bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-313 Synaptojanin 2 Binding Protein Is Required for Efficient Somatostatin Receptor 2A Phosphorylation by G Protein Coupled Receptor Kinases and Signaling to the ERK/MAPK Pathway
Authors: Carr Heather S , Frost Jeffrey A
Published: May 2020

Somatostatin receptor 2A (Sst2A) agonists are the primary pharmacological treatment for growth hormone (GH) secreting pituitary tumors to inhibit GH secretion and limit the destructive effects of these tumors. Sst2A agonists are also widely used as imaging agents for neuroendocrine tumors, and are under investigation for treatment of these cancers. However, despite the clinical importance of Sst2A agonists, regulatory mechanisms controlling Sst2A internalization and signaling are not fully understood. Sst2A contains a C-terminal PDZ binding site that serves as a docking platform for PDZ domain containing proteins. In an unbiased screen for PDZ domain proteins that can interact with Sst2A, we identified Synaptojanin 2 binding protein (SYNJ2BP) / Outer mitochondrial protein 25 (OMP25). SYNJ2BP is an outer mitochondrial protein that has been shown previously to promote the internalization of the Activin Type II receptor. We find that SYNJ2BP interacts with Sst2A in a ligand-dependent manner. Importantly, we show that SYNJ2BP promotes interaction of Sst2A with the G protein couple receptor kinase 2 (GRK2), and that siRNA-mediated knockdown of SYNJ2BP dramatically inhibits Sst2A phosphorylation by endogenous GRKs. Moreover, overexpression of SYNJ2BP strongly potentiates Sst2A phosphorylation on the GRK phosphorylation sites. Modulation of SYNJ2BP expression also regulates somatostatin-stimulated β-arrestin recruitment to the plasma membrane. Interestingly, in contrast to the large effects on Sst2A phosphorylation and β-arrestin recruitment, modulation of SYNJ2BP expression only caused a small change in ligand-stimulated receptor internalization. When we assessed downstream signaling, we found that SYNJ2BP overexpression potently stimulated receptor-dependent activation of ERK1/2, but had little effect on the ability of Sst2A to repress forskolin-stimulated cAMP production. Taken together, these data demonstrate for the first time that interaction of Sst2A with a PDZ domain protein affects receptor regulation and signaling. Because multiple PDZ domain containing proteins have been shown to interact with Sst2A, these data also suggest that interaction of Sst2A with this class of proteins may be an important regulatory mechanism to bias its function within the cell.
SAT-180 Adrenocortical Carcinoma - A Tertiary Center’s Recent 5-Year Experience
Authors: Ehrenwald Michal , Tordjman Karen Michele , Stern Naftali , Klausner Joseph , Nachmany Ido , Lahat Guy , Lubezky Nir , Goykhman Yaakov , Wolf Ido , Geva Ravit , Aizic Asaf , Barnes Sophie , Greenman Yona , Osher Esther
Published: May 2020

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The aim of this study was to characterize patients diagnosed with ACC at a single center between 2014-2019.

METHODS: We retrospectively reviewed data regarding demographics, tumor characteristics and functionality, treatment and survival.

RESULTS: The study cohort included 27 subjects (56% females), followed for 27±10.6 months. The mean age at diagnosis was 49.4±9 years. Co-morbidities at presentation included hypertension (63%), diabetes mellitus (22%) and dyslipidemia (26%). 74.1% of tumors were functioning – of which 85% were cortisol-secreting and 15% androgen-secreting. Aldosterone was secreted additionally in 15%. ENSAT stage at diagnosis was stage 1 in 15%, stage 2 in 35%, stage 3 in 12% and stage 4 in 38%. Eighty-nine % of patients underwent surgery. Treatment with mitotane was initiated in 82% of patients, reaching a mean maximal dose of 3.3 ±0.4 grams/day. Chemotherapy and/or radiation were given in 37% and 22%, respectively. Several patients (14.8%) had a second primary cancer, diagnosed before ACC in 75%. Progression was observed in 48% of patients, with a progression-free survival of 8.3±6.6 months. Thirty-five % of patients died during follow up, time to death was 12.8±0.4 months. Twenty two % of patients survived over 30 months after diagnosis. KI67 above 20% or stage above 2 negatively affected survival.

CONCLUSIONS: ACC remains a rare disease with a poor prognosis. However, it is a heterogeneous disease, with some patients achieving survival of over 30 months after diagnosis. Further characterization of this population may improve our understanding of the biology and treatment of this rare disease.
OR23-03 Post-Operative Day One Morning Cortisol Value as a Biomarker to Predict the Recurrence of Cushing Disease
Authors: Wang Fang , Catalino Michael , Bi W Linda , Dunn Ian , Smith Timothy , Guo Yunlei , Kaiser Ursula B , Laws Edward Raymond , Min Le
Published: May 2020

Tumor removal by transsphenoidal surgery (TSS) is the first line treatment for Cushing disease (CD). However, recurrence is relatively common. A one week post-operative (post-op) nadir cortisol has been used as a biomarker to predict recurrence1. We identified 299 CD patients from our longitudinal multidisciplinary clinic or our institutional RPDR search tool who met biochemical diagnostic criteria1 and had undergone TSS between May 2008 and May 2018, to evaluate post-op cortisol levels as biomarkers to predict long-term remission and to characterize clinical features of Cushing syndrome. Predictors of recurrence were identified with logistic regression, using recurrence as the dependent variable, and a Kaplan-Meier survival curve analysis was performed to compare long-term remission after TSS among the 202 patients who reached initial remission and had at least 1 year of follow-up. The post-op day 1 morning (AM) cortisol had significant association with CD recurrence (OR=1.025, 95%CI:1.002-1.048, p=0.032). The time to recurrence was significantly longer in patients with post-op day 1 AM cortisol <5 μg/dL. In contrast, one week post-op nadir cortisol (OR=1.081, 95%CI: 0.989-1.181, p=0.086), urinary free cortisol (OR=1.032,95%CI: 0.994-1.07, p=0.098), or late night salivary cortisol (OR=1.383, 95%CI:0.841-2.274, p=0.201) had no significant correlation with recurrence. There were no significant differences in time to recurrence for post-op day 2 AM cortisol <5 μg/dL. Among patients who developed post-op adrenal insufficiency, recurrence was significantly lower if glucocorticoid replacement continued for more than one year. In addition, tumor proliferative index (MIB-1) had a significant correlation with recurrence (OR=1.287, 95%CI:1.106-1.498, p=0.001). The most common symptoms and signs of initial presentation of CD were weight gain (91.6%), central obesity (79.6%), menstrual disorders (77.9%), round face (65.9%), hypertension (63.2%), mood disorders (60.2%), dorsocervical fat deposition (59.9%), supraclavicular fat deposition (59.9%), osteoporosis (58.9%), fatigue (58.2%), bruising (55.9%) and facial hirsutism (54.2%). Most of the best discriminating CD features did not have high sensitivity, such as purple striae (31.4%), facial plethora (33.4%) and proximal muscle weakness (30.8%). Our data show that post-op day one morning cortisol level above 5 μg/dL had significant association with recurrence. In contrast, the one week post-op nadir cortisol level had no significant value to predict recurrence. Our data also suggest that nonspecific symptoms and signs of CD are more common than stereotypical signs. Reference: Nieman LK, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100:2807-2831
SUN-201 Adrenal Insufficiency After Treatment for Vaping Associated Pulmonary Injury
Authors: Pierce Melinda , Griffiths Anne
Published: May 2020

Background: In 2019 a record number of patients were admitted to our children’s hospital with e-cigarette or vaping-associated lung injury (EVALI). The majority of patients were treated with high-dose prednisone therapy including 3 days of 1000 mg daily followed by a 4 week wean. Because of the concern for iatrogenic adrenal insufficiency, all patients were then placed on a 3-4 weak hydrocortisone taper followed by ACTH stimulation testing. The purpose of this study is to document the incidence of iatrogenic adrenal insufficiency following a 2 months glucocorticoid wean. Methods: All patients seen by the Pulmonary team for EVALI who also received high dose prednisone therapy were referred to Pediatric Endocrinology for ACTH testing. A low dose (1 mcg) ACTH stimulation test was performed with cortisol measurements at baseline, 30 minutes, and 60 minutes. A passing result was any cortisol over 18 ug/dl. Results: An anticipated 20-25 patients will have had ACTH stimulation testing by the time of abstract presentation. Of those that have already completed testing, three of four patients failed the first time. Discussion: High-dose prednisone therapy for EVALI is associated with significant rates of iatrogenic adrenal insufficiency, even after slow hydrocortisone wean. Structures need to be implemented to teach patients about adrenal insufficiency prior to hospital discharge and organize adequate post-discharge follow-up until HPA function returns.
SAT-475 New Breast Cancer Therapy Atezolizumab, Leads to Thyroiditis
Authors: Parimi Joseph Theressa Nehu , Patel Richa
Published: May 2020

Background: A NSABP B 59 trial is currently underway to check the efficacy of an experimental drug, Atezolizumab (Anti-PDL 1 monoclonal antibody) in the treatment of triple negative breast cancer. In the trail, the drug is added to the usual neoadjuvant chemotherapy given before surgery and prolonged treatment with it is continued after surgery to reduce the recurrence. Listed adverse effects are immune medicated hyperthyroidism in 2% of population.

Clinical Case:

32 y old Asian woman was diagnosed with triple negative left breast cancer in May 2018. She was started on paclitaxel, carboplatin and study medication Atezolizumab/Placebo in June 2018 and she received 4 cycles of the same and then it was stopped in August 2018. She was started back on the same in September 2018 which ended in November 2018. Patient tested positive for BRCA1 gene mutation and underwent bilateral mastectomy in December 2018. The study medication was restarted in January 2019.

Patient is received a total of 11 doses of study medication and was due to receive 16 doses if she had finished the trial in June 2019. Patient received radiation therapy starting in January 2019 till February 2019.

On her oncology visit in April 2019 patient was found to have a suppressed TSH of 0.009 with a high free thyroxine of 1.72 and an elevated free T3 of 5.4. She was referred to endocrinology for evaluation of thyroid abnormalities, as the study medication can cause thyroid problems. She denied symptoms of hyperthyroidism. TPO, TSI and anti-thyroglobulin antibodies were negative. Thyroid uptake scan showed uniformly decreased tracer distribution in both thyroid lobes consistent with thyroiditis.

As per the protocol for the study medication as well as recommendations by the American Society of oncology, we waited for normalization of the thyroid function test before resuming the study medication. In July 2019, TSH normalized to 2.99 and free T4 0.97.

She was noted to have low random cortisol level of 3.27 at 1000AM. ACTH stimulation test was performed and she responded appropriately.

Hence could not take the remainder of the study medication that were scheduled until June 2019. She is on observation phase since June 2019 and currently doing well.
SUN-590 27-Hydroxycholesterol Triggers the Whitening of Brown Adipose Tissue
Authors: Asghari Arvand , Bui Linh , Stephen Robert , Umetani Michihisa
Published: May 2020

27-Hydroxycholesterol (27HC) is the most abundant oxysterol in circulation and metabolized by a P450 enzyme CYP7B1. Its levels closely correspond to those of cholesterol in the body. In addition, previously it was found that 27HC is an endogenous selective estrogen receptor modulator (SERM), which links cholesterol metabolism to estrogen receptor actions (1). Brown adipose tissue (BAT) is the primary source of energy expenditure and energy homeostasis, as well as body temperature maintenance. While previously it was believed that BAT activity is limited to neonates and young children, it is now recognized that BAT is also active in adult humans and its function is impaired by metabolic diseases such as obesity. BAT is also a secretory organ and produces brown adipokines, although the exact function of BAT and adipokines from this tissue in obesity has not been completely understood. Recently, it was reported that 27HC plays an important role in obesity and augments body weight gain in response to a high fat, high cholesterol (HFHC) diet by increasing pre-adipocyte population in the white adipose tissue. 27HC mimics the effects by HFHC diet-feeding on white adipose tissue, such as promoting the inflammation and macrophage infiltration (2). In this study, we explored the effect of 27HC on BAT morphology and function. First, we compared the morphology of BAT from wild-type mice and Cyp7b1-/- mice that have elevated levels of 27HC using H&E staining. Interestingly, brown adipocytes from Cyp7b1-/- mice were larger in cell size than those from wild-type mice, and the cells were mostly unilocular compared to the multilocular cells from wild-type mice, indicating the transition toward a “whitening” phenotype. Next, We treated mice fed a normal chow or a HFHC diet with 27HC or vehicle control for 8 weeks to examine the direct effect by 27HC on BAT. Similar to the phenotype in Cyp7b1-/-mice, 27HC increased the “whitening” of BAT regardless of the diet. We also determined the gene expression of brown adipocyte markers such as UCP1, PGC1a, and DIO2, and found that 27HC significantly decreased the expression of the BAT markers regardless of the diet, confirming the “whitening” observed in the morphology. Moreover, the energy expenditure in mice treated with 27HC was decreased compared to the vehicle control on a HFHC diet, suggesting that 27HC also alters BAT function. These results show that 27HC causes the whitening of BAT, and shed light on the important role of 27HC in brown adipose tissue function. Future experiments will be warranted toward further understanding of the role of 27HC in BAT function. Reference:(1) Umetani, Michihisa, et al. Nature medicine 13.10 (2007): 1185. (2) Asghari, Arvand, et al. Endocrinology 160.10 (2019): 2485-2494.
SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
Authors: Abe Kiyomi , Gastelum Gilberto , Li Chengju , Rubinos Harmie , Yamada Alexandr , Liu Yan-Yun , Brent Gregory A
Published: May 2020

Thyroid hormone (TH) plays an essential role in normal development. TH action requires binding to its receptor. There are two types of thyroid hormone receptor, alpha (THRA) and beta (THRB). THRB is important for regulation of the Hypothalamic-Pituitary-Thyroid axis and regulating cholesterol metabolism. THRA is involved in the development and the function of brain, adipose tissue, small intestine, bone and heart. Both THRA and THRB are post-translationally modified by small ubiquitin-like modifier (SUMO). Previously, we showed in an in vitro model that mutation of a THRA sumoylation motif impairs proliferation and differentiation of human primary white adipocytes. This is due to interference of the desumolyated THRA in the cell cycle at G1/S phase and disruption of PPAR signaling. To determine the in vivo effects of a desumoylated THRA, we generated a mouse model carrying a mutation of the THRA gene, which eliminates SUMO conjugation at lysine (K) 283. At 12 weeks of age, there was no difference in body composition (body weight, fat mass, and lean mass) in THRA mutant mice compared to wild-type (WT). From 12 weeks onward mutant mice and WT did not have significant change body weight compared to Wt mice. However, THRA sumoylation mutant mice had much lower percent body fat. Dissected WAT fat pads from mutant mice were significantly smaller compared to WT mice. Histological analysis showed that the cell size of white adipose tissue in mutant mice was significantly smaller than that in Wt mice as well. Serum leptin levels in the mutant mice were significantly lower than that in mice, consistent with reduced fat mass. We isolated fat stem cells from stromal vesicular fraction of 6 week old mice and found that the number of fat stem cells was significant less in mutant mice compared to those in WT mice. This data suggest that de-sumoylated THRA is associated with reduced fat stem cells at a young age, resulting in reduced adipose tissue mass in adult. THRA sumoylation is important for thyroid hormone modulation of fat mass.

Reference: (1) Yan-Yun Liu et al, JBC 2012 (2) Yan-Yun Liu et al., JBC 2015
SAT-617 Potential Utility of the Mixed Meal Test for Differential Diagnosis of Partial Lipodystrophy from Common Type 2 Diabetes and Truncal Obesity
Authors: Guraya Armaan , de Freitas Maria Cristina Foss , Akinci Baris , Eldin Abdelwahab Jalal , Oral Elif A
Published: May 2020

Background: Better clinical tools are needed to improve the differential diagnosis of partial lipodystrophy (PL) from type 2 diabetes (DM) with truncal obesity. Here, we investigated differences in metabolic parameters during a mixed meal test in PL and DM patients to determine if this test may have a role in this regard. Methods: We retrospectively evaluated data collected from 17 PL patients (4M/13F, ages 12-64) and 20 DM patients (13F/7M, ages 24-72) with truncal obesity, who also had nonalcoholic fatty liver disease. All patients underwent a Mixed Meal Test (MMT) with 474 ml of Optifast (320 kcal, 50% carbs, 15% fat, and 35% protein). Blood was collected before and at 30, 60, 90, 120, and 180 minutes post-meal to measure glucose, insulin, free fatty acids (FFA), triglycerides, inflammatory markers, GIP, GLP-1, PYY, and Ghrelin. All samples of the same cohort were run at the same time in duplicates and results were averaged. Mixed linear models were constructed to compare PL and DM cohorts taking into account within-subject effects. Data were controlled for BMI, sex and age, and glucose when necessary. Results: Patients with PL had higher glucose and triglyceride levels throughout the MMT at all-time points (p < 0.05). While the glucose levels showed an increase and subsequent decrease, the triglyceride levels remained flat throughout the test in both groups. Free fatty acid levels were suppressed compared to baseline during the test, but PL patients had significantly higher FFA from time 30 to time 180 (p < 0.05) and tended to suppress less. While controlling for the differences in glucose levels, GIP levels displayed a large peak at time 30 min in both groups but were significantly higher over the course of the test in the PL group (AUC: 32542, pg/mL x min (20528-57728) vs. 3343 pg/mL x min (1728-4498), p < 0.05). In contrast, GLP-1 levels (also peaking at time 30 min in both groups), were significantly lower in PL throughout the test (AUC: 3017 pg/mL x min (2309-6051) vs. 28387 pg/mL x min (20422-36045), p < 0.05). Ghrelin and PPY levels did not differ significantly between the two groups. Interpretation/Conclusion: PL patients displayed more profound hyperglycemia and impaired suppression of FFAs. Interestingly, PL patients did not show substantial increases in triglyceride levels during MMT. There was a striking difference in the incretin responses between the two populations despite controlling for glucose, suggesting that MMT may have a role in differential diagnosis PL. Also, altered incretin response should be investigated as a contributor to metabolic perturbations and pathophysiology of PL.
SAT-587 Molecular Markers of Beige Adipose Following ESR1 Knockdown in the Mediobasal Hypothalamus of Adult Female Rhesus Monkeys
Authors: Bandaru Sindhura , Flowers Matthew T , Perlin Sona , Willging Molly M , Greinwald Emily P , Levine Jon E , Abbott David Howard
Published: May 2020

Our studies in female marmoset monkeys show that the ablation of ovarian estradiol (E2) production fails to alter energy homeostasis or body fat accumulation. Peripheral E2 may therefore not play a crucial role in metabolic regulation in female primates. shRNA-mediated knockdown of ESR1 expression in the hypothalamic ventromedial nucleus (VMN) in adult female rodents, however, induces obesity and suggests ESR1 is a hypothalamic target for E2 regulation of energy homeostasis, and likely mediates thermogenesis in brown/beige adipose depots. In female primates, including humans, the hypothalamic estrogen receptor mediating metabolic regulation is unknown. To test the hypothesis that ESR1 mediates female primate regulation of energy homeostasis, 11 ovary intact, adult female rhesus macaques, pair housed with female peers, received five 12µl MRI-guided MBH infusions into the rostral-to-caudal extent of both right and left VMN. Each infusion comprised a gadolinium contrast agent and ~3–4 x 1010 adeno-associated virus 8 (AAV8) particles containing either an shRNA specific for ESR1 (n=6, ERaKD) or scrambled shRNA (n=5, control). Mid-surgery MRI scans identified targeting accuracy. ~ 1.5 yrs following AAV8 infusion, pronounced gain in BMI enabled conversion of 83% of ERaKD females to overweight/obese compared to 20% of controls (p=0.08). Percent increase in BMI remained intermittently greater (p<0.05) than controls thereafter. Adipose depots were harvested at necropsy ~2.5–3 yrs following treatment. Total RNA was isolated using the Qiagen AllPrep DNA/RNA/miRNA Universal kit. RNA was reverse transcribed with High-Capacity cDNA Reverse Transcription kit (Applied Biosystems). All quantitative real-time PCR (qRT-PCR) were performed on a StepOnePlus System using Power SYBR Green master mix (Applied Biosystems). Primer sequences were designed using NCBI Primer-Blast. Expression of TATA-box binding protein (TBP) was used as the internal control housekeeping gene. The relative expression of target genes was measured using the comparative cycle threshold (Ct) method with results expressed as target mRNA expression relative to TBP using the formula 2^-delta Ct. Upper body beige adipose represents an organ system in primates, including humans, involved in thermogenesis. Axillary beige adipose depots in ERaKD females, however, did not exhibit significantly diminished gene expression for selected markers of beige adipocytes, including PAT2, CD137 and C/EBPβ, compared to control females. More crucially, thermogenically relevant UCP1 expression also did not differ between ERaKD females and controls. Taken together, these results suggest that knockdown of VMN ESR1 in adult female monkeys, while inducing modest weight gain after 1.5 years, may not markedly alter beige adipose gene expression of initially selected thermogenically relevant genes.
MON-293 The Prevalence of Impulse Control Disorders in Patients with Acromegaly and Prolactinomas Treated with Dopamine Agonists
Authors: Ozkaya Hande Mefkure , Sahin Serdar , Korkmaz Ozge Polat , Durcan Emre , Sahin Humeyra Rekali , Poyraz Burc Cagri , Kadioglu Pinar
Published: May 2020

Objective: There is emerging evidence linking dopamine agonist (DA) use with the development of impulse control disorders (ICD) in patients with prolactinomas. On the other hand, no data exist whether DA use in acromegaly is associated with ICD. We aimed to evaluate the prevalence of ICD, psychiatric symptoms in patients with prolactinoma and acromegaly receiving DA in comparison to those with nonfunctioning pituitary adenomas (NFA) and healthy controls (HC).

Material and Method: Forty patients with prolactinoma, 40 patients with acromegaly, 38 patients with NFA and 32 HC were included in this study. All patients and controls included in the study were evaluated with revised version of Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). All of the patients with prolactinoma and acromegaly had been receiving cabergoline therapy but patients with NFA had not been receiving cabergoline therapy at the time of the study.

Results: We detected DA associated with ICD in 3 patients (7.5%) with prolactinoma, and 2 patients with acromegaly (5%). All patients’ symptoms resolved after either discontinuation of the drug or surgical intervention. There was no significant difference between patients with acromegaly and prolactinoma in terms of ICD prevalence. On the other hand, ICD was not detected in non functional adenoma and HC. There was no correlation between BIS-11 scores and total dose, mean monthly dose and duration of DA.

According to SCL-90-R, obsession and interpersonal sensitivity positivity was significantly higher in patients with prolactinoma than acromegaly (p: 0.040, p:0.010, respectively). There was no significant difference between the groups in terms of BAI, BDI and BIS-11’s subscales and total scores (p> 0.005). Scl-90 somatization and depression positivity was significantly higher in patients with NFA than acromegaly (p: 0.043, p: 0.024 respectively). Likewise, scl-90 depression, interpersonal sensitivity and additional items subscale positivity was significantly higher in patients with NFA than HC (p: 0.005, p: 0.045, p: 0.045 respectively).

Conclusion: Although DA dose was significantly higher in patients with acromegaly compared to patients with prolactinoma, there was no significant difference in the prevalence of DA -related ICD. We have showed that there was no association between BIS-11 scores and total DA dose, mean monthly DA dose and duration of DA treatment. The higher prevalence of depression, interpersonal sensitivity in patients with NFA in comparison to HC supports the hypothesis the presence of a pituitary adenoma per se might cause a large psychiatric symptom burden.
SUN-041 Hispanic Medical Student’s Knowledge and Attitudes Towards Transgender Patient’s Care
Authors: Muns Sofía , Ortiz-Ramos Kevin J , González-Rodríguez Loida , Romaguera Josefina
Published: May 2020

Transgenders are characterized by having a gender identity and/or expression that is different from their sex at birth. There are guidelines about the proper management of this population. However, health disparities are still present. The lack of education and training about transgender care in the medical curriculum is one of the most significant contributors to these disparities. The aim of this study is to explore the knowledge and attitudes towards transgender care among Hispanic medical students at the University of Puerto Rico (UPR). Medical students (MS) from the UPR were invited to participate in an online anonymous questionnaire to assess their attitudes and knowledge about the healthcare of transgender patients. Data was analyzed as percentages and as means using Likert scale. Responses from pre-clinical and clinical MS were compared. A total of 141 participants were recruited. The majority of MS (80%) claimed to be exposed to transgender patients at least once. A total of 74% of MS reported feeling comfortable taking care of transgender patients. The overall Likert scale score for perceived knowledge about transgender topics among pre-clinical and clinical MS were 2.91 and 2.68, respectively. The scores for how comfortable students felt about working with transgender patients were 3.99 and 4.13 for both pre-clinical and clinical MS, respectively. Sixty percent of MS reported not being familiar with hormonal regimens used for gender reassignment therapy. Significantly more pre-clinical MS thought that discussing sexual behavior with transgender patients was more challenging than discussing it with heterosexual patients when compared to clinical MS (2.90 and 2.36 respectively; p=0.02). The majority of medical students (87%) believed that physicians are responsible for the treatment of transgender patients. Our study reveals that even though there is willingness to treat transgender patients among UPR medical students, there are limitations in their knowledge and training regarding specific healthcare topics. Strategies to improve MS knowledge and training about this topic must be considered.
SAT-492 Impending Thyroid Storm Induced by Checkpoint Inhibitors
Authors: Zhou Ya , Jobbins Kathryn , Panta Raju
Published: May 2020

Introduction:

Thyroid storm is a rare but life threatening condition due to thyroid hormone excess and is usually caused by Graves disease, toxic nodular goiter or rarely due to thyroiditis. Immune checkpoint inhibitors (ICI) are a novel choice for treating cancers, and carry a risk for development of endocrinopathies. We report a case of impending thyroid storm 5 weeks after initiation of ICI.

Case Presentation:

81-year-old Caucasian male with metastatic renal cell carcinoma presented with generalized weakness and fatigue 5 weeks after ipilimumab and nivolumab were started. He had no prior history of thyroid disease and had normal thyroid functions before the treatment. He complained of palpitations, heat intolerance and loose stools on admission. On examination he was disoriented, tachycardic (128bpm) with new onset atrial fibrillation, had moist skin and brisk reflexes. He had non-tender thyroid, no thyromegaly, and no nodules palpated. Burch-Wartofsky score was 35, suggesting impending thyroid storm. Laboratory investigation showed elevated free T4 (>7.77), elevated free T3 (8.6) with a suppressed TSH (< 0.02). He had positive anti-TPO but Thyrotropin receptor antibody was negative. He was treated with propranolol 40 mg three times daily, prednisone 40 daily, methimazole 30mg three times a day with significant improvement in free T4 (5.67) within first 48 hours.

Discussion:

Imipimumab and nivolumab are monoclonal antibodies against cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1) respectively. The reported incidence of thyroid dysfunction after combined imipimumab and nivolumab therapy can be as high as 22%1. Thyroiditis could present as early as 2-6 weeks 2 after treatment, and hypothyroidism tends to present between 5 months and 3 years3. According to a current consensus4, baseline TSH and FT4 should be drawn prior to initiating ICI. Thyroid storm is a clinical diagnosis and Burch-Wartofsky score can help in diagnosis. A high degree of suspicion and prompt diagnosis of thyroid storm and treatment is of utmost importance especially in this patient population. Rapid improvements in thyroid hormone levels suggest thyroiditis as a potential cause for thyrotoxicosis.

Conclusion:

ICI induced thyroid disease is not an uncommon condition. It could present as either thyrotoxicosis or hypothyroidism. Both patient and clinician should be aware of potential signs and symptoms of thyroid storm for early recognition and timely treatment of this life-threatening condition.

[1] Byun DJ et al.Nat Rev Endocrinol. 2017 Apr;13(4):195-207 [2] Iyer PC et al. Thyroid. 2018 Oct;28(10):1243-1251 [3] Endocr Relat Cancer. 2014 Mar 7;21(2):371-81 [4] Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95
SAT-381 Adjunct Benefit of Aquatic Therapy in Juvenile Hypophosphatasia Initiated in an Adult
Authors: Khan Abdul Mannan , Lightell James , Majors Corey
Published: May 2020

Background: This is a case of improvement in visual analog scale pain rating and objective functional capacity in juvenile hypophosphatasia (HPP) following treatment with asfotase alfa and adjunct physical therapy (PT) performed in an aquatic environment. Clinical Case: A 45-year-old female with a history of psoriatic arthritis and osteoarthritis was referred for low serum alkaline phosphatase (ALKP) (<10 U/L). Her history of eight fractures over the preceding 25 years including bilateral femur nonunion repaired with rods eight years prior to presentation led to a diagnosis of juvenile HPP, and asfostase alfa was ordered. She is ambulatory only with a rolling walker from a deficit in dynamic standing balance and chronic pain. Referrals were made for both PT and pain management for these symptoms. The initial PT evaluation established reasonable goals to include the performance of in-home exercise, increase strength and range of motion, decrease pain, improve standing balance, and progress from walker to cane. Aquatic therapy was chosen in order to reduce patient’s effective weight. The right hip complex, lumbar spine, and left leg were chosen as areas of focus based on pain reports. A four-week follow-up evaluation by the therapist reported patient had been performing at home exercises. Pain scale reports of the lumbar spine, right hip, and left leg were within the moderate range and near or meeting the patient’s self-reported least pain experienced. Goniometric measurements of the right hip showed range of motion improvements averaging 9%. The lumbar spine’s range of motion increased an average of 18%. Discussion: HPP is capable of creating severe disability, and its rarity has led to a dearth of investigation into appropriate treatment. Recommendations have been made previously for PT in children and infants presenting with juvenile or infantile HPP; this case suggests these recommendations are applicable to adults as well. The mechanisms of these improvements remain unclear; however, evidence exists that weight-bearing exercise may result in increased levels of bone-specific isoforms of ALKP. This endogenous path to increased serum ALKP may play a role in potentiating the effects of asfostase alfa. 1. Shapiro JR, Lewiecki EM. Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations. Journal of Bone and Mineral Research 2017;32(10):1977–1980. 2. Phillips D, Case LE, Griffin D, Hamilton K, Lara SL, Leiro B, Monfreda J, Westlake E, Kishnani PS. Physical therapy management of infants and children with hypophosphatasia. Molecular Genetics and Metabolism 2016;119(1–2):14–19. 3. Rudberg A, Magnusson P, Larsson L, Joborn H. Serum Isoforms of Bone Alkaline Phosphatase Increase During Physical Exercise in Women. Calcified Tissue International 2000;66(5):342–347.
MON-276 Post-Surgical Metabolic Outcomes in Adult-Onset Craniopharyngioma: A Single Pituitary Center Experience
Authors: Duan Daisy , Wehbeh Leen , Mukherjee Debraj , Hamrahian Amir H , Ahima Rexford S , Maruthur Nisa M , Salvatori Roberto
Published: May 2020

Background:

Craniopharyngiomas, while benign, have the highest morbidity of all pituitary tumors. Hypothalamic obesity (HO), one of the most devastating consequences, is commonly studied in the pediatric population, but few data are available on weight and other metabolic outcomes in adult-onset craniopharyngiomas (AOCP).

Methods:

We conducted a retrospective chart review of 49 adult patients with AOCP who underwent surgery between 1/2014 and 5/2019 at an academic pituitary center. Weight, BMI, metabolic diseases (type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, OSA), and pituitary hormone deficiencies were recorded pre-surgery and at last follow up and analyzed using paired t-tests or McNemar’s test.

Results:

Median age was 56 years (51% women), 45% had >1 surgery (range 1-5), and 49% had radiotherapy. Of 72 total surgeries, 54% were craniotomies and 68% of surgeries resulted in subtotal resections. Median follow up was 25 months. Median BMI was 29.2 and 30.5 kg/m2 at baseline and at last follow up, respectively. Weight was higher at last follow up (mean increase 2.7 kg; p=0.043), with an average of 4% weight gain. Patients with baseline normal and overweight BMI had significant weight gain (mean increase 5.1 kg, p=0.045; mean increase 5.5 kg, p=0.015 respectively), while those who were obese at baseline did not (mean increase 2.0 kg, p=0.302). The proportion of patients with obesity (BMI>30) increased from 37% to 53% (p=0.008). 31% of patients had >5% weight gain, with mean increase in BMI of 4.1 kg/m2 (p<0.0001) and mean weight gain of 13.1 kg (p<0.0001). 24.5% had an increase in the total number of metabolic diseases (p=0.07). Of 43 patients who were overweight or obese at last follow up, obesity was addressed in 51%, most commonly through lifestyle counseling (49%) and adjustment of hormone replacement in response to weight gain (23%). Two patients had bariatric surgery within one year of pituitary surgery. The proportion of patients with ≥3 hormone deficiencies increased from 18% to 55% (p=0.0003). At last follow-up, only one patient had GHD, diagnosed by low age-adjusted IGF-1 level. 14 of 15 patients with ≥3 hormone deficiencies had normal age-adjusted IGF-1 levels and one patient had normal GH provocative testing.

Conclusion:

Weight significantly increased after surgery for AOCP, with mean weight gain of 4%. 31% of patients had a marked increase in BMI and weight, suggesting possible HO. GHD is likely under-diagnosed in AOCP, and IGF-1 may not be a sensitive tool. Obesity-directed treatment is under-utilized in this patient population.
SUN-905 A Case of Adrenal Cushings a Primary Hyperparathyroidism
Authors: Davern Recie , Bell Marcia
Published: May 2020

We present the case of a 31 year old female referred with weight gain, secondary amenorrhea, facial plethora and buffalo hump x6-9/12. Background medical history of caesarean section. She was on no regular medications. She rarely consumed alcohol. There was no relevant family history.

She experienced secondary amenorrhea x6/12. Her menarche was at the age of 14 and had regular periods thereafter. She had gained 13kg over the previous 9/12. Examination revealed an intrascapular fat pad, abdominal striae and facial plethora. Her BP was 150/87.

Initial investigations were as follows: Overnight DST: Cortisol 642 nmol/L, DHEAS <0.4 µmol/L, hCG <1 U/L, TSH 0.71 mIU/L, FT4 15.1 pmol/L, Prolactin 380 mIU/L, IGF-I 152 µg/L, FSH 4.4 IU/L, LH 3.0 IU/L, oestradiol <100 pmol/L, 17-OH Progesterone <1.0 nmol/L. She then underwent a low dose 48 hour dexamethasone suppression test the results showed: Cortisol Day 1(time 0) 704 nmol/L, Day 2 (time 24 hours) 702nmol/L, Day 3 (time 48 hours) 703 nmol/L and paired ACTH 1.4ng/L.

She was admitted from clinic with BP 189/107 and was started on metyrapone and ramipril. On this admission her bloods showed calcium 2.70 mmol/L, iPTH 113.5 ng/L, 25 (OH) D27nmol/L. Ct abdomen and pelvis revealed a 3.3x2.2 cm right adrenal lesion with hounsfeld units <10 and unremarkable left adrenal. ARR, plasma metanephrines and HbA1c were all normal. The case was discussed at MDM and referred for retroperitoneal laprascopic right adrenalectomy. She was discharged day 2 post op off anti hypertensives and on hydrocortisone 10mg/5mg/5mg. Histology confirmed adrenocortical adenoma and Ki67 <5%.

Synacthen test done one month post operatively showed time 0 cortisol 35 nmol/L, time 30 cortisol 56 nmol/L, time 60 cortisol 60 nmol/L and time 0 ACTH 51 ng/L. Post operatively her menses returned.

When vitamin D replete, we re-evaluated her hypercalcemia. This revealed 2.77 mmol/L, iPTH 100.7ng/L, calcium: creatinine ratio 0.72 mmol/mol. She had an ultrasound neck and sestamibi which both lateralised to right lower lobe of thyroid. A synacthen test was repeated which revealed time 0 cortisol 183 nmol/L and ACTH 44 ng/L, time 30 cortisol 258 nmol/L and time 60 cortisol 302 nmol/L. She was referred for 4 gland exploration with intra operative PTH. Her baseline intra operative PTH was 193 ng/L and her 10 minute post excision value was 55 ng/L which demonstrates a 65% drop in concentration and intra operative PTH returned to within the reference interval.

The histology was atypical displaying extension of the tumour through the capsule and possible vascular extension. Ki 67 was <2%. It has been sent to St. Guy’s and Thomas’ for a second opinion. Her calcium and iPTH returned to normal post operatively. MEN1 and CDKN1B genes were negative. We’re awaiting gene sequencing on the following - RET, CDC73, CASR, CDKNIA, CDKN2C AND CDKN2B. This case represents a case of multiple endocrinopathies with no found genetic link.
SUN-294 The Effects of Traumatic Brain Injury on Pituitary Function: A Systematic Review and Meta-Analysis
Authors: Beyer Christian , Zaytsev Julia , Donegan Diane , Bancos Irina , Hamidi Oksana
Published: May 2020

Background: The impact of traumatic brain injury (TBI) on pituitary function remains unclear. Yet, applying appropriate diagnostic and treatment strategies for affected patients is crucial for mitigating morbidity related to hypopituitarism and improving patient outcomes. Currently, data regarding the prevalence of post-TBI hypopituitarism and its predisposing factors are inconsistent. The goals of this systematic review and meta-analysis were to evaluate the prevalence of acute and chronic post-TBI hypopituitarism and assess for predictors of pituitary dysfunction.

Methods: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Web of Science, and references of key articles were searched from inception to 2019. Studies enrolling ≥20 adult patients with TBI and reporting on pituitary dysfunction were included. A total of 992 studies were generated by the initial search. Titles and abstracts were screened in duplicate by two independent reviewers for inclusion criteria. Of these, 265 full text manuscripts were subsequently reviewed for eligibility. Predefined data were extracted from 14 representative studies for the preliminary analysis (7 cross-sectional studies, 6 prospective studies, and 1 retrospective study).

Results: There was a total of 813 (78% male) patients with TBI. Of those with available data, 124/248 (50.0%) had mild TBI, 112/476 (23.5%) had moderate TBI, and 308/569 (54.1%) had severe TBI. Mean age at TBI diagnosis was 34.2±4.6 years, with time to evaluation of pituitary function following TBI ranging from 0 days to 120 months (mean, 27.1±35.1 months). Acute and chronic hypopituitarism was reported in 10.7% and 19.6% of patients, respectively. TBI was associated with increased risk for hypopituitarism compared to the general population (RR=765.8, 95% CI 538.8-1088.5). Secondary hypogonadism was noted in 15.7% of patients, growth hormone deficiency in 15.7%, secondary adrenal insufficiency in 11.6%, secondary hypothyroidism in 8.7%, and diabetes insipidus in 0.2%. Older age (40.4±5.5 vs 36.7±1.0 years, P<0.0001) and higher BMI (25.0±0.7 vs 23.9±0.2 kg/m2, P<0.0001) were associated with increased risk of post-TBI hypopituitarism.

Conclusion: Available moderate- to low-quality evidence suggests that post-TBI hypopituitarism is common and correlates with older age and higher BMI. Secondary hypogonadism and growth hormone deficiency are the most predominant pituitary deficiencies. Further investigations are warranted to determine the most effective strategies for identifying patients at risk for post-TBI hypopituitarism in order to implement prompt assessment and management.
MON-908 Carcinoid Causing Catastrophic Calcemia
Authors: Franquemont Stephanie , Allemon Ashely , Archuleta Travis , Mathew Jacob
Published: May 2020

Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.
SAT-132 The Secretory Vesicle Membrane Protein, CYB561, Promotes the Growth and Metastatic Potential of Castration-Resistant Neuroendocrine Prostate Cancer
Authors: Olarte Kevin Christian V , Bagamasbad Pia D
Published: May 2020

An increase in the population of neuroendocrine (NE) differentiated (NED) cells and their secretory products are closely correlated with prostate cancer (PCa) resistance to existing therapies and eventual progression to castration-resistant PCa (CRPC). It is hypothesized that NED cells secrete neuropeptides that support tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. A gene that is constitutively expressed in secretory vesicles of NE cells, and has been previously found to be highly expressed in CRPC and cancer of several tissues is Cytochrome b561 (CYB561). The CYB561 gene encodes a secretory vesicle transmembrane protein that primarily functions in the regeneration of ascorbic acid, a necessary step in the α-amidation activation process in the biosynthesis of most neuropeptides. The CYB561 protein also exhibits ferrireductase activity and may contribute in regulating iron transport and metabolism, which are two other pathways often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression of prostate cancers into the more aggressive NE subtype. In our study, we found that CYB561 expression is higher in metastatic and NE PCa (NEPC) models compared to normal prostate epithelia, and that its expression is not affected by androgen treatment or steroid deprivation. Lentiviral-mediated knockdown of CYB561 in the NEPC cell line, PC-3, decreased the expression of genes involved in NE differentiation and labile iron pool storage, decreased cell proliferation, reduced cell survival in a colony formation assay, and slowed down cell migration in a wound-healing assay. Treatment of normal prostate epithelial cells, PNT1A, with conditioned media from CYB561 knockdown PC-3 cells led to a decrease in proliferation rate when compared to treatment of PNT1A cells with media from CYB561 expressing (control) PC-3 cells. Taken together, our findings demonstrate the role of CYB561 in supporting the growth and metastatic potential of NEPC cells, and highlights the potential use of CYB561 as a therapeutic target and biomarker that can be used to identify more aggressive disease.