Iñiguez‐Ariza, Nicole M.

SummaryContextAbdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality.ObjectiveTo assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy.DesignRetrospective cohort study.PatientsTwenty‐five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included.MethodsMedical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT).ResultsIn patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by −10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002).ConclusionsThe severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT‐based markers may allow for a more reliable and objective assessment of glucocorticoid‐related disease severity in patients with adrenal adenomas.

AbstractBackgroundContemporary guidelines for managing PTC advise an approach wherein primary tumor and regional metastases (RM) are completely resected at first surgery and radioiodine remnant ablation (RRA) is restricted to high‐risk patients, policies our group has long endorsed. To assess our therapeutic efficacy, we studied 190 children and 4242 adults consecutively treated during 1936–2015. Subjects and methodsMean follow‐up durations for children and adults were 26.9 and 15.2 years, respectively. Bilateral lobar resection was performed in 86% of children and 88% of adults, followed by RRA in 30% of children and 29% of adults; neck nodes were excised in 86% of children and 66% of adults. Tumor recurrence (TR) and cause‐specific mortality (CSM) details were taken from a computerized database.ResultsChildren, when compared to adults, had larger primary tumors which more often were grossly invasive and incompletely resected. At presentation, children, as compared to adults, had more RM and distant metastases (DM). Thirty‐year TR rates were no different in children than adults at any site. Thirty‐year CSM rates were lower in children than adults (1.1 vs. 4.9%; p = 0.01). Comparing 1936–1975 (THEN) with 1976–2015 (NOW), 30‐year CSM rates were similar in MACIS <6 children (p = 0.67) and adults (p = 0.08). However, MACIS <6 children and adults in 1976–2015 had significantly higher recurrence at local and regional, but not at distant, sites. MACIS 6+ adults, NOW, compared to THEN, had lower 30‐year CSM rates (30 vs. 47%; p < 0.001), unassociated with decreased TR at any site.ConclusionsChildren, despite presenting with more extensive PTC when compared to adults, have postoperative recurrences at similar frequency, typically coexist with DM and die of PTC less often. Since 1976, both children and adults with MACIS <6 PTC have a <1% chance at 30 years of CSM; adults with higher MACIS scores (6 or more) have a 30‐year CSM rate of 30%.

6087 Background: NTRK1-3 fusions, identified in pediatric radiation-associated thyroid cancers, are low frequency oncogenic drivers that can trigger constitutive activation of TrK1-3 tyrosine kinase domains with responsively heightened downstream signaling through RAS-MAPK, PI3K-AKT, and/or PLCγ-PKC. NTRK point mutations are rare and of largely uninvestigated oncogenic potential, but some appear oncogenic. Methods: Advanced thyroid cancer (TC) patients (pts) requiring systemic therapy at Mayo Clinic sites underwent tumor genetic interrogation using Foundation One analyses with the goal of informing salvage therapeutic strategies. In this IRB-approved study, data from pts with TCs bearing NTRK point mutations were retrospectively analyzed, as this occurrence was unexpected but potentially of prognostic and/or therapeutic relevance. Results: Five of 55 pts (9%) with advanced TCs subject to Foundation One tumor interrogation had NTRK1-3 point mutations (allele frequency, AF, 15-49%); none had fusions. All 5 tumors had microsatellite stability; 4/5 had low tumor mutation burden (2-5 mutations/megabase). NTRK mutations in 3 anaplastic TC (ATC) pts (15% prevalence) were: NTRK3 I749M (AF 15%; overall survival, OS, 15 mos), NTRK1 R744H (AF not available; OS 9.5 mos), and NTRK1 R583H (AF 20.1%; OS > 4.9 mos); NTRK2 S167Y (AF 49%; OS > 51 mos) or NTRK1 R6W (AF 42%; OS > 60 mos) were found in one papillary (PTC) and one Hürthle cell (HCC) TC pt respectively (summary table below). Conclusions: NTRK point mutations, but not fusions, were unexpectedly identified in 9% of assessed advanced TCs - but remarkably in 15% of ATCs. Mutated NTRKs, along with oncogenic p53 and TERT, may contribute to TC progression, especially in ATC, consequent to downstream activation of MAPK and PI3K-AKT pathways. We posit that NTRK point mutations may have therapeutic implications for treatment of refractory disease. [Table: see text]

Abstract Context Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited. Objective We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival. Design Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016. Setting Referral center. Patients The group comprised 272 patients. Main Outcome Measures Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188). Results Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P &lt; 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P &lt; 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation. Conclusions The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.

Background: Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. Methods: A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Results: Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2–3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57–84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. Conclusion: This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.