A Deep Learning Framework for Analysis of the Eustachian Tube and the Internal Carotid Artery.

OBJECTIVE: Obtaining automated, objective 3-dimensional (3D) models of the Eustachian tube (ET) and the internal carotid artery (ICA) from computed tomography (CT) scans could provide useful navigational and diagnostic information for ET pathologies and interventions. We aim to develop a deep learning (DL) pipeline to automatically segment the ET and ICA and use these segmentations to compute distances between these structures. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. METHODS: From a database of 30 CT scans, 60 ET and ICA pairs were manually segmented and used to train an nnU-Net model, a DL segmentation framework. These segmentations were also used to develop a quantitative tool to capture the magnitude and location of the minimum distance point (MDP) between ET and ICA. Performance metrics for the nnU-Net automated segmentations were calculated via the average Hausdorff distance (AHD) and dice similarity coefficient (DSC). RESULTS: The AHD for the ET and ICA were 0.922 and 0.246 mm, respectively. Similarly, the DSC values for the ET and ICA were 0.578 and 0.884. The mean MDP from ET to ICA in the cartilaginous region was 2.6 mm (0.7-5.3 mm) and was located on average 1.9 mm caudal from the bony cartilaginous junction. CONCLUSION: This study describes the first end-to-end DL pipeline for automated ET and ICA segmentation and analyzes distances between these structures. In addition to helping to ensure the safe selection of patients for ET dilation, this method can facilitate large-scale studies exploring the relationship between ET pathologies and the 3D shape of the ET.

Long-term Quality of Life After Thyroidectomy: Transoral Endoscopic Thyroidectomy Vestibular Approach Versus Transcervical Approach.

OBJECTIVE: To compare long-term health-related quality of life (HRQOL) after Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA) and transcervical approach (TCA) thyroidectomy. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. METHODS: A web-based survey was distributed to patients at our institution who met the criteria for TOETVA and underwent thyroidectomy by TOETVA or TCA between August 2017 and October 2021. All survey participants were at least 6 months postsurgery. Minors, non-English speakers, and patients who received concomitant neck dissection or reoperative thyroidectomy were excluded from the study. The survey assessed quality of life through 4 standardized instruments: the Dermatology Life Quality Index (DLQI), the Eating Assessment Tool (EAT-10), the Voice Handicap Index (VHI-10), and the Short Form Health Survey (SF-36). RESULTS: A total of 108 TOETVA and 129 TCA patients were included in the study. The median age of respondents was 44 (36, 54; 25th, 75th percentile) years and median time from surgery to survey was 35 (22, 45; 25th, 75th percentile) months. TOETVA group DLQI (0.63 vs 0.99; P = .17), VHI-10 (1.94 vs 1.67; P = .35), EAT-10 (2.14 vs 2.32; P = .29), SF-36 physical component (52.25 vs 51.00; P = .25), and SF-36 mental component (47.74 vs 47.29; P = .87) scores were all similar to those of the TCA group. Scrutinizing specific DLQI questions, individuals in the TOETVA group were less self-conscious of their skin as compared to the TCA group (Q2; 0.08 vs 0.26, P = .03). CONCLUSION: Long-term HRQOL after TOETVA is similar to TCA, with significantly lower skin-related self-consciousness.

Longitudinal Performance of Cochlear Implants in Neurofibromatosis Type 2.

OBJECTIVE: Cochlear implants (CIs) are a well-established treatment modality for hearing loss due to neurofibromatosis type 2 (NF2). Our aim is to investigate variables that affect longitudinal performance of CIs among patients with NF2. STUDY DESIGN: Retrospective review at a single academic institution consisting of patients who have received cochlear implants following hearing loss due to NF2. METHODS: The primary outcome examined was CI disuse or explantation. Associated clinical and surgical variables were analyzed using descriptive statistics. These included postoperative pure tone average (PTA) at 500, 1000, and 2000 Hz, tumor size, previous surgery, and comorbid depression. RESULTS: A total of 12 patients and 14 cochlear implants received at our institution from 2001 to 2022 were included. Notably, 35.7% of CIs (5 out of 14 cases) resulted in disuse or explantation. The average interval until explant was 9.4 years (range 3-14 years). In explanted CI cases, 20% had previous surgery and 80% had a diagnosis of comorbid depression as compared to 22.2% and 22.2%, respectively, in intact CI cases. Maximum tumor diameter was the only variable found to impact CI usage outcome (p = 0.028). Long-term data showed that on average, patients benefit from 13.85 years of CI utility and a maximum PTA improvement of 45.0 ± 29.0 dB. CONCLUSION: Despite the recurrent nature of NF2, patients continue to receive audiological benefit from cochlear implants. We found that larger tumor size may be associated with longitudinal CI failure. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1847-1853, 2024.

Utilizing a Functional Lumen Imaging Probe for Evaluation of the Pediatric Airway, A Pilot Study.

OBJECTIVES: Accurate and reproducible measurements of the pediatric airway are critical for diagnostic evaluation and management of subglottic and tracheal stenosis. The endoluminal functional lumen imaging probe (EndoFLIP) is a catheter-based imaging probe which utilizes impedance planimetry to calculate luminal parameters, including cross-sectional area and compliance. Herein, we demonstrate the feasibility of this system for multidimensional evaluation of the pediatric airway. METHODS: 3D-printed pediatric laryngotracheal models were created based on computed tomography scans, then artificially deformed to simulate both circumferential and posterior subglottic stenosis. Two observers made six measurements of the minimum cross-sectional area (MCSA) and length of stenosis of each model with EndoFLIP. Agreement between observer measurements and model dimensions was evaluated using Lin's concordance correlation coefficient; inter-observer reliability was assessed using intraclass correlation. RESULTS: Four models were created: two without pathology (MCSA: 132.4, 44.3 mm2 ) and two with subglottic stenosis (MCSA: 28.7, 59.7 mm2 , stenotic length 27.8, 24.4 mm). Observer measurements of MCSA and length of stenosis demonstrated high concordance with the models (r = 0.99, 0.95, p < 0.001) with a mean error of 4.5% and 18.2% respectively. There was a low coefficient of variation (0.6%-2.8%) for measurements, indicating high precision. Interrater reliability was high for both MCSA and stenotic length (ICC: 0.99, 0.98). CONCLUSIONS: The EndoFLIP system allows for accurate and reproducible measurements of cross-sectional area and stenotic length in pediatric airway models. This method may provide further advantages in the evaluation of airway distensibility, as well as measurements of asymmetric airway pathology. LEVEL OF EVIDENCE: NA Laryngoscope, 134:108-112, 2024.

TOETVA parathyroid autofluorescence detection: hANDY-i endoscopy attachment.

Background: Treatment options for thyroid pathologies have expanded to include scarless and remote access methods such as the transoral endoscopic thyroidectomy vestibular approach (TOETVA). Currently, no standardized methods exist for locating parathyroid glands (PGs) in patients undergoing TOETVA, which can lead to parathyroid injury and subsequent hypocalcemia. This early feasibility study describes and evaluates the hANDY-i endoscopic attachment for detecting PGs in transoral thyroidectomy. Methods: We used a prototype parathyroid autofluorescence imager (hANDY-i) that was mounted to a 10-mm 0-degree endoscope. The device delivers a split screen view of Red-green-blue (RGB) and near-infrared autofluorescence (NIRAF) which allows for simultaneous anatomical localization and fluorescence visualization of PGs during endoscopic thyroid dissection. Results: One cadaveric case and two patient cases were included in this study. The endoscopic hANDY-i imaging system successfully visualized PGs during all procedures. Conclusion: The ability to leverage parathyroid autofluorescence during TOETVA may lead to improved PG localization and preservation. Further human studies are needed to assess its effect on postoperative hypocalcemia and hypoparathyroidism.

A Self-Configuring Deep Learning Network for Segmentation of Temporal Bone Anatomy in Cone-Beam CT Imaging.

OBJECTIVE: Preoperative planning for otologic or neurotologic procedures often requires manual segmentation of relevant structures, which can be tedious and time-consuming. Automated methods for segmenting multiple geometrically complex structures can not only streamline preoperative planning but also augment minimally invasive and/or robot-assisted procedures in this space. This study evaluates a state-of-the-art deep learning pipeline for semantic segmentation of temporal bone anatomy. STUDY DESIGN: A descriptive study of a segmentation network. SETTING: Academic institution. METHODS: A total of 15 high-resolution cone-beam temporal bone computed tomography (CT) data sets were included in this study. All images were co-registered, with relevant anatomical structures (eg, ossicles, inner ear, facial nerve, chorda tympani, bony labyrinth) manually segmented. Predicted segmentations from no new U-Net (nnU-Net), an open-source 3-dimensional semantic segmentation neural network, were compared against ground-truth segmentations using modified Hausdorff distances (mHD) and Dice scores. RESULTS: Fivefold cross-validation with nnU-Net between predicted and ground-truth labels were as follows: malleus (mHD: 0.044 ± 0.024 mm, dice: 0.914 ± 0.035), incus (mHD: 0.051 ± 0.027 mm, dice: 0.916 ± 0.034), stapes (mHD: 0.147 ± 0.113 mm, dice: 0.560 ± 0.106), bony labyrinth (mHD: 0.038 ± 0.031 mm, dice: 0.952 ± 0.017), and facial nerve (mHD: 0.139 ± 0.072 mm, dice: 0.862 ± 0.039). Comparison against atlas-based segmentation propagation showed significantly higher Dice scores for all structures (p < .05). CONCLUSION: Using an open-source deep learning pipeline, we demonstrate consistently submillimeter accuracy for semantic CT segmentation of temporal bone anatomy compared to hand-segmented labels. This pipeline has the potential to greatly improve preoperative planning workflows for a variety of otologic and neurotologic procedures and augment existing image guidance and robot-assisted systems for the temporal bone.

Augmented Reality in Otology/Neurotology: A Scoping Review with Implications for Practice and Education.

OBJECTIVE: To determine how augmented reality (AR) has been applied to the field of otology/neurotology, examine trends and gaps in research, and provide an assessment of the future potential of this technology within surgical practice and education. DATA SOURCES: PubMed, EMBASE, and Cochrane Library were assessed from their inceptions through October 2022. A manual bibliography search was also conducted. REVIEW METHODS: A scoping review was conducted and reported according to PRISMA-ScR guidelines. Data from studies describing the application of AR to the field of otology/neurotology were evaluated, according to a priori inclusion/exclusion criteria. Exclusion criteria included non-English language articles, abstracts, letters/commentaries, conference papers, and review articles. RESULTS: Eighteen articles covering a diverse range of AR platforms were included. Publication dates spanned from 2007 to 2022 and the rate of publication increased over this time. Six of 18 studies were case series in human patients although the remaining were proof of concepts in cadaveric/artificial/animal models. The most common application of AR was for surgical navigation (14 of 18 studies). Computed tomography was the most common source of input data. Few studies noted potential applications to surgical training. CONCLUSION: Interest in the application of AR to otology/neurotology is growing based on the number of recent publications that use a broad range of hardware, software, and AR platforms. Large gaps in research such as the need for submillimeter registration error must be addressed prior to adoption in the operating room and for educational purposes. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:1786-1795, 2023.

DescePrep Significantly Increases Descemet Membrane Endothelial Keratoplasty Processing Efficiency and Success Rate in Diabetic Human Donor Corneas in Comparison With Manual Dissection.

PURPOSE: The purpose of this study was to compare the safety, efficacy, and efficiency of a Descemet membrane endothelial keratoplasty (DMEK) graft processing device, DescePrep, with a manual dissection technique through the measurement of tissue yield, processing time, and graft viability in nondiabetic and diabetic donor corneas. METHODS: Nondiabetic (n = 20) and diabetic (n = 20) donor corneas were processed using DescePrep, which standardizes the liquid bubble technique. Nondiabetic (n = 20) and diabetic (n = 24) donor corneas were also processed through manual dissection. Corneas were stained, processed, and then evaluated for processing success rate and time. Randomly selected corneas (n = 5, each) were evaluated for cell viability using live/dead staining. RESULTS: One hundred percent of nondiabetic and 95% of diabetic corneas were processed successfully with DescePrep in an average of 3.37 minutes. Ninety percent of nondiabetic and 50% of diabetic corneas were processed successfully with manual dissection in an average of 9.87 minutes. DescePrep had a significantly lower processing time ( P < 0.0001) and significantly higher success rate in comparison with manual dissection. DescePrep grafts had an average cell viability of 91.1% ± 3.3% in nondiabetic and 91.5% ± 2.4% in diabetic corneas. Grafts prepared with manual dissection had an average cell viability of 89.5% ± 5.8% in nondiabetic and 88.1% ± 4.3% in diabetic corneas. CONCLUSIONS: DescePrep provides a more effective and efficient method of cornea preparation in comparison with the current standard, particularly in diabetic corneas, while providing comparable cell viability. Thus, DescePrep offers standardized DMEK processing that produces high-quality grafts at high yields, with the potential to expand access and improve the quality of DMEK graft preparation in a larger pool of donors.

Statistical Shape Model of the Temporal Bone Using Segmentation Propagation.

HYPOTHESIS: Automated image registration techniques can successfully determine anatomical variation in human temporal bones with statistical shape modeling. BACKGROUND: There is a lack of knowledge about inter-patient anatomical variation in the temporal bone. Statistical shape models (SSMs) provide a powerful method for quantifying variation of anatomical structures in medical images but are time-intensive to manually develop. This study presents SSMs of temporal bone anatomy using automated image-registration techniques. METHODS: Fifty-three cone-beam temporal bone CTs were included for SSM generation. The malleus, incus, stapes, bony labyrinth, and facial nerve were automatically segmented using 3D Slicer and a template-based segmentation propagation technique. Segmentations were then used to construct SSMs using MATLAB. The first three principal components of each SSM were analyzed to describe shape variation. RESULTS: Principal component analysis of middle and inner ear structures revealed novel modes of anatomical variation. The first three principal components for the malleus represented variability in manubrium length (mean: 4.47 mm; ±2-SDs: 4.03-5.03 mm) and rotation about its long axis (±2-SDs: -1.6° to 1.8° posteriorly). The facial nerve exhibits variability in first and second genu angles. The bony labyrinth varies in the angle between the posterior and superior canals (mean: 88.9°; ±2-SDs: 83.7°-95.7°) and cochlear orientation (±2-SDs: -4.0° to 3.0° anterolaterally). CONCLUSIONS: SSMs of temporal bone anatomy can inform surgeons on clinically relevant inter-patient variability. Anatomical variation elucidated by these models can provide novel insight into function and pathophysiology. These models also allow further investigation of anatomical variation based on age, BMI, sex, and geographical location.

Public perceptions of radiofrequency ablation versus standard surgery for benign thyroid nodules.

BACKGROUND: Ultrasound-guided radiofrequency ablation has shown promising results for nonsurgical treatment of benign thyroid nodules. The purpose of this study is to investigate public perceptions of radiofrequency ablation and identify salient decision factors for benign thyroid nodules treatment. METHODS: An internet-based survey was distributed via an online platform. Survey participants were prompted to envision having a benign thyroid nodules and were assessed on risk acceptance, willingness to pay, and importance of decision factors (eg, cost, risk, scarring) regarding treatment with either radiofrequency ablation or standard surgery. RESULTS: A total of 830 respondents (male 46.3%, median age 35 years) were included. Respondents ranked the most important factors for benign thyroid nodules treatment as risk of missing cancer and risk of permanent hoarseness (mean score 5.23 and 4.50 out of 7, respectively). Female respondents ranked missing cancer higher in importance compared with other decision factors (coefficient = 0.251, P = .0002). Younger respondents (coefficient = 0.009, P = .014) or those with higher education levels (coefficient = 0.092, P = .010) ranked having a scar as a more important decision factor. Prior scars were associated with choosing a nonsurgical procedure over surgery (coefficient = 0.478, P = .00), even if scars were well-healed (coefficient = 0.781, P < .0001). On average, respondents are willing to pay less for radiofrequency ablation than for standard surgery (radiofrequency ablation: $7,612.44 vs surgery: $8,298.50; P < .0001). CONCLUSION: Respondents identified risk of missing cancer and risk of permanent hoarseness as the most important decision factors for benign thyroid nodules treatment. Education level and history of previous scars are both associated with a proclivity toward nonsurgical treatment and radiofrequency ablation.

Understanding Public Perceptions Regarding Cochlear Implant Surgery in Adults.

BACKGROUND AND OBJECTIVE: Approximately 6% of adults eligible for cochlear implantation (CI) undergo surgery. This study aims to understand how general perceptions about CI contribute to barriers causing this low utilization rate. METHODS: Participants completed an online survey regarding their perceptions about cochlear implantation. They were asked to rank CIQOL-10 Global priorities and corresponding risk tolerance for minor complications (changes in taste, vertigo) and major complications (infections requiring hospitalization, meningitis, reimplantation, facial paralysis, and cerebrospinal fluid [CSF] leak). RESULTS: A total of 615 responses (female 55%, mean age 39 years [range 20-78]) were included. Respondents identified issues with insurance (46%) and fear of undergoing surgery (21%) as barriers preventing eligible adults from receiving CI. Regarding surgical risk, respondents significantly underestimated rates of minor complications (p < 0.0001) and almost all major complications (all p < 0.0001) while overestimating rates of serious infections and need for reimplantation (both p < 0.005). The ability to hear strangers in noisy environments was identified as the highest priority for CI (26%). Individuals who knew someone with a cochlear implantation were willing to tolerate higher rates of all minor and major complications (all p < 0.05). Healthcare workers were similarly willing to tolerate significantly higher rates of meningitis, facial paralysis, and CSF leak to achieve their highest priority (all p < 0.05). CONCLUSIONS: Respondents identify insurance coverage and fear of surgery as primary reasons for low utilization of adult CI in the United States. However, healthcare workers or those who knew someone with a cochlear implantation indicated significantly higher rates of risk tolerance to achieve their highest quality of life priorities, indicating the potential that the benefits of cochlear implantation are underappreciated in the general population.

Automated Extraction of Anatomical Measurements From Temporal Bone CT Imaging.

OBJECTIVE: Proposed methods of minimally invasive and robot-assisted procedures within the temporal bone require measurements of surgically relevant distances and angles, which often require time-consuming manual segmentation of preoperative imaging. This study aims to describe an automatic segmentation and measurement extraction pipeline of temporal bone cone-beam computed tomography (CT) scans. STUDY DESIGN: Descriptive study of temporal bone measurements. SETTING: Academic institution. METHODS: A propagation template composed of 16 temporal bone CT scans was formed with relevant anatomical structures and landmarks manually segmented. Next, 52 temporal bone CT scans were autonomously segmented using deformable registration techniques from the Advanced Normalization Tools Python package. Anatomical measurements were extracted via in-house Python algorithms. Extracted measurements were compared to ground truth values from manual segmentations. RESULTS: Paired t test analyses showed no statistical difference between measurements using this pipeline and ground truth measurements from manually segmented images. Mean (SD) malleus manubrium length was 4.39 (0.34) mm. Mean (SD) incus short and long processes were 2.91 (0.18) mm and 3.53 (0.38) mm, respectively. The mean (SD) maximal diameter of the incus long process was 0.74 (0.17) mm. The first and second facial nerve genus had mean (SD) angles of 68.6 (6.7) degrees and 111.1 (5.3) degrees, respectively. The facial recess had a mean (SD) span of 3.21 (0.46) mm. Mean (SD) minimum distance between the external auditory canal and tegmen was 3.79 (1.05) mm. CONCLUSIONS: This is the first study to automatically extract relevant temporal bone anatomical measurements from CT scans using segmentation propagation. Measurements from these models can streamline preoperative planning, improve future segmentation techniques, and help develop future image-guided or robot-assisted systems for temporal bone procedures.

Evaluation of Efficacy, Efficiency, and Cell Viability of a Novel Descemet Membrane Endothelial Keratoplasty Graft Preparation Device, DescePrep, in Nondiabetic and Diabetic Human Donor Corneas.

PURPOSE: The purpose of this study was to evaluate the safety, efficacy, and efficiency of a Descemet membrane endothelial keratoplasty (DMEK) graft preparation device, DescePrep, through measurement of graft viability, yield, and preparation time in both healthy and diabetic (high-risk) donor eyes. METHODS: Twenty nondiabetic and 10 diabetic donor corneas were processed using DescePrep, which standardizes the liquid bubble technique. Corneas were stained with trypan blue and then processed. Cell counts through specular microscopy, optical coherence tomography imaging, and slit-lamp analysis were used for the evaluation of graft separation and viability in 5 nondiabetic corneas. The remaining 25 corneas (15 nondiabetic and 10 diabetic) were evaluated for preparation success rate and processing time. Ten corneas (5 nondiabetic and 5 diabetic) were randomly selected for further evaluation of global cell loss through staining. RESULTS: Ninety-seven percent of corneas (29 of 30) were prepared successfully with DescePrep. The average preparation time was 2.83 ± 1.8 minutes. There was no significant difference in the time of preparation between the nondiabetic and diabetic groups (P = 0.077). The overall average cell death after processing was 7.9% ± 3.7% for all corneas. There was no significant difference in cell viability between diabetic and nondiabetic tissues after DescePrep processing (P = 0.769). CONCLUSIONS: DescePrep is a new DMEK preparation technique that can process both nondiabetic and diabetic donor corneas at high yields in minutes. High-yield preparation of diabetic corneas may offer eye banks access to a larger donor pool, which is important because the demand for DMEK grafts continues to rise worldwide.

Automated Registration-Based Temporal Bone Computed Tomography Segmentation for Applications in Neurotologic Surgery.

OBJECTIVE: This study investigates the accuracy of an automated method to rapidly segment relevant temporal bone anatomy from cone beam computed tomography (CT) images. Implementation of this segmentation pipeline has potential to improve surgical safety and decrease operative time by augmenting preoperative planning and interfacing with image-guided robotic surgical systems. STUDY DESIGN: Descriptive study of predicted segmentations. SETTING: Academic institution. METHODS: We have developed a computational pipeline based on the symmetric normalization registration method that predicts segmentations of anatomic structures in temporal bone CT scans using a labeled atlas. To evaluate accuracy, we created a data set by manually labeling relevant anatomic structures (eg, ossicles, labyrinth, facial nerve, external auditory canal, dura) for 16 deidentified high-resolution cone beam temporal bone CT images. Automated segmentations from this pipeline were compared against ground-truth manual segmentations by using modified Hausdorff distances and Dice scores. Runtimes were documented to determine the computational requirements of this method. RESULTS: Modified Hausdorff distances and Dice scores between predicted and ground-truth labels were as follows: malleus (0.100 ± 0.054 mm; Dice, 0.827 ± 0.068), incus (0.100 ± 0.033 mm; Dice, 0.837 ± 0.068), stapes (0.157 ± 0.048 mm; Dice, 0.358 ± 0.100), labyrinth (0.169 ± 0.100 mm; Dice, 0.838 ± 0.060), and facial nerve (0.522 ± 0.278 mm; Dice, 0.567 ± 0.130). A quad-core 16GB RAM workstation completed this segmentation pipeline in 10 minutes. CONCLUSIONS: We demonstrated submillimeter accuracy for automated segmentation of temporal bone anatomy when compared against hand-segmented ground truth using our template registration pipeline. This method is not dependent on the training data volume that plagues many complex deep learning models. Favorable runtime and low computational requirements underscore this method's translational potential.

Sensorineural Hearing Loss After Teprotumumab Therapy for Thyroid Eye Disease: A Case Report.

BACKGROUND AND OBJECTIVE: Teprotumumab is a fully human IgG1 monoclonal antibody against insulin-like growth factor-1 receptor (IGF-1R). It has been approved by the FDA to treat thyroid eye disease (TED) by reducing extraocular muscle and orbital fat volume. In clinical trials, hearing loss was noted as a side effect in 7 to 12% of patients, but no formal audiometric investigations of these patients were reported. Furthermore, the FDA and manufacturer offer no formal guidelines for audiometric monitoring. This case report is the first to describe sensorineural hearing loss (SNHL) in a patient undergoing treatment with teprotumumab. PATIENT: A 77-year-old woman presenting with bilateral SNHL after treatment with teprotumumab therapy for TED. INTERVENTION: Audiometric testing was performed due to worsening and prolonged SNHL after subsequent teprotumumab infusions. MAIN OUTCOME MEASURES: Word recognition scores, pure tone average. RESULTS: Audiometry after discontinuation of therapy showed moderate to moderate-severe SNHL with word recognition scores of 64% in the right ear and 68% in the left ear. CONCLUSIONS: There are currently no formal guidelines for routine audiograms before, during, and after infusion of teprotumumab. Given that such guidelines exist for ototoxic medications such as gentamicin and cisplatin, we strongly encourage audiometric monitoring for patients undergoing treatment with teprotumumab.

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02.

OBJECTIVE: Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi-CDK inhibitor, TG02. METHODS: Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software. RESULTS: TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs. CONCLUSIONS: The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.

Volumetric Accuracy Analysis of Virtual Safety Barriers for Cooperative-Control Robotic Mastoidectomy.

HYPOTHESIS: Virtual fixtures can be enforced in cooperative-control robotic mastoidectomies with submillimeter accuracy. BACKGROUND: Otologic procedures are well-suited for robotic assistance due to consistent osseous landmarks. We have previously demonstrated the feasibility of cooperative-control robots (CCRs) for mastoidectomy. CCRs manipulate instruments simultaneously with the surgeon, allowing the surgeon to control instruments with robotic augmentation of motion. CCRs can also enforce virtual fixtures, which are safety barriers that prevent motion into undesired locations. Previous studies have validated the ability of CCRs to allow a novice surgeon to safely complete a cortical mastoidectomy. This study provides objective accuracy data for CCR-imposed safety barriers in cortical mastoidectomies. METHODS: Temporal bone phantoms were registered to a CCR using preoperative computed tomography (CT) imaging. Virtual fixtures were created using 3D Slicer, with 2D planes placed along the external auditory canal, tegmen, and sigmoid, converging on the antrum. Five mastoidectomies were performed by a novice surgeon, moving the drill to the limit of the barriers. Postoperative CT scans were obtained, and Dice coefficients and Hausdorff distances were calculated. RESULTS: The average modified Hausdorff distance between drilled bone and the preplanned volume was 0.351 ±â€Š0.093 mm. Compared with the preplanned volume of 0.947 cm3, the mean volume of bone removed was 1.045 cm3 (difference of 0.0982 cm3 or 10.36%), with an average Dice coefficient of 0.741 (range, 0.665-0.802). CONCLUSIONS: CCR virtual fixtures can be enforced with a high degree of accuracy. Future studies will focus on improving accuracy and developing 3D fixtures around relevant surgical anatomy.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

OBJECTIVE: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma. METHODS: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. RESULTS: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004). CONCLUSIONS: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.

Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

Targeting Myeloid Cells in Combination Treatments for Glioma and Other Tumors.

Myeloid cells constitute a significant part of the immune system in the context of cancer, exhibiting both immunostimulatory effects, through their role as antigen presenting cells, and immunosuppressive effects, through their polarization to myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. While they are rarely sufficient to generate potent anti-tumor effects on their own, myeloid cells have the ability to interact with a variety of immune populations to aid in mounting an appropriate anti-tumor immune response. Therefore, myeloid therapies have gained momentum as a potential adjunct to current therapies such as immune checkpoint inhibitors (ICIs), dendritic cell vaccines, oncolytic viruses, and traditional chemoradiation to enhance therapeutic response. In this review, we outline critical pathways involved in the recruitment of the myeloid population to the tumor microenvironment and in their polarization to immunostimulatory or immunosuppressive phenotypes. We also emphasize existing strategies of modulating myeloid recruitment and polarization to improve anti-tumor immune responses. We then summarize current preclinical and clinical studies that highlight treatment outcomes of combining myeloid targeted therapies with other immune-based and traditional therapies. Despite promising results from reports of limited clinical trials thus far, there remain challenges in optimally harnessing the myeloid compartment as an adjunct to enhancing anti-tumor immune responses. Further large Phase II and ultimately Phase III clinical trials are needed to elucidate the treatment benefit of combination therapies in the fight against cancer.