bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-070 Cross-Reactivity of Human Insulin and Insulin Analogues in Human Insulin Immunoassay Complicates Case of Medical Child Abuse
Authors: Walch Abby , Long Roger
Published: May 2020

Background: Measurement of insulin levels with human insulin immunoassays is important in the investigation of hypoglycemia; however, cross-reactivity with insulin analogues complicates clinical assessment.

Clinical Case: A 2-month-old male presented with hypoglycemia. Initial tests were consistent with hyperinsulinemic hypoglycemia: low serum glucose (29 mg/dL, n 70 to 99), elevated insulin (90.1 mU/L, n 3.0 to 19.0), suppressed beta-hydroxybutyrate (0.16 mmol/L, n 0.02 to 0.27), and suppressed free fatty acids (0.27 mmol/L, n 0.50 to 1.60). C-peptide level resulted undetectable (<0.1 ng/mL, n 0.8 to 3.5) raising suspicion for exogenous insulin administration. History revealed an older brother with type 1 diabetes mellitus treated with insulins glargine and lispro. Only one caregiver was present in the hospital, who denied knowledge of exogenous insulin administration. Hypoglycemia persisted despite placement of a continuous 1:1 sitter, high-dose intravenous glucose (glucose infusion rate up to 21.6 mg/kg/min), and treatment with diazoxide. A repeat insulin measurement with the Roche Diagnostics assay specific for human insulin was performed on a critical sample and resulted elevated (13.9 uIU/L, n 2.6 to 24.9), suggestive of endogenous insulin. However, an extensive study of commercial human insulin immunoassays by Heurtault et al., including the Roche Diagnostics assay, has demonstrated cross-reactivity with insulin analogues and their metabolites [1]. Given persistent concern for exogenous insulin administration, the patient’s caregiver was asked to leave the bedside for an extended period of time which resulted in normoglycemia. Diazoxide and dextrose-containing IV fluids were discontinued. Patient maintained normoglycemia for the remainder of the admission and was discharged in the care of child protective services.

Conclusions: Cross-reactivity exists in human insulin immunoassays with insulin analogues and their metabolites complicating the determination of endogenous versus exogenous insulin as the cause of hyperinsulinemic hypoglycemia. It is important to know the cross-reactivity of the assay used if a diagnosis of surreptitious insulin administration is suspected. Separation of patient and possible perpetrators and involvement of child protective services is essential in suspected cases of exogenous insulin administration. Evaluation in cases where self-injection of insulin is suspected may be more difficult to decipher, and inclusion of c-peptide measurement at the time of hypoglycemia is critical.

Reference: [1] Heurtault B, Reix N, Meyer N, et al. Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification. Clin Chem Lab Med. 2014; 52:355-362.
SUN-603 Electronic Cigarette Exposure Induces Pro-Inflammatory Changes in Adipose Tissue in Apolipoprotein E (APOE) Knockout Mice
Authors: Espinoza-Derout Jorge , Shao Xuesi M , Molina-Mancio Jocelyn , Hasan Kamrul M , Mtume Norma , Sinha-Hikim Amiya P , Friedman Theodore C
Published: May 2020

Electronic nicotine delivery systems or electronic cigarettes (e-cigarettes) are becoming exceptionally popular in the world as an alternative to conventional nicotine cigarettes, both in smokers and people who have never smoked. Nicotine can induce lipolysis in adipose tissue, leading to increased serum free fatty acids (FFA). Increased levels of FFA are one of the key elements in inducing a pro-inflammatory response and lead to ectopic lipid accumulation, lipotoxicity, mitochondrial dysfunction and metabolic disease. Our laboratory has shown that chronic e-cigarette exposure induces cardiac dysfunction, atherosclerosis and hepatic steatosis in the ApoE knockout (KO) model associated with increased levels of serum FFA. In this study, we investigated the role of adipose tissue in the metabolic changes associated with e-cigarette exposure. ApoE KO mice were exposed to saline, e-cigarette without nicotine [e-cigarette (0%)] and e-cigarette with 2.4% nicotine [e-cigarette (2.4%)] aerosol for 12 weeks. Western blot analyses from adipose tissue showed that mice treated with e-cigarette (2.4%) had decrease levels of SIRT1 when compared to mice treated with saline or e-cigarette (0%). Transcriptomic analysis of the differentially expressed genes shows a differential transcriptional response to e-cigarette (2.4%) in adipose tissue in comparison with e-cigarette (0%) or saline. The RNA-seq examination using ingenuity pathway analysis (IPA) software, revealed dysregulation of fibrosis, agranulocyte and granulocyte adhesion and diapedesis pathways in e-cigarette (2.4%) -exposed adipose tissue. Overall, we found an inflammatory phenotype associated with decreased levels of SIRT1 in adipose tissue of mice treated with e-cigarette (2.4%). Understanding the consequences of e-cigarette use on metabolic disease is directly relevant to the development of policies related to e-cigarette use.
SUN-751 RORγ Is a Master Regulator of Tumor Lipid Metabolism
Authors: Chen Hong-Wu
Published: May 2020

Lipid and cholesterol metabolism reprogramming is strongly linked to tumorigenesis and therapeutic resistance. Our recent genetic disruptions via CRISPR KO and gene silencing and pharmacological inhibition clearly demonstrated that nuclear receptor RORγ plays a crucial role in control of lipid and cholesterol biosynthesis gene programs specifically in certain types and subtypes of cancer cells and tumors. Indeed, its antagonists display potent tumor inhibitions in patient-derived xenografts (PDX) and in immune-intact tumor models. Interestingly, RORγ inhibition resulted in decreased cholesterol synthesis rate specifically in tumors without significant impact to the host animal cholesterol homeostasis. Our ChIP-seq demonstrated that in a subtype of breast cancer RORγ cistrome is largely overlapping with that of SREBP2, a well-established master regulator of lipid and cholesterol biosynthesis. Our further analyses found that RORγ functions dominantly over that of SREBP2 via its association with SREBP2 and facilitation of its genome-wide recruitment and histone H3K27 acetylation. Inhibition of RORγ completely negates the negative feedback activation of the cholesterol program induced by cholesterol-lowering drug statins and mediated by SREBP2. Treatment of animals with the antagonists in combination with statins showed a highly synergistic anti-tumor effects. Together, our study uncovers RORγ as a novel master regulator of lipid and cholesterol metabolism operating selectively in subtypes of cancer.
SAT-493 A Case of Profound Hypothyroidism Secondary to Immune Check Point Inhibitors
Authors: Tun Yin Nwe , Rodriguez Giovanna , Bahtiyar Gul
Published: May 2020

Background: The discovery of immune check-point inhibitors (ICI) revolutionized cancer treatment. CTLA-4, anti-PD-1 and anti-PD-L1 monoclonal antibodies have been approved in recent years. However, the advantageous clinical outcomes can also be associated with potentially severe immune related adverse effects (irAEs) such as hypophysitis, thyroiditis, type 1 diabetes mellitus, and adrenal insufficiency [1]. We report to highlight the importance of awareness of irAEs and collaboration of endocrinology and oncology specialties in managing oncology patients with ICI in an underserved community hospital in Brooklyn, NY.

Clinical case: 62 years old woman with unremarkable thyroid history presented with chronic mid-chest pain and dysphagia in 2016 found to have a mass in middle third of esophagus. Biopsies revealed invasive squamous cell carcinoma (T3N0). She underwent radiotherapy and esophagectomy.

On 1/2018, surveillance imaging detected a new tracheobronchial angle lymph node, which was confirmed as hypermetabolic and likely malignant by PET scan. Patient received additional 5 cycles of radiotherapy followed with 5 cycles of chemotherapy with Oxaliplatin and Capecitabine. Since post-chemotherapy PET scan showed local recurrence, patient was started on PD1 inhibitor, Pembrolizumab 200 mg Q3 week. After 3 doses patient developed cold intolerance, weight gain and low mood. Her TSH was 173 uIU/ml (0.27-0.42), FT4 <0.1 ng/dL (0.9-1.8) and referred to endocrine clinic. Repeat TSH was 190 uIU/ml, FT4 0.2 ng/dL, TPOAbs 619 IU/ml (<35) and TSI<0.1 IU/L (<0.55). Adrenal insufficiency was ruled out and started on levothyroxine 50 mcg in the morning, increased to 75 mcg. After 2 months of levothyroxine use, TSH was 11.8 uIU/ml and FT4 1.3. Pembrolizumab therapy is restarted shortly after.

Conclusion: National Comprehensive Cancer Network guideline for management of immunotherapy related toxicities recommends routine monitoring of TSH and FT4 at baseline and every 4-6 weeks during immunotherapy, follow up every 12 weeks and TPO antibodies if TSH is high. This patient’s clinical symptoms of hypothyroidism might be confused by nonspecific symptoms of underlying malignancy. Combination radiotherapy and immunotherapy place this patient at higher risk of developing hypothyroidism. This case showed the successful collaboration of endocrinology and oncology team in giving vulnerable patient an optimized care with good clinical outcome.

References:

(1). Ferrari SM, et al. Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies. Int J Mol Sci. 2019;20(10):2560. Published 2019 May 24.

(2). John A. Thompson, et al. Management of ImmunotherapyRelated. Toxicities, Version 1.2019J Natl Compr Canc Netw 2019;17(3):255–289
SUN-125 Phase Ib Study of Dual Therapy with an Aromatase Inhibitor Exemestane and Carboplatin-Based Therapy for Postmenopausal Women with Advanced Non-Small Cell Lung Cancer
Authors: Young Patricia A , Marquez-Garban Diana C , Goodglick Lee , Noor Zorawar S , Moatamed Neda , Elashoff David , Grogan Tristan , Romero Tahmineh , Sasano Hironobu , Saito Ryoko , Rausch Rebecca , Hamilton Nalo , Dubinett Steven M , Garon Edward , Pietras Richard J
Published: May 2020

Objectives: Estrogen receptors (ER-alpha, ER-beta) and aromatase (key enzyme for estrogen synthesis) are expressed in most human non-small cell lung cancers (NSCLCs). High intratumoral estrogens and elevated aromatase in NSCLC are reported to predict poor clinical outcome. In vitro, estrogen stimulates NSCLC gene expression and, tumor progression and diminishes tumor cell apoptosis. Furthermore, preclinical NSCLC models demonstrate that aromatase inhibitors (AIs) prevent these processes, and that cisplatin with AIs elicits dramatic growth inhibition. Additionally, depletion of autocrine/paracrine estrogen production hypersensitizes cells to DNA-damaging effects of platinum therapy, providing a rationale for this trial. This open-label, phase 1b, single-center study evaluated safety and tolerability of AI exemestane combined with carboplatin and pemetrexed in postmenopausal women with stage IV non-squamous, NSCLC.

Materials/Methods: Exclusion criteria included untreated CNS metastasis, major surgery in prior 4-weeks to therapy, prior/concurrent investigational or standard therapy (except TKI and/or immunotherapy in prior 4-weeks). Trial patients received escalating doses of exemestane (starting 1-week before chemotherapy) at 25 mg PO daily (Cohort 1) or 50 mg PO daily (Cohort 2) with carboplatin (AUC 6 mg x min/mL) and pemetrexed (500 mg/m2) IV q3 weeks for 4 cycles. Thereafter, patients could continue therapy with exemestane and/or pemetrexed.

Result: Ten patients consented for study and 2 patients screen-failed. Three patients completed therapy in Cohort 1, and five patients were treated in Cohort 2. The median number of cycles was 15 (range 1-54). The MTD was exemestane 50 mg PO daily with combination chemotherapy. Intention to treat analysis showed an overall response rate (ORR) of 62.5% [5 of 8 patients with partial remission (PR)] and clinical benefit rate was 87.5% (7 of 8 patients with stable disease or PR). ORR was significantly associated with tumor aromatase expression (p=0.02). There was no correlation between ORR and ER-alpha or progesterone receptor by IHC. Circulating estrogen levels decreased with exemestane, and quality of life measures did not significantly change. No patients left the study for adverse events.

Conclusion: CCombination chemotherapy with exemestane in postmenopausal women with Stage IV non-squamous, NSCLC is safe and well-tolerated. Biomarker studies show that ORR correlates significantly with tumor aromatase expression. These findings support future clinical trials to confirm antitumor efficacy with this combination therapy.
OR23-05 Human Absorption, Metabolism, Excretion, and Absolute Oral Bioavailability of 14C-CRN00808, an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sST2) Biased Agonist for the Treatment of Acromegaly
Authors: Madan Ajay , Luo Rosa , Cook Stephen Ferrara , Struthers Scott , van Marle Sjoerd , Krasner Alan
Published: May 2020

Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808, a small molecule nonpeptide selective somatostatin receptor 2 (sst2) agonist, is being evaluated for efficacy and safety in patients with acromegaly. The current Phase 1 study was conducted in two Parts: In Part A, the absorption, metabolism, excretion, and mass balance of a single oral dose of 20 mg [14C]-CRN00808 (3.0 MBq) oral solution was characterized in six healthy male subjects. Plasma, blood, urine, and feces were collected for up to 432 hours, and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Metabolite profiling was conducted on the plasma, urine, and feces samples. In Part B, the absolute bioavailability of CRN00808 was determined by administering a single oral dose of 20 mg CRN00808 compared with a single micro-tracer intravenous (IV) bolus injection of 50 µg [14C]-CRN00808 (0.0185 MBq) in five healthy male subjects. The IV dose was administered approximately 90 minutes after the oral dose. Plasma samples were collected for up to 144 hours and were analyzed for total radioactivity and CRN00808 concentrations (plasma only).

Key data from Part A and Part B will be presented. Available data from Part A of the study show that >90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (<10%). Absorption of total [14C]-CRN00808-derived radioactivity in plasma was rapid (median Tmax=1 hour), and the mean Cmax, AUC0-∞, and t1/2 were determined to be 194 ng-equivalents/mL, 3340 ng-equivalents.hr/mL, and 31 hours, respectively. The pharmacokinetic parameters of unchanged CRN00808 in plasma were similar, suggesting that majority of the circulating drug-derived radioactivity is accounted for by unchanged CRN00808 and there are no abundant circulating metabolites. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this clinical trial in healthy volunteers confirm that CRN00808 has excellent drug-like properties for chronic once-daily oral treatment of patients with acromegaly.
MON-154 Inhaled Corticosteroids and Adrenal Insufficiency: A Meta-Analysis and Systematic Review
Authors: Pare Aurelie , Tsoukas Michael
Published: May 2020

Inhaled corticosteroids have been associated with adrenal insufficiency in adult and pediatric populations¹,². When inhaled corticosteroids are absorbed orally, they can have a systemic effect. Corticosteroid type, particle size, delivery method, liver metabolism via CYP 3A4, protein binding, and half-life all impact the magnitude of the systemic effect of inhaled corticosteroids³. We conducted a systematic review and meta-analysis in order to establish the prevalence of adrenal insufficiency among adult patients taking inhaled corticosteroids. We searched the PubMed, Embase and Cochrane databases for “adrenal insufficiency” AND “inhaled corticosteroids”, yielding 318 search results. We also hand-searched the references of relevant articles. In total, 30 studies were included in our meta-analysis. Amongst these, 15 studies were RCTs and 13 studies were cross-sectional studies. All of these studies used ACTH stimulation testing to diagnose adrenal insufficiency. Risk of bias assessment was completed for all studies using the Cochrane risk of bias assessment tool. Patients with asthma were the population examined in 90% of the included studies. Prevalence of adrenal insufficiency demonstrated by ACTH stimulation testing varied from under 5% to up to 55% among different studies. We recommend that further studies carefully examine and report the clinical impact of abnormal ACTH stimulation testing results, the concomitant use of oral corticosteroids, and the impact of the inhaled corticosteroid delivery method, the corticosteroid type, the corticosteroid dosage, and the duration of therapy.

References:

1. Lapi F, Kezouh A, Suissa S, Ernst P. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur Respir J. 2013;42(1)-79-86.

2. Goldbloom EB, Mokashi A, Cummings EA, et al. Symptomatic adrenal suppression among children in Canada. Arch Dis Child. 2017;102(4)-338-339.

3. Ahmet A, Kim H, Spier S. Adrenal suppression- A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol. 2011;7-13.
SUN-096 Incidentally Found Severe Hypercalcemia in a Pediatric Patient, Diagnostic Challenge
Authors: Burdea Liliana , Salazar Natalia , Minutti Carla , Mantis Stelios
Published: May 2020

Introduction: Idiopathic infantile hypercalcemia is an intriguing feature of Williams syndrome (WS), occurring in ~15% of diagnoses and is typically not clinically severe. Symptomatic hypercalcemia usually resolves during childhood, but lifelong abnormalities of calcium(Ca) and vitamin D metabolism may persist. The cause of the abnormality in Ca metabolism is still unknown. Hypercalciuria generally accompanies hypercalcemia, but isolated hypercalciuria, especially after infancy, can also occur. Nephrocalcinosis is relatively rare, found in less than 10% of patients undergoing renal ultrasonography. We report a 13-month-old female infant with a history of peripheral pulmonary stenosis and constipation, who presented with severe hypercalcemia that led to a new diagnosis of WS. Case presentation: A 13-month-old girl with a history of peripheral pulmonary stenosis, global developmental delay, and constipation presented to the neurology clinic for evaluation of gross motor delay. She was found to have upper body part hypotonia, decreased reflexes, and on laboratory evaluation, severe hypercalcemia with Ca level of 15.0 mg/dL (8.7 - 10.7). The patient was admitted for management of severe hypercalcemia. Physical exam was also remarkable for subtle features of WS: a happy baby, very social, with prominent eyes, full cheeks, flat nasal bridge, round nasal tip, full lips, and a wide smile. Repeated Ca level on admission was 15.9 mg/dL, with normal albumin level of 4.6 g/dL (2.9-5.5), elevated ionized calcium (iCal) of 1.99 mmol/L (0.95 - 1.32), and intact parathyroid hormone (PTH) of <4.0 pg/mL (8.0 - 85.0). Further evaluation revealed a normal 25 hydroxy-vitamin D:41 ng/mL (30-80) and low 1,25-dihydroxy vitamin D:10pg/mL (31-87). Further evaluation revealed elevated urine calcium to creatinine ratio of 0.7 (normal for age <0.56) and renal ultrasound remarkable for medullary nephrocalcinosis. The patient had a complete blood count within normal limits and a PTH related protein of 26 pg/mL (14-27), ruling out malignancy. Hypercalcemia responded well to intravenous fluids and diuretics, the patient being discharged home after two days on furosemide and potassium supplements with close electrolytes monitoring. The patient required calcium reducing therapy for four months to maintain Ca levels within 9-12 range. The medication was decreased gradually based on calcium and ical levels. The patient is currently doing well, with a normal calcium level, and has being off medication for the past three months. Conclusion: This is a rare case of severe hypercalcemia, which led to the diagnosis of WS. Although idiopathic infantile hypercalcemia occurs in 15% of patients with WS, usually the presentation is mild, and the patients do not require medical interventions. Our patient presented with severe hypercalcemia and subtle physical features of WS that led to genetic testing and final diagnosis.
OR19-03 Effects of Nonpeptide Orally Bioavailable ACTH Antagonists on Adrenal Gland Size and Function in Rats
Authors: Markison Stacy , Fowler Melissa A , Athanacio Jon , Kredel Taylor A , Antwan Agnes , Johns Michael , Tsivkovski Oleg , Cruz Shirley , Luo Rosa , Reinhart Greg , Kusnetzow Ana Karin , Madan Ajay , Betz Stephen F , Struthers Scott
Published: May 2020

Cushing’s disease (CD) and Ectopic ACTH syndrome (EAS) stem from excess circulating adrenocorticotropic hormone (ACTH) and resulting hypercortisolemia. In CD, excess ACTH is secreted from pituitary tumors, whereas excess ACTH in EAS arises from nonpituitary tumors. ACTH acts on the adrenal melanocortin type 2 (MC2) receptor to control the synthesis and secretion of adrenal hormones, including the stress hormone cortisol (corticosterone in rats) which accounts for the comorbidities of CD and EAS. Availability of a potent ACTH antagonist that can normalize cortisol in patients with diseases of excess ACTH will be a major advance in endocrinology. Additionally, an ACTH antagonist will have utility in congenital adrenal hyperplasia (CAH) because of its ability to block production of excess adrenal androgens.

Crinetics is evaluating and developing ACTH antagonists for the treatment of diseases of excess ACTH. To our knowledge, these compounds represent the first potent nonpeptide ACTH antagonists to demonstrate in vitro potency and in vivo efficacy. As a result, the direct effects of sustained MC2 receptor blockade on the structure and function of the adrenal gland have never been able to be assessed. We examined the effects of several orally bioavailable ACTH antagonists across a range of doses on Sprague-Dawley rat adrenal gland weight, histology, and hormone levels in repeat dosing (7-14 days) studies. Sustained MC2 receptor antagonism dose dependently blocked activity of ACTH at the level of the adrenal gland and reduced plasma corticosterone levels. In the normal rat, this resulted in dose-dependent atrophy of the adrenal gland as assessed by organ weights and microscopically. The atrophy was primarily observed in the cortisol producing zona fasciculata, as well as in the zona reticularis, with smaller reductions noted in the aldosterone producing zona glomerulosa. Additionally, hypertrophy of the adrenal glands caused by continuous subcutaneous administration of exogenous ACTH was reversed by treatment with an ACTH antagonist. The adrenal effects were accompanied by expected changes in corticosterone levels. These preclinical findings demonstrate the therapeutic potential of ACTH antagonism and provide a strong rationale for development of an orally bioavailable drug that can be used to combat CD, EAS, and CAH.
MON-665 Hypothalamic Gliosis in Adolescents with Type 1 Diabetes and Disordered Eating Behaviors
Authors: Nip Angel Siu Ying
Published: May 2020

Background:

The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating appetite and weight. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behaviors. Hypothalamic inflammation and reactive gliosis mediate disruptions in energy homeostasis, especially with obesity. Data from SEARCH in Youth for Diabetes has demonstrated high prevalence of disordered eating behaviors (DEB) including insulin omission and binge eating, in individuals with type 1 diabetes (T1D). Limited studies have used neuroimaging techniques for investigation of hypothalamic gliosis in individuals with T1D and DEB.

Objectives: To determine the feasibility of assessing hypothalamic gliosis with structural MRI in adolescents with T1D with and without DEB.

Research design and methods:

Adolescents with T1D, aged 13-19, were invited to participate. Participants with current use of medications known to alter appetite were excluded. Participants completed the Diabetes Eating Problem Survey – Revised (DEPS-R). A score ≥ 20 was considered indicative of DEB. Height, weight and waist circumference were obtained, and BMI was calculated. HbA1C was obtained from their prior clinic visit, within 2 months of the study visit. Participants came in fasting for the MRI study visit. Basal insulin (glargine) was administered the night before, and participants on insulin infusion continued with their basal insulin infusion. Participants received rapid-acting insulin prior to the MRI study, and blood glucose was measured before and after the MRI. Mediobasal hypothalamic (MBH) gliosis was measured by T2 relaxation time.

Results:

Eight subjects (50% female, mean age 17.8±2.3 years) have completed the study without adverse outcomes. Mean HbA1c was 8.5% (range 7.3-10%). Five subjects screened positive for DEB. There was no significant difference in BMI between DEB and non-DEB groups. In this cohort, females had longer T2 relaxation times in left MBH than males (p=0.035). Compared to non-DEB group, participants with DEB had longer T2 relaxation time in left MBH, adjusted for sex and age (p=0.001). In this initial sample, relationships between MBH T2 relaxation times and glycemic control, BMI or waist circumference did not emerge.

Conclusion:

The study protocol with insulin injection and MRI to study the hypothalamic gliosis in individuals with T1D is feasible. Structural MRI indicated increased T2 relaxation times as a marker of hypothalamic gliosis in participants with DEB. Further studies with larger sample size are crucial to validate these findings and to study specific eating behaviors and their associations with MBH gliosis in individuals with T1D.
SUN-382 Craniopharyngioma Patients Are at Risk of Impaired Bone Health
Authors: van Santen Selveta Sanne
Published: May 2020

Introduction

Craniopharyngioma (CP) are benign tumors originating from the sellar/hypothalamic region that are associated with neurological damage, epilepsy and endocrinopathies, which all could negatively affect bone health. Our objective was to determine fracture risk, bone mineral density (BMD) and final height in CP and evaluate independent determinants for fractures.

Methods

In this retrospective study, Dutch/Swedish patients with CP were included if data was available on fractures, bone mineral density (BMD) (T/Z-score), or final height (age >18 years). Data is presented as mean±SD unless stated otherwise. Logistic regression models were developed to evaluate determinants for fractures and osteoporosis. Low BMD was defined as T- or Z-score ≤-1 and osteoporosis as ≤-2.5 or ≤-2.0, respectively.

Results

We included 177 patients (48% female, 48% childhood-onset disease), with a median age at last follow-up of 45 years (range 15-92 years). Fractures occurred in 31 patients (18%); a fracture rate of 5.8 per 1000 person years. Eight patients suffered from multiple fractures (26%). In a multivariable logistic regression model for fractures, significant protective factors were female sex (OR 0.3 P=0.004) and surgery (OR 0.1, P=0.009), whereas a risk factor was use of anti-epileptics (OR 3.0, P=0.07). A significant risk factor for osteoporosis was age (OR 1.03, P=0.03); growth hormone replacement therapy tended to be protective (OR 0.2, P=0.10). Osteoporosis was not an explanatory variable for fractures (OR 2.1, P=0.21). Mean BMD T- and Z-scores were normal: Z-scores for L2-L4, femur neck and total body were 0.0±2.0 (range -3.5 - 6.8), -0.1±1.3 (range -2.7 - 4.7) and 0.1±1.5 (range -4.1 - 3.5), respectively. Osteoporosis occurred in 22 patients (24%); mean age of patients with osteoporosis was 53 ± 20 years. Low BMD occurred in 47 patients (50%). Medication to improve BMD was less often used in men than in women(7% vs. 18%, P=0.02). Mean final height was normal and did not differ between males/females, or adulthood/childhood-onset patients.

Conclusions

Patients with CP have a high fracture rate. In this population, epilepsy treatment was a risk factor, female sex a protective factor whereas osteoporosis did not affect the risk for fractures. Mean BMD Z-score was normal, but with a very wide range, resulting in low BMD in 50% and osteoporosis in 24% of the patients. Male CP patients are potentially undertreated with medication to improve bone health.
SUN-939 Case Report: Malignant Pheochromocytoma
Authors: Lima Jose Viana , Biscolla Rosa Paula Mello , Chiamolera Maria Izabel , Oliveira Marco Antonio Conde
Published: May 2020

Introduction: The concept of malignancy for pheochromocytoma is complex and the best definition is the presence of metastases, according to WHO. Anatomopathological scoring systems are not effective in predicting metastases. Malignancy should be considered when tumors larger than 8cm (> 80g), paragangliomas (especially retroperitoneal), dopamine / methoxythyramine increase, Ki67> 6% and SDHB mutation. At 5 years, survival ranges from 50-69%. Metastases may appear 20-40 years after initial treatment of pheochromocytoma. We describe a case that metastasis was identified 33 years after pheochromocytoma excision

Case report: A 57-year-old female patient with a postoperative history of 33 years of right adrenal pheochromocytoma was discharged from the endocrinologist after 10 years of follow-up. At diagnosis 33 years ago, she had symptoms of hypertension with paroxysms and weight loss that disappeared after tumor removal. 2 years investigating weight loss with general practitioner without another celebratory. On physical examination, orthostatic hypotension was highlighted. Plasma methanephrine 0.8 nmol / L (VR <0.5) and plasma normetanephrine 1.8 nmol / L (VR <0.9), chromogranin A 5.7 nmol / L (VR <3 nmol / L) and clonidine test with 36.6% suppression of metanephrines, suggesting tumor recurrence. MRI localized recurrence of the adrenals and MIBG scintigraphy with I131 that showed, respectively, in the topography next to the paracaval and retroportal right diaphragmatic crura, isointense T1 and slightly hyperintense T2 at 1.8 cm and radiopharmaceutical hypercaptation in right adrenal topography. Genetic panel by NGS did not identify germline mutation in 22 pheochromocytoma-related genes. FDG PETCT was consistent with MRI and MIBG images. Gallium PETCT68 DOTATOC detected the lesions already described, in addition to a lytic lesion in the left femoral intertrochanteric medulla. Anatomopathological approached abdominal lesion confirming pheochromocytoma metastasis in lymph node conglomerate. Currently has a negative methanephrine plasma, however chromogranin A 142 ng / mL (VR <93), and was chosen by the observant approach.

Conclusion: The case of the patient illustrates that pheochromocytoma should be followed indefinitely, as metastases may appear many years later and may present different aggressiveness potentials.
SUN-544 Immunologic Effects of GLP-1 Activation in Obese Adipose Tissue
Authors: Mashayekhi Mona , Wanjalla Celestine N , Pilkinton Mark A , Warren Christian M , Smith Rita M , Bailin Samuel S , Gabriel Curtis L , Kalams Spyros A , Brown Nancy J , Koethe John R
Published: May 2020

Background: Obesity is associated with systemic inflammation which is thought to stem, in part, from adipose tissue (AT). Obese AT is characterized by infiltration of pro-inflammatory T cells that promote macrophage activation and inflammation. GLP-1 has been shown to have anti-inflammatory effects in previous studies. We hypothesized that promotion of GLP-1 signaling with liraglutide or sitagliptin would reduce inflammation in association with an increase in the number of anti-inflammatory invariant natural killer T cells (iNKTs), group 2 innate lymphoid cell (ILC2s) and regulatory T cells (Treg) in blood and AT.

Methods: Obese adults with pre-diabetes were randomized to pharmacologic treatment resulting in increased GLP-1 signaling (liraglutide or sitagliptin, N=8), or hypocaloric diet (N=3). This ongoing study is blinded, so the effects of liraglutide and sitagliptin are combined in analyses and referred to as “drug”. Subcutaneous abdominal AT and peripheral blood mononuclear cells (PBMCs) were collected at baseline (“pre”) and after 12 weeks of therapy (“post”). Phenotypic marker expression of blood and AT T cells were characterized by flow cytometry. Whole AT inflammatory gene expression in the pre and post groups was assessed by Nanostring.

Results: Using the Nanostring inflammation panel, we found that a number of pro-inflammatory genes were significantly downregulated in whole AT after treatment with drug, including CD163, CD86, CCR1, MCP-2, and MCP-4.

Blood ILC2s were significantly decreased with drug treatment (pre 3.95%±3.05, post 1.71% ±1.65, p=0.01), but not diet (pre 2.17% ±1.91, post 1.46% ±1.68, p=0.18). We did not detect a change in Treg numbers after treatment with either diet (pre 5.78% ±1.91, post 6.09% ±1.50, p=0.29) or drug (pre 6.49% ±2.29, post 5.94% ±2.15, p=0.12). Similarly, no difference in blood iNKT numbers was detected after diet (pre 0.063% ±0.044, post 0.082% ±0.049, p=0.11) or drug (pre 0.077% ±0.106, post 0.091% ±0.130, p=0.67).

As observed in the PBMCs, adipose ILC2s were decreased after drug (pre 2.04% ±1.67, post 1.32% ±1.58, p=0.07, N=4). We did not detect a change in AT Treg and iNKT numbers (Treg pre 9.24% ±5.36, post 6.23% ±1.55, p=0.14; iNKT pre 0.12% ±0.08, post 0.09% ±0.05, p=0.47, N=4).

Conclusions: In a small pilot study of obese pre-diabetic patients treated with drugs that activate GLP-1 signaling (liraglutide or sitagliptin) or hypocaloric diet, global transcriptional analysis of whole AT suggested decreased inflammation with drug therapy. However, we found decreased percentages of ILC2 cells (considered anti-inflammatory in adipose) in both blood and AT after drug treatment. Future experiments will further characterize the function of these cell types, and evaluate other immune subsets in PBMC and AT that may be responsible for decreasing inflammation.
MON-181 Clinical Features of Immune Checkpoint Inhibitor-Related Adrenal Insufficiency: A Retrospective Analysis
Authors: Zhou Qinwen Jenny , Patel Sandip , Hamidi Vala
Published: May 2020

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment over the past decade. Despite their increasing use in clinical practice, there are few established, evidence-based guidelines for the screening and management of immune-related adverse events (irAEs), particularly with regard to autoimmune endocrinopathies. Adrenal insufficiency is an irAE that is poorly characterized due to the nonspecific nature of its presentation and can be life-threatening if not promptly recognized and treated. Our aim is to better define the clinical, biochemical, and imaging features of ICI-related adrenal insufficiency (AI) to mediate earlier recognition and treatment. Methods: We identified a total of 54 patients treated with either nivolumab, pembrolizumab, or ipilimumab combination therapy between January 2010 and August 2018 found to have a random cortisol level less than 2 or morning cortisol less than 5 during or following therapy. Patients who had been on prednisone or dexamethasone at the time of cortisol testing, had a history of adrenalectomy or radiation to the adrenal glands, or had adrenal or pituitary metastasis were excluded. Results: 11 patients met criteria for new onset ICI-related AI based on clinical and biochemical findings. 78% were formally diagnosed with AI, 61% had subsequent workup with ACTH, 17% had dedicated MRI pituitary imaging, 22% had HPA axis testing, 50% were referred to Endocrinology, and 45% were appropriately treated with hydrocortisone. Mean time to onset was 137 days from initiation of ICI. Peripheral eosinophilia was observed in 55% of patients. No anti-21 hydroxylase antibodies were drawn, and no patients had known underlying autoimmune disease or auto-antibody positivity. Six patients (55%) were felt to have secondary AI from ICI-related hypophysitis and one patient (9%) was felt to have ICI-related adrenalitis. Conclusions: As ICIs are being used with increasing frequency, it is crucial for health care providers to recognize the characteristics of immune-mediated adrenal insufficiency and initiate the appropriate workup, treatment, and referrals. Cortisol levels are routinely ordered as part of screening of ICI infusion but often dismissed without proper workup or follow up when levels meet criteria for AI. Our findings suggest that ICI-related AI more frequently manifests as ACTH deficiency in the context of hypophysitis, though primary AI can occur as well. Ultimately, further investigation is necessary to develop a systematic approach to diagnosing and managing ICI-related AI. References: 1. Chang et al. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr Rev. 2019;40(1):17-65. 2. Castinetti et al. French Endocrine Society Guidance on endocrine side-effects of immunotherapy. Endocr Relat Cancer. 2018;26(2):G1-G8.
SUN-280 A Brute of a Case: Pituitary Apoplexy in a Patient Treated for Chronic Lymphocytic Leukemia with Ibrutinib
Authors: Guido Paul Anthony , Treasure Madeline , DeCherney G Stephen
Published: May 2020

Background- Patients treated for chronic lymphocytic leukemia are frequently administered ibrutinib. Ibrutinib inhibits Bruton’s tyrosine kinase, blocks the B-cell receptor signaling pathway, thereby reducing downstream effects such as proliferation; effectively treating the malignancy. Adverse events such as bleeding have been reported and are suspected to be caused by inhibition of kinases in the platelet aggregation pathway.

Clinical Case- A 60-year-old man with chronic lymphocytic leukemia, treated with ibrutinib for five months, was diagnosed with pituitary apoplexy and consequent panhypopituitarism. He presented with a severe headache one month prior to diagnosis. At this time, a non-contrast head CT was interpreted as unremarkable. On second presentation one month later, studies showed a serum sodium of 116 mmol/L (135-145 mmol/L), glucose of 43 mg/dL (65-179 mg/dL), and blood pressure of 95/52. An MRI brain demonstrated an enlarged pituitary with areas of intrinsic T1 hyperintense signal noted within the sella turcica suggestive of blood products. Serum cortisol rose from 0.3 to 8.9 ug/dL (4.5-22.7 ug/dL) one hour after IV injection of 250 mcg cosyntropin. Paired ACTH was < 5 pg/mL (7.2-63 pg/mL). Hydrocortisone was started and blood pressure, sodium, and glucose normalized. LH was 0.9 mIU/mL (3-10 mIU/mL), FSH was 4.7 mIU/mL (1.6-9.7 mIU/mL), and total testosterone was < 0.7 ng/dL (240-950 ng/dL). TSH was 0.115 uIU/mL (0.6-3-3 uIU/mL) with FT4 of 0.84 ng/dL (0.71-1.4 ng/dL). Prolactin was 2.4 ng/mL (4-18 ng/mL) and IGF-1 Z score was -1.28 (-2.0-2.0). Replacement levothyroxine and testosterone were started. Oncology stopped ibrutinib and switched therapy to rituximab and venetoclax. A pituitary MRI two months later showed significant improvement of the T1 hyperintensity (blood products) and a 1.1 cm adenoma was found. During the entire course of his illness his platelet counts ranged from 275 to 431 109/L (150-440 109/L). His INR was 1.14 and PT 13.2 sec (10.2-13.2 sec). He has recovered well on hormone replacement.

Discussion- Pituitary apoplexy often has underlying risk factors, including pituitary adenomas and coagulopathies. To our knowledge apoplexy has not been reported in patients taking ibrutinib, though bleeding and platelet dysfunction have been well described. Knowledge of the possible side effects of newer anti-cancer drugs is increasingly important for the endocrinologist.
SAT-476 Alemtuzumab Induced Graves Disease
Authors: Caputi Rafael C , Raj Kavin , Jimenez-Zuluaga Jose Nicolas , Patel Sima , Luo Hongxiu
Published: May 2020

Introduction: Immune reconstitution therapy (IRT) with the monoclonal antibody alemtuzumab (anti-CD 52) has been shown to be superior to β-interferon in relapsing-remitting multiple sclerosis. It can cause early hyper-population of immature B cells which increases the risk of autoimmune disorders. The most common autoimmune adverse effect is autoimmune thyroid disorder (AITD) which has not been well recognized by internists, especially primary care physicians. We present a case of alemtuzumab-related hyperthyroidism. Most of these cases are mild and can be easily managed.

Case presentation: A 44-year-old female with history of multiple sclerosis (MS) presented to the office with a two-month history of fatigue, palpitations, tremors, weight loss and pruritus after completing a course of Alemtuzumab. Her symptoms started 1 month after completing 2 years of a consecutive series with IRT. Her thyroid function panel was not checked before starting IRT. She had no previous history of thyroid disease. Family history is positive for goiter in her mother. She had no exposure to contrast dye, steroids, amiodarone, supplements or biotin use. On exam, she had tachycardia, dry skin, tremors on outstretched hands and a non-tender goiter with no palpable nodules. Her initial labs showed a suppressed TSH (<0.005 mIU/L), elevated FT4 (>7.77 ng/dL), elevated T3 (647 NG/dL) and TSI of 338% (<140%), consistent with Graves’ Disease. She was started on methimazole. Two months into treatment, she became clinical and biochemical euthyroid without medication side effects.

Discussion: This patient might have Graves’ disease before IRT which can be easily treated if TFTs were routinely checked; or her Grave’s disease was induced by IRT later. Lack of TFTs checked before, during and after IRT put those patients at risk of unawareness of thyroid abnormalities. Based on this case, we strongly recommend doing routine TFTs (TSH, free T4) check before starting IRT to rule out existing thyroid function abnormalities and provide treatment accordingly. We also recommend checking TSI, TPO antibody for high-risk patients (positive family history, past history) and thyroid US for those who have nodules or goiters before starting IRT. For those found to have abnormal TFTs, TSI or TPO, routine follow up with an Endocrinologist should be recommended during, and even after therapy completion.

References:

1. Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis. L. Scappaticcio et al.

2. Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management. Decallone B et al.

3. 2019 European Thyroid Association Guidelines on the Management of Thyroid dysfunction following immune reconstitution therapy. Muller et al.
OR24-05 Identifying Regulatory Elements Within a Novel Enhancer of FSHB Containing Two PCOS-Associated Single Nucleotide Polymorphisms
Authors: Bohaczuk Stephanie C , Thackray Varykina G , Mellon Pamela L
Published: May 2020

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility, affecting approximately 10 percent of women by Rotterdam criteria, and is comorbid with obesity, type II diabetes, hypertension, and non-alcoholic fatty liver disease. As twin studies reveal that genetics account for approximately 70% of PCOS risk, genome-wide association studies (GWAS) can provide powerful insight into PCOS etiology. PCOS GWAS studies from several populations identified a risk locus containing the FSHB gene, which encodes the beta subunit of follicle-stimulating hormone (FSH). As FSH supplementation can restore ovulation in some PCOS patients, deficient FSH signaling could be a causative factor of anovulation and potentially other facets of PCOS. Two of the lead single nucleotide polymorphisms (SNPs) in association with PCOS, rs11031005 and rs11031006, fall within a highly conserved genomic region in mammals. We hypothesized that the conserved region (~450 base pairs) enhances FSHB transcription, and that one or both PCOS-related SNPs alter its function. We have shown that the conserved region from both human and mouse can act as an enhancer of FSHB in LβT2 cells, an immortalized, mouse-derived, mature pituitary gonadotrope cell line, and that its function is altered by the rs11031006 minor allele through modification of an SF1 consensus site. As elimination of the SF1 site reduced but did not completely abolish the function of the enhancer, we continued our investigation to identify additional regulatory sites. Transient transfection of LβT2 cells revealed a possible role for the rs11031005 SNP in FSHB regulation, with the minor allele decreasing enhancer-mediated FSHB transcription. This effect may be due to decreased binding of an unidentified transcription factor, as gel shift revealed that the rs11031005 minor allele reduced the intensity of a binding complex. Using truncations and sliding deletions, we identified three additional putative transcription factor binding sites with consensus sequences for ZEB1, PTX1, and SMAD. To support a role for the conserved region as an enhancer in native chromatin, we assessed the histone status in LβT2 chromatin. Compared to the proximal Fshb promoter, the enhancer-specific marker, H3K4me1, was enriched near the conserved region. Neither promoter/enhancer markers of active (H3K27Ac) or repressed (H3K27me3) chromatin were enriched near the conserved region, although levels of both modifications were consistent with the Fshb proximal promoter. Overall, our data support the role of this conserved region as a novel regulator of FSHB/Fshb transcription and reveal a possible mechanism to explain the contribution of PCOS-associated SNPs through FSHB regulation.
MON-494 Quality of Life in Patients with Papillary Thyroid Microcarcinoma According to the Treatment: Total Thyroidectomy Versus Total Thyroidectomy with Radioactive Iodine Remnant Ablation
Authors: Ahn Jonghwa , Jeon Min Ji , Song Eyun , Kim Tae Yong , Kim Won Bae , Shong Young Kee , Kim Won Gu
Published: May 2020

Background: Recently, the role of radioactive iodine (RAI) ablation in the treatment of low risk differentiated thyroid carcinoma (DTC), especially for papillary thyroid microcarcinoma (PTMC), is controversial. This study aims to compare quality of life (QoL) parameters in patients with PTMC underwent total thyroidectomy (TT) versus TT with RAI ablation.

Methods: In this cross-sectional study, patients with PTMC who underwent TT with/without RAI remnant ablation were prospectively enrolled between June 2016 and October 2017. All patients completed three questionnaires: 12-item short-form health survey (SF-12), thyroid cancer specific quality of life (THYCA-QOL), and fear of progression (FoP).

Results: The TT and TT with RAI groups comprised 107 and 183 patients, respectively. The TT with RAI group had significantly lower serum TSH level than TT group. However, after matching of TSH level between the groups (TT with RAI = 100, TT = 100), there was no significant difference in baseline characteristics. According to the SF-12, the score for general health showed significantly lower in TT with RAI group than TT group (p = 0.047). The THYCA-QOL also showed statistically significant difference in felt chilly score between the groups (p = 0.023). No significant differences in FoP scores were seen between the groups.

Conclusion: Patients with PTMC underwent TT with RAI ablation experienced more health-related problems than those managed by TT alone. These findings support RAI ablation should be carefully determined in patients with low-risk DTCs.