bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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 &gt;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

Abstract
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 (&gt; 80g), paragangliomas (especially retroperitoneal), dopamine / methoxythyramine increase, Ki67&gt; 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 &lt;0.5) and plasma normetanephrine 1.8 nmol / L (VR &lt;0.9), chromogranin A 5.7 nmol / L (VR &lt;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 &lt;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

Abstract
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

Abstract
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

Abstract
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 &lt; 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 &lt; 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

Abstract
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 (&lt;0.005 mIU/L), elevated FT4 (&gt;7.77 ng/dL), elevated T3 (647 NG/dL) and TSI of 338% (&lt;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.