitivity to locally varying fields, which is typically concealed in standard signal power calculations. SIGNIFICANCE/CONCLUSIONS:These findings show that µECoG arrays can reliably perform in chronic applications in vivo for over one year, which facilitates the development of a high-density, clinically viable interface.

Importance/UNASSIGNED:Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery. Objective/UNASSIGNED:To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules. Design, Setting, and Participants/UNASSIGNED:A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017. Exposures/UNASSIGNED:Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data. Main Outcomes and Measures/UNASSIGNED:The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules. Results/UNASSIGNED:Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58). Conclusions and Relevance/UNASSIGNED:The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.

Posterior glottic stenosis (PGS) describes a laryngeal disorder in which worsening degrees of scarring limit abduction of the vocal folds and/or arytenoids. It can be congenital or acquired. Generally, the acquired form is the result of chronic endotracheal tube trauma to the posterior larynx. Symptoms of acquired PGS usually begin four to eight weeks after extubation, and present as gradually worsening stridor and shortness of breath as the laryngeal obstruction becomes more severe. Without intervention, PGS can cause total obstruction and respiratory failure. The mainstay of treatment for PGS is surgery. We present a case in which an infant patient with PGS was treated with a posterior cricoid split and insertion of a thyroid ala graft. The graft was bolstered in place with an appropriately-sized endotracheal tube during a six-day period of postoperative intubation. We report this as a novel surgical approach, as a literature review did not uncover that this technique has been previously described. Our patient has had excellent airway and voice outcomes. His swallow outcomes have been difficult to assess, as the patient has shown signs of global delay.

PURPOSE/OBJECTIVE:The International Lymphoma Radiation Oncology Group (ILROG) published consensus guidelines on the management of Hodgkin disease (HD) and nodal non-Hodgkin lymphoma (NHL), which became the most downloaded articles from International Journal of Radiation Oncology, Biology, and Physics. E-contouring workshops allow for interactive didactic sessions, allowing participants to see case-based contouring in real time. A pilot 1-hour curriculum was developed with the objective of reviewing ILROG guidelines for HD and NHL management with incorporation of e-contouring tools. This represents the first international education intervention in Spanish using e-contouring with a pre- and postintervention questionnaire. METHODS:A 1-hour presentation was prepared in Spanish reviewing the ILROG recommendations for HD and NHL. The review was followed by the author's demonstration of contour creation using patients with HD and NHL prepared for the American Society for Radiation Oncology's 2015 e-contouring lymphoma session. A five- question evaluation was prepared and administered before and after intervention. A two-tailed paired t test was performed to evaluate any significant change in test value before and after intervention. RESULTS:A total of nine quizzes were collected before and after the intervention. The average test score before the intervention was 75.6%, and the average test score after the intervention was 86.7% ( P = .051). Four students scored 100% on both the pre- and postintervention evaluations, and no student had a decrease in score from pre- to postintervention evaluation. The topic with the lowest score tested dose consideration. CONCLUSION/CONCLUSIONS:A substantial but nonsignificant improvement in test evaluation was seen with this pilot curriculum. This pilot intervention identified obstacles for truly interactive didactic sessions that, when addressed, can lead to fully developed interactive didactic sessions.

Purpose/UNASSIGNED:Head and neck surgery and radiation cause tissue fibrosis that leads to functional limitations and lymphedema. The objective of this study was to determine whether lymphedema therapy after surgery and radiation for head and neck cancer decreases neck circumference, increases cervical range of motion, and improves pain scores. Methods and materials/UNASSIGNED:A retrospective review of all patients with squamous cell carcinoma of the oral cavity, oropharynx, or larynx who were treated with high-dose radiation therapy at a single center between 2011 and 2012 was performed. Patients received definitive or postoperative radiation for squamous cell carcinoma of the oral cavity, oropharynx, or larynx. Patients were referred to a single, certified, lymphedema therapist with specialty training in head and neck cancer after completion of radiation treatment and healing of acute toxicity (typically 1-3 months). Patients underwent at least 3 months of manual lymphatic decongestion and skilled fibrotic techniques. Circumferential neck measurements and cervical range of motion were measured clinically at 1, 3, 6, 9, and 12 months after completion of radiation therapy. Pain scores were also recorded. Results/UNASSIGNED:Thirty-four consecutive patients were eligible and underwent a median of 6 months of lymphedema therapy (Range, 3-12 months). Clinically measured total neck circumference decreased in all patients with 1 month of treatment. Cervical rotation increased by 30.2% on the left and 27.9% on the right at 1 month and continued to improve up to 44.6% and 55.3%, respectively, at 12 months. Patients undergoing therapy had improved pain scores from 4.3 at baseline to 2.0 after 1 month. Conclusions/UNASSIGNED:Lymphedema therapy is associated with objective improvements in range of motion, neck circumference, and pain scores in the majority of patients.