Faculty Bibliography

BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

PURPOSE/OBJECTIVE:Locoregionally recurrent head and neck cancer is a complex clinical scenario that often requires multimodality treatment. These patients have often previously received definitive treatment with a combination of surgery, radiation therapy, and systemic therapy, which can make further management difficult. A second isolated locoregional failure is rare and clinicians are faced with a challenge to optimize disease control while minimizing treatment-related toxicity. METHODS AND MATERIALS/METHODS:In this report, we present the diagnosis, management, and outcomes of a patient with an isolated locoregional recurrence who was previously treated with two courses of radiation. The patient was treated with a second course of reirradiation using interstitial brachytherapy as well as a discussion regarding patient selection and optimal management for recurrent head and neck cancer. RESULTS:Repeat reirradiation using interstitial HDR-brachytherapy with the use of an alloderm spacer was successfully delivered to the patient for an in-field right neck nodal recurrence. He received a total EQD2/BED dose of 127.70/153.24 Gy. At 1-year followup, the patient was without evidence of recurrent disease or new significant side effects. CONCLUSION/CONCLUSIONS:Recurrent head and neck cancer should be managed with a multidisciplinary approach given the complex clinical scenario. Reirradiation is a commonly used salvage measure for recurrent head and neck cancer that requires careful planning and patient selection due to prior treatment-related effects and dose constraints. We reported a case of a second course of reirradiation using interstitial HDR-brachytherapy for locoregionally recurrent head and neck cancer and showed no recurrence of disease or worsening long term side effects at 1 year.

INTRODUCTION/UNASSIGNED:In spite of its apparent ease, comprehension of spoken discourse represents a complex linguistic and cognitive operation. The difficulty of such an operation can increase when the speech is degraded, as is the case with cochlear implant users. However, the additional challenges imposed by degraded speech may be mitigated to some extent by the linguistic context and pace of presentation. METHODS/UNASSIGNED:An experiment is reported in which young adults with age-normal hearing recalled discourse passages heard with clear speech or with noise-band vocoding used to simulate the sound of speech produced by a cochlear implant. Passages were varied in inter-word predictability and presented either without interruption or in a self-pacing format that allowed the listener to control the rate at which the information was delivered. RESULTS/UNASSIGNED:Results showed that discourse heard with clear speech was better recalled than discourse heard with vocoded speech, discourse with a higher average inter-word predictability was better recalled than discourse with a lower average inter-word predictability, and self-paced passages were recalled better than those heard without interruption. Of special interest was the semantic hierarchy effect: the tendency for listeners to show better recall for main ideas than mid-level information or detail from a passage as an index of listeners' ability to understand the meaning of a passage. The data revealed a significant effect of inter-word predictability, in that passages with lower predictability had an attenuated semantic hierarchy effect relative to higher-predictability passages. DISCUSSION/UNASSIGNED:Results are discussed in terms of broadening cochlear implant outcome measures beyond current clinical measures that focus on single-word and sentence repetition.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

OBJECTIVE:To describe the natural history of primary inner ear schwannomas over a long follow-up period. STUDY DESIGN/METHODS:Retrospective case series. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Patients with primary inner ear schwannomas with serial audiometric and radiologic follow-up. MAIN OUTCOME MEASURES/METHODS:Patterns of hearing loss, rate of hearing decline, presence of vestibular symptoms, and rate of tumor growth. RESULTS:A total of 12 patients with 13 tumors were identified. The mean duration of follow-up was 7 years. Forty-six percent of tumors were intracochlear, 15% were intravestibular, 23% were transmodiolar, and 15% were intravestibular-cochlear. Hearing loss was the most common presenting symptom, occurring in all patients. Among patients with serviceable hearing (AAO Class A or B) at the time of presentation, the average time to decline to a nonserviceable hearing level was 57.3 months (range, 21-117 mo). Hearing loss was sudden in 31% of patients, progressive in 61% and fluctuating in 8%. No patients had intractable vertigo; however, two required vestibular physiotherapy. On initial magnetic resonance imaging, the mean largest tumor dimension was 3.1 mm (standard deviation, 1.2 mm), and the mean largest dimension on most recent magnetic resonance imaging was 4.4 mm (standard deviation, 1.1 mm). Two tumors exhibited no growth over a follow-up of 11.3 and 2.8 years, respectively. Overall, the mean growth was 0.25 mm per year followed. Two patients underwent cochlear implantation with simultaneous tumor resection and had favorable outcomes. CONCLUSION/CONCLUSIONS:Long-term follow-up suggests a conservative approach, with possible hearing rehabilitation at the time of deterioration, is a safe management strategy for primary inner ear schwannomas.

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.

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.

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.

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.