Faculty Bibliography

Neoadjuvant therapy (NAT) is increasingly used for pancreatic ductal adenocarcinoma (PDAC); yet most patients only achieve partial response. Pathological treatment response grading focuses on assessing residual tumor burden, often overlooking changes in tumor microenvironment (TME). To address this gap, we compared tumor cells and TME of 13 NAT-naïve and 23 post-NAT PDACs using integrated spatial pathomics and transcriptomics, with validation in an independent single-cell spatial dataset. NAT significantly reduced tumor burden (14.7%-6.2%, p = 0.004), but systemic comparison of 13 cytomorphometric features of tumor cells alone did not reliably distinguish between naïve and NAT cases. In contrast, NAT profoundly remodeled TME by increasing cancer-associated fibroblast (CAF) and CD8⁺ T cell densities, promoting CD8⁺ T cell-tumor cell proximity and fibrosis, reducing tumor-associated neutrophils, and redistributing tertiary lymphoid structures (TLSs). Spatial transcriptomics shows NAT induced apoptosis, DNA-damage response, and AGC-kinase (S_TK_X) signaling in tumor cells, and upregulated complement pathway, p53 signaling, and cellular senescence program in TME. Cross-platform single-cell spatial analysis revealed decreased regulatory T cells (Treg) and a shift from myofibroblastic (mCAF) to inflammatory CAF (iCAF). Importantly, post-NAT patients with more fibrosis had longer overall survival (p = 0.02), and higher B-cell density showed a favorable trend (p = 0.06). Together, these results suggest that beyond tumor debulking, NAT induces a coordinated TME remodeling characterized by fibroblast reprogramming, matrix fibrosis, and immune spatial reorganization. Incorporating assessment of NAT-induced stromal and immune changes into TRG may improve prognostication and guide more precise therapy in post-NAT PDAC.

BACKGROUND:Although most adrenal incidentalomas are benign, many are identified by single-phase contrast-enhanced computed tomography, which is unreliable for excluding malignancy. Virtual noncontrast computed tomography is a newer modality with the potential to better characterize adrenal nodules. METHODS:Virtual noncontrast computed tomography of adrenal nodules with available reference standard of true noncontrast computed tomography were identified (2016-2024). Images were evaluated for nodule characteristics including Hounsfield unit attenuation and variability. Nodules were classified as benign (≤10 Hounsfield units) or indeterminate/suspicious (>10 Hounsfield units) by true noncontrast computed tomography. Hounsfield units were compared between virtual noncontrast computed tomography and true noncontrast computed tomography. Variability in attenuation measurements was compared by evaluating Hounsfield unit differences 1 slice up and down from the chosen mid-depth image. Receiver operating characteristic analysis was used to define optimal virtual noncontrast computed tomography accuracy thresholds. RESULTS:After excluding 5 adrenal nodules due to suboptimal imaging, 67 nodules were identified. Based on true noncontrast computed tomography Hounsfield units, 23 nodules (34.3%) were benign, and 44 (65.7%) were indeterminate/suspicious. Hounsfield unit measurements for each nodule exhibited wide variability by both virtual noncontrast computed tomography and true noncontrast computed tomography. Virtual noncontrast computed tomography and true noncontrast computed tomography were significantly correlated with moderate effect size (Pearson coefficient 0.69, P < .001). Conflicting impressions occurred for 6 nodules (9.0%). Overall, virtual noncontrast computed tomography exhibited outstanding discrimination between benign and indeterminate/suspicious nodules (area under the curve 0.94). Maintaining a threshold of ≤10 Hounsfield units achieved 93% sensitivity, 76% specificity, and 84% negative predictive value, whereas ≤7 Hounsfield units achieved 100% negative predictive value. The functional utility of virtual noncontrast computed tomography as a rule-out test applied to 16% of nodules. CONCLUSION/CONCLUSIONS:Despite wide variability in Hounsfield unit measurements, adrenal nodules are well defined by both virtual noncontrast computed tomography and true noncontrast computed tomography. Well-reconstructed virtual noncontrast computed tomography images can accurately rule out malignancy in selected patients, potentially obviating the need for additional imaging.

BACKGROUND:Guidelines do not recommend routine screening for thyroid nodules when starting a glucagon-like peptide-1 receptor agonist. Patients, however, increasingly present with incidental nodules from imaging ordered at glucagon-like peptide-1 receptor agonist initiation. METHODS:This retrospective case-control study examined patients in a single academic health system from 1 January 2019 to 31 December, 2024 who underwent thyroid ultrasound, fine-needle aspiration biopsy, molecular testing, and/or surgery with glucagon-like peptide-1 receptor agonist initiation compared with patients not prescribed a glucagon-like peptide-1 receptor agonist. Patient, prescription, and intervention data were collected. Chart review was also performed for a subset of patients. RESULTS:From 2019 to 2024, 2,523 patients prescribed a glucagon-like peptide-1 receptor agonist underwent thyroid ultrasound; from 2020 to 2023, there was a higher growth rate of ultrasound scans ordered for them. A random sample of 415 patients prescribed a glucagon-like peptide-1 receptor agonist showed that most ultrasounds were ordered for "thyroid nodules" by the endocrinologist who prescribed glucagon-like peptide-1 receptor agonist. In this subset, 757 nodules were detected on ultrasound; 10.6% (80/757) had fine-needle aspiration biopsy. Cytology showed 3.8% were Bethesda I (3/80), 72.5% Bethesda II (58/80), 15% Bethesda III (12/80), 0% Bethesda IV (0/80), 2.5% Bethesda V (2/80), and 6.6% Bethesda VI (5/80). Of 15 indeterminate nodules, 11 had molecular testing: 5 were positive or suspicious, including fusions, alterations, RAS and BRAF mutations. Sixteen patients had thyroid surgery after glucagon-like peptide-1 receptor agonist initiation (8 total thyroidectomies, 8 hemithyroidectomies, 1 completion). Final pathology demonstrated 6 benign, 10 malignant, 1 NIFTP. The rate of malignancy in the subset was 2.4% (10/415). CONCLUSION/CONCLUSIONS:The malignancy rate in patients prescribed a glucagon-like peptide-1 receptor agonist remains low, but ultrasound screening rates increased for a period. Strong clinical suspicion should govern screening.

INTRODUCTION/BACKGROUND:Papillary thyroid cancer (PTC) often follows an indolent course with a favorable prognosis. This has led to evolving guideline-based, low-intensity treatment options for low-risk patients. Recently, the purported benefit of total thyroidectomy (TT) over unilateral lobectomy for PTC with clinical lateral neck nodal metastasis (cN1b) has come into question. MATERIALS AND METHODS/METHODS:A retrospective analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results database was performed to study patients with PTC with ipsilateral cN1b disease from 1975 to 2020. Kaplan-Meier curves and log-rank tests were used to compare disease-specific survival (DSS) difference between lobectomy and TT at 10 y. Multivariable Cox proportional hazards analysis was performed to determine the independent association of lobectomy versus TT with DSS, correcting for age and lymph node ratio, defined as the ratio of pathologically positive lymph nodes to total number examined. RESULTS:Among 2943 patients (median [interquartile range] age, 45 [26] y), 42 underwent lobectomy and 2901 underwent TT. Unadjusted DSS at 10 y in the lobectomy and TT groups were 51.0% (95% confidence interval, 31.4%-82.8%) and 86.8% (95% confidence interval, 84.8%-88.9%), respectively. On multivariable analysis of all patients, older age (hazard ratio [HR], 1.08; P < 0.001) and male gender (HR, 1.74; P < 0.001) were associated with lower adjusted DSS, whereas treatment with TT (HR, 0.387; P = 0.005) and receipt of radioactive iodine (RAI) (HR, 0.604; P < 0.001) were associated with improved adjusted DSS. In addition, we observed that the magnitude of survival benefit conferred by RAI and TT were reduced with decreasing age (P < 0.001). CONCLUSIONS:This longitudinal cohort study suggests that, while TT is associated with a DSS benefit in most patients with PTC and ipsilateral cN1b disease, this association may not exist in a smaller cohort of younger patients. These findings raise the possibility that unilateral surgical clearance without RAI could offer adequate oncologic outcomes in selected younger individuals; however, further investigation is warranted to confirm these observations and inform clinical decision-making.

We present a case highlighting innominate vein reconstruction for resection of Hurthle cell carcinoma with complex vascular invasion. A 69-year-old man presented with a rapidly enlarging neck mass, dysphagia and dysphonia. Workup demonstrated a 11.2 × 7.0 × 6.5 cm Hurthle cell carcinoma invading the oropharynx and superior mediastinum. We proceeded with left thyroid lobectomy and modified left radical neck dissection. Median sternotomy, resection of the left clavicular head, and partial resection of the left manubrium were performed to circumferentially expose the innominate vein. Tumor thrombus was extruded from the innominate vein followed by patch angioplasty, which remains patent 14 months postoperatively.

INTRODUCTION/BACKGROUND:The influence of baseline health-related quality of life (HRQoL) on peri-operative outcomes in pancreatobiliary (PB) patients is not well established. This study investigated the impact of baseline HRQoL on peri-operative outcomes and the effect of surgery on HRQoL. METHODS:A secondary post-hoc analysis of a multicenter trial (2011-2016) assessed PB patients undergoing pancreatectomy. Pre-operative and 30-day post-operative FACT-G surveys were analyzed. Logistic regressions determined associations between baseline HRQoL scores and 60-day major complications. Subgroup analysis evaluated change in HRQoL (pre-operative to 30-day scores). RESULTS:Among 391 patients, higher baseline HRQoL (FACT-G overall OR 0.54,p ​= ​0.04) was associated with decreased likelihood of developing major complications. Surgery resulted in improvement in HRQoL for patients with chronic pancreatitis (10.2 points) compared to other pathologies (-7 to 3.9 points). CONCLUSION/CONCLUSIONS:Baseline HRQoL was associated with post-operative complications and HRQoL significantly improved for patients with chronic pancreatitis, highlighting the importance of HRQoL on patient-centered outcomes.

BACKGROUND:Four-dimensional computed tomography is routinely used to localize parathyroid disease, with consistently excellent parathyroid gland localization rates reported. This study evaluated whether pairing 4-dimensional computed tomography results with preoperative clinical variables can accurately predict single-gland disease in primary hyperparathyroidism. METHODS:Patients with primary hyperparathyroidism who underwent both 4-dimensional computed tomography imaging and parathyroidectomy between January 2019 and September 2021 at a large academic health system were included. Patient demographics, preoperative characteristics, and peri- and postoperative data were collected. The accuracy of 4-dimensional computed tomography in correctly identifying patients with single-gland disease with and without preoperative calcium and parathyroid hormone levels was calculated. Single-gland disease was defined by intraoperative parathyroid hormone decrease >50% and a hypercellular gland on pathology. RESULTS:One hundred seventy-five patients had 4-dimensional computed tomography results suggestive of single gland disease. One hundred fifty-two patients (87%) were predicted correctly to have single-gland disease. The predictive accuracy increased when stratifying by preoperative calcium (≥10.5 mg/dL, ≥11 mg/dL, and ≥12 mg/dL) and parathyroid hormone levels (≥65 pg/mL, ≥100 pg/mL, and ≥200 pg/dL). The accuracy further increased when stratifying by age (≤50 years). Accuracy for single gland disease was 100% when combined with any of the following: (1) calcium ≥12 mg/dL, (2) parathyroid hormone ≥200 pg/dL, or (3) calcium ≥11 mg/dL in patients ≤50 years. CONCLUSION/CONCLUSIONS:Four-dimensional computed tomography alone accurately predicted single gland disease in 87% of patients with primary hyperparathyroidism. When combined with preoperative calcium, parathyroid hormone and age thresholds, predictive accuracy for single-gland disease approached 100%. Given the high likelihood of single-gland disease in these scenarios, clinicians may consider offering focused unilateral parathyroidectomy without intraoperative parathyroid hormone monitoring in selected patients.

Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC). This study investigates how NAT differentially impacts PDAC's carcinoma cells and the tumor microenvironment (TME). Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME of 23 NAT-treated versus 13 NAT-naïve PDACs. Findings were validated by single-nucleus RNA sequencing (snRNA-seq) analysis. NAT induces apoptosis and inhibits proliferation of carcinoma cells and coordinately upregulates multiple complement genes (C1R, C1S, C3, C4B and C7) within the TME. Higher TME complement expression following NAT is associated with increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4⁺ T cells; reduced immune exhaustion gene expression, and improved overall survival. snRNA-seq analysis demonstrates C3 complement is mainly upregulated in CAFs. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response, and guiding therapeutic strategies in NAT-treated PDAC patients.

BACKGROUND:The existence of sociodemographic disparities in pancreatic cancer has been well-studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care. METHODS:Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment-related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses. RESULTS:Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010-2017 [range-OR]:0.19-0.29), Black race (range-OR: 0.61-0.78), lower SES (range-OR: 0.52-0.94), and uninsured status (range-OR: 0.46-0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range-OR: 0.11-0.84), lower SES (range-OR: 0.41-0.63), and uninsured status (range-OR: 0.38-0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005). CONCLUSIONS:Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care.

BACKGROUND:Racial and ethnic disparities in thyroid cancer care may be mitigated by improving enrollment of more diverse patient populations in clinical trials. We studied trial eligibility criteria and enrollment to assess barriers to equitable representation. METHODS:ClinicalTrials.gov was searched for studies on thyroid cancer treatment conducted between 1993 and 2023. The inclusion and exclusion criteria of each study were examined. For published studies, reported demographic information was collected. Observed enrollment by race was compared with the expected distribution as determined using data from the US Census and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) databases. Over- and under-representation was defined as the ratio of observed to expected (O/E) enrollment by the race and ethnicity group. RESULTS:Of 309 thyroid cancer-related trials, 23 (7.4%) used language as an exclusion criterion. Most were interventional (n = 239, 77.3%), university-initiated (194, 62.8%), and drug/device-focused (195, 63.1%). Of studies that excluded by language, 20 (87.0%) were university-initiated. Eighty-eight trials were subsequently published, with 16 (18.2%) reporting race and/or ethnicity distributions. When comparing O/E ratios, White American participants were over-represented (O/E ratio: 1.2, P < .0001). Under-represented groups included Asian/Native Hawaiian (O/E ratio: 0.6, P = .0085), Black (0.6, P = .014), Native American (0.2, P = .072), and Hispanic patients (0.2, P < .0001). CONCLUSION/CONCLUSIONS:Over the last 3 decades, 1 in 13 thyroid cancer-related clinical trials excluded patients based on language. In the fraction of published studies to report on racial and ethnic demographics, Asian/Native Hawaiian, Black, and Hispanic patients were under-represented. Improved reporting of demographics in published studies and elimination of exclusion criteria such as language that hinder enrollment of minority patients could improve equitable representation of patients in thyroid cancer clinical trials.