ABSTRACT
OBJECTIVE: Patients with recurrent oropharyngeal cancer can achieve survival benefits from surgical salvage, and often require simultaneous free-flap reconstruction. Resection and reconstruction can impact function, leading to tube dependence. PRIMARY OBJECTIVE: describe rates of tracheostomy and gastrostomy tube dependence after oropharyngeal resection and free flap after prior radiation. SECONDARY OBJECTIVE: evaluate patient, tumor, and treatment factors associated with tube dependence. STUDY DESIGN: Retrospective, multi-institutional cohort study. Patients treated from 2003 to 2020. Average follow-up 21.4 months. SETTING: Five tertiary care centers. METHODS: Consecutive cohort of patients undergoing resection and simultaneous free-flap reconstruction for oropharyngeal squamous cell carcinoma after head and neck radiation. PRIMARY OUTCOMES: gastrostomy tube dependence and tracheostomy or tracheostoma 1 year after surgery. Univariable and multivariable logistic regression were performed to identify factors associated with dependence. RESULTS: 89 patients underwent oropharyngectomy and free-flap reconstruction; 18 (20%) underwent total laryngectomy as part of tumor extirpation. After surgery, 51 patients (57%) lived 12 months. Among patients alive at 12 months, 22 (43%) were at least partially-dependent on gastrostomy tube, and 15 (29%) had either tracheostomy or tracheostoma. On multivariable analysis, extensive glossectomy (OR 16.6, 95% CI 1.83-389, p = 0.026) and total laryngectomy (OR 11.2, 95% CI 1.71-105, p = 0.018) were associated with long-term gastrostomy tube. No factors were associated with long-term tracheostomy on multivariable analysis. CONCLUSION: Even among long-term survivors after salvage resection and free-flap reconstruction, rates of tube dependence are significant. This multi-institutional review is the largest such study to the date and may help inform shared decision-making. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2141-2147, 2023.
Subject(s)
Free Tissue Flaps , Head and Neck Neoplasms , Humans , Gastrostomy , Tracheostomy , Retrospective Studies , Cohort Studies , Neoplasm Recurrence, Local , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/surgery , Treatment OutcomeABSTRACT
Hearing loss affects more than 430 million people, worldwide, and is the third most common chronic physical condition in the United States and Europe (GBD Hearing Loss Collaborators, 2021; NIOSH, 2021; WHO, 2021). The loss of hearing significantly impacts motor and cognitive development, communication, education, employment, and overall quality of life. The inner ear houses the sensory organs for both hearing and balance and provides an accessible target for therapeutic delivery. Antisense oligonucleotides (ASOs) use various mechanisms to manipulate gene expression and can be tailor-made to treat disorders with defined genetic targets. In this review, we discuss the preclinical advancements within the field of the highly promising ASO-based therapies for hereditary hearing loss disorders. Particular focus is on ASO mechanisms of action, preclinical studies on ASO treatments of hearing loss, timing of therapeutic intervention, and delivery routes to the inner ear.
Subject(s)
Deafness , Hearing Loss , Humans , Quality of Life , Hearing Loss/therapy , Hearing Loss/drug therapy , Deafness/drug therapy , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , Gene ExpressionABSTRACT
Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.
Subject(s)
Cell Cycle Proteins/genetics , Cytoskeletal Proteins/genetics , Ear, Middle/drug effects , Genetic Therapy/methods , Hair Cells, Auditory/drug effects , Mutation , Oligonucleotides, Antisense/administration & dosage , Usher Syndromes/genetics , Usher Syndromes/therapy , Vestibule, Labyrinth/drug effects , Administration, Topical , Animals , Animals, Newborn , Disease Models, Animal , Female , Gene Knock-In Techniques , Hair Cells, Auditory/metabolism , Hearing/drug effects , Injections , Male , Mice , Mice, Inbred C57BL , Tympanic Membrane/drug effects , Vestibule, Labyrinth/metabolismABSTRACT
With a rapidly aging population, studies of neuroinflammation and degeneration associated with eugeric aging are becoming critical. Using the unique archive at the Tulane National Primate Research Center as a resource, we have developed tools to quantify morphological changes in astrocytes and microglia across the life span of monkeys. This method can be used for morphometric studies of multiple parameters simultaneously in an unbiased manner.
Subject(s)
Aging , Astrocytes/cytology , Brain/cytology , Microglia/cytology , Aging/metabolism , Animals , Astrocytes/metabolism , Biomarkers , Brain/metabolism , DNA-Binding Proteins/metabolism , Glial Fibrillary Acidic Protein/metabolism , Image Processing, Computer-Assisted , Immunohistochemistry , Macaca mulatta , Microglia/metabolism , SoftwareABSTRACT
How aging impacts the central nervous system (CNS) is an area of intense interest. Glial morphology is known to affect neuronal and immune function as well as metabolic and homeostatic balance. Activation of glia, both astrocytes and microglia, occurs at several stages during development and aging. The present study analyzed changes in glial morphology and density through the entire lifespan of rhesus macaques, which are physiologically and anatomically similar to humans. We observed apparent increases in gray matter astrocytic process length and process complexity as rhesus macaques matured from juveniles through adulthood. These changes were not attributed to cell enlargement because they were not accompanied by proportional changes in soma or process volume. There was a decrease in white matter microglial process length as rhesus macaques aged. Aging was shown to have a significant effect on gray matter microglial density, with a significant increase in aged macaques compared with adults. Overall, we observed significant changes in glial morphology as macaques age indicative of astrocytic activation with subsequent increase in microglial density in aged macaques.