Faculty Bibliography

PURPOSE:No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC. PATIENTS AND METHODS:Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice. RESULTS:gene expression. CONCLUSIONS:Spartalizumab demonstrated a safety profile consistent with other anti-PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.

HYPOTHESIS/OBJECTIVE:This study tests the hypothesis that it is possible to find tone or noise vocoders that sound similar and result in similar speech perception scores to a cochlear implant (CI). This would validate the use of such vocoders as acoustic models of CIs. We further hypothesize that those valid acoustic models will require a personalized amount of frequency mismatch between input filters and output tones or noise bands. BACKGROUND:Noise or tone vocoders have been used as acoustic models of CIs in hundreds of publications but have never been convincingly validated. METHODS:Acoustic models were evaluated by single-sided deaf CI users who compared what they heard with the CI in one ear to what they heard with the acoustic model in the other ear. We evaluated frequency-matched models (both all-channel and 6-channel models, both tone and noise vocoders) as well as self-selected models that included an individualized level of frequency mismatch. RESULTS:Self-selected acoustic models resulted in similar levels of speech perception and similar perceptual quality as the CI. These models also matched the CI in terms of perceived intelligibility, harshness, and pleasantness. CONCLUSION/CONCLUSIONS:Valid acoustic models of CIs exist, but they are different from the models most widely used in the literature. Individual amounts of frequency mismatch may be required to optimize the validity of the model. This may be related to the basalward frequency mismatch experienced by postlingually deaf patients after cochlear implantation.

PURPOSE:), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS:DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS:= .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION:Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

OBJECTIVE:Carbonation as a sensory enhancement strategy for prevention of aspiration of thin liquids has not been thoroughly studied. The aim of our study was to examine the effect of carbonation on penetration-aspiration and pharyngeal residue in dysphagia patients using Fiber-Optic Endoscopic Evaluation of Swallowing (FEES) and to identify parameters associated with a response to carbonation. METHODS:A cross-sectional study of patients undergoing FEES in a dysphagia clinic. Patients were offered 100 cc of dyed water. Penetration-aspiration was scored using the penetration-aspiration scale (PAS). Residue was scored using the Yale Pharyngeal Residue Severity Rating Scale (YPR-SRS). Patients with a PAS ≥ 2 for water were subsequently offered 100 cc of carbonated water. PAS, YPR-SRS and residue clearance were compared between thin and carbonated liquids. Multivariate logistic regression analysis was used to identify predictors for good response to carbonation. RESULTS:84 patients were enrolled, 77.4% males, with diverse dysphagia etiologies (58.3% neurogenic, 11.9% radiation-induced, 23.8% deconditioning-induced, and 6% neck surgery induced). Median PAS was 7 (IQR 4-8) for thin liquids and 4.5 (IQR 2-8) for carbonated liquids (P = 0.0001). YPR-SRS was reduced for carbonated compared to thin liquids in the vallecula (1.58 ± 0.83 vs 1.76 ± 0.93, P = 0.001) and piriform sinuses (1.5 ± 0.87 vs 1.67 ± 0.9, P = 0.002). 31 patients had improvement in PAS with carbonation. Deconditioning as a dysphagia etiology was found to predict good response to carbonation on multivariate logistic regression analysis. CONCLUSION/CONCLUSIONS:Carbonation may prevent aspiration and improve residue management for some patients with dysphagia for liquids. LEVEL OF EVIDENCE/METHODS:IV.

OBJECTIVES:To determine which surgical factors are associated with quality-of-life (QOL) outcomes in oral cavity cancer survivors after free flap reconstruction of the oral cavity. PATIENTS AND METHODS:A cross-sectional study was conducted from a multidisciplinary head and neck cancer (HNC) survivorship clinic. Oral cavity cancer survivors with at least 6-months of postoperative follow-up from ablation and free flap reconstruction were included. Primary outcome measures were validated patient-reported outcome measures (PROMs) including the Eating Assessment Tool-10 (EAT-10) measure of swallowing-specific QOL, University of Washington Quality of Life (UW-QOL) physical and social-emotional subscale scores and feeding tube dependence. RESULTS:Extent of tongue resection was associated with EAT-10 and the UW-QOL Physical subscale scores. Patients with oral tongue defects reported worse scores than with composite defects in the EAT-10 and UW-QOL physical domain (p = 0.0004, 0.0025, respectively). This association no longer applies when controlling for differences in extent of tongue resection. Patients with anterior composite resections reported worse EAT-10 scores than lateral resections (p = 0.024). This association no longer applies when controlling for extent of tongue resection (p = 0.46). Gastric tube dependence demonstrates similar trends to PROMs. CONCLUSION:Extent of tongue resection was strongly associated with poor QOL outcomes after free tissue reconstruction of the oral cavity and mediates the associations between other defect characteristics and QOL. These findings demonstrate the need for emphasis on expected oral tongue defects when counseling patients and highlight the need to address QOL in a multidisciplinary fashion post-operatively.

OBJECTIVE:The role of sclerotherapy for vascular lesions of the head and neck is well established. However, the efficacy of sclerotherapy for benign cystic lesions of the head and neck is less clear. The objective of this review is to determine the efficacy and safety of sclerotherapy for benign cystic lesions of the head and neck. DATA SOURCES:PubMed/MEDLINE, Cochrane Library, and Embase. REVIEW METHODS:The PRISMA guidelines (Preferred Reporting Systems for Systematic Reviews and Meta-analyses) were followed for this systematic review. Studies of patients with benign head and neck cystic masses treated primarily with sclerotherapy were included. Thirty-two studies met criteria for inclusion. RESULTS:= .015). Fifty-three cases (11.2%) required further surgical management. One case of laryngeal edema was reported and managed nonoperatively. CONCLUSION:Sclerotherapy appears to be a safe and efficacious option for benign cystic lesions if malignancy is reliably excluded. Efficacy rates are comparable to those of sclerotherapy for vascular malformations. The rate of serious complications is low, with 1 incident of airway edema reported in the literature.

Speech prosody, including pitch contour, word stress, pauses, and vowel lengthening, can aid the detection of the clausal structure of a multi-clause sentence and this, in turn, can help listeners determine the meaning. However, for cochlear implant (CI) users, the reduced acoustic richness of the signal raises the question of whether CI users may have difficulty using sentence prosody to detect syntactic clause boundaries within sentences or whether this ability is rescued by the redundancy of the prosodic features that normally co-occur at clause boundaries. Twenty-two CI users, ranging in age from 19 to 77 years old, recalled three types of sentences: sentences in which the prosodic pattern was appropriate to the location of a clause boundary within the sentence (congruent prosody), sentences with reduced prosodic information, or sentences in which the location of the clause boundary and the prosodic marking of a clause boundary were placed in conflict. The results showed the presence of congruent prosody to be associated with superior sentence recall and a reduced processing effort as indexed by the pupil dilation. The individual differences in a standard test of word recognition (consonant-nucleus-consonant score) were related to the recall accuracy as well as the processing effort. The outcomes are discussed in terms of the redundancy of the prosodic features, which normally accompany a clause boundary and processing effort.

BACKGROUND:TDP-43 pathology is linked to cognitive deficits in diverse neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). The effects of TDP-43 pathology in different cell types, including astrocytes, are not clear. METHOD/METHODS:In this study, we used postmortem human brain samples, extensive behavioral testing in numerous cohorts of doubly transgenic mice, gene profiling in different isolated brain regions and cells, glial-neuronal co-culture assays and physiology, and biochemical assays to identify specific signaling cascades linked to TDP-43. RESULT/RESULTS:Our results show that astrocytic TDP-43 is mislocalized in postmortem human hippocampal tissue from AD cases. To assess the effects of widespread or hippocampus specific dysregulation of astrocytic TDP-43 in complementary systems, we generated three novel astrocyte specific mouse models of TDP-43 dysfunction. Consistently, these mouse models indicated that astrocytic TDP-43 dysfunction causes progressive hippocampus-dependent memory loss, but not motor deficits. Manipulation of astrocytic TDP-43 also increased hippocampal levels of interferon -inducible chemokines CXCL9 and CXCL10, and altered cell-autonomous antiviral signaling and defense against viral pathogens. Moreover, expression of CXCR3, the shared receptor for CXCL9 and CXCL10, was increased selectively in hippocampal presynaptic terminals. Acute or chronic stimulation of presynaptic CXCR3 modulated neuronal activities and presynaptic vesicles. CONCLUSION/CONCLUSIONS:Overall, our findings shed new light on TDP-43 dysregulation in astrocytes and its potential contributions to disease-related impairments in cognitive and immune-related functions. We report a novel chemokine-mediated astrocytic-neuronal pathway that is likely downstream of aberrant antiviral immune signaling in astrocytes that affects presynaptic release and neuronal activities. Together, these results implicate astrocytic TDP-43 dysregulation in the pathogenesis of dementia and point to chemokine signaling and CXCR3 as potential therapeutic targets for alleviating cognitive decline.