Faculty Bibliography

BACKGROUND:Current staging systems for head and neck cutaneous squamous cell carcinoma (HNCSCC), such as AJCC8 and BWH, often fail to adequately stratify high-risk patients, particularly due to the exclusion of important biological and host factors. This study aimed to identify independent prognostic factors for HNCSCC outcomes in the largest multi-institutional retrospective series to date. METHODS:De-identified data from 8,610 primary HNCSCC tumors, treated with curative intent surgery across multiple international centers, were analyzed. Outcomes included local recurrence (LR), locoregional metastasis (LM), distant metastasis (DM), and disease-specific death (DSD). Multivariable Fine-Gray subdistribution hazard regression models with robust standard errors clustered at the patient level were fitted to generate exploratory hypotheses regarding independent hazard determinants. RESULTS:During a median follow-up of 31.4 months (IQR 14.2-52.8), the cumulative incidence was 3.3% for LR, 2.7% for LM, 0.5% for DM, and 1.2% for DSD. Multivariable analysis confirmed that tumor diameter, poor differentiation, deep invasion, and large-caliber perineural invasion (LCPNI) were the strongest predictors, being significantly associated with at least three of the four outcomes. Notably, factors currently excluded from or weighted differently in staging systems also proved critical: Immunosuppression was significantly associated with LR (SHR 2.03) and DSD (SHR 1.70); and lymphovascular invasion (LVI) was independently associated with LM (SHR 3.00). Poor differentiation demonstrated high prognostic impact, being a significant predictor for all four endpoints. CONCLUSION/CONCLUSIONS:Tumor diameter, poor differentiation, deep invasion, LCPNI, immunosuppression status, and LVI are the most critical independent factors for HNCSCC prognosis. Our multi-institutional data provide a robust framework for hypothesis generation, highlighting that incorporating host biological features and non-anatomic variables could significantly refine future staging system discussions.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Concurrent chemoradiotherapy (CCRT) is an effective treatment for various head and neck cancers; however, CCRT can result in significant swallowing impairment, presumably due largely to dysfunction of the muscles of swallowing, which are within the field of radiation. This translational study examines the mechanisms underlying CCRT-induced muscle dysfunction using (1) a rat model of CCRT and (2) analysis of archival human specimens. METHODS:131 Sprague Dawley rats were divided into experimental and control groups. Experimental rats received cisplatin and 5-fluorouracil intravenously, followed by 7 Gray radiation daily for 5 days. Rats were further split into three time points: acute (2 weeks), intermediate (5 months), and long-term (10 months), at which time tissue was harvested for analysis. Human samples included preexisting CCRT-treated and age- and sex-matched control muscle samples from head and neck cancer patients. Quantitative analyses of Paired Box Homeotic Gene 7-positive cells (Pax7 in rats; PAX7 in humans), fibrosis, muscle fiber size, and neuromuscular junctions were conducted and compared between groups in both rats and humans. RESULTS:Analysis demonstrated a significant decline in the percent of Pax7/PAX7-positive cells (a marker of muscle stem cells) after CCRT in both rats and humans, increased collagen percent, and decreased muscle percent in rats at 10 months. CCRT was associated with significantly reduced muscle fiber size in human specimens. Neuromuscular junction presence and morphology in rats were not affected. CONCLUSION/CONCLUSIONS:This translational study demonstrates significant alterations in head and neck muscles in both a rat model and human specimens from subjects exposed to CCRT. LEVEL OF EVIDENCE/METHODS:NA.

Understanding trauma-related psychopathology increasingly requires tools capable of capturing how symptoms and underlying mechanisms unfold across real-world contexts. Traditional assessments, which depend on retrospective recall and intermittent clinical contact, are limited in their ability to reflect the dynamic and context-sensitive processes that shape trauma-related mental health outcomes. Emerging digital health technologies and computational approaches address this gap by enabling the continuous measurement of behavior and physiology, whereas biological markers provide mechanistic insights into processes such as stress-related neuroendocrine, autonomic, immune, and sleep-wake functioning that reflect the biological embedding of trauma over time. This review integrates recent advances in digital and biological measurement in posttraumatic stress disorder (PTSD) and outlines principles for combining these approaches within computational frameworks. We emphasize the importance of grounding digital proxies in established biological theory; modeling intraindividual dynamics rather than relying solely on cross-sectional group differences; and integrating multimodal behavioral, physiological, and contextual data. We further highlight essential considerations for ethical, inclusive, and methodologically rigorous implementation, including privacy-by-design, data quality, and clinical interpretability. Together, these approaches support a more mechanistic, dynamic, and personalized understanding of trauma-related risk and recovery, with the potential to enhance early risk stratification and guide preventive and individualized models of care.

INTRODUCTION/UNASSIGNED:Burnout and declining fulfillment are prevalent among facial plastic surgeons (FPS), yet the organizational drivers of these challenges remain underexplored. Ownership structure, workplace autonomy, and collective representation may influence surgeon well-being and workforce sustainability. OBJECTIVES AND HYPOTHESES/UNASSIGNED:To assess how autonomy, ownership, and unionization relate to satisfaction and stress among FPS. We hypothesized that private practitioners would report greater autonomy and satisfaction, that academic and hospital-employed surgeons would experience more stress and diminished control, and that prior union exposure would correspond with more favorable views of collective representation. STUDY DESIGN/UNASSIGNED:Cross-sectional observational survey (STROBE). METHODS/UNASSIGNED:A 26-item anonymous survey was distributed to all 1,041 members of the American Academy of Facial Plastic and Reconstructive Surgery; 104 responded (10%). Variables included practice type, ownership, union history, autonomy, compensation satisfaction, stressors, and openness to unionization. Analyses employed chi-square tests and qualitative content analysis. RESULTS/UNASSIGNED:Surgeons in private practice reported the highest autonomy and compensation satisfaction and the lowest rates of feeling rushed. Hospital-employed and academic surgeons were more likely to report diminished autonomy, administrative stress, and lack of influence over workplace decisions. Only 11% of respondents expressed interest in unionizing, though prior union members generally described positive experiences. Surgeons' beliefs about whether unionization affects patient care did not vary significantly by practice setting. CONCLUSION/UNASSIGNED:Structural factors, particularly the autonomy and ownership model, are strongly linked to satisfaction and stress among FPS. Organizational reforms that enhance autonomy and support collective voice may reduce burnout and improve workforce sustainability.

BACKGROUND:The optimal number of pulsed field ablation (PFA) applications during atrial fibrillation (AF) ablation is unclear. We hypothesized that the number of PFA applications would predict atrial tachyarrhythmia (ATA) recurrence rates. OBJECTIVE:To determine whether higher numbers of PFA applications would decrease ATA recurrence rates. METHODS:We studied cases of patients with AF undergoing first-time ablation with PFA between 5/6/24 and 10/7/24. All patients underwent pulmonary vein and posterior wall isolation. The primary outcome was ATA recurrence. Additional outcomes included stroke, post-procedural acute kidney injury (AKI), total procedure time, and major periprocedural complications. Univariable and multivariable analyses were performed to determine if the number of PFA applications predicted ATA recurrence. RESULTS:In a cohort consisting of 177 patients, univariable and multivariable analysis showed that the number of PFA applications split at the smallest quartile (< 57 applications) versus the largest three quartiles (≥ 57 applications) was the strongest predictor of ATA recurrence (p = 0.03). ATA recurrence at 1 year (29% vs. 8%; p < 0.01) and AF burden on continuous monitor (4% vs. 0%; p < 0.01) was higher with the standard (< 57 applications) vs higher (≥ 57 applications) PFA dose groups. When comparing the standard versus higher PFA dose groups, there was no difference in total procedure time (106 vs. 107 min; p = 0.77), major periprocedural complications (0% vs. 2%; p = 0.33), or post-procedural AKI (2% vs. 2%; p = 0.69). CONCLUSION/CONCLUSIONS:Increasing number of PFA applications is associated with reduced ATA recurrence. A higher number of PFA applications may decrease ATA recurrence without affecting procedure times or complication rate.

OBJECTIVE:VEXAS syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS-specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease-related inflammation across affected organ systems in patients with VEXAS syndrome. METHODS:Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS-DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. RESULTS:Consensus on the VEXAS-DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurological, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. CONCLUSION/CONCLUSIONS:The VEXAS-DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS syndrome. Prospective validation within a clinical trial setting is ongoing.

INTRODUCTION/BACKGROUND:Serotonin (5-hydroxytryptamine [5-HT]) plays an important role in early development, and fetal 5-HT has been reported to arise from placental and maternal sources. Previous human studies have established an association between maternal 5-HT levels and neurodevelopmental outcomes in populations with autism. In this study, we analyze umbilical cord blood and placental 5-HT levels at birth to further investigate the relationship of gestational 5-HT levels with birth outcomes and offspring cognitive development. METHODS:Participants were enrolled in the Safe Passage Study conducted by the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network. Infant cord blood and placental samples were collected postdelivery, and 5-HT levels were measured using high-performance liquid chromatography-fluorometric analysis. The Mullen Scales of Early Learning (MSEL) assessed child development at 12 months. Associations between 5-HT levels and birth outcomes or developmental outcomes were assessed using linear regression models. RESULTS:No significant association was found between cord blood (n = 418) and placental (n = 89) 5-HT levels. Preterm birth was associated with lower cord blood 5-HT levels, and increasing gestational age among full-term infants was associated with higher cord blood 5-HT levels. Cord blood 5-HT was significantly associated with the Mullen Scales of Early Learning Composite Score, and follow-up analyses revealed a significant association between cord blood 5-HT and fine motor skills. No association was found between placental 5-HT and the Mullen composite score. CONCLUSION/CONCLUSIONS:To our knowledge, this study is the first to evaluate the relationship between placental 5-HT levels and cord blood 5-HT levels at birth. The lack of association suggests that cord blood 5-HT levels are likely to be a better index of fetal 5-HT exposure. Associations between cord blood 5-HT and child cognitive development are consistent with previous studies showing an association between maternal 5-HT levels and neurodevelopmental trajectories. Further research is needed to better characterize these relationships and to elucidate the distinct contributions of maternal, placental, and fetal 5-HT sources across developmental time points.

BACKGROUND:To evaluate whether quantitative craniospinal MRI assessment of baseline tumor burden provides prognostic value in patients with recurrent, previously irradiated medulloblastoma undergoing MEMMAT (Metronomic Antiangiogenic) therapy. METHODS:We analyzed craniospinal MRI of 40 patients with recurrent, previously irradiated medulloblastoma enrolled in the MEMMAT trial (April 1, 2014, and March 31, 2021). Ependymal, leptomeningeal, and local relapse lesions were retrospectively manually segmented on T1-contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) at baseline and follow-up (best response). Lesion count and volume were quantified. Bland-Altman analyses and intraclass correlation coefficients (ICC) assessed inter-sequence agreement., logistic regression evaluated associations between baseline tumor burden and progressive disease. RESULTS:Patients achieving Complete Response (n = 6/40) showed mean monthly decreases of - 12.7% in T1CE lesion count and - 12.9% in volume. Partial Response patients (n = 9/40) showed similar declines (-10.3% and - 13.0%). Stable Disease patients (n = 5/40) demonstrated minimal decreases (-0.8% and - 2.3%). Progressive Disease patients (n = 16/40) showed increases of 33.7% in lesion count and 56.2% in volume. Logistic regression indicated trends toward higher baseline tumor burden predicting PD (volume OR 1.18, p = 0.08; lesion count OR 1.05, p = 0.075). Agreement between T1CE and DWI was limited (ICC 0.35 for lesion count, 0.47 for volume), with 23% of patients misclassified using either modality alone. Survival analyses demonstrated significantly shorter overall survival in patients with baseline lesion volumes ≥ 5.5 ml (log-rank p = 0.003), while a similar association for progression-free survival did not reach statistical significance (p = 0.053). CONCLUSIONS:Combined intracranial and intraspinal T1CE and intracranial DWI assessment improves response evaluation. Exploratory analyses suggested that higher baseline tumor burden may be associated with progression, although the observed associations were of borderline statistical significance and require validation in larger cohorts.