A fluorescent photoimmunoconjugate for imaging of cholesteatoma.

Cholesteatoma is a potentially serious complication of chronic ear infections and requires surgical intervention for definitive management. Long-term complications include a frequent need for repeat surgical intervention for disease recurrence, and techniques to improve efficacy of single-stage surgery are an important area of continued research. This study investigates a novel application of the photosensitizer immune conjugate (PIC) cetuximab-benzoporphyrin derivative (Cet-BPD) for in vitro localization of human cholesteatoma tissue, coupled with an in vivo safety study for middle ear application of Cet-BPD in a murine model. In fresh human cholesteatoma tissues, Cet-BPD demonstrates selective localization to the hyperplastic squamous cell tissue associated with cholesteatoma, without localizing to other tissues such as middle ear mucosa. Applied to the murine middle ear, Cet-BPD does not demonstrate any deleterious effect on murine hearing when assessed by any of auditory brainstem response (ABR) thresholds, distortion product otoacoustic emission thresholds, or ABR wave I amplitudes. These findings demonstrate the technical promise and encouraging safety profile for the use of PICs for intraoperative localization and treatment of cholesteatoma.

Genetics of noise-induced hearing loss in the mouse model.

Hearing loss is the most common sensory deficit worldwide, with the majority of preventable injury attributed to noise-induced hearing loss (NIHL). Highly conserved cochlear genetics between humans and mice have made this animal model a high-yield candidate for better characterizing the biologic and genetic underpinnings of human NIHL. This review aims to summarize advances in understanding the genetics of noise-induced hearing loss in mouse models dating from the early 1990s. We review the genetic mechanisms underpinning NIHL as understood in the mouse model, including histopathological and phenotypic associations, molecular and cellular mechanisms of changes in cochlear structures, synaptopathy and neuropathy, and transcriptomics. We describe variations in pathophysiology of hearing loss between mouse strains, with particular emphasis on susceptibility of different strains to different mechanisms of damage after acoustic trauma, and the potential of novel targeted therapeutic approaches for NIHL based on understanding of genetic mechanisms. Finally, we review the current state of research on the cochlear transcriptome after noise exposure in the mouse and implications for translation of these findings to humans.

Sporadic Vestibular Schwannoma Size and Location Do not Correlate With the Severity of Hearing Loss at Initial Presentation.

Vestibular schwannoma (VS) is a non-malignant intracranial neoplasm arising from the vestibular branch of the 8th cranial nerve; sensorineural hearing loss (SNHL) is the most common associated symptom. Understanding whether VS imaging characteristics at the time of VS diagnosis can be associated with severity of VS-induced SNHL can impact patient counseling and define promising areas for future research. Patients diagnosed with VS at Massachusetts Eye and Ear (MEE) from 1994 through 2018 were analyzed if magnetic resonance imaging at VS presentation and sequential audiometry were available. Results were compared with original studies available in PubMed, written in English, on VS imaging characteristics and their impact on hearing in patients. A total of 477 patients with unilateral VS from the MEE database demonstrated no significant correlation between any features of tumor imaging at the time of VS diagnosis, such as VS size, impaction or location, and any hearing loss metric. Twenty-three published studies on the impact of VS imaging characteristics on patient hearing met inclusion criteria, with six solely involving NF2 patients and three including both sporadic and NF2-related VS patients. Fifteen studies reported a significant relationship between SNHL and at least one VS imaging characteristic; however, these trends were universally limited to NF2 patients or involved small patient populations, and were not reproduced in larger studies. Taken together, SNHL in sporadic VS patients is not readily associated solely with any tumor imaging characteristics. This finding motivates future studies to define how VS microenvironment and secreted molecules influence VS-induced SNHL.

The impact of failed novel technology and technical errors on the revision burden in total hip arthroplasty: what percentage of revision hip arthroplasty was potentially avoidable?

BACKGROUND: Despite the high success rate of total hip arthroplasty (THA), new implant technologies continue to be developed. Although potentially useful, such novel developments may result in unintended consequences, leading to revision surgery, often prematurely. In several instances, new technology that appeared promising was later found to be inferior to existing technology and resulting in early revision surgery. Additionally, technical surgical errors may also lead to early revisions. Some have argued that revisions related to such phenomena are potentially avoidable. The present analysis investigates to what extent the contribution of "failed new technology" and "technical errors" contributes to the revision burden and to the need for premature revision arthroplasty. METHODS: We retrospectively analysed 432 revision THAs and categorised them as either "late revisions" based on survivorship of 10 years or "premature revisions". Among both cohorts, we determined what percentage of revisions were potentially avoidable and due to failed novel technologies and technical errors, and what percent were "unavoidable". RESULTS: Of the 432 revisions, 267 (62%) were considered premature and 38% were considered late. Of the premature revisions, 108 were considered potentially avoidable (81 failed novel technologies, 27 technical errors). CONCLUSIONS: Our data demonstrates that new technology and surgical techniques can result in premature failure of THA. Surgeons should take caution when incorporating new implant technology or surgical techniques into their practice.

Accelerated Long-Term Hearing Loss Progression After Recovery From Idiopathic Sudden Sensorineural Hearing Loss.

Background and Introduction: Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by rapid onset, typically unilateral presentation, and variable recovery. This case-control observational study aimed to improve patient counseling by objectively characterizing long-term hearing loss progression following ISSNHL, using sequential audiometry in the largest-to-date cohort of patients with ISSNHL. Methods: Patients diagnosed with ISSNHL at a tertiary referral hospital from 1994 through 2018 with sequential audiometry were studied. Case controls with sensorineural hearing loss (SNHL) were matched by age, sex, baseline hearing status, and frequency of sequential audiometry. Hearing loss progression was quantified using Kaplan-Meier (K-M) analysis to account for variable follow-up duration. A subgroup analysis was performed by age, sex, preexisting comorbidities, ISSNHL-associated symptoms, ISSNHL treatment, and degree of post-ISSNHL hearing recovery. Results: A total of 660 patients were identified with ISSNHL. In patients with post-ISSNHL recovery to good hearing [pure tone average (PTA) <30 dB and word recognition score (WRS) > 70%], median time to progression to non-serviceable (PTA > 50 dB or WRS <50%) SNHL was 16.4 years. In patients with incomplete post-ISSNHL hearing recovery, contralateral ears were also at significantly higher risk of SNHL progression over the following 12-year period. Male sex was associated with increased risk of SNHL progression [odds ratio (OR) 3.45 male vs. female] at 5-year follow up. No other subgroup factors influenced the likelihood of SNHL progression. Discussion and Conclusion: Patients should be counseled on continued risk to long-term hearing after stabilization of hearing post-ISSNHL, with particular emphasis on greater risk to the contralateral ear in those with incomplete ipsilateral recovery.

Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models.

Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.

Initial Method for Characterization of Tympanic Membrane Drug Permeability in Human Temporal Bones In Situ.

Background and Introduction: Acute otitis media is the most common reason for a visit to the pediatrician, often requiring systemic administration of oral antibiotics. Local drug therapy applied to the middle ear could avoid side effects associated with systemic antibiotic administration, however in the majority of patients this would require drugs to diffuse across an intact tympanic membrane. Experimental methods for testing trans-tympanic drug flux in human tissues in situ would be highly valuable to guide drug therapy development for local drug delivery to the middle ear. Materials and Methods: A total of 30 cadaveric human temporal bones were characterized by trans-tympanic impedance testing to determine how steps in tissue processing and storage might impact intactness of the tympanic membrane and thus suitability for use in studies of trans-tympanic drug flux. Ciprofloxacin drug solutions of varying concentrations were then applied to the lateral surface of the tympanic membrane in eight samples, and middle ear aspirate was collected over the following 48 h to evaluate trans-tympanic flux to the middle ear. Results: Tissue processing steps that involved extensive tissue manipulation were consistently associated with evidence of microperforations in the tympanic membrane tissue. Maintaining the tympanic membrane in situ within the temporal bone, while using an otologic drill to obtain transmastoid access to the middle ear, was demonstrated as a reliable, non-damaging technique for accessing both lateral and medial surfaces for trans-tympanic flux testing. Results in these bones demonstrated trans-tympanic flux of ciprofloxacin when administered at sufficiently high concentration. Discussion and Conclusion: The study describes key techniques and best practices, as well as pitfalls to avoid, in the development of a model for studying trans-tympanic drug flux in human temporal bones in situ. This model can be a valuable research tool in advancing progress toward eventual clinical studies for trans-tympanic drug delivery to the middle ear.

Long-Term Retrospective Follow-Up of Fresh Osteochondral Allograft Transplantation for Steroid-Associated Osteonecrosis of the Femoral Condyles.

OBJECTIVE: No studies currently exist with long-term follow-up of use of osteochondral allografting (OCA) for treatment of steroid-associated osteonecrosis of femoral condyles in young, active patients who wish to avoid total knee arthroplasty (TKA). We evaluate the extent to which fresh osteochondral allografts can (1) prevent or postpone need for prosthetic arthroplasty and (2) maintain long-term clinically meaningful decrease in pain and improvement in function at mean 11-year follow-up. DESIGN: Twenty-five patients (33 knees) who underwent OCA transplantation for osteonecrosis of the knee between 1984 and 2013 were evaluated, including 22 females and 11 males with average age of 25 years (range, 16-48 years). Mean total allograft surface area was 10.6 cm2 (range, 4.0-19.0 cm2). Evaluation included International Knee Documentation Committee (IKDC) scores, Knee Society function (KS-F) score, and modified (for the knee) Merle d'Aubigné-Postel (18-point) score. RESULTS: OCA survivorship was 90% at 5 years and 82% at 10 years. Twenty-eight of 33 knees (85%) avoided arthroplasty and 25 of 33 knees (73%) avoided other surgical intervention. Mean IKDC pain score improved (P = 0.001) from 7.2 preoperatively to 2.8 at latest follow-up, mean IKDC function score increased (P = 0.005) from 3.3 to 6.5, and mean IKDC total score improved (P = 0.001) from 31.9 to 61.1. Mean KS-F score improved (P = 0.003) from 61.7 to 87.5. Mean modified Merle d'Aubigné-Postel (18-point) score improved (P < 0.001) from 11.4 to 15.1. CONCLUSIONS: Our findings suggest that OCA transplantation is a reasonable surgical treatment option for steroid-associated osteonecrosis of the femoral condyles, with durable long-term outcomes.

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma.

Background and Introduction: Vestibular schwannomas (VSs) are the most common tumors of the cerebellopontine angle, typically presenting unilaterally with ipsilateral sensorineural hearing loss (SNHL). The mechanism of tumor-induced hearing loss has recently been shown to be related to secreted tumor factors, in addition to mechanical compression of the adjacent auditory nerve, and these factors may percolate through CSF or blood to affect contralateral hearing as well. Methods: This is a retrospective study of medical records for patients treated for VS at Mass Eye and Ear from January 1994 through October 2018. Included patients had unilateral VS and sequential audiometry allowing for longitudinal assessment of hearing over time. Mass Eye and Ear's audiology database was used to select age- and sex-matched case controls, also with sequential audiometry, from the non-VS population. Subgroup analysis was performed by age, sex, baseline hearing, and tumor size at initial diagnosis. Hearing loss progression was performed using Kaplan-Meier analysis to account for variable follow-up times. Results: A total of 661 patients were identified with VS and sequential audiometry. The population was predominantly female vs. male (368 vs. 293, p = 0.0035), driven primarily by younger patients with Koos 4 tumors (76 female vs. 49 male, p = 0.016). Patients with normal baseline hearing bilaterally (N = 241) demonstrated no significant difference in hearing loss progression in VS-contralateral vs. control ears. Patients with abnormal baseline VS-ipsilateral hearing (N = 190), however, demonstrated significantly higher likelihood of reaching moderate SNHL in VS-contralateral ears. Subgroup analysis by age, sex, and baseline tumor size did not yield any subgroup-specific trends for hearing loss progression. Discussion and Conclusion: This is the largest study to date tracking long-term bilateral hearing outcomes in patients with VS, and demonstrates that, in patients with abnormal hearing in the VS-ipsilateral ear, there exists a long-term risk of progression to moderate hearing loss in the contralateral ear as well. Combined with the absence of significant changes in word understanding in the affected ears, these findings may provide clues to the nature of tumor-secreted factors involved in VS-associated hearing loss. Female predominance within the VS patient population is confirmed, driven mostly by younger female patients with Koos 4 tumors.

Professional Advancement and Performance of Amateur Baseball Players Selected in the Major League Baseball Draft With Previous Anterior Cruciate Ligament Reconstruction.

BACKGROUND: The effect that an anterior cruciate ligament injury requiring reconstructive surgery has on the professional advancement and performance of amateur baseball players selected in the Major League Baseball draft is not known. Return to sports after anterior cruciate ligament reconstruction (ACLR) in professional athletes has been shown to be high, but mixed results with regard to performance and return to preinjury level have been demonstrated in other sports. PURPOSE: To (1) investigate the highest level of professional advancement among Major League Baseball draftees with a history of ACLR before entering the draft, (2) examine how much time these players spent on the disabled list (DL) and determine if it was related to the knee, and (3) compare the batting and pitching performance of these players against healthy matched controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Predraft medical records of all players selected in the Major League Baseball draft from 2004 to 2008 were reviewed. Players with a documented anterior cruciate ligament injury treated with ACLR before the draft were included. For each study player, 3 controls were identified. Data were accumulated from the time when players were drafted through the 2015 season. Outcome variables included highest professional level of advancement, DL time, and batting and pitching performance. RESULTS: Forty draftees with a history of ACLR (22 pitchers, 18 position players) were identified and matched to 120 controls (66 pitchers, 54 position players). The difference in the highest level of professional advancement between the groups was not statistically significant (P = .488). The mean total number of times and the mean total number of days on the DL were similar between the groups (1.83 vs 1.47, P = .297; 121.54 vs 109.62, P = .955); however, the mean number of times on the DL because of a knee injury was significantly different (0.28 vs 0.11, P = .004), as was the mean number of days on the DL because of a knee injury (17.36 vs 7.72, P = .009). Among pitchers, there were no differences in performance. Similarly, there were no differences among position players in batting performance. CONCLUSION: There was no difference between draftees with a history of ACLR and their controls in terms of advancement from the minor to the major leagues. Additionally, pitching and batting performance were similar. Although the 2 groups spent similar time on the DL, the ACLR group spent more time on the DL because of a knee injury than the control group.

A novel microneedle device for controlled and reliable liquid biopsy of the human inner ear.

Sensorineural hearing loss is the most common sensory deficit worldwide, yet our understanding of the underlying pathophysiology is limited by the challenges of access to the inner ear in a safe and reliable manner. We present a novel microneedle device for trans-round window membrane liquid biopsy, which utilizes controlled depth of perforation and microliter aspiration control to safely biopsy fluids of the inner ear. Of eleven devices tested in fresh frozen human temporal bones, seven demonstrated alignment between electrical, visual and tactile detection of round window membrane perforation, and nine were successful in aspiration of meaningful diagnostic samples from the perilymphatic space. Purity of the average perilymph sample was 69% for a 5 µL sample volume, equivalent to 3.5 µL attributable to perilymph. Diagnostic success was shown both by transmastoid facial recess and transcanal tympanotomy approach. This device can enable new advances in the understanding of inner ear pathology, and brings us one step closer to liquid biopsy of the inner ear becoming a routine part of clinical care.

Professional advancement, performance, and injury characteristics of baseball players entering the Major League Baseball draft after treatment for shoulder injuries.

BACKGROUND: How shoulder injuries treated before the Major League Baseball (MLB) draft affect the player's performance over their career is unclear. The purpose of this study was to determine whether prior shoulder injuries were associated with a difference in the level of performance and advancement of MLB draftees. METHODS: Before entering the draft, 119 professional baseball players from 2004 to 2010 were treated for a shoulder injury (73% treated surgically) as an amateur. A 3:1 matched case-control was performed to players without prior shoulder injuries by age, position, round selected, and signing bonus. Follow-up data were collected in 2016, and professional advancement, disabled list time, and in-game performance statistics for pitchers were analyzed and compared. RESULTS: Players with a prior shoulder injury had a statistically higher chance to be assigned to the disabled list then controls (P = .03), but there was no difference in disabled list time or professional advancement. Pitchers with a prior shoulder injury pitched a statistically lower number of innings per game than controls (P = .04). All other in-game performance statistics were not statistically different. The type of treatment did not have any effect on future performance or advancement. CONCLUSIONS: Professional baseball players treated for prior shoulder injuries at the amateur level were more likely to sustain future disability than their matched controls, but it did not affect professional advancement.

Fresh Osteochondral Allograft Transplantation for Spontaneous Osteonecrosis of the Knee: A Case Series.

BACKGROUND: Spontaneous osteonecrosis of the knee (SONK) is a clinical entity identified by acute knee pain usually associated with joint effusion, with radiographic findings of a radiolucent defect on the weightbearing area of the femoral condyle. Conservative treatment is initially undertaken; however, surgical procedures are often necessary. Historically, surgical options have included core decompression, cartilage repair, high tibial osteotomy, or joint arthroplasty. Few studies in the literature have reported the use of fresh osteochondral allograft (OCA) for the treatment of SONK lesions. HYPOTHESIS: OCA transplantation is an effective treatment for SONK lesions on the medial femoral condyle. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A case series was analyzed of 7 patients treated with OCA for large SONK lesions of the medial femoral condyle with a minimum 4-year follow-up. All patients experienced failure of at least 6 months of conservative treatment and declined arthroplasty as the form of definitive treatment for medial femoral condyle lesion. All patients underwent OCA of the medial femoral condyle. Mean lesion size was 4.6 cm2 (range, 3.24-6.25 cm2), with a mean condylar width of 41.7 mm (range, 35.4-48.6 mm), resulting in a median proportion (lesion size/condylar width) of 56.8% (range, 32.7%-62.6%). The median surface allograft area was 5.1 cm2 (range, 3.2-6.3 cm2). RESULTS: The median follow-up was 7.1 years (range, 4.5-14.1 years). No patient had additional surgery following OCA transplant; the allograft failure rate was 0%. Subjective outcome scores from the International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score, and modified Merle d'Aubigné-Postel scale improved from preoperative assessment to the latest follow-up. All patients were extremely satisfied with the results of the OCA transplant. CONCLUSION: Fresh OCA transplantation demonstrated excellent efficacy, durability, and satisfaction in this group of patients with isolated stage 2 and 3 SONK lesions who had experienced failure of conservative treatment. Fresh osteochondral allografts are an attractive method for surgical management of selected patients with spontaneous osteonecrosis of the knee.