A xenograft study of human adipose stromal cell-based vocal fold mucosal replacement in rabbits.

Objectives: Vocal fold (VF) scarring, manifested by increased collagen, decreased glycosaminoglycans (GAGs), and disrupted elastic fibers, remains a negative consequence of VF injury or resection. The objective of this study is to compare four reconstructive options after Vf mucosal resection in rabbits. A Cell-Based Outer Vocal fold Replacement (COVR) using human adipose-derived mesenchymal stromal cells (hASCs) in fibrin scaffold is directly compared with a decellularized scaffold implant, hASC injection, and resection alone without reconstruction. The primary hypothesis is that the cells-in-scaffold construct better reconstitutes the VF structure than either cells or scaffold alone, or than healing by secondary intention. Methods: A total of49 rabbits received bilateral VF cordectomy, followed by either COVR implant, decellularized scaffold implant, hASC injection, or no reconstruction (injured control group). Larynges were harvested after 6 weeks. Results: Histology demonstrated greater lamina propria thickness, less collagen deposition, and more GAGs in COVR animals versus all other treatment groups. Evidence of persistent human cells was found in about half of the cell-treated animals. RNA levels of fibrosis pathway and macrophage phenotype markers were statistically unchanged among treatment groups at 6 weeks. Conclusion: These data support the efficacy of COVR implantation in restoring VF microstructure in rabbits. The intact COVR was required; isolated components of decellularized scaffold or injected hASC still produced histologic scarring. We propose that the unique bilayered cell structure within fibrin enables controlled matrix remodeling to minimize wound contraction and fibrosis, and to promote GAG deposition. Level of Evidence: Basic science study.

Heterogeneous Presentations of Pharyngoesophageal Diverticula Occurring after Cervical Spine Surgery.

Dysphagia after anterior cervical spine surgery (ACSS) may be secondary to pharyngoesophageal diverticulum. Our objectives are to (1) highlight the heterogeneity in clinical presentation, (2) discuss pathophysiology and management, and (3) present a comprehensive literature review of these diverticula. All patients undergoing pharyngoesophageal diverticulum repair between 2013 and 2019 were identified. Cases with ACSS history underwent detailed review of clinical presentation, assessment, and management. Literature review and analysis of all reported ACSS-associated pharyngoesophageal diverticula was performed. Two hundred forty-three cases of pharyngoesophageal diverticulum repair were performed during the study period; 13 cases were ACSS-associated. Four types of clinical presentation were identified: (Type A) Spinal hardware present, with videofluoroscopic evidence of exposed hardware; (Type B) Spinal hardware present, without videofluoroscopic evidence of exposed hardware; (Type C) Spinal hardware absent due to prior spinal hardware removal or ACSS performed without hardware; and (Type D) Concurrent esophago-esophageal fistula (EEF) present. All of our cases were evaluated using modified barium swallow study and esophagoscopy and definitively managed with endoscopic diverticulotomy. Literature review identified 21 cases of ACSS-associated pharyngoesophageal diverticulum repair from 18 publications. The majority of cases were identified using barium esophagram (N = 18, 86%) and managed with open diverticulectomy (N = 19, 90%). There were no reports of EEF. ACSS-associated pharyngoesophageal diverticulum must be evaluated with fluoroscopy and endoscopy, which determine presentation type. Presentation type guides management. Esophageal perforation requires hardware removal and perforation repair with flap placement. Endoscopic diverticulotomy was found essential to definitive management.Level of Evidence: 4.

Stem cell treatments for oropharyngeal dysphagia: Rationale, benefits, and challenges.

Dysphagia, defined as difficulty swallowing, is a common symptom negatively impacting millions of adults annually. Estimated prevalence ranges from 14 to 33 percent in those over age 65 to over 70 percent in a nursing home setting. The elderly, those with neurodegenerative diseases, head and neck cancer patients, and those with autoimmune conditions such as Sjögren's syndrome are disproportionately affected. Oropharyngeal dysphagia refers specifically to difficulty in initiating a swallow due to dysfunction at or above the upper esophageal sphincter, and represents a large proportion of dysphagia cases. Current treatments are limited and are often ineffective. Stem cell therapy is a new and novel advancement that may fill a much-needed role in our treatment regimen. Here, we review the current literature regarding stem cell treatments for oropharyngeal dysphagia. Topics discussed include tissue regeneration advancements as a whole and translation of these principles into research surrounding tongue dysfunction, xerostomia, cricopharyngeal dysfunction, and finally an overview of the challenges and future directions for investigation. Although this field of study remains in its early stages, initial promising results show potential for the use of stem cell-based therapies to treat oropharyngeal dysphagia and warrant further research.

Upfront Magnetic Resonance Imaging-Guided Stereotactic Laser-Ablation in Newly Diagnosed Glioblastoma: A Multicenter Review of Survival Outcomes Compared to a Matched Cohort of Biopsy-Only Patients.

BACKGROUND: Laser ablation (LA) is used as an upfront treatment in patients with deep seated newly diagnosed Glioblastoma (nGBM). OBJECTIVE: To evaluate the outcomes of LA in patients with nGBM and compare them with a matched biopsy-only cohort. METHODS: Twenty-four nGBM patients underwent upfront LA at Cleveland clinic, Washington University in St. Louis, and Yale University (6/2011-12/2014) followed by chemo/radiotherapy. Also, 24 out of 171 nGBM patients with biopsy followed by chemo/radiotherapy were matched based on age (< 70 vs ≥ 70), gender, tumor location (deep vs lobar), and volume (<11 cc vs ≥11 cc). Progression-free survival (PFS), overall survival (OS), and disease-specific PFS and OS were outcome measures. Three prognostic groups were identified based on extent of tumor ablation by thermal-damage-threshold (TDT)-lines. RESULTS: The median tumor volume in LA (n = 24) and biopsy only (n = 24) groups was 9.3 cm3 and 8.2 cm3 respectively. Overall, median estimate of OS and PFS in LA cohort was 14.4 and 4.3 mo compared to 15.8 mo and 5.9 mo for biopsy only cohort. On multivariate analysis, favorable TDT-line prognostic groups were associated with lower incidence of disease specific death (P = .03) and progression (P = .05) compared to other groups including biopsy only cohort. Only age (<70 yr, P = .02) and tumor volume (<11 cc, P = .03) were favorable prognostic factors for OS. CONCLUSION: The maximum tumor coverage by LA followed by radiation/chemotherapy is an effective treatment modality in patients with nGBM, compared to biopsy only cohort. The TDT-line prognostic groups were independent predictor of disease specific death and progression after LA.

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging.

OBJECTIVE: To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms. METHODS: Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4ß2* nicotinic cholinergic receptor binding using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used. RESULTS: 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: rs = -0.55, p = 0.008; right: rs = -0.50, p = 0.02; N = 22) and hippocampus (left: rs = -0.65, p = 0.001; right: rs = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: rs = -0.50, p = 0.01; right: rs = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score. CONCLUSION: Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.

Comparison of clinical characteristics between familial and non-familial early onset Alzheimer's disease.

Although familial Alzheimer's disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.