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Context Broad genomic analyses among thyroid histologies have been described from relatively small cohorts. Objective Investigate the molecular findings across a large, real-world cohort of thyroid fine-needle aspiration (FNA) samples. Design Retrospective analysis of RNA sequencing data files. Setting Clinical Laboratory Improvement Amendments laboratory performing Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) testing. Participants A total of 50 644 consecutive Bethesda III-VI nodules. Intervention None. Main Outcome Measures Molecular test results. Results Of 48 952 Bethesda III/IV FNAs studied, 66% were benign by Afirma GSC. The prevalence of BRAF V600E was 2% among all Bethesda III/IV FNAs and 76% among Bethesda VI FNAs. Fusions involving NTRK, RET, BRAF, and ALK were most prevalent in Bethesda V (10%), and 130 different gene partners were identified. Among small consecutive Bethesda III/IV sample cohorts with one of these fusions and available surgical pathology excision data, the positive predictive value of an NTRK or RET fusion for carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features was >95%, whereas for BRAF and ALK fusions it was 81% and 67%, respectively. At least 1 genomic alteration was identified by the expanded Afirma XA panel in 70% of medullary thyroid carcinoma classifier–positive FNAs, 44% of Bethesda III or IV Afirma GSC suspicious FNAs, 64% of Bethesda V FNAs, and 87% of Bethesda VI FNAs. Conclusions This large study demonstrates that almost one-half of Bethesda III/IV Afirma GSC suspicious and most Bethesda V/VI nodules had at least 1 genomic variant or fusion identified, which may optimize personalized treatment decisions.

Background In the face of the COVID‐19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. Methods An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID‐19, aligned with phases of care published by the ACS. Results Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. Conclusions These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID‐19.

Background: The purpose of this study was to test the hypothesis that there is no significant difference in vascular flow patterns between cytopathologically-proven colloid nodules and papillary thyroid carcinoma (PTC) even when adjusting for nodule size. Methods: Doppler vascular flow patterns in 200 colloid nodules and 166 nodules with PTC were retrospective reviewed independently by 2 neuroradiologists blinded to the cytopathological results. Absence of vascular flow, perinodular and/or intranodular flow, and diffuse vascular flow were recorded. The vascular flow patterns were compared without (Fisher exact test) and with (Kruskal-Wallis test) an adjustment for nodular size. Using the most common flow pattern as the reference group, multiple logistic regression was used to compare the flow patterns. Sample skewness was calculated to determine degree of symmetry of the size distribution for each vascular flow category. Results: No significant difference was found in the tested vascular flow patterns between colloid nodules and PTC both without and with an adjustment for nodular size (P>0.05). Intranodular flow only was the largest group (n=111/366) and used as the reference for multiple logistic regression. No significant difference was noted between the vascular flow patterns (P>0.05). Sample skewness showed that nodules were generally smaller in size with outliers of larger size on the opposite end of the spectrum. Conclusions: Independent of nodule size the absence or presence of vascular flow is not significantly different between colloid nodules and PTC. Therefore, vascular flow may not be useful in distinguishing between colloid nodules and PTC.

Systemic therapy options have emerged for treatment of progressive, radioiodine-refractory differentiated thyroid carcinoma. Approved therapies that target tumor angiogenesis, lenvatinib and sorafenib, improve progression-free survival and, in an older subset, lenvatinib can prolong overall survival. Treatments based on targeting specific somatic genetic alterations are also available, which potentially also may prolong progression-free survival but are not yet approved for use by the Food and Drug Administration for this specific disease. More novel approaches that may benefit select patients include resensitization therapies that allow further radioiodine utilization and new immunotherapy concepts.

Background: Ectopic Cushing’s Syndrome is a rare but often aggressive condition caused by ACTH-hypersecretion from non-pituitary tumors. In patients with metastatic cancer, as well as those with occult tumors, the diagnosis and management can be extremely challenging. Clinical Case: A 25-year old woman recently diagnosed with poorly differentiated metastatic liver carcinoma of unknown primary was admitted for lower extremity edema and worsening fatigue for the preceding month. Since being diagnosed with liver cancer, she developed uncontrolled hypertension, persistent severe hypokalemia and facial “puffiness”. Physical exam was remarkable for moon facies and truncal obesity but no evidence of striae. An overnight 1-mg dexamethasone suppression test resulted in an elevated morning cortisol level of 93.4 mcg/dL and elevated ACTH of 299 pg/mL. A 24-hour urine cortisol was significantly elevated at 4,448 mcg/24 hours. These findings were consistent with hypercortisolism due to hypersecretion of ACTH. An MRI of the sella revealed no pituitary abnormality. A high-dose dexamethasone suppresion test (single 8 mg dose) was performed and her morning cortisol level remained elevated at 98.6 mcg/dL, consistent with ectopic ACTH secretion. She was treated for the underlying malignancy with carboplatin and paclitaxel. After a thorough discussion of therapeutic options, she was prescribed Ketoconazole with the plan to medically control the hypercortisolism potentially followed by bilateral adrenalectomy. Ketoconazole was up-titrated and Spironolactone was added resulting in significant improvement of hypokalemia and hypertension. Unfortunately, one week after discharge she was re-admitted due to worsening performance status, watery diarrhea and abdominal pain. A serum cortisol level was elevated at 124 mcg/dL and Metyrapone was added to her regimen. Unfortunately, her performance status continued to decline due to progression of cancer and uncontrolled hypercortisolism. As a result, she was deemed a poor surgical candidate for bilateral adrenalectomy. The patient’s condition rapidly deteriorated and she developed malignant ascites as well as altered mental status. In accordance with her wishes, a DNR order was placed and she passed away shortly thereafter. Conclusion: Ectopic ACTH-syndrome is the etiology of 10–20% of cases of Cushing’s syndrome. Clinical presentation is often sudden and rapidly progressive. Severe hypertension and hypokalemia are seen more commonly than in Cushing’s disease. Cases secondary to occult tumors or metastatic cancer can be particularly challenging to treat when it is not possible to eliminate the source of ACTH hypersecretion via surgical or medical treatment. In patients such as this, early bilateral adrenalectomy should be considered after starting medical therapy in order to reduce morbidity and mortality due to hypercortisolism.

Introduction: Receptor tyrosine kinases (RTKs) initiate signaling cascades, including growth and differentiation. Activation can occur through chromosomal rearrangements that lead to gene fusions. RTK fusions are potential targets for small molecule inhibitors to treat advanced cancers. The original Afirma Xpression Atlas (XA) reported 761 selected variants and 130 fusion pairs in Bethesda III/IV Afirma Genomic Sequencing Classifier (GSC) suspicious or Bethesda V/VI nodules. The landscape of additional potentially actionable gene fusions has not been explored in treatment-naïve patients. Methods: Anonymized RNA-seq data from >37,000 Bethesda III-VI samples were examined with STAR-fusion to determine gene/gene fusions. All samples were examined for NTRK1, NTRK3, RET, ALK, and BRAF fusions, regardless of fusion partner. Fusions were evaluated for being in-frame, with an intact kinase domain at the 3’ end of the fusion pair. Fusion pairs not currently reported by XA and not reported in thyroid TCGA fusion data are denoted “additional”. All fusion pairs were searched for in the literature and public fusion databases. Results: Examining the Veracyte clinical database revealed 7 additional NTRK1/3 fusions, with 3 NTRK fusions observed more than once - SQSTM1/NTRK3, VIM/NTRK3, and EML4/NTRK3. One of the 7 NTRK fusions had not been previously reported. Eight additional ALK fusions were identified, with 4 observed more than once- ITSN2/ALK, PPP1R21/ALK, PDE8B/ALK, NPAT/ALK. Five of these 8 ALK fusions had not been previously described. Seventeen additional RET fusions were identified, with 5 observed recurrently - KIAA1217/RET, AFAP1L2/RET, ACBD5/RET, SQSTM1/RET, and TFG/RET. Six of the 17 RET fusions had not been previously reported. Seventy-two additional BRAF fusions were identified, and 58 of them have not been previously reported. Eight of the 72 BRAF fusions were observed more than once. Examining >50,000 Afirma samples, NTRK1, NTRK3, RET, ALK, or BRAF fusions were not identified among the Afirma GSC Benign, and were present in 3.2% of 16,594 Bethesda III/IV Afirma GSC Suspicious samples, and 8.0% of 1,692 Bethesda V/VI samples. Correlation with surgical histology is unknown. Conclusions: By examining a large cohort of patients with an unbiased, whole-transcriptome RNA-seq assay, we identified potentially actionable kinase fusions in thyroid nodules beyond those described in TCGA. All fusions described here are either novel and not previously reported, rarely reported in one or two case studies, or not described in thyroid cancers. Additional NTRK, ALK, RET and BRAF fusions were found, all of which may be targeted with specific kinase inhibitors currently available. Future studies may determine genotype-phenotype correlations regarding the natural history of these neoplasms. Because of the potential clinical implications of these genomic markers for patient management, all 104 fusions described here are now included among the 235 gene pairs reported by the expanded Afirma XA.

6083 Background: Receptor tyrosine kinase (RTK) fusions may be targeted by small molecule inhibitors to treat various advanced tumors, including thyroid cancer. Clinical trials have studied selective inhibitors of ALK, BRAF, NTRK and RET, leading to several FDA-approved therapies. The Afirma Genomic Sequencing Classifier (GSC) classifies cytologically indeterminate thyroid nodules as molecularly benign or suspicious. The Xpression Atlas reports 905 genomic variants and 235 fusion pairs on GSC Suspicious, Suspicious for Malignancy (SFM), and Malignant FNA samples at the time of diagnosis. Here we report the prevalence of these fusion genes in real-world clinical practice. Methods: We analyzed anonymized data from 50,644 consecutive Bethesda III-VI nodule FNA samples submitted to the Veracyte CLIA laboratory for molecular testing using whole transcriptome RNA sequencing (RNA-Seq). Gene pairs are listed alphabetically. Results: 32,080 Bethesda III/IV nodules were classified as GSC Benign and 278 were Parathyroid Classifier positive. No ALK, BRAF, NTRK1/3, or RET fusions were identified among these samples. Among 16,594 Bethesda III/IV GSC Suspicious FNAs, 3% (n = 529) were positive for ALK, BRAF, NTRK1/3 or RET fusions. Among the 1,692 Bethesda V/VI FNAs, the proportion of positive nodules was 8% (n = 135). Among these combined cohorts of Bethesda III/IV GSC Suspicious and Bethesda V/VI, the most common gene fusions observed for each of the 5 studied RTK genes was: ETV6/NTRK3 (n = 164, 72% of NTRK3 fusions), CCDC6/RET (n = 104, 55% of RET), BRAF/SND1 (n = 32, 20% of BRAF), ALK/STRN (n = 20, 37% of ALK), and NTRK1/TPM3 (n = 14, 50% of NTRK1). BRAF showed the highest diversity of fusions, with 80 gene partners. Different gene partners with RET, ALK, NTRK1, and NTRK3 numbered 25, 11, 9, and 5 , respectively . Conclusions: Whole-transcriptome RNA-seq on small sample thyroid FNA specimens can identify clinically relevant ALK, BRAF, NTRK, and RET fusions across Bethesda categories. The prevalence ranges from 3% in Bethesda III/IV Afirma GSC Suspicious specimens to 8% among Bethesda V/VI specimens. Future studies need to determine if detection of precision medicine candidates by pre-operative FNA can optimize initial treatment, predict response to treatment, and prioritize selective targeted therapy should systemic treatment be needed.[Table: see text]

Background Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Several treatment trials are available, but the number of eligible patients to participate is very low because of the rarity and aggressiveness of the disease. Methods Facilitating Anaplastic Thyroid Cancer Specialized Treatment (FAST) is a quality improvement project aimed at decreasing time from referral to disposition (scheduling of first appointment) to our institution. After identifying reasons for delays, we created a new process flow specifically for patients with ATC allowing patients to be scheduled immediately. Results Historical data revealed a mean referral to disposition time for patients with ATC of 8.7 days before our intervention. After the intervention, the mean referral to disposition time was reduced to 0.5 days. Participation in treatment trials for all patients with ATC was 34%. Conclusion Since the implementation of FAST, the access time has decreased and the number of successful referrals for ATC has increased significantly.

Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking.We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry.The study was conducted at a tertiary cancer center.We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs.Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11).In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.

Background The Afirma Genomic Sequencing Classifier (GSC) uses RNA sequencing to assess FNA specimens from cytologically indeterminate thyroid nodules, which are also tested for specific molecular aberrations associated with thyroid cancer via a suite of highly accurate malignancy classifiers. This suite can also be applied independently to Bethesda V/VI nodules. The Afirma Xpression Atlas (XA) is an optional add-on test to GSC and the malignancy classifiers that reports nucleotide variants and fusions across 511 cancer-associated genes. Medullary thyroid cancer (MTC) is a rare subtype of thyroid cancer that can appear in every Bethesda category. Herein, we report the prevalence and genomic landscape of MTC classifier positive (MTC+) FNA samples in a CLIA certified clinical laboratory. Methods All Afirma GSC and malignancy classifier tests run between July 2017 and November 2018 were deidentified and examined for MTC+ cases. Afirma XA was run on all MTC cases and all variants and fusions were tabulated. Results Examination of 22,130 FNAs revealed 77 MTC cases. Among consecutive GSC tests, 28 were Bethesda III (0.16% out of 17,245) and 27 were Bethesda IV (0.65% out of 4,182). Provider-ordered testing was done on an additional 14 and 8 MTC cases from Bethesda V and VI nodules, respectively. Examining all MTC+ samples revealed that 55.8% harbored a RET variant (+/- others), 9.1% contained a KRAS variant (+/- others), 6.5% had an HRAS variant, 2.6% possessed fusions, and 26.0% included no variant/fusion. Conclusions In indeterminate FNA samples, the Afirma GSC can help to clarify the risk of MTC. In our cohort, the Afirma XA identified a variant or fusion in 74.0% of MTC+ FNAs. Limitations of this study include the lack of knowledge regarding germline RET status (which should be checked in all patients with an identified RET variant or confirmed MTC) and final pathology on MTC+ samples. Future studies may investigate how the preoperative identification of a known MTC driver mutation in a biopsy sample can inform the pre-operative evaluation, the surgical plan, and the potential role of targeted therapy. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Although patients with thyroid cancer generally fare well, there is a subset for which this is not necessarily true. Progress in understanding the molecular aberrations in thyroid cancer has led to a change in the management of these cases. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. This change in the treatment landscape has raised challenges for practitioners who may not be familiar with the use of MKIs or with the treatment and natural history of advanced thyroid cancer in general. This article reviews the epidemiology, molecular drivers, and initial treatment of patients with thyroid cancer and offers practical guidance to assist with the determination of when to appropriately start an MKI. As an example, cabozantinib and its efficacy are discussed in detail. Close monitoring is required for all patients on targeted agents to assess for adverse effects and response to therapy. An approach to managing drug-related adverse events is detailed. Since these drugs are not curative and have not yet proven to prolong overall survival, it is critical to weigh the risks and benefits of treatment at every visit. The potential value of changing to a different agent following failure of an MKI is also addressed.

6087 Background: Systemic therapies targeting specific genomic alterations in advanced MTC are available or under investigation. The Afirma Genomic Sequencing Classifier (GSC) uses RNA sequencing to assess FNA specimens from cytologically indeterminate thyroid nodules, which are also tested for specific molecular aberrations associated with thyroid cancer via a suite of highly accurate malignancy classifiers. This suite can be applied independently to Bethesda V/VI nodules. The Afirma Xpression Atlas (XA) is an additional test that can be combined with Afirma GSC to report nucleotide variants and fusions across 511 cancer-associated genes. Here we report the prevalence and genomic landscape of MTC classifier positive (MTC+) FNA samples. Methods: All Afirma GSC and malignancy classifier tests run in the Veracyte Clinical Laboratory between July 2017 and January 2019 were deidentified and examined for MTC+ cases. Afirma XA was run on all such cases, and all variants and fusions were tabulated. Results: Examination of 29,895 FNAs revealed 90 MTC cases. Of 22,793 Bethesda III cases, 32 (0.14%) were MTC+. Of 5,491 Bethesda IV cases, 33 (0.60%) were MTC+. Provider-ordered testing was done on an additional 16 and 9 MTC cases from Bethesda V and VI nodules, respectively. 58% of all MTC+ samples harbored a RET variant (+/- others), 9% contained a KRAS variant (+/- others), 6% included an HRAS variant, 1% had a BRAF fusion, 1% demonstrated other fusions, and 26% held no variant/fusion. Conclusions: In our cohort, Afirma XA identified a variant or fusion in 74% of MTC+ FNAs. Currently approved or investigational therapies exist for cancers with RET, BRAF and HRAS alterations, suggesting that 64% of our series might be eligible for treatment based on genomic information from FNA. In advanced MTC, noninvasive FNA sample collection at the time of diagnosis may ultimately impact on targeted therapy selection, with the option to repeat FNA testing should the disease progress. Future studies may investigate how finding a genomic alteration by FNA can inform the management of MTC and, in the case of progressive disease, improve our understanding of the mechanisms of disease progression and drug resistance.

Girard may have been on to something when he attempted to trace religious violence back to a struggle between mimetic rivals, but the resulting theory has been rightly criticized for its indifference to the particulars of historical context. With help from post-colonial scholarship, this paper aims to rethink the concept of mimicry as used by scholars of religion by situating an example from ancient Judaism, Josephus's description of the Samaritans as hostile doubles of the Jews, in the particular cultural environment in which this ancient historian wrote. The author hopes to contribute to our understanding of the Samaritans, and of Josephus as a slippery double in his own right, but the essay's real point is to caution against any generalizing approach to mimicry by stressing it as an adaptive behavior, a tactic, whose motives and workings are best understood within the particular cultural habitat to which the mimic is responding.

While noticing that the tactics and weapons prescribed in the War Scroll resemble those used by Greek and Roman armies, previous scholarship has been dubious of the idea that the scroll actually guided real-life military practice because its battle-plan seems so impractical, assuming a conflict that unfolds in a highly scripted way and relying on ritual and supernatural assistance. This essay aims to rethink the role that the War Scroll played in early Jewish military practice by reading it in light of Greco-Roman theories of how to deploy emotion in battle. Military thinkers like Xenophon and Julius Caesar recognized troop psychology as an important tactical variable that could be manipulated through ritual and supernatural portents. The War Scroll mirrors these practices in a way that supports reading it as a similar effort to manipulate troop psychology arising under the influence of—and perhaps in reaction against—Greco-Roman military practice.