Eric J. Formeister

Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium.

SOX transcription factors have the capacity to modulate stem/progenitor cell proliferation and differentiation in a dose-dependent manner. SOX9 is expressed in the small intestine epithelial stem cell zone. Therefore, we hypothesized that differential levels of SOX9 may exist, influencing proliferation and/or differentiation of the small intestine epithelium. Sox9 expression levels in the small intestine were investigated using a Sox9 enhanced green fluorescent protein (Sox9(EGFP)) transgenic mouse. Sox9(EGFP) levels correlate with endogenous SOX9 levels, which are expressed at two steady-state levels, termed Sox9(EGFPLO) and Sox9(EGFPHI). Crypt-based columnar cells are Sox9(EGFPLO) and demonstrate enriched expression of the stem cell marker, Lgr5. Sox9(EGFPHI) cells express chromogranin A and substance P but do not express Ki67 and neurogenin3, indicating that Sox9(EGFPHI) cells are postmitotic enteroendocrine cells. Overexpression of SOX9 in a crypt cell line stopped proliferation and induced morphological changes. These data support a bimodal role for SOX9 in the intestinal epithelium, where low SOX9 expression supports proliferative capacity, and high SOX9 expression suppresses proliferation.

Multi-material 3D Models for Temporal Bone Surgical Simulation.

Hypothesis: A simulated, multicolor, multi-material temporal bone model can be created using 3-dimensional (3D) printing that will prove both safe and beneficial in training for actual temporal bone surgical cases. Background: As the process of additive manufacturing, or 3D printing, has become more practical and affordable, a number of applications for the technology in the field of Otolaryngology–Head and Neck Surgery have been considered. One area of promise is temporal bone surgical simulation. Methods: Three-dimensional representations of human temporal bones were created from temporal bone computed tomography (CT) scans using biomedical image processing software. Multi-material models were then printed and dissected in a temporal bone laboratory by attending and resident otolaryngologists. A 5-point Likert scale was used to grade the models for their anatomical accuracy and suitability as a simulation of cadaveric and operative temporal bone drilling. Results: The models produced for this study demonstrate significant anatomic detail and a likeness to human cadaver specimens for drilling and dissection. Conclusion: Simulated temporal bones created by this process have potential benefit in surgical training, preoperative simulation for challenging otologic cases, and the standardized testing of temporal bone surgical skills.

Comparative analysis of promoter methylation and gene expression endpoints between tumorous and non-tumorous tissues from HCV-positive patients with hepatocellular carcinoma

Transcriptional silencing of tumor suppressor genes and other cancer-related genes induced by promoter CpG island hypermethylation is an important epigenetic mechanism of hepatocarcinogenesis. Previous studies have established methylation profiles of hepatocellular carcinomas (HCCs) and demonstrated that methylation of several candidate genes in resected tissues may be associated with time to recurrence. The goals of our study were to test whether specific promoter methylation and mRNA levels of candidate genes, as well as global changes in DNA methylation, can be linked with time to recurrence and clinicopathological variables in a homogenous study group of HCC patients. Forty-three tumorous and 45 non-tumorous liver tissue samples from the surgical margin were obtained from HCV-positive, HBV-negative HCC patients who underwent tumor resection surgery and who were monitored for tumor recurrence thereafter (median follow-up time: 16 months (range, 0-79 months)). Methylation-specific PCR was used to assess the promoter methylation status of P16(INK4a), SOCS-1, RASSF1A, APC, GSTP1, RIZ1, and MGMT genes, while the level of LINE-1 methylation was used as marker of global DNA methylation levels. Methylation frequencies in P16(INK4a), RASSF1A, APC, GSTP1, and RIZ1 genes were significantly greater in tumorous versus non-tumorous tissues. Methylation of RIZ1 in non-tumorous tissues was significantly associated with time to recurrence. Additionally, genomic DNA was significantly more hypomethylated in tumorous tissues, and this change was associated with shorter recurrence, but not with clinicopathological features. In conclusion, this study supports the role of aberrant methylation in the pathobiology of HCV-positive HCCs. The finding that RIZ1 methylation and increased levels of LINE-1 hypomethylation in non-tumorous tissues are associated with time to recurrence underscores the importance of assessing the epigenetic state of the liver remnant.

Pre-operative simulation of pediatric mastoid surgery with 3D-printed temporal bone models

OBJECTIVES As the process of additive manufacturing, or three-dimensional (3D) printing, has become more practical and affordable, a number of applications for the technology in the field of pediatric otolaryngology have been considered. One area of promise is temporal bone surgical simulation. Having previously developed a model for temporal bone surgical training using 3D printing, we sought to produce a patient-specific model for pre-operative simulation in pediatric otologic surgery. Our hypothesis was that the creation and pre-operative dissection of such a model was possible, and would demonstrate potential benefits in cases of abnormal temporal bone anatomy. METHODS In the case presented, an 11-year-old boy underwent a planned canal-wall-down (CWD) tympano-mastoidectomy for recurrent cholesteatoma preceded by a pre-operative surgical simulation using 3D-printed models of the temporal bone. The models were based on the childs pre-operative clinical CT scan and printed using multiple materials to simulate both bone and soft tissue structures. To help confirm the models as accurate representations of the childs anatomy, distances between various anatomic landmarks were measured and compared to the temporal bone CT scan and the 3D model. RESULTS The simulation allowed the surgical team to appreciate the childs unusual temporal bone anatomy as well as any challenges that might arise in the safety of the temporal bone laboratory, prior to actual surgery in the operating room (OR). There was minimal variability, in terms of absolute distance (mm) and relative distance (%), in measurements between anatomic landmarks obtained from the patient intra-operatively, the pre-operative CT scan and the 3D-printed models. CONCLUSIONS Accurate 3D temporal bone models can be rapidly produced based on clinical CT scans for pre-operative simulation of specific challenging otologic cases in children, potentially reducing medical errors and improving patient safety.

Round window electrocochleography and speech perception outcomes in adult cochlear implant subjects: Comparison with audiometric and biographical information

Hypothesis Intraoperative round window (RW) electrocochleography (ECoG) can help predict speech perception outcomes in adult cochlear implant (CI) recipients. Background Speech perception outcomes using CIs are highly variable. Recent data demonstrated that intraoperative ECoG could account for nearly half the variance in postoperative word scores. The present study seeks to update this correlation with a larger sample size and determine if addition of clinical variables improves the prediction. Methods Intraoperative RW ECoG was performed in adult subjects undergoing CI. Amplitudes of the ongoing response to tone bursts of multiple frequencies at 85 to 95 dB HL were summed to obtain the total response (ECoG-TR). ECoG-TR was correlated with postoperative speech perception scores. Multiple linear regression was used to combine clinical factors with the ECoG-TR. Results The ECoG-TR accounted for 40% of the variance in CNC word scores (n = 32). The preoperative pure tone average (PTA) was the only clinical factor with a significant correlation (r2 = 20%). The ability to predict word scores using ECoG-TR and PTA, or after addition of age and duration of hearing loss, was not significantly different from using ECoG-TR alone. For 2 outliers, ECoG-TR predicted a better word score than obtained. Conclusions The measurement of cochlear physiology before CI, reduced to a single variable, is a better predictor of postoperative speech perception than common clinical factors. Additional analysis of the outliers showed that waveform morphology can provide distinct information in individual cases.

Intraoperative round window electrocochleography and speech perception outcomes in pediatric cochlear implant recipients.

Objectives: The goal was to measure the magnitude of cochlear responses to sound in pediatric cochlear implant recipients at the time of implantation and to correlate this magnitude with subsequent speech perception outcomes. Design: A longitudinal cohort study of pediatric cochlear implant recipients was undertaken. Intraoperative electrocochleographic (ECoG) recordings were obtained from the round window in response to a frequency series at 90 dB nHL in 77 children totaling 89 ears (12 were second side surgeries) just before device insertion. The increase in intraoperative time was approximately 10 min. An ECoG “total response” metric was derived from the summed magnitudes of significant responses to the first, second, and third harmonics across a series of frequencies. A subset of these children reached at least 9 months of implant use and were old enough for the phonetically balanced kindergarten (PB-k) word test to be administered (n = 26 subjects and 28 ears). PB-k scores were compared to the ECoG total response and other biologic and audiologic variables using univariate and multiple linear regression analyses. Results: ECoG responses were measurable in almost all ears (87 of 89). The range of ECoG total response covered about 60 dB (from ~0.05 to 50 &mgr;V). Analyzing individual ECoG recordings in bilaterally implanted children revealed poor concordance between the measured response in the first versus second ear implanted (r2 = 0.21; p = 0.13; n = 12). In a univariate linear regression, the ECoG total response was significantly correlated with PB-k scores in the subset of 26 subjects who were able to be tested and accounted for 32% of the variance (p = 0.002, n = 28). Preoperative pure-tone average (PTA) accounted for slightly more of the variance (r2 = 0.37, p = 0.001). However, ECoG total response and PTA were significantly but only weakly correlated (r2 = 0.14, p = 0.001). Other significant predictors of speech performance included hearing stability (stable versus progressive) and age at testing (22 and 16% of the variance, respectively). In multivariate analyses with these four factors, the ECoG accounted for the most weight (&bgr; = 0.36), followed by PTA (&bgr; = 0.26). In a hierarchical multiple regression analysis, the most parsimonious models that best predicted speech perception outcomes included three variables: ECoG total response, and any two of preoperative PTA, age at testing, or hearing stability. The various three factor models each predicted approximately 50% of the variance in word scores. Without the ECoG total response, the other three factors predicted 36% of variance. Conclusions: Intraoperative round window ECoG recordings are reliably and easily obtained in pediatric cochlear implant recipients. The ECoG total response is significantly correlated with speech perception outcomes in pediatric implant recipients and can account for a comparable or greater proportion of variance in speech perception than other bio-audiologic factors. Intraoperative recordings can potentially provide useful prognostic information about acquisition of open set speech perception in implanted children.

Surgical management of chronic sialorrhea in pediatric patients: 10-year experience from one tertiary care institution

BACKGROUND Chronic sialorrhea is a common problem for pediatric patients with disorders that affect swallowing. While many patients are successfully treated with medical therapies such as Robinul and Scopolamine, a number of such children are not able to tolerate the side effects of these medications. In these cases, surgical treatments can include Botulinum toxin A (Botox) injections into the major salivary glands, sublingual or submandibular gland excision (SMGE), submandibular duct ligation, parotid duct ligation (PDL), or any combination of the above procedures. The purpose of this study is to report on the 10-year experience with the surgical management of chronic sialorrhea at one tertiary care institution, and compare the efficacy of open surgical procedures versus Botox injections for reduction in salivary flow. METHODS A retrospective chart review identified 27 pediatric patients with chronic sialorrhea; 21 of whom underwent Botox injections and 15 of whom underwent surgical procedures. Preoperative and follow-up clinic notes were reviewed to determine the level and severity of drooling as well as the effectiveness of sialorrhea reduction, as assessed by the Teacher Drooling Scale (TDS). RESULTS 42% of those receiving Botox injections reported a reduction in drooling, with the average pre- and post-Botox TDS of 4.3 and 3.9, respectively (p=0.02 by the Wilcoxon signed rank test). Nine of the patients receiving Botox injections (43%) required multiple injections, with an average duration of effect of 3.9 months, and 7 patients (33%) eventually required surgery. All of the children who underwent surgery (7 bilateral SMGE with PDL, 6 SMGE only, and 2 PDL only) experienced a reduction in drooling, with average pre- and post-operative TDS of 4.5 and 2.2, respectively. This reduction was significant by the Wilcoxon signed rank test (p=0.001). CONCLUSIONS The ten-year experience at our institution demonstrates the safety, efficacy and long-term control of drooling in the patients undergoing surgery for intractable sialorrhea.

Round window electrocochleography before and after cochlear implant electrode insertion

Previous reports have documented the feasibility of utilizing electrocochleographic (ECoG) responses to acoustic signals to assess trauma caused during cochlear implantation. The hypothesis is that intraoperative round window ECoG before and after electrode insertion will help predict postoperative hearing preservation outcomes in cochlear implant recipients.

Facial Cutaneous Necrosis Associated With Suspected Levamisole Toxicity From Tainted Cocaine Abuse

Objective: This study aimed to illustrate the otorhinolaryngologic manifestations of levamisole toxicity and illuminate the features of this diagnosis. Methods: We describe a case of a known cocaine abuser with suspected levamisole toxicity who developed cutaneous necrosis of the cheeks, earlobes, nose, upper and lower lip, and the midline hard palate. We also review the existing clinical literature about this emerging phenomenon. Results: Levamisole is a common adulterant in cocaine distributed in the United States and has been reported to cause microvascular thrombosis and vasculitis with resultant skin necrosis in cocaine abusers. The distribution of skin findings characteristically involves the cheeks, earlobes, nose, lips, and hard palate and responds variably to cessation of cocaine use. In its most severe cases, immune suppression and/or surgical debridement may be required. Conclusion: Levamisole toxicity can frequently involve the ears, nose, and throat tissues. Otorhinolaryngologists should recognize these manifestations to expeditiously diagnose and manage this condition. Failure to do so promptly can lead to complications that may necessitate reconstructive or amputation surgery.

Cochlear Implants in Single-Sided Deafness

Single-sided deafness presents a unique challenge to otolaryngologists and audiologists. While the normal hearing ear may allow listeners to perform adequately on audiometric screening, individuals with only one functioning cochlea suffer when resolving speech in noisy environments and in sound localization—which both contribute to a reduced quality of life. Though there are a variety of strategies that provide contralateral routing of sound signals, the cochlear implant is the only treatment to truly restore binaural hearing. Only very recently has cochlear implantation (CI) for single-sided deafness begun in earnest, with encouraging results that demonstrate the strengths and pitfalls of implantation over traditional extracochlear methods. The purpose of this review is to update the field by emphasizing binaural benefits, discussing historical treatments of single-sided deafness, critically evaluating recent data on outcomes of CI for single-sided deafness, and recommending indications for cochlear implants in single-sided deafness in children, adults, and subjects with concurrent ipsilateral tinnitus.