Background/Objective Pheochromocytomas are rare catecholamine-secreting tumors arising from adrenomedullary chromaffin cells. Very rarely, they co-secrete adrenocorticotropic hormone (ACTH), causing ectopic Cushing syndrome. Because of its rarity, clinicians may not consider this etiology, despite the high morbidity associated with simultaneous catecholamine and cortisol excess. We present a case in which a systematic and methodical diagnostic approach led to identification and successful treatment of an ACTH-producing pheochromocytoma. Case Report A 48-year-old man presented with altered mental status, rapid-onset hypertension and diabetes, profound hypercortisolism and proximal muscle weakness. Imaging revealed a 3.4 cm left adrenal mass and contralateral adrenal hyperplasia. ACTH, cortisol, and metanephrines were markedly elevated, and DOTATATE PET demonstrated intense uptake in the adrenal mass, raising suspicion for an ACTH-secreting pheochromocytoma. After alpha-blockade, he underwent laparoscopic adrenalectomy. Postoperatively, ACTH became undetectable and he developed transient adrenal insufficiency, confirming cure. Pathology showed pheochromocytoma with positive ACTH staining. His hypertension, diabetes, mental status, and myopathy improved, and genetic testing for hereditary syndromes was negative. Discussion ACTH-secreting pheochromocytomas can present with abrupt and severe hypercortisolism that may overshadow adrenergic symptoms. Clues include profound ACTH elevation, abnormal dexamethasone suppression test, elevated metanephrines, and a unilateral adrenal mass with contralateral adrenal hyperplasia. Early recognition is essential, considering higher morbidity associated with dual secretion of catecholamines and cortisol. Conclusion ACTH-producing pheochromocytoma is an uncommon but important cause of ectopic Cushing syndrome. Incorporating this entity into the differential diagnosis of rapidly progressive hypercortisolism enables timely intervention and reduces morbidity associated with combined catecholamine and cortisol excess.

Context Oncocytic cells can occur in benign and malignant thyroid nodules, posing a diagnostic challenge. This has reduced the diagnostic performance of molecular testing for indeterminate oncocytic thyroid nodules.Objective To evaluate the performance of Afirma genomic sequencing classifier (GSC) in thyroid nodules with Bethesda III or IV cytology and oncocytic predominance.Design, setting, patients, and intervention A multicenter retrospective study was conducted in adults with Bethesda III and IV thyroid nodules showing oncocytic predominance who underwent a fine-needle aspiration biopsy and Afirma GSC testing between July 2017 and December 2023. Variables included presence of Hashimoto's thyroiditis and Thyroid Imaging Reporting and Data System (TIRADS) classification.Main outcome measures Outcomes included benign call rate (BCR), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Afirma GSC testing.Results Of 359 nodules (57% Bethesda III, 43% Bethesda IV) tested with Afirma GSC, the mean nodule size was 2.0 cm. BCR was 81% and 74% for Bethesda III and IV nodules, respectively. GSC sensitivity, specificity, PPV, and NPV were 89%, 86%, 24%, and 99% for Bethesda III nodules and 94%, 87%, 50%, and 99% for Bethesda IV nodules, respectively. A concurrent diagnosis of Hashimoto's thyroiditis significantly reduced the specificity and PPV in Bethesda III nodules. TIRADS classification did not affect the BCR or PPV in Bethesda III or IV nodules.Conclusion Afirma GSC has a high BCR and improved performance over earlier generation molecular tests in oncocytic thyroid nodules, particularly for Bethesda IV. However, the PPV in Bethesda III nodules remains low, especially in the presence of Hashimoto's thyroiditis.

Background/Objective:Pheochromocytomas are rare catecholamine-secreting tumors arising from adrenomedullary chromaffin cells. Very rarely, they cosecrete adrenocorticotropic hormone (ACTH), causing ectopic Cushing syndrome. Because of its rarity, clinicians may not consider this etiology, despite the high morbidity associated with simultaneous catecholamine and cortisol excess. We present a case in which a systematic and methodical diagnostic approach led to identification and successful treatment of an ACTH-producing pheochromocytoma. Case Report:A 48-year-old man presented with altered mental status, rapid-onset hypertension and diabetes, profound hypercortisolism and proximal muscle weakness. Imaging revealed a 3.4 cm left adrenal mass and contralateral adrenal hyperplasia. ACTH, cortisol, and metanephrines were markedly elevated, and DOTATATE positron electron tomography demonstrated intense uptake in the adrenal mass, raising suspicion for an ACTH-secreting pheochromocytoma. After alpha-blockade, he underwent laparoscopic adrenalectomy. Postoperatively, ACTH became undetectable and he developed transient adrenal insufficiency, confirming cure. Pathology showed pheochromocytoma with positive ACTH staining. His hypertension, diabetes, mental status, and myopathy improved, and genetic testing for hereditary syndromes was negative. Discussion:ACTH-secreting pheochromocytomas can present with abrupt and severe hypercortisolism that may overshadow adrenergic symptoms. Clues include profound ACTH elevation, abnormal dexamethasone suppression test, elevated metanephrines, and a unilateral adrenal mass with contralateral adrenal hyperplasia. Early recognition is essential, considering higher morbidity associated with dual secretion of catecholamines and cortisol. Conclusion:ACTH-producing pheochromocytoma is an uncommon but important cause of ectopic Cushing syndrome. Incorporating this entity into the differential diagnosis of rapidly progressive hypercortisolism enables timely intervention and reduces morbidity associated with combined catecholamine and cortisol excess.

Supplementary Table S3. Comparison of clinical and pathologic characteristics of differentiated thyroid cancers with diploid versus heterozygous losses at chromosome 22q

Supplementary Table S1. List of all variants detected by Oncopanel in 78 RAS-mutant thyroid tumors

Supplementary Table S2. Characteristics of patients with RAS-mutant anaplastic thyroid cancer

Disclosure: A. Bikas: None. E. Su: None. H. Patankar: None. M. Alshalalfa: Veracyte, Inc. Y. Hao: Veracyte, Inc. J.P. Klopper: Veracyte, Inc.. T. Pappa: None. Introduction: Alterations in cell cycle regulatory genes may lead to abnormal cellular proliferation, tumor development, and malignancy. The aim of this study was to characterize the expression of cell cycle proliferation genes in thyroid nodules/cancer and assess the molecular and clinical associations of their expression. Methods: A set of 47 genes implicated in cell cycle progression (CCP) genes (i.e. TOP2A, MKI67) were identified from The Cancer Genome Atlas (TCGA) Thyroid. A CCP activity z-score was derived from the expression of the 47 genes and subsequently associated with genomic alterations and outcomes data in TCGA. In addition, 2,205 fine needle aspiration (FNA) samples with (B)ethesda V/VI cytology sent for Afirma testing were extracted from the Afirma thyroid nodule database. The CCP score was analyzed in reference to TERT promoter mutation status and common oncogenic alterations reported by the Afirma Xpression Atlas (XA - the variant and fusion panel), as well as other molecular markers of tumor aggressiveness. Fisher’s exact test was used to assess statistical differences. Results: TCGA samples were stratified based on the CCP score and then grouped into 4 quartiles (Q4: top 25%, Q3:50-75%, Q2:25-50%, Q1: low 25%). Comparing Q4 to Q1, Q4 was enriched with TERT promoter mutations (14.4% vs 2.4%, p<0.001), disease progression (20% vs 8%, p=0.001), MACIS>8 (9.6% vs 3.2%, p=0.06), and stage IV disease (13.6% vs5.6%, p=0.05). The Q4 group is associated with a shorter time to disease progression (HR:2.56, 95%CI [1.23-5.3], p=0.01) relative to the Q1 group. In Afirma B V/VI samples, Q4 CCP score was more enriched with TERT promoter mutations (11.2% vs 4.9%, p p<0.001) compared to Q1, but less enriched with BRAFV600E (40% vs 69%, p<0.001), and RAS family variants (1.8% vs 6.4%, p<0.001). Within this subset, CCP was negatively correlated with TDS (r= -0.48, p<0.001) but not correlated with ERK activity or BRAF-RAS score. Mutations in genes of the PI3K/AKT/mTOR pathway were present, though in small numbers, in Q3 and Q4 groups, but not in Q1-Q2 groups. The CCP score was not correlated with sex or age. Conclusion: The CCP score may be a useful tool in pre-operative thyroid tumor samples to predict tumor aggressiveness, especially in the absence of known molecular alterations or in intermediate risk mutations (such as BRAFV600E) that present with a heterogeneous histologic phenotype. Interestingly, the highest CCP quartile, associated with worse progression free survival in the TCGA cohort, was less enriched with BRAFV600E compared to the lowest CCP quartile. Future analysis incorporating pathology and recurrence outcomes will be necessary to assess the validity and clinical utility of the preoperative CCP score. Presentation: Monday, July 14, 2025

Context Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery.Objective This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing.Methods Adult patients who underwent a biopsy at 3 major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. The primary outcomes were the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of GSC in Bethesda III and IV nodules.Results The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false-negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance.Conclusion GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC-benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

CONTEXT:Active surveillance for papillary thyroid cancer (PTC) meeting criteria for surgical resection is uncommon. Which patients may prove reasonable candidates for this approach is not well defined. OBJECTIVE:This work aimed to examine the feasibility and safety of active surveillance for patients with known or suspected intrathyroidal PTC up to 4 cm in diameter. METHODS:A retrospective review was conducted of all consecutive patients who underwent nonoperative active surveillance of suspicious or malignant thyroid nodules over a 20-year period from 2001 to 2021. We included patients with an initial ultrasound-fine-needle aspiration confirming either (a) Bethesda 5 or 6 cytology or (b) a "suspicious" Afirma molecular test. The primary outcomes and measures included the rate of adverse oncologic outcomes (mortality and recurrence), as well as the cumulative incidence of size/volume growth. RESULTS:Sixty-nine patients were followed with active surveillance for 1 year or longer (average 55 months), with 26 patients (38%) having nodules 2 cm or larger. No patients were found to develop new-incident occurrence of lymph node or distant metastasis. One patient, however, demonstrated concern for progression to a dedifferentiated cancer on repeat core biopsy 17 years after initial start of nonoperative selection. A total of 21% of patients had an increase in maximum diameter more than 3 mm, while volume increase of 50% or greater was noted in 25% of patients. Thirteen patients ultimately underwent delayed (rescue) surgery, and no disease recurrence was noted after such treatment. Age and initial nodule size were not predictors of nodule growth. CONCLUSION:These data expand consideration of active surveillance of PTC in select patients with intrathyroidal suspected malignancy greater than 1 cm in diameter. Rescue surgery, if required at a later time point, appears effective.

Anaplastic thyroid cancers (ATC) are fast-growing, undifferentiated tumors and almost invariably fatal, primarily due to the lack of effective therapeutic options. The recent approval of dabrafenib plus trametinib for the treatment of BRAFV600E-mutant ATCs improved the prognosis of a subset of patients, but ineligibility and acquired resistance still limit their use. Overall, ATC patients remain in great need of tailored therapeutic options. We previously showed that loss-of-function alterations targeting histone acetyltransferase (HAT) genes, namely CREBBP and EP300, occur in 15-20% of ATCs, but only in <1% of their well-differentiated counterparts. What remains unknown are the specific mechanisms by which HAT disruptions perturb chromatin architecture, impact gene homeostasis, and unleash cellular processes in these aggressive tumors. We are assessing the HAT-mediated thyroid cancer progression. CREBBP/EP300 knockouts enhanced thyroid cancer cell proliferation in vitro and induced thyroid gland growth in a thyroid-specific mouse model of HAT loss. We are leveraging these animals to characterize the in vivo effects of Crebbp/Ep300 knockout, alone or in combination with BrafV600E, in thyroid cancer phenotypes and epigenetic reconfiguration. In addition, we are exploiting the molecular consequences of HAT loss to explore tailored treatments. CRISPR/Cas9 screens identified a mutual CREBBP/EP300-dependency of HAT-mutant human cancer cell models. Our experiments in thyroid cancer cells employing CREBBP/EP300-targeting proteolysis-targeting chimera (PROTAC) compounds specifically degraded these proteins and decreased histone acetylation. Our findings prove the oncogenicity of HAT loss in thyroid cancer progression and support exploring synthetic lethality dependencies in CREBBP/EP300-mutant ATCs. In summary, we provide pre-clinical basis to inform genomics-driven and mechanism-oriented decisions for the clinical management of patients with HAT-altered ATC. Citation Format: Jacob Haase, Talia A. Gebhard, Qi Liu, Sara G. Bernabé, Jingzhu Hao, Chisom Unegbu, Athanasios Bikas, Jun Qi, Iñigo Landa. CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3068.

AbstractPurpose: RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC). Experimental Design: We performed a clinical–genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next-generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations. Results: Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared with DTCs harboring a solitary RAS mutation, patients with DTC with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P < 0.001) and to have larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P < 0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%; P = 0.011) when additional mutations were identified. Conclusions: Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision-making.

Background: While the diagnosis of papillary thyroid carcinomas (PTCs) with tall cell features (PTCtcf) is often made for carcinomas with histological features intermediate between classic and tall cell subtypes of PTC (tcPTC), its comparative signature to that of either tcPTC or classic PTC is less clear. The objective of this study was to perform an integrative clinicopathologic and genomic analysis elucidating the spectrum of tcPTC, PTCtcf, and classic PTC.Methods: We analyzed all consecutive patients with tcPTC and PTCtcf evaluated at a tertiary academic referral center between 2005 and 2020, as well as a comparative cohort of classic PTC, in a retrospective observational cohort analysis. Clinicopathologic data were compared among the three groups, including progression-free survival (PFS), recurrent/persistent disease, and a negative composite outcome of death, progression, or need for advanced therapy. To specifically understand differences between tcPTC and PTCtcf, targeted next-generation sequencing was performed in a subset of these cohorts.Results: A total of 292 patients were analyzed (81 tcPTC, 65 PTCtcf, 146 classic PTC). Thirteen percent of tcPTC versus 8% of PTCtcf versus 1% of classic PTC had the advanced American Joint Committee on Cancer stage (p = 0.002). Similarly, macroscopic extrathyroidal extension was observed in 38% of tcPTC, 14% of PTCtcf, and 12% of classic PTC (p < 0.001). The 5-year PFS was 76.5%, 81.5%, and 88.3% for tcPTC, PTCtcf, and classic PTC, respectively, while the rates of the negative composite outcome 40.2% for tcPTC, 20.7% for PTCtcf, and 11.2% for classic PTC (p < 0.001). In a multivariable Cox regression analysis, the negative composite outcome was independently associated with tcPTC (HR 4.3 [confidence interval 1.1-16.1], p = 0.03). tcPTC demonstrated substantially more hotspot TERT promoter mutations than PTCtcf (44% vs. 6%, p = 0.012).Conclusions: Our study demonstrates a continuum of disease-specific risk of PTC, pointing at PTCtcf as an intermediate entity between tcPTC and classic PTC. These data provide a more refined understanding of risk at time of presentation, while better elucidating the diversity of genomic drivers.

Context The natural history of benign thyroid nodules is typically characterized by slow growth and minimal risk of malignant transformation. Available data have, to date, been unable to elucidate the diversity of benign nodule growth patterns over time nor predictive of which patients follow which pattern. Objective We aimed to better define the diverse patterns of benign nodule behavior and their predictors. Methods We prospectively studied 389 consecutive patients with solitary, solid, cytologically benign thyroid nodules ≥1 cm and follow-up ultrasound for at least 4 years. Demographic, sonographic, biochemical data were collected at initial evaluation, and subsequent growth patterns were identified over the follow-up. Predictors of growth at initial evaluation and 3 years of follow-up were defined. Results The mean (±SD) follow-up was 7.7 (±2.7) years. Three distinct growth patterns were identified: A) stagnant nodules with average growth rate < 0.2 mm/year; B) slow-growing nodules with a rate 0.2 to 1.0 mm/year; and C) fast-growing nodules increasing > 1.0 mm/year. Fast-growing nodules represented 17.2% of the cohort, and were more frequent in patients younger than 50 years (OR 2.2 [1.2-4.1], P = 0.016), and in larger nodules (2.0-2.9 cm, OR 3.5 [1.7-7.1], P = 0.001; >3.0 cm, OR 4.4 [1.8-10.4], P = 0.001 vs reference 1-1.9 cm). In a multiple regression model, nodule growth at 3 years at an average growth rate over 0.2 mm/year over 3 years since initial evaluation was an independent predictor of longer-term fast nodule growth, even after adjusting for age, biological sex, TSH level, and nodule size (P < 0.001). Conclusion The natural history of benign nodule growth is diverse, with over 80% of nodules demonstrating minimal to no growth long-term. Nearly 20% of cytologically benign nodules may exhibit a fast, continued growth pattern, which can be predicted by the 3-year growth rate pattern. These findings can help inform decision making for tailored benign nodule follow-up and monitoring.

Abstract Disclosure: G.A. Stamatiades: None. A. Bikas: None. H.J. Shah: None. K. Wong: None. A. Vaidya: None. M. Nehs: None. S.S. Basaria: None. Background: Pheochromocytomas are rare catecholamine-secreting tumors that arise from sympathetic adrenomedullary chromaffin tissue. Rarely, pheochromocytomas co-secrete ACTH and patients present with Cushing syndrome. Due to its rarity, clinicians may not consider this etiology of Cushing syndrome. We report a case of a man with ACTH-producing pheochromocytoma in whom methodic systematic approach led to its diagnosis and successful treatment. Clinical Case: A 48-year-old man presented with altered mental status. His family confirmed depressed mood, paucity of thought, and occasional blank stares. The patient was diagnosed with type-2 diabetes mellitus and hypertension 3 months ago, which were not controlled despite being on multiple anti-hypertensives and anti-diabetic agents. His EEG, head CT, and brain MRI were normal. On admission, his laboratory tests were notable for hypokalemia (3.0 mmol/L, n<5.3 mmol/L) and metabolic alkalosis (HCO3 33 mmol/L, n<32 mmol/L). Physical examination showed facial plethora, multiple ecchymoses and profound proximal muscle weakness. CT scan of the abdomen showed a 3.4 cm left adrenal nodule with a density of 33 Hounsfield units and a 73% absolute washout. The right adrenal gland was hyperplastic. Plasma and urinary metanephrines were significantly elevated (plasma metanephrines 1.6 nmol/l, n < 0.50 nmol/l, urinary metanephrines 1,685 mcg/24h, n <646 mcg/24h). Midnight salivary cortisol was 11,500 ng/dl (n<100 ng/dl) and 24h urinary free cortisol was 13,099 mcg/24h (n < 45 mcg/24h). ACTH was 450 pg/ml (n<63pg/ml) with a serum cortisol of 93 ug/dl (n<18.4 ug/dl). His serum cortisol after 8 mg Dexamethasone Suppression test was 100 ug/dl. DOTATATE PET CT scan showed uptake in the left adrenal nodule. The workup was suggestive of left-sided pheochromocytoma producing ectopic ACTH. The patient underwent laparoscopic left adrenalectomy. Postoperative ACTH was undetectable, indicating surgical cure. His blood pressure and plasma glucose gradually improved and remained normal after discontinuation of all medications. Surgical pathology was consistent with pheochromocytoma with positive staining for ACTH, confirming the diagnosis of ACTH-producing pheochromocytoma. He was discharged home after successful rehabilitation. Clinical Lessons: Pheochromocytomas are a rare cause of ectopic ACTH production, resulting in clinical Cushing syndrome. Imaging of the contralateral adrenal gland provides a valuable clue in making the diagnosis of ectopic ACTH production (as the gland is enlarged rather than atrophic). Reference: (1) Elliott PF, Berhane T, Ragnarsson O, Falhammar H. Ectopic ACTH- and/or CRH-Producing Pheochromocytomas. J Clin Endocrinol Metab. 2021 Jan 23;106(2):598-608. doi: 10.1210/clinem/dgaa488. PMID: 32710791. Presentation: Friday, June 16, 2023

Context Predictive models of thyroid nodule cancer risk are presently based upon nodule composition, echogenicity, margins, and the presence of microcalcifications. Nodule shape has shown promise to be an additive factor helping determine the need for nodule biopsy. Objective We sought to determine if calculation of a nodule’s spherical shape independently associates with cancer risk. Methods This prospective cohort study, conducted at a single large academic healthcare system in the United States, included patients with 1 or 2 clinically relevant thyroid nodules (predominantly solid and over 1 cm) presenting for diagnostic evaluation. Thyroid ultrasound, cytological evaluation with fine-needle biopsy, and/or histopathological examination on occasion of thyroid surgery were performed. We calculated the nodule’s long to short ratio (spherical shape), and its association with tissue proven benign or malignant endpoints. Results The long to short nodule ratio was significantly lower in malignant compared to benign nodules indicating greater risk of malignancy in more spherical nodules (1.63 ± 0.38 for malignant nodules vs 1.74 ± 0.47 for benign, P < 0.0001). The risk of malignancy continually increased as the long to short ratio approached a purely spherical ratio of 1.0 (ratio > 2.00, 14.6% cancer; ratio 1.51-2.00, 19.7%; ratio 1.00-1.50, 25.5%, P < 0.0001). In multiple regression analysis, younger age, male sex, and nodule’s spherical shape were each independently associated with cancer risk. Conclusion The more a thyroid nodule is spherically shaped, as indicated by a long to short ratio approaching 1.0, the greater its risk of malignancy. This was independent of age, sex, and nodule size. Incorporating a nodule’s sphericity in the risk stratification systems may improve individualized clinical decision making.

Background Immunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism. Methods A retrospective analysis was conducted using patients who received immunotherapy between 2010‐2019 within a multicenter hospital system. Participants were separated in three groups—those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated. Results 822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6‐8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009). Conclusion It is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg.

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25–82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

Objectives: Most pediatric medullary thyroid cancers (MTC) result from dominantly inherited or de novo activating mutations in the Rearranged-during-transfection (RET) proto-oncogene.(1) Our group previously demonstrated that RET-positive MTC-derived cells have significantly increased mitochondrial respiratory chain molecules as compared to normal thyroid tissue. In this study, we examined how inhibition of oxidative phosphorylation affects expression of genes controlling response to oxidative stress and DNA damage in MTC-derived cells. Methods: Human MTC-derived TT cells (harboring C634W RET mutation) were grown in RPMI 1640 …