Jacome, Cristian Soto

Abstract Context Incidental thyroid findings (ITFs) are increasingly detected on imaging performed for non-thyroid indications. Their prevalence, features, and consequences remain undefined. Objective To develop, validate, and deploy a natural language processing (NLP) pipeline to identify ITFs in radiology reports and assess their prevalence, features, and clinical outcomes. Design Retrospective cohort study. Setting Mayo Clinic sites (Rochester, Arizona, Florida, Mayo Clinic Health System). Participants Adults without prior thyroid disease undergoing thyroid-capturing imaging from July 1, 2017, to September 30, 2023. A transformer-based NLP pipeline identified ITFs and extracted nodule characteristics from image reports from multiple modalities and body regions. Outcomes ITF prevalence, downstream thyroid ultrasound, biopsy, thyroidectomy, and cancer diagnosis. Logistic regression identified demographic and imaging-related factors. Results Among 115 683 patients (mean age, 56.8 [SD 17.2]; 52.9% women), 9077 (7.8%) had an ITF (92.9% nodular). ITFs were more likely in women, older adults, higher BMI, and in imaging ordered by specialties different from Emergency Medicine. Compared with chest CT, ITFs were more likely via neck CT, PET, and nuclear medicine scans. Nodule characteristics were poorly documented, with size reported in 44% and other features in fewer than 15%. Compared with patients without ITFs, those with ITFs had higher odds of thyroid nodule diagnosis (OR 45, 95%CI 41.1-49.3), biopsy (OR 46.8, 95%CI 39.0-56.2) thyroidectomy (OR 55.8, 95%CI 31.3-99.3), and thyroid cancer diagnosis (OR 61.7, 95%CI 38.6-98.5). Most cancers were papillary (88.5%) and larger when detected after ITFs (2 cm SD 1.4) vs no ITF (1.3 cm SD 0.8). Conclusion ITFs were common and strongly associated with cascades leading to the detection of small, low-risk cancers, highlighting their role in overdiagnosis and the need for standardized reporting and more selective follow-up.

Abstract Context Benign thyroid nodules (BTNs) are highly prevalent, and current treatment options are primarily invasive. There is a need for effective, noninvasive alternatives. Objective To systematically evaluate the efficacy of repurposed pharmacologic agents in reducing the size of BTNs. Data Sources MEDLINE, EMBASE, Cochrane databases, and Scopus were searched from inception to December 18, 2024. Study Selection We included preclinical and clinical studies evaluating repurposed drugs for BTNs in adults. Of 1499 records screened, 20 studies met inclusion criteria: 6 randomized controlled trials (RCTs), 6 prospective cohorts, 3 retrospective observational studies, 3 case reports, 1 cross-sectional study, and 1 preclinical study. Data Extraction Data were extracted independently in duplicate using a standardized form. Data Synthesis Narrative synthesis was conducted due to heterogeneity. Metformin was the most frequently evaluated agent (7 studies), with 5 studies (including 2 RCTs) reporting statistically significant reductions in dominant nodule volume. One prospective study demonstrated a reduction in the maximum nodule diameter, which was not statistically significant, and 1 RCT showed no changes in nodule size after intervention. Statins (4 studies) and somatostatin analogues (4 studies) showed mixed results. Myo-inositol with selenium, herbal formulations, and immune checkpoint inhibitors showed promise in single studies or case reports. Conclusion Metformin shows the most consistent potential for noninvasive reduction of BTN size, particularly in patients with metabolic comorbidities. However, current evidence is limited and heterogeneous. Further large-scale studies are needed to confirm efficacy and guide clinical use.

Abstract Purpose Overuse of thyroid ultrasound (TUS) has contributed to rising thyroid cancer diagnoses and is projected to increase US healthcare costs from $1.5 billion to $3.5 billion by 2030. This study evaluated the healthcare cost of inappropriately ordered TUS in a national multicenter academic system. Methods This is a secondary cost analysis of a retrospective cohort study across 4 Mayo Clinic sites (Rochester, MN; Jacksonville, FL; Scottsdale, AZ; and the Midwest Mayo Clinic Health System). Adult patients (≥18 years) undergoing their first TUS between January 1, 2017, and December 31, 2021, with at least 1 year of follow-up were included. TUS indications were classified as appropriate or inappropriate using a guideline-based natural language processing algorithm. The primary outcome was a comparison of adjusted 1-year all-cause healthcare costs. A secondary analysis calculated the direct procedural costs of the inappropriate TUS cascade. Results Among 6984 patients (mean age 56 [SD 16.4]; 76.2% female; 90.9% White), 546 (7.8%) underwent TUS for inappropriate indications. These patients were younger (mean age 53.0 vs 56.3 years, P < .0001) but otherwise demographically similar. Adjusted total healthcare costs over 90 days and 1 year were comparable: $4842 vs $5794 and $13 748 vs $14 257 for inappropriate vs appropriate TUS, respectively. The inappropriate TUS cascade, including an estimated 56 subsequent biopsies and 22 thyroidectomies, resulted in a minimum of $576 134 in direct procedural costs. Conclusion While adjusted total costs were similar, inappropriate TUS represents potentially avoidable spending and remains a viable target for cost-reduction strategies. Reducing low-value imaging remains a critical target for cost-saving interventions.

ImportanceThyroid cancer incidence has tripled in the past 3 decades, largely driven by increased detection of small, indolent papillary thyroid cancers. Overuse of thyroid ultrasonography (TUS) contributes to overdiagnosis, leading to unnecessary biopsies, procedures, and potential patient harm.ObjectiveTo evaluate the frequency of and factors associated with inappropriate TUS (iTUS) orders and assess related clinical outcomes.Design, Setting, and ParticipantsThis retrospective cohort study analyzed adult patients 18 years and older who underwent their first TUS from January 1, 2017, to December 30, 2021, at 4 Mayo Clinic sites. Patients with previous thyroid nodule, thyroid cancer, thyroid surgery, or TUS were excluded. Based on documented clinical indications, a validated natural language processing model classified TUS orders as appropriate or inappropriate. Data were analyzed from April 2024 to May 2025.ExposuresBaseline characteristics of patients, clinicians, and clinical encounters investigated for their association with an iTUS order.Main Outcomes and MeasuresThe primary outcome was the proportion of iTUS orders. Secondary outcomes included factors associated with iTUS (sociodemographic, clinical, order-specific, and clinician-related factors) and clinical outcomes following iTUS, including the detection of thyroid nodules, thyroid procedures, and thyroid cancer diagnoses.ResultsOf 11 442 included patients, 8422 (73.6%) were female, and the mean (SD) age was 57.3 (15.8) years with a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 29.7 (7.0). Among 11 442 TUS orders, 866 (7.6%) were classified as inappropriate. In multivariable analysis, younger age (age of 18 to 54 years vs older than 65 years; odds ratio [OR], 1.86; 95% CI, 1.56-2.22), hyperthyroidism (OR, 9.04; 95% CI, 6.75-12.11), ordering by nonendocrinology specialties (eg, oncology/hematology; OR, 3.43; 95% CI, 2.47-4.76), and orders not linked to an in-person appointment (eg, portal messages; OR, 2.42; 95% CI, 2.08-2.82) were strongly associated with increased odds of iTUS. Compared with appropriate TUS, iTUS led to lower rates of thyroid nodule detection (202 of 866 [23.3%] vs 6885 of 10 576 [65.1%]; OR, 0.16; 95% CI, 0.14-0.19), biopsies (89 [10.3%] vs 2647 [25.0%]; OR, 0.34; 95% CI, 0.27-0.43), partial thyroidectomies (14 [1.6%] vs 424 [4.0%]; OR, 0.39; 95% CI, 0.23-0.67), and confirmed thyroid cancer cases (16 [1.8%] vs 425 [4.0%]; OR, 0.45; 95% CI, 0.27-0.74).Conclusions and RelevanceIn this cohort study, approximately 1 in 13 TUS orders were inappropriate. iTUS was more common in younger patients, those with thyroid dysfunction, those not seen in person, and in those referred by nonendocrinology specialties. These findings highlight the need for targeted strategies to optimize TUS use and mitigate overdiagnosis and overtreatment.

Abstract Context Levothyroxine is one of the most prescribed medications in the United States. Objective This study explores the appropriateness of levothyroxine prescriptions. Methods A retrospective multicenter study was conducted on adult patients who were prescribed levothyroxine for the first time between 2017 and 2020 at three academic centers in the United States. We classified each case of levothyroxine initiation into one of three mutually exclusive categories: appropriate (clinically supported), indeterminate (clinically unclear), or nonevidence based (NEB, not clinically supported). Results A total of 977 participants were included. The mean age was 55 years (SD 19), there was female (69%) and White race predominance (84%), and 44% had possible hypothyroid symptoms. Nearly half of the levothyroxine prescriptions were considered NEB (528, 54%), followed by appropriate (307, 31%) and indeterminate (118, 12%). The most common reason for NEB prescription was an index thyrotropin (TSH) value of less than 10 mIU/L without previous TSH or thyroxine values (131/528, 25%), for appropriate prescription, was overt hypothyroidism (163/307, 53%), and for an indeterminate prescription was a nonconfirmed subclinical hypothyroidism with TSH greater than or equal to 10 mIU/L (no confirmatory testing) (51/118, 43%). In multivariable analysis, being female (odds ratio [OR]: 1.3; 95% CI, 1.0-1.7) and prescription by a primary care provider (OR: 1.5; 95% CI, 1.2-2.0) were associated with NEB prescriptions. Conclusion There is a considerable proportion of NEB levothyroxine prescriptions. These results call for additional research to replicate these findings and to explore the perspective of those prescribing and receiving levothyroxine.

e18807 Background: CUP represents both a diagnostic and a management challenge. Despite improvements through sophisticated imaging modalities, specific and sensitive testing using immunohistochemistry, a concrete determination of the site of origin of the primary tumor can still be a diagnostic challenge Hereby, we described the genomic landscape of patients with CUP treated at our institution. Methods: Retrospective study of patients with CUP treated at Mayo Clinic Rochester MN from 2010 to 2021. Next generation sequencing (NGS) information was abstracted, and alterations were ranked into different levels of actionability following the Onco KB framework. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, we identified 67 (32%) patients in whom NGS was performed. Among patients with available NGS the median age was 64 years (range: 35-86) and 51% were female. the most prevalent histology included adenocarcinoma (39%), carcinoma NOS (31%), and neuroendocrine tumors (12%). NGS on tumor (t-NGS) was available in 56 (84 %) patients, circulating tumor NGS (b-NGS) was available in 12 (18%) patients, and only 1 patient had both testing available. Among the 56 patients with available t-NGS, MSI-high was detected in 9 patients, whereas among the 12 patients with available b-NGS, MSI-high was detected in 8 patients; yielding an MSI-high detection rate of 16% and 67% for t-NGS and b-NGS. In this cohort, there were a total of 474 genomic alterations detected from which 103 (22 %) were able to be ranked into one therapeutic level following the OncoKB framework. Genomic alterations were most observed among patients with carcinoma (n = 50, 48.53%) adenocarcinoma (n = 33, 32.03 %), squamous cell carcinoma (n = 3, 2.91 %) and neuroendocrine tumor (n = 2, 1.94%). Following the OncoKB framework, 39-level 1 genomic alterations were detected in a total of 14 genes. The most common level 1 genomic alterations comprised the BRCA2 (20.51%), NF1 ATM (17.95%) and HER2/NEU (ERBB2) (15.38%) genes. Therapeutic level 2 included 51 genomic alterations in 13 genes of which KRAS (17.65%), BRAF (15.69%), and BRCA2 (15.69%) were the most prevalent mutated genes. Additionally, level R comprised 13 genomic alterations in the following genes: KRAS (69.23) NRAS (23.08%) and PDGFRA (7.69%). Conclusions: CUP are malignancies rich in potentially actionable alterations, and NGS of tissue and blood samples can inform systemic therapy decisions. Alteration-specific targeted therapy may be an option for a substantial proportion of patients. NGS of tumor tissue or blood should be considered for all patients with CUP.

e18803 Background: CUPs are a heterogeneous group of metastatic cancers for which a standardized diagnostic work-up fails to identify the site of origin at the time of diagnosis. CUP accounts for 3%-5% of all cancer diagnoses worldwide, and the natural history of patient with CUP differs from that of patients (pts) with cancer with known primary tumor. Here we report and summarize the clinical features of patients with CUP treated at Mayo Clinic. Methods: Retrospective study of patients treated at Mayo Clinic Rochester MN from 2010 to 2021. Patient demographics, tumor-related variables, treatment-related variables, and clinical data were extracted. Descriptive statistics were used, and all data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 pts, 207 pts were included, as primary tumor site was identified in 7 patients after initial evaluation. The pts in this study were predominantly white (87%) of female (50.2%) gender with a mean age of 63 (SD: 13) without history of smoking (51%) and either private or public insurance (82.6%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (27%), and carcinoma NOS (not otherwise specified) (25%). The most prevalent grade in this cohort was grade III with poorly differentiated tumor cells. All pts had diagnostic imaging and the most used imaging modalities included CT (81.2%), and PET-CT (43.5%). In our cohort, the 3 most common sites of metastases included lymph nodes (57.5%), liver (37.8%), lung (34.3%), and bone (23.7%); and in 64% of pts, there was a specific presentation pattern including liver-predominant (24.6%), lymph node-predominant (24.6%), bone-predominant (7.7%), and peritoneal carcinomatosis (7.7%). The majority of pts received systemic therapy (69%) as first line of therapy and the most frequent first line regimens included platinum-doublet (26.5%), gemcitabine-based regimen (20.7%), 5FU-based regimens (18%) and somatostatin analogs (16.7%); whereas salvage radiation and ablation were offered to 11% of pts and surgery to 17%. The median follow-up time was 22 months (IQR: 45) with a median survival time of 23 months and the 3-year cumulative survival rate was 30%. Conclusions: The heterogenous nature of CUPs and lack of specific immunohistochemical signature prevents primary tissue of origin diagnoses in CUP pts. Without the identification of a primary origin site, treatment is restricted to generic chemotherapy with limited benefit as demonstrated in this cohort.

e18802 Background: CUP is a rare cancer with an incidence of 7–12 cases per 100,000/year. CUP is defined as metastatic cancer with no identifiable primary tumor despite comprehensive evaluation. Despite its heterogeneous clinicopathological presentation, the treatment of CUP has primarily been with platinum-based combination chemotherapies but results are poor and survival is short. Here, we describe survival outcomes in real-world dataset of patients with CUP seen at a tertiary referral center. Methods: Retrospective study of patients treated at Mayo Clinic, Rochester MN, from 2010 to 2021. Survival probabilities were estimated with the Kaplan-Meier method. We used Cox proportional hazard regression with forward modeling to explore the association between each variable and death. Overall survival (OS) analysis was conducted in the entire cohort, and it was stratified by histological subtype. For the hypothesis test, we considered p < 0.05 to be statistically significant; all tests were two-sided. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, 198 patients were included in the survival analysis. The patients were predominantly white (87%), female (50.2%), with a mean age of 63 (SD: 13) without history of smoking (51%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (NEN) (27%), carcinoma NOS (25%), squamous cell carcinoma (SCC) (10%) and non-classifiable tumors (7%). The median follow-up time was 23 months, and medial OS was 23 months in the entire cohort. OS by histology was as follows: 51 months for NEN, 34 months for SCC, 18 months for carcinomas NOS and 11 months for adenocarcinomas (p < 0.001) (fig.1). Similar OS trends were observed when we restricted the analysis to poorly differentiated tumors. The 3- and 5-year cumulative survival by histology were as follows: 7% and 0% for adenocarcinoma, 25% and 8% for carcinoma NOS, 39% and 17% for SCC, and 56% and 22% for NEN. In Cox regression models we did not identify any prognostic factors among patients with adenocarcinoma. Conclusions: Patients with adenocarcinoma of unknown primary possess a considerable challenge and the OS is short. CUP of other histologies have higher OS. This study highlights the need of accurate tumor identification and better treatment, perhaps as a multiomics therapeutic approach.