Faculty Bibliography

BACKGROUND:Radioactive iodine therapy (RAI) is a frequently chosen therapy for Graves' disease. The aim of this study was to determine whether RAI for Graves' disease increases the risk of thyroid malignancy. METHODS:A retrospective analysis was performed of all Graves' disease patients who underwent thyroidectomy at a single institution between 2013 and 2022. Comparative analyses were performed with cohorts based on RAI therapy as the primary grouping variable. RESULTS:413 patients were identified, of which 38 received RAI prior to surgery. RAI treated patients were more likely to undergo surgery for known malignancy or indeterminate nodules. RAI patients were also more likely to have malignancies larger than 1 ​cm. Among RAI treated patients, those who developed malignancy were older at the time of Graves' diagnosis and received early RAI therapy. CONCLUSIONS:Use of RAI for treatment of Graves' disease increases the progression of thyroid carcinoma, but not the prevalence. Older age and early RAI therapy may be risk factors for malignancy in RAI treated patients.

BACKGROUND:Radioactive iodine therapy (RAI) is a frequently chosen therapy for Graves' disease. The aim of this study was to determine whether RAI for Graves' disease increases the risk of thyroid malignancy. METHODS:A retrospective analysis was performed of all Graves' disease patients who underwent thyroidectomy at a single institution between 2013 and 2022. Comparative analyses were performed with cohorts based on RAI therapy as the primary grouping variable. RESULTS:413 patients were identified, of which 38 received RAI prior to surgery. RAI treated patients were more likely to undergo surgery for known malignancy or indeterminate nodules. RAI patients were also more likely to have malignancies larger than 1 ​cm. Among RAI treated patients, those who developed malignancy were older at the time of Graves' diagnosis and received early RAI therapy. CONCLUSIONS:Use of RAI for treatment of Graves' disease increases the progression of thyroid carcinoma, but not the prevalence. Older age and early RAI therapy may be risk factors for malignancy in RAI treated patients.

BACKGROUND:Patient electronic messaging has increased clinician workload contributing to burnout. Large language models can respond to these patient queries, but no studies exist on large language model responses in thyroid disease. METHODS:This cross-sectional study randomly selected 33 of 52 patient questions found on Reddit/askdocs. Questions were found through a "thyroid + cancer" or "thyroid + disease" search and had verified-physician responses. Additional responses were generated using ChatGPT-3.5 and GPT-4. Questions and responses were anonymized and graded for accuracy, quality, and empathy using a 4-point Likert scale by blinded providers, including 4 surgeons, 1 endocrinologist, and 2 physician assistants (n = 7). Results were analyzed using a single-factor analysis of variance. RESULTS:For accuracy, the results averaged 2.71/4 (standard deviation 1.04), 3.49/4 (0.391), and 3.66/4 (0.286) for physicians, GPT-3.5, and GPT-4, respectively (P < .01), where 4 = completely true information, 3 = greater than 50% true information, and 2 = less than 50% true information. For quality, the results were 2.37/4 (standard deviation 0.661), 2.98/4 (0.352), and 3.81/4 (0.36) for physicians, GPT-3.5, and GPT-4, respectively (P < .01), where 4 = provided information beyond what was asked, 3 = completely answers the question, and 2 = partially answers the question. For empathy, the mean scores were 2.37/4 (standard deviation 0.661), 2.80/4 (0.582), and 3.14/4 (0.578) for physicians, GPT-3.5, and GPT-4, respectively (P < .01), where 4 = anticipates and infers patient feelings from the expressed question, 3 = mirrors the patient's feelings, and 2 = contains no dismissive comments. Responses by GPT were ranked first 95% of the time. CONCLUSIONS:Large language model responses to patient queries about thyroid disease have the potential to be more accurate, complete, empathetic, and consistent than physician responses.

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.

Thyroid carcinoma of follicular cell origin exists on a histopathologic and clinical spectrum. The authors focus on the category of tumors that fall between the very favorable well-differentiated thyroid carcinomas and the very unfavorable anaplastic thyroid carcinomas. These intermediately aggressive tumors include poorly differentiated thyroid carcinoma and the newly defined differentiated high-grade thyroid carcinoma. Both diagnoses require certain histopathologic requirements be met in order to accurately identify these tumors post-operatively. Management remains primarily surgical though adjunctive treatments such as molecular targeted therapies (eg, tyrosine kinase inhibitors) and differentiation therapy (to restore tumor response to radioactive iodine) are also becoming available.

BACKGROUND AND OBJECTIVE/UNASSIGNED:Thyroid nodules are frequently incidentally found on physical exam or imaging for an unrelated work-up. Although surgery remains the gold standard for treating symptomatic benign and/or malignant thyroid nodules, radiofrequency ablation (RFA) has emerged as a minimally invasive treatment option for high risk patients and those who decline surgery. The novel application of RFA to treat thyroid disease was originally described for symptomatic, benign thyroid nodules. Since then, several studies have tried to expand its indication to treat primary and recurrent well-differentiated thyroid cancer. The high success rates and the low complication profile, has allowed for quick adoption of RFA as a treatment option for well-selected patients with benign thyroid nodules and locoregional recurrent thyroid malignancy. As such, multidisciplinary guidelines and consensus statements were developed to standardize indications, techniques, outcome measures, and follow-up to ensure the best patient care. This article summarizes the current indications and recommendations to help guide clinicians on how best to effectively and safely utilize RFA to treat thyroid disease. METHODS/UNASSIGNED:A PubMed/MEDLINE search between 2000-2022 using a combination of "radiofrequency ablation", "RFA", "thyroid nodule", and "guidelines" was conducted. The inclusion criteria were articles published in English which offered recommendations on RFA use for thyroid nodules. KEY CONTENT AND FINDINGS/UNASSIGNED:For symptomatic, benign thyroid nodules, RFA is effective at significantly reducing nodule volume. For large nodules, multiple RFA sessions may be needed to achieve clinically significant volume reduction. Patients undergoing RFA for autonomously functioning thyroid nodules may see symptomatic relief but success rates are variable. RFA may serve a curative or palliative role in recurrent well-differentiated thyroid cancers. There is little data describing the use of RFA for primary well-differentiated thyroid cancer >1 cm and the role of RFA for thyroid microcarcinomas remains controversial. CONCLUSIONS/UNASSIGNED:RFA is a safe minimally invasive technique and may be considered, in appropriate circumstances, a first-line treatment option for benign thyroid nodules. Practices adopting RFA will likely increase as more clinicians become familiar with this technique, highlighting the importance of developing standardized guidelines.

BACKGROUND:Fluorodeoxyglucose uptake on positron emission tomography imaging has been shown to be an independent risk factor for malignancy in thyroid nodules. More recently, a new positron emission tomography radiotracer-Gallium-68 DOTATATE-has gained popularity as a sensitive method to detect neuroendocrine tumors. With greater availability of this imaging, incidental Gallium-68 DOTATATE uptake in the thyroid gland has increased. It is unclear whether current guideline-directed management of thyroid nodules remains appropriate in those that are Gallium-68 DOTATATE avid. METHODS:We retrospectively reviewed Gallium-68 DOTATATE positron emission tomography scans performed at our institution from 2012 to 2022. Patients with incidental focal Gallium-68 DOTATATE uptake in the thyroid gland were included. Fine needle aspiration biopsies were characterized via the Bethesda System for Reporting Thyroid Cytopathology. Bethesda III/IV nodules underwent molecular testing (ThyroSeq v3), and malignancy risk ≥50% was considered positive. RESULTS:In total, 1,176 Gallium-68 DOTATATE PET scans were reviewed across 837 unique patients. Fifty-three (6.3%) patients demonstrated focal Gallium-68 DOTATATE thyroid uptake. Nine patients were imaged for known medullary thyroid cancer. Forty-four patients had incidental radiotracer uptake in the thyroid and were included in our study. Patients included in the study were predominantly female sex (75%), with an average age of 62.9 ± 13.9 years and a maximum standardized uptake value in the thyroid of 7.3 ± 5.3. Frequent indications for imaging included neuroendocrine tumors of the small bowel (n = 17), lung (n = 8), and pancreas (n = 7). Thirty-three patients underwent subsequent thyroid ultrasound. Sonographic findings warranted biopsy in 24 patients, of which 3 were lost to follow-up. Cytopathology and molecular testing results are as follows: 12 Bethesda II (57.1%), 6 Bethesda III/ThyroSeq-negative (28.6%), 1 Bethesda III/ThyroSeq-positive (4.8%), 2 Bethesda V/VI (9.5%). Four nodules were resected, revealing 2 papillary thyroid cancers, 1 neoplasm with papillary-like nuclear features, and 1 follicular adenoma. There was no difference in maximum standardized uptake value between benign and malignant nodules (7.0 ± 4.6 vs 13.1 ± 5.7, P = .106). Overall, the malignancy rate among patients with sonography and appropriate follow-up was 6.7% (2/30). Among patients with cyto- or histopathology, the malignancy rate was 9.5% (2/21). There were no incidental cases of medullary thyroid cancer. CONCLUSION/CONCLUSIONS:The malignancy rate among thyroid nodules with incidental Gallium-68 DOTATATE uptake is comparable to rates reported among thyroid nodules in the general population. Guideline-directed management of thyroid nodules remains appropriate in those with incidental Gallium-68 DOTATATE uptake.

OBJECTIVE:Hungry bone syndrome (HBS) is a known complication of parathyroidectomy. Patients with renal hyperparathyroidism are particularly vulnerable to HBS because of their prolonged exposure to electrolyte abnormalities and elevated parathyroid hormone (PTH). However, in-depth characterization of predictive factors for HBS in these patients is lacking. METHODS:A retrospective analysis was performed of patients with renal hyperparathyroidism who underwent parathyroidectomy at a single institution from 2011-2021. Patient demographics, clinical characteristics, and biochemical data were collected and analyzed. Boruta and binary logistic regression analyses were used to develop a scoring system. RESULTS:Thirty-three patients were identified; 16 (48%) developed HBS. Patients with HBS had significantly higher preoperative levels of serum PTH (mean difference [MS] = 2167.2 pg/mL, P <.001), phosphorus (MD = 3.5 mg/dl, P <.001), and alkaline phosphatase (ALP) (MD = 344.2 U/L, P =.002) and significantly lower levels of preoperative serum calcium (MD = -0.96 mg/dL, P =.004). Stepwise regression analysis identified elevated ALP (>150 U/L) and markedly elevated PTH (>1000 pg/mL) as positive predictors of HBS. A two-point scoring system with these 2 variables had overall diagnostic accuracy of 96.8% (sensitivity 100% and specificity 94.1%) with 1 point conferring 93.8% positive predictive value and 2 points conferring 100% positive predictive value. CONCLUSION/CONCLUSIONS:Preoperative serum PTH and ALP are significantly associated with HBS in patients with renal hyperparathyroidism undergoing parathyroidectomy for renal hyperparathyroidism. A scoring system with these 2 variables may be of clinical utility in predicting patients at high risk of HBS.

CONTEXT/BACKGROUND:Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine-needle aspiration (FNA) samples has not been reported. OBJECTIVE:To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. DESIGN/METHODS:Retrospective analysis of FNA samples tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier. SETTING/METHODS:UPMC MGP laboratory. PARTICIPANTS/METHODS:A total of 50,734 BCIII-VI nodules from 48,225 patients. INTERVENTION/METHODS:None. MAIN OUTCOME MEASURES/METHODS:Prevalence of diagnostic, prognostic, and targetable genetic alterations. RESULTS:Among 50,734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alteration. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.2% of cases. CONCLUSIONS:In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutationsand targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.