Faculty Bibliography

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Direct glucocorticoid (GC) injection for vocal fold (VF) scarring has evolved as a therapeutic strategy, but the mechanisms underlying the antifibrotic effects remain unclear. GCs act via the glucocorticoid receptor (GR), which is phosphorylated at multiple serine residues in a hormone-dependent manner to affect bioactivity. We hypothesize that GCs regulate SMAD signaling via GR phosphorylation in vocal fold fibroblasts (VFFs). STUDY DESIGN/METHODS:In vitro. METHODS:phosphorylation was examined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunocytochemistry. Quantitative polymerase chain reaction was employed to determine GR-mediated effects of DM on genes related to fibrosis. RESULTS:phosphorylation increased. RU486 limited the effects of DM. SMAD3 and SMAD7 mRNA expression significantly decreased 4 hours after DM administration (P < 0.05); this response was negated by RU486. COL1A1 remained unchanged, and ACTA2 significantly increased following 24 hours of DM treatment (P < 0.05). CONCLUSION/CONCLUSIONS:DM regulated TGF-β1 signaling via altered SMAD3 and SMAD7 expression. This response was associated with altered GR phosphorylation. These findings provide insight into the mechanisms of steroidal effects on vocal fold repair; ultimately, we seek to enhance therapeutic strategies for these challenging patients. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2018.

OBJECTIVE:Patients with globus, the sensation of something stuck in the throat, are evaluated by otolaryngologists, gastroenterologists, and speech pathologists and often undergo multiple tests and interventions. We hypothesize that a videofluoroscopic swallow study (VFSS) is useful to characterize globus etiology and correlate subjective globus location to atypical VFSS findings. METHOD/METHODS:Retrospective chart review of all patients undergoing VFSS over a 24-month period with a primary complaint of globus. Globus was characterized by the patient as above the thyroid notch, between the thyroid notch and sternum, or substernal. VFSS findings were categorized as oropharyngeal, pharyngoesophageal, or esophageal based on nine VFSS abnormalities and then further broken out for subgroup analyses. RESULTS:Of 216 patients meeting study criteria, 109 patients localized globus above the thyroid notch, 74 between the thyroid notch and sternum, and 33 substernal. One hundred ninety-five patients (90.3%) had at least one finding on VFSS that could account for symptoms, and the majority had multiple. In fact, 21 patients (9.7%) with dysphagia localized above the thyroid notch had evidence of distal esophageal abnormalities, and 15 (6.9%) with dysphagia localized substernal had oropharyngeal abnormalities. CONCLUSION/CONCLUSIONS:Whereas VFSS was likely to identify abnormalities, these areas relate poorly overall with the patient's subjective globus location, and the clinical utility of the study is questionable. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:New advances in osseous microvascular mandibular rigid fixation are being employed at many institutions. These include standardized prebent/preformed reconstruction plates as well as computer-aided design/computer-aided manufacturing (CAD/CAM) custom plates that are patient specific. Our goal was to assess and compare the outcomes of both of these new technologies when utilized for mandibular microvascular reconstruction. STUDY DESIGN/METHODS:Retrospective chart review. METHODS:, Fisher exact test, and multivariable regression models. RESULTS:A total of 142 subjects underwent microvascular mandibular reconstruction in a 6-year period. Eighty-nine subjects utilized prebent/preformed plates, and 53 employed CAD/CAM custom plates. Perioperative complications occurred in 32 of 89 (35.9%) subjects with prebent/preformed plates and 11 of 53 (20.7%) subjects using CAD/CAM custom plates. Reoperation requiring hardware explantation occurred in 18 of 89 (20.2%) subjects and three of 53 (5.6%) using CAD/CAM custom plates. Statistical comparison of perioperative complications between the two groups approached significance (P = .0556), and the rate of reoperation was significant favoring CAD/CAM implants (P = .0180). CONCLUSIONS:In our experience, CAD/CAM custom plates utilized for rigid fixation during microvascular mandibular reconstruction demonstrated fewer complications and statistically lower reoperation rates when compared with prebent/preformed plates. LEVEL OF EVIDENCE/METHODS:2c Laryngoscope, 2018.

BACKGROUND:A current challenge in osteoporosis is identifying patients at risk of bone fracture. PURPOSE/OBJECTIVE:To identify the machine learning classifiers that predict best osteoporotic bone fractures and, from the data, to highlight the imaging features and the anatomical regions that contribute most to prediction performance. STUDY TYPE/METHODS:Prospective (cross-sectional) case-control study. POPULATION/METHODS:. Field Strength/ Sequence: 3D FLASH at 3T. ASSESSMENT/RESULTS:Quantitative MRI outcomes by software algorithms. Mechanical and topological microstructural parameters of the trabecular bone were calculated for five femoral regions, and added to the vector of features together with bone mineral density measurement, fracture risk assessment tool (FRAX) score, and personal characteristics such as age, weight, and height. We fitted 15 classifiers using 200 randomized cross-validation datasets. Statistical Tests: Data: Kolmogorov-Smirnov test for normality. Model Performance: sensitivity, specificity, precision, accuracy, F1-test, receiver operating characteristic curve (ROC). Two-sided t-test, with P < 0.05 for statistical significance. RESULTS:The top three performing classifiers are RUS-boosted trees (in particular, performing best with head data, F1 = 0.64 ± 0.03), the logistic regression and the linear discriminant (both best with trochanteric datasets, F1 = 0.65 ± 0.03 and F1 = 0.67 ± 0.03, respectively). A permutation of these classifiers comprised the best three performers for four out of five anatomical datasets. After averaging across all the anatomical datasets, the score for the best performer, the boosted trees, was F1 = 0.63 ± 0.03 for All-features dataset, F1 = 0.52 ± 0.05 for the no-MRI dataset, and F1 = 0.48 ± 0.06 for the no-FRAX dataset. Data Conclusion: Of many classifiers, the RUS-boosted trees, the logistic regression, and the linear discriminant are best for predicting osteoporotic fracture. Both MRI and FRAX independently add value in identifying osteoporotic fractures. The femoral head, greater trochanter, and inter-trochanter anatomical regions within the proximal femur yielded better F1-scores for the best three classifiers. LEVEL OF EVIDENCE/METHODS:2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

OBJECTIVE:Upper airway stimulation (UAS) is an effective second-line treatment for obstructive sleep apnea (OSA). In certain patients, there is a considerable need for advanced programming, notably with inadequate palatal response to therapy. The aim of the study was to investigate the impact of uvulopalatopharyngoplasty and tonsillectomy (UPPP-TE) on UAS therapy outcomes from a 2-year perspective after implantation. METHODS:This study included all consecutive patients implanted with UAS in which a full set of 1- and 2-year follow-up assessments (M12 and M24) were obtained. Cases were analyzed in three groups: patients with UPPP-TE after (group 1) and before (group 2) UAS, and those without UPPP-TE (group 3). RESULTS:Therapy success could be achieved in about 80% of the entire cohort. Groups 2 and 3 did not differ significantly with regard to obesity, Apnea-Hypopnea Index, or Oxygen Desaturation Index. With regard to initial sleep endoscopy, there were fewer patients without any obstruction at the palatal and oropharyngeal levels and higher prevalence of lateral obstruction patterns at oropharynx in group 1 in contrast to groups 2 and 3. Groups 2 and 3 showed similar results, although group 2 patients underwent UPPP-TE before UAS implantation. CONCLUSION/CONCLUSIONS:UPPP-TE should be considered in patients with persistent OSA after UAS implantation if the obstruction is identified at the level of velum and oropharynx. Although this approach has higher response rates and better outcomes can be achieved in patients with UAS, there is no indication for patients to routinely undergo UPPP-TE prior to UAS implantation. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:We describe the clinical features of granulomas of the membranous vocal fold secondary to endotracheal intubation, bronchoscopy or esophagogastroduodenoscopy. STUDY DESIGN/METHODS:Retrospective case series. METHODS:Review of cases at a single tertiary institution with evaluation of patient demographic characteristics, time to presentation, time to treatment, and clinical outcomes. RESULTS:Thirteen adult patients were identified with postintervention granuloma of the membranous vocal fold. All patients were female, with a mean age of 60 years (range, 28-81 years). None noted hoarseness prior to the intervention, and all noted significant hoarseness postoperatively. Conservative treatment with proton pump inhibitors and vocal rest was initially implemented in all patients. Four cases resolved without further intervention. Nine underwent surgical management because of airway symptoms, failure to improve, or patient request. One patient had injury to the contralateral vocal fold upon intubation. None experienced recurrence. Five had complete recovery of voice postoperatively, four did not. CONCLUSION/CONCLUSIONS:Iatrogenic granulomas of the membranous vocal fold after intubation or other upper airway instrumentation are rare complications presenting in the early postprocedure period with worsening hoarseness. Initial conservative treatment may be sufficient to yield resolution, and surgical treatment is effective for those failing medical management. Permanent voice damage may result from the original injury. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.

OBJECTIVE:Radiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers. METHODS:Dose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87  H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study. RESULTS:The median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites. CONCLUSION/CONCLUSIONS:There are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness. Advances in knowledge: This study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced intensity conditioning (RIC) regimen for myelofibrosis (MF) patients undergoing transplant in a two stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and non-relapse mortality (NRM) in comparison to previous Myeloproliferative Disorders Research consortium 101 study. The plan was to enrol 11 patients each in related donor (RD), and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) or ≥6 failures occurred in the RD and URD arm, respectively. A total of 21 patients were enrolled (RD, 7; URD, 14). The RD arm did not meet the pre-determined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated due to poor accrual and significant failures. F Of the 19 patients undergoing transplant, ruxolitinib was tapered successfully in each patient without significant side effects, and 9 patients (47%) had significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute and chronic graft-versus-host disease at 24 months were 16%, 28%, 64% and 76%, respectively. On an intention to treat basis, the 2-year overall survival (OS) for RD and URD arms was 51% and 70%, respectively. Ruxolitinib can be integrated as pre-transplant treatment for MF patients, and a tapering strategy prior to transplant is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant. The trial is registered at www.clinicaltrials.gov (NCT01790295).

OBJECTIVE:Age-related muscle atrophy of the laryngeal muscles contributes to presbyphonia. Remodeling of the neuromuscular junction is one aspect underlying age-related muscle atrophy. Although muscle disuse has been shown to exacerbate age-related neuromuscular changes in the limb muscles, it is unknown if reduced vocal use has a similar effect in the laryngeal muscles. The objective of this study was to examine the use of social isolation as a novel method to reduce vocal use in old rats-and the impact of that reduced vocal use on ultrasonic vocalization acoustics and neuromuscular junction morphology in the thyroarytenoid muscle. STUDY DESIGN/METHODS:Animal group comparison. METHODS:Old F344/BN rats (31 months of age) were socially isolated (n = 8) or communally housed (n = 8) for 8 weeks. Effect of housing condition on ultrasonic vocalization acoustics was assessed by calculating the changes in vocalization fundamental frequency and amplitude from baseline to 8 weeks. Neuromuscular junction morphology was measured in the lateral and medial portions of the thyroarytenoid muscle at the conclusion of the experiment. RESULTS:Vocalization amplitude decreased by a mean of -4.4 dB (standard deviation [SD], 4.49) after social isolation, whereas amplitude increased by a mean of 5.7 dB (SD, 5.07) in the communally housed rats (P = 0.002). There was no significant difference in the change in fundamental frequency between groups. Furthermore, there were no group differences in any measure of neuromuscular junction morphology. CONCLUSION/CONCLUSIONS:These results suggest that neuromuscular junctions in the thyroarytenoid muscle of old rats are unaffected by 8 weeks of social isolation, despite functional changes in vocalizations. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2018.

Motherhood in mammals involves tremendous changes throughout the body and central nervous system, which support attention and nurturing of infants. Maternal care consists of complex behaviors, such as nursing and protection of the offspring, requiring new mothers to become highly sensitive to infant needs. Long-lasting neural plasticity in various regions of the cerebral cortex may enable the perception and recognition of infant cues, important for appropriate caregiving responses. Recent findings have demonstrated that the neuropeptide oxytocin is involved in a number of physiological processes, including parturition and lactation and dynamically shaping neuronal responses to infant stimuli as well. Here, we review experience-dependent changes within the cortex occurring throughout motherhood, focusing on plasticity of the somatosensory and auditory cortex. We outline the role of oxytocin in gating cortical plasticity and discuss potential mechanisms regulating oxytocin release in response to different sensory stimuli.