Faculty Bibliography

Background: The ability to maintain balance is an evolutionarily-conserved behavior that is frequently disrupted found in patients with neurodegenerative diseases. One of the most prominent balance disorders is found in patients with progressive supranuclear palsy (PSP), a primary tauopathy pathologically characterized by tau over-representation in the brainstem vestibulospinal (VS) nucleus, where they frequently exhibit accidental-backward falls starting from the early stage of the disease. Although pathological features of PSP correlate well with its clinical phenotype, how tau aggregation affects neuronal and circuit functions, which eventually leads to behavioral deficits, remains unclear. Method: To dissect disease mechanisms across molecular, cellular, circuitry, and behavioral levels, we generated tau fish by expressing human 0N/4R-Tau in zebrafish VS nucleus. Tau expression and phosphorylation were validated using immunohistochemistry staining with PHF-1 antibody. To examine the effect of tau on balance behavior, we measured postural control of free-swimming tau fish and compared to that of tau-negative siblings. Moreover, we tested response of VS neurons to nose-down and nose-up tilt stimulus using 2-photon calcium imaging. Result: Ttau-expressing zebrafish exhibit impaired balance control while maintaining normal locomotor ability. Interestingly, we did not observe any neuronal death in the VS nucleus. Functional imaging of the VS nucleus shows impaired directional tuning in tau-expressing neurons in response to tilt stimulus. We also found ectopic accumulation of acidic organelles in the cell bodies of tau-positive neurons, suggesting abnormal lysosomal function. Conclusion: Our results demonstrate how molecular abnormalities disrupt specific behavior in tauopathies before neurodegeneration appeared.

OBJECTIVE:To prospectively evaluate the frailty phenotype in a population of older adults and determine its association with 1) perioperative complications, 2) need for vestibular rehabilitation after surgery, and 3) early speech perception outcomes. STUDY DESIGN/METHODS:Prospective cohort study. SETTING/METHODS:Tertiary care hospital. PATIENTS/METHODS:Adults older than 65 years undergoing cochlear implantation. INTERVENTIONS/METHODS:The Fried Frailty Index was used to classify patients as frail, prefrail, or not frail based on five criteria: 1) gait speed, 2) grip strength, 3) unintentional weight loss, 4) weekly physical activity, and 5) self-reported exhaustion. MAIN OUTCOMES MEASURES/METHODS:Rates of intraoperative and postoperative complications, postoperative falls, need for vestibular rehabilitation, and early speech perception outcomes. RESULTS:Forty-six patients were enrolled in this study. Five patients (10.8%) were categorized as frail and 10 (21.7%) as prefrail. The mean ages of frail, prefrail, and not frail patients were 80.9, 78.8, and 77.5, respectively. There were no intraoperative complications among all groups. Three patients required postoperative vestibular rehabilitation; all were not frail. One postoperative fall occurred in a nonfrail individual. Mean (standard deviation) device use times at 3 months in frail, prefrail, and not frail patients were 7.6 (3.5), 11.1 (3.6), and 11.6 (2.9) hours per day, respectively. Consonant-nucleus-consonant word scores 3 months after surgery in frail, prefrail, and not frail patients were 13% (12.2), 44% (19.7), and 51% (22.4), respectively. The median (range) number of missed follow-up visits (surgeon, audiologist, speech language pathologist combined) was 7 (1-10) in frail patients, compared with a median of 3 (0-4) and 2 (0-5) in prefrail and not frail patients. CONCLUSIONS:Frail patients did not have increased rates of surgical complications, need for vestibular rehabilitation, or postoperative falls. However, frail patients experienced challenges in accessing postoperative care, which may be addressed by using remote programming and rehabilitation.

Importance/UNASSIGNED:Over time, the American Thyroid Association (ATA) guidelines have increasingly promoted more limited treatments for well-differentiated thyroid cancers. Objective/UNASSIGNED:To determine whether the 2009 and 2015 ATA guidelines were associated with changes in the management of low-risk papillary thyroid carcinomas on a national scale. Design, Setting, and Participants/UNASSIGNED:This historical cohort study used the National Cancer Database. All papillary thyroid carcinomas diagnosed from 2004 to 2019 in the National Cancer Database were selected. Patients with tumors of greater than 4 cm, metastases, or clinical evidence of nodal disease were excluded. Data were analyzed from August 1, 2021, to September 1, 2022. Main Outcomes and Measures/UNASSIGNED:The primary aim was to tabulate changes in the rates of thyroid lobectomy (TL), total thyroidectomy (TT), and TT plus radioactive iodine (RAI) therapy after the 2009 and 2015 ATA guidelines. The secondary aim was to determine in which settings (eg, academic vs community) the practice patterns changed the most. Results/UNASSIGNED:A total of 194 254 patients (155 796 [80.2%] female patients; median [range] age at diagnosis, 51 [18-90] years) who underwent treatment during the study period were identified. Among patients who underwent surgery, rates of TL decreased from 15.1% to 13.7% after the 2009 guidelines but subsequently increased to 22.9% after the 2015 changes. Among patients undergoing TT, rates of adjuvant RAI decreased from 48.7% to 37.1% after 2009 and to 19.3% after the 2015 guidelines. Trends were similar for subgroups based on sex and race and ethnicity. However, academic institutions saw larger increases in TL rates (14.9% to 25.7%) than community hospitals (16.3% to 19.5%). Additionally, greater increases in TL rates were observed for tumors 1 to 2 cm (6.8% to 18.9%) and 2 to 4 cm (6.6% to 16.0%) than tumors less than 1 cm (22.8% to 29.2%). Conclusions and Relevance/UNASSIGNED:In this cohort study among patients with papillary thyroid carcinomas up to 4 cm, ATA guideline changes corresponded with increased TL and reduced adjuvant RAI. These changes were primarily seen in academic institutions, suggesting an opportunity to expand guideline-based care in the community setting.

OBJECTIVE:Objective evaluation of physiological responses using non-invasive methods for the assessment of vocal performance and voice disorders has attracted great interest. This paper, for the first time, aims to implement and evaluate perilaryngeal-cranial functional muscle networks. The study investigates the variations in topographical characteristics of the network and the corresponding ability to differentiate vocal tasks. METHOD/METHODS:Twelve surface electromyography (sEMG) signals were collected bilaterally from six perilaryngeal and cranial muscles. Data were collected from eight subjects (four females) without a known history of voice disorders. The proposed muscle network is composed of pairwise coherence between sEMG recordings. The network metrics include (a) network degree and (b) weighted clustering coefficient (WCC). RESULTS:|=0.12) in differentiating the vocal tasks. CONCLUSION/CONCLUSIONS:Perilaryngeal-cranial functional muscle network was proposed in this paper. The study showed that the functional muscle network could robustly differentiate the vocal tasks while the classic assessment of muscle activation fails to differentiate. SIGNIFICANCE/CONCLUSIONS:For the first time, we demonstrate the power of a perilaryngeal-cranial muscle network as a neurophysiological window to vocal performance. In addition, the study also discovers tasks with the highest network involvement, which may be utilized in the future to monitor voice disorders and rehabilitation.

Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.

Introduction: Thyroid fine-needle aspiration (FNA) cytology combined with molecular testing guides individualized patient management by providing information regarding tumor biology and the risk of recurrence associated with specific mutations in the indeterminate groups (Bethesda group III-V). Thyroid adenomaassociated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms, but the clinical-pathologic features and subsequent management are not well-established. Here we report the findings associated with thyroid nodules with THADA-IGFBP3 fusions in our institution.
Material(s) and Method(s): FNA cytology samples of thyroid nodules during 01/2015-12/2016 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III), follicular neoplasm/ suspicious for follicular neoplasm (FN/SFN; Bethesda IV) and suspicious for malignancy (Bethesda V) with corresponding ThyroSeqV2 data were assessed. Molecular test results yielding a THADA gene fusion were identified. In addition, follow-up surgical pathology and available radiology results were reviewed.
Result(s): 186 out of 558 (33.3%) thyroid nodules displayed molecular alterations; 7 out of 186 (3.8%) Bethesda category III-V nodules with ThyroSeq molecular alterations displayed isolated THADA-IGFBP2 fusions (Table 1). The median age was 45 years. The female to male ratio was 5:2. The nodule sizes ranged from 1.8 to 5.0 cm. Four (57%) patients had surgery; three cases displayed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on histology; one case was a follicular adenoma. No patients had recurrence or metastasis on follow-up.
Conclusion(s): Our pilot study shows that thyroid nodules with THADA-IGF2BP3 fusions display low-risk/indolent features. These findings may aid in clinical management decisions in patients presenting with thyroid nodules with isolated THADAIGF2BP3 fusions on molecular testing

Multiplexed immunofluorescence imaging allows the multidimensional molecular profiling of cellular environments at subcellular resolution. However, identifying and characterizing disease-relevant microenvironments from these rich datasets is challenging. Here we show that a graph neural network that leverages spatial protein profiles in tissue specimens to model tumour microenvironments as local subgraphs captures distinctive cellular interactions associated with differential clinical outcomes. We applied this spatial cellular-graph strategy to specimens of human head-and-neck and colorectal cancers assayed with 40-plex immunofluorescence imaging to identify spatial motifs associated with cancer recurrence and with patient survival after treatment. The graph deep learning model was substantially more accurate in predicting patient outcomes than deep learning approaches that model spatial data on the basis of the local composition of cell types, and it generated insights into the effect of the spatial compartmentalization of tumour cells and granulocytes on patient prognosis. Local graphs may also aid in the analysis of disease-relevant motifs in histology samples characterized via spatial transcriptomics and other -omics techniques.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To create a model of the anatomic distribution, recurrence, and growth patterns of recurrent respiratory papillomatosis (RRP). STUDY DESIGN/METHODS:Prospective, multi-institutional cohort study. METHODS:Adult patients with a diagnosis of RRP evaluated between August 1, 2018 and February 1, 2021 at six participating centers were invited to enroll. At each office or operating room encounter, laryngologists recorded the location and size of RRP lesions using a 22-region schematic. A generalized linear mixed effects model was used to compare region variations in lesion prevalence and recurrence. RESULTS:The cohort comprised 121 patients: 74% were male, 81% had been diagnosed with adult-onset RRP, and a plurality (34%) had undergone 0 to 3 RRP interventions prior to enrollment. Across the study period, the odds of a lesion occurring in the glottis was significantly higher (odds ratio [OR]: 26.51; 95% confidence interval [CI]: 11.76-59.75, P < .001) compared with all other areas of the larynx and trachea. Within the true vocal folds, the membranous vocal folds had significantly higher odds (OR: 6.16; 95% CI: 2.66-14.30, P < .001) of lesion occurrence compared to the cartilaginous vocal folds. Despite these strong trends in lesion distribution, there were no differences in the odds of lesion recurrence, growth, or in the time to recurrence, between anatomic subsites. CONCLUSIONS:RRP lesions are most likely to occur in the glottis, particularly the membranous vocal folds, compared with other regions of the larynx or trachea. However, all lesions demonstrate similar behavior with respect to recurrence, growth, and time to recurrence regardless of anatomic location. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2022.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage^1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes^4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas⁸ (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus⁹ (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.