bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-927 Ectopic Cushing Syndrome Due to a Metastatic Neuroendocrine Tumor to the Breast
Authors: Zhang Jian , Katznelson Laurence
Published: May 2020

Introduction:

We present a rare case of ectopic Cushing syndrome (CS) due to a neuroendocrine tumor (NET) metastatic to the breast.

Case:

A 38-year-old female was referred for ACTH-dependent CS. She had rapid development of cushingoid features and hypertension three months prior to presentation. A 24-hour urinary free cortisol (UFC) was elevated to 2548 μg (0-50 μg/24hr), and ACTH was 228 pg/mL (10-60 pg/mL). A pituitary MRI was normal, and inferior petrosal sinus sampling was not consistent with a central ACTH source. A DOTA-TATE scan showed mediastinal lymphadenopathy and a 0.8cm area of uptake in the right breast. The patient was placed on ketoconazole and UFC normalized. Following biopsy, she underwent breast lumpectomy at an outside hospital, and pathology showed triple negative invasive carcinoma of the breast. Chemotherapy was initiated.

However, her CS rapidly worsened: repeat UFC was 4867 μg, and ACTH was 369 pg/mL. Re-review of her pathology slides at our facility showed that the tumor stained negative for breast markers and positive for markers of NET and ACTH. Ki67 staining was approximately 30%. Chemotherapy for breast cancer was immediately stopped. A follow-up PET-CT continued to show uptake in the mediastinal lymph nodes. FNA of these lymph nodes revealed metastatic NET. In order to maximize control of her CS prior to chemotherapy, she underwent bilateral adrenalectomy (BLA). Afterwards, the patient received 10 cycles of chemotherapy with modified FOLFOX-7 for her NET. Thus far, the tumor burden appears stable, and she has been recommended to hold off on radiation therapy. She is currently taking replacement doses of hydrocortisone and fludrocortisone.

Conclusion:

In this challenging case, determination of source of ACTH hypersecretion led to an initial diagnosis of breast cancer. Primary breast carcinoma with neuroendocrine differentiation has been reported to show significant overlap in pathology with NET metastatic to the breast1. However, worsening of the CS in this case led to consideration of an alternative diagnosis, resulting in diagnosis of an ACTH producing NET metastatic to the breast. Prior to chemotherapy, she underwent BLA, which may lower morbidity and mortality associated with ACTH-dependent CS2, particularly given plan for further chemotherapy.

Reference:

1. Mohanty SK, Kim SA, DeLair DF, et al. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. Mod Pathol. 2016;29(8):788-798. doi:10.1038/modpathol.2016.69.2.

2. Morris LF, Harris RS, Milton DR, et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormone-dependent Cushing’s syndrome. Surgery. 2013;154(6):1174-1183; discussion 1183-1184.
SUN-119 Identification of Novel Mirnas Found to Be Differentially Expressed Between ATA Risk Stratification Groups in Papillary Thyroid Carcinoma
Authors: A Luisa Fernanda Olaya , Malek Joanne , Hookins Brodie , Joshi Tripti , Zara Watson , Gargya Ash , Gupta Ruta , Elliott Michael , Chua Elizabeth Lian , McLennan Susan
Published: May 2020

The study of miRNAs in PTC has shown that these molecules can help in the diagnosis, prognosis and also as therapeutic candidates [1]. miRNAs are known to be differentially expressed in PTC compared to non-cancerous tissue and a few studies have shown association with some clinico-pathological features. However, little is known regarding their expression in relation to risk of disease progression. In this study, we examined the expression of miRNAs in patients diagnosed with PTC in association with risk of disease recurrence and/or persistence.

Patients were classified by three endocrinologists to either high (H) or low (L) risk according to ATA Risk Stratification. PTC tissue was micro-dissected from Formalin Fixed Paraffin Embedded (FFPE) tissue for analysis. OPenArray analysis showed that 21 miRNAs were differentially expressed in H-L groups (n=4/grp). qRT-PCR was used to confirm these differences in a larger cohort of PTC (H=46; L=58). This comparison also included comparisons between cancer and normal tissue and investigation of miRNAs known to be differentially expressed (i.e miRNAs 222, 221 and 146b). All analysis was performed in Rstudio using ΔΔCt relative to expression of miR-16 which was not altered by PTC.

By qRT-PCR, only 3 of the 21 miRNAs identified by OpenArray analysis, were differentially expressed in H vs L risk (each P<0.05). These miRNAs are known to be involved in cancer progression pathways but have not been reported in PTC. Individual Receiver Operating Characteristic (ROC) curve analysis of these 3 miRNAs had AUC as follows (miR 1: 0.62, miR 2: 0.62, miR 3: 0.64,) and when analyzed together, the AUC model was improved (AUC=0.76). Examination of cancer vs normal tissue confirmed higher expression miR-146b, miR-221 and miR-222 (each P<0.05). However, these miRNAs were not differentially expressed when H vs L risk were analysed.

In this study, we identified 3 miRNAs with potential utility for the stratification of patients into those with H or L risk disease recurrence/persistence. As the current ATA 3-tiered system used is still a reflection of the continuum of risk that patients have, whether these 3 miRNAs may have the utility to further stratify those in the intermediate group remains to be investigated.

Reference: 1.

Ramírez-Moya, J. and P. Santisteban, miRNA-Directed Regulation of the Main Signaling Pathways in Thyroid Cancer. Frontiers in Endocrinology, 2019. 10: p. 430.
MON-512 The Anti-Cancer Agent, Homoharringtonine, Induces the Sodium Iodide Symporter (NIS) Gene Expression in Culture Cells from Papillary Thyroid Cancer, as Well as Non-Thyroid Cancers
Authors: Kato Kanako
Published: May 2020

BACKGROUND: The therapeutic effect of thyroid cancer by radioiodide treatment is dependent on enhancement of NIS expression by TSH, especially its much greater magnitude in target tissue(s) compared to other healthy tissues. We preliminarily found that a protein synthesis inhibitor cycloheximide (CHX) markedly enhanced NIS mRNA expression, followed by increased iodide uptake, in several cancer cell lines, though CHX is highly toxic for clinical use.

Aims: To evaluate the possibility of clinical application of such a pathway to enhance NIS expression, we tried another weak protein synthesis inhibitor, homoharringtonine (HHT), a natural plant alkaloid already utilized as an anti-leukemia agent, in several human cancer cell lines, including thyroid cancer.

Methods: BHP 2-7 papillary thyroid cancer cells, MCF7 breast cancer cells, and MKN gastric cancer cells were treated with HHT and/or a p38 inhibitor, and harvested for quantitative RT-PCR of NIS.

Results: HHT significantly induced the NIS mRNA expression in all of the cell lines tested, up to 298-fold in BHP cells, 38-fold in MCF7 cells, and 235-fold in MKN cells. Time course experiments indicated a biphasic induction of NIS in BHP cells with two peaks at 48 hours and 96 hours, with the EC50 of 664 ng/mL and 767 ng/mL, respectively. In contrast, NIS induction by HHT was monophasic in MCF7 cells at 24 hours with EC50 of 24.6 ng/mL, as well as MKN cells at 96 hours with EC50 of 255.7 ng/mL. Roles of p38 MAPK in the NIS induction has been reported previously, however, p38 inhibitors, SB239063 (10μM), as well as ML3403 (30μM), did not significantly reduce the NIS expression in HHT-treated BHP cells.

Conclusion: These results indicated that HHT has a potential to enhance NIS expression in some NIS-expressing cancer tissues, including papillary thyroid cancer, although its functionality and efficacy are to be validated. The heterogeneity of response in the NIS expression to HHT in three cell lines could be due to differential mechanisms of NIS gene regulation in different tissues.
MON-098 Risk of Long-Term Endocrine Sequelae in Survivors of Progressing Childhood Optic Pathway Glioma Treated by Upfront Chemotherapy: Preliminary Analyses of 102 Subjects from the French Multicentric BB-SFOP Registry
Authors: Hippolyte Helene , De Carli Emilie , Pellier Isabelle , Rialland Xavier , Coutant Regis
Published: May 2020

For the brain tumor committee of SFCE (Societe ́ Française des Cancers de l’Enfant). Objective: Therapeutic approach favors chemotherapy as the first-line-treatment in progressing OPG. There are few data on long term endocrine outcomes of aggressive OPG treated by upfront chemotherapy. Our main objective was to describe the long-term endocrine sequelae in these patients and to identify potential early predictors of the endocrine involvement. Subjects and methods: Children diagnosed with OPG at an age younger than 16 years from the French multicentric BBSFOP registry were included. They were treated with upfront chemotherapy according to the BB-SFOP protocol in France between June 1990 and December 2004, and subsequent treatment (second-line chemotherapy, surgery, radiotherapy) was used depending on tumor progression. They underwent a late evaluation with clinical and biological assessment between January 2011 and March 2016. Results: One hundred and two patients were included in our study. The mean age at tumor diagnosis was 3.3±0.3 years. The mean time of follow-up was 13.9±3.7 years. A history of precocious puberty was present in 36% of the subjects. At least one endocrine deficiency was present in 93% of the subjects (GHD 74%, TSH deficiency 57%, ACTH deficiency 36%, hypogonadotropism 33%, gonadic deficiency 30%, diabetes insipidus 15%; inappropriate AVP secretion 7%). 37% of males and 39% of females were overweight or obese. Mean adult height, reached in 51 subjects, was -1.2±1.3 SDS in males, and -0.7±1.4 SDS in females. Chemotherapy only was protective from pituitary deficiencies (odds ratio 0.19 to 0.37, P < 0.05). NF1 was protective from TSH and ACTH deficiencies (odds ratio 0.25 to 0.35, P < 0.05). Tumor volume on diagnostic MRI was not predictive of pituitary deficiencies. Gonadic deficiency was significantly more frequent in males than females (46,5% vs 12.2%, P < 0.05), and associated with chemotherapy only (OR 3.2, P < 0.05) and NF1 (OR 4.8, P < 0.05). Overweight/Obesity was associated with ACTH deficiency (OR 5, P < 0.05).Conclusion: Obesity and late endocrine dysfunction were frequent in subjects treated by upfront chemotherapy for aggressive OPG during childhood. However, chemotherapy only, when possible, was protective from pituitary involvement.
SAT-399 Baseline Characteristics from the Observational PARADIGHM Registry of Patients with Chronic Hypoparathyroidism
Authors: Clarke Bart L , Rejnmark Lars , Ing Steven W , Brandi Maria Luisa , Björnsdottir Sigridur , Hofbauer Lorenz C , Houillier Pascal , Khan Aliya A , Levine Michael A , Mannstadt Michael , Shoback Dolores M , Vokes Tamara J , Zhang Pinggao , Marelli Claudio , Germak John , Gittoes Neil
Published: May 2020

PARADIGHM is an actively recruiting, prospective, observational registry (NCT01922440/EUPAS16927). The primary objective is to evaluate the safety and effectiveness of recombinant human parathyroid hormone, rhPTH(1-84), treatment in patients with chronic hypoparathyroidism (HypoPT) under routine clinical care. The secondary objective is to characterize the clinical course of chronic HypoPT under conditions of routine clinical practice. At enrollment, registry inclusion criteria are patients having a HypoPT diagnosis >6 months and receiving conventional therapy (CT; eg, calcium supplements and active vitamin D), rhPTH(1-84) plus CT, or rhPTH(1-84). We present baseline characteristics of patients as of a June 30 2019 data cut. Baseline was defined as the value entered at the time of enrollment (Visit 1). Baseline symptom data exclude patients who initiated rhPTH(1-84) prior to enrollment (n=68) and are herein presented as two groups: those subsequently prescribed with rhPTH(1-84) after enrollment or those treated with CT. All data are summarized descriptively. Patient data from 64 centers in Europe and North America were analyzed. In the analysis population (n=737), 587 patients (79.6%) were female, 620 (84.1%) were white, and the mean (SD) age was 49.1 (16.45) years. The mean (SD) BMI was 19.3 (5.73) kg/m2 and 30.0 (7.72) kg/m2 in patients aged <18 (n=25) and ≥18 (n=587) years, respectively. The primary cause of HypoPT was thyroid surgery (n=547 [74.2%]; of these, 281 [60.0%] underwent surgery for thyroid cancer). Endocrinologists were the prescribing specialists for most patients (n=660 [89.6%]). Vitamin D and analogs were prescribed for 90.1% of patients (calcitriol, 74.2%, native vitamin D, 47.4%, alfacalcidol, 7.9%,), calcium for 81.0% (calcium carbonate, 57.9%, calcium citrate, 27.1%), and thyroid hormones for 71.2% (levothyroxine, 73.4%; liothyronine, 5.8%). Symptoms reported at enrollment for the rhPTH(1-84) (n=66) and the CT groups (n=603), respectively, included fatigue (53.0%, 39.3%), paresthesia (48.5%, 29.2%), muscle twitching (48.5%, 21.1%), muscle cramping (40.9%, 33.0%), headaches (33.3%, 17.6%), anxiety (28.8%, 20.1%), muscle pain (28.8%, 19.2%), tetany (28.8%, 12.1%), and brain fog (27.3%, 16.3%). The baseline data for the overall population appear to be representative of patients with chronic HypoPT. Baseline data suggest that at enrollment patients prescribed rhPTH(1-84) after enrollment appear to have an increased burden of disease than patients receiving CT based on symptoms. PARADIGHM will be a valuable resource of real-world longitudinal data for patients with chronic HypoPT.
MON-167 Use of a Morning Cortisol Level to Predict Recovery of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Secondary Adrenal Insufficiency Following Remission of Cushing’s Syndrome
Authors: McGlotten Raven , Nieman Lynnette K
Published: May 2020

BACKGROUND: Remission of Cushing’s syndrome (CS) is generally defined as morning serum cortisol values <5mcg/dL (<138 nmol/L) or Urine Free Cortisol <10-20ug/dL (< 28 – 56 nmol/d) after tumor resection, which reflects suppression of the hypothalamic-pituitary-adrenal (HPA) axis by sustained hypercortisolism. Endocrine Society guidelines recommend glucocorticoid replacement until the HPA axis is normal as assessed by a morning (AM) or post-ACTH stimulation test cortisol level of approximately 18 ug/dL (500 nmol/L) or greater (1). Patients with subnormal cortisol levels remain on glucocorticoid until retested in 3-6 months. The goal of this study was to determine whether a baseline cortisol value predicts a normal response to the ACTH stimulation test.

Methods: We reviewed 235 ACTH stimulation (stim) tests conducted on 76 patients with secondary adrenal insufficiency following remission of CS. Patients had resection of a single adrenal gland (n=7), pituitary adenoma [with (n=3) or without (n = 47) subsequent radiation], 70% of pituitary tissue (n=5), or ACTH secreting intrathoracic tumor (n=13). One had an ectopic ACTH secreting tumor in spontaneous remission (n=1). ACTH stim tests were conducted between 0800h and 0900h, 24 hours after the last dose of glucocorticoid, using 250 mcg of cosyntropin intravenously. Cortisol levels were measured just before administration of cosyntropin, and 30 and 60 minutes afterwards. Patients were considered to have passed the test if baseline or peak cortisol values reached > 18mcg/dL. Baseline cortisol values were compared to the ‘pass’ rate.

Results: Baseline F values (ug/dL) and passing rates (# pass/total) were:

<4: 1/91;

4-4.9: 2/27;

5-5.9: 8/31;

6-6.9: 2/21;

7-7.9: 7/25;

8-8.9: 4/12;

9-9.9: 8/12;

>10 - < 15: 6/11

15 – 19.5: 5/5

Thus, Am cortisol values >9 ug/dl were significantly more likely to predict a normal response to ACTH stim than lower values (p<0.0001). ACTH values (n=184) did not predict peak F levels. However, no patient with ACTH value <5 pg/ml passed the test; all had peak F values of 0-10.5.

Conclusion: Baseline cortisol can be a guide as to whether the more costly stimulation test is needed. In the small cohort with baseline 0800h – 0900h cortisol >15 ug/dL, all passed the test, suggesting that it is not needed in such patients. We recommend use of an ACTH stimulation test to assess recovery of the HPA axis when a morning cortisol reaches 9 mcg/dL, with an expected pass rate of about 66%.

Reference: 1. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100:2807, 2015.
SAT-734 HSD3B1 Expression in the Human Immune System
Authors: McManus Jeffrey M , Le Thi Hong Nga , Min Booki , Asosingh Kewal , Zein Joe , Erzurum Serpil , Sharifi Nima
Published: May 2020

3β-hydroxysteroid dehydrogenase-1 (3βHSD1), catalyzing conversion of dehydroepiandrosterone (DHEA) to Δ 4-androstenedione, is an essential enzyme in the pathway toward production of biologically active androgens such as dihydrotestosterone from the adrenally produced precursor DHEA sulfate, the most predominant steroid hormone in circulation. We previously identified, in the gene (HSD3B1) that encodes 3βHSD1, a germline gain-of-function missense-encoding variant that has now been validated in several studies as predicting more rapid progression in prostate cancer patients treated with gonadal testosterone deprivation. Production of androgens from adrenal precursors is important not just in the context of prostate cancer but in other physiologic and pathophysiologic processes, which could include asthma. Androgens are associated with better lung function in both asthma and healthy cohorts, and increasing circulating androgen levels in males help explain the switchover in asthma being more common in boys than girls but then more common in women than men. A main treatment for asthma, as well as other inflammatory processes, is administration of glucocorticoids, yet unresponsiveness to glucocorticoids in a subset of patients remains a major problem. Systemic glucocorticoid administration suppresses adrenally produced DHEA and DHEA-S, suggesting a depleted pool for biologically active androgen production as a mechanism for glucocorticoid resistance. Our surprising preliminary data support a link between glucocorticoid responsiveness and the more active HSD3B1 allele: patients homozygous for the adrenal-permissive HSD3B1(1245C) allele exhibit better response to oral glucocorticoids than those homozygous for the adrenal-restrictive HSD3B1(1245A), with heterozygous patients falling in the middle. This suggests a model in which patients with the more active (adrenal-permissive) form of 3βHSD1 produce sufficient androgens despite the depleted pool of precursor hormones whereas patients with the less active (adrenal-restrictive) form cannot. To further elucidate the link between 3βHSD1 activity and immune response, we assayed HSD3B1 expression in different types of white blood cells. Leukocyte subsets from asthma patients and healthy controls were purified using fluorescence-activated cell sorting, and HSD3B1 expression was analyzed using qPCR. White blood cells of several types expressed HSD3B1 at levels comparable to or greater than both prostate cancer and placental choriocarcinoma cell lines with very robust 3βHSD1 activity. Further determining the cell type specific expression and activity of this key enzyme is an important step in unraveling the link between the HSD3B1 polymorphism and asthma along with potentially many other immune processes.
SUN-160 Development of Adrenocortical Carcinoma in an Adrenal Nodule After Nine Years of Size Stability on Imaging: A Case for Critical Review of Efficacy of Radiographic Size Criteria
Authors: Tam Matthew , Sharma Sona
Published: May 2020

BACKGROUND: Current consensus guidelines for adrenal incidentalomas smaller than 4 cm recommend re-evaluation up to 2 years. Although there is no consensus for imaging surveillance beyond 2 years, in general, stability in size over time is considered a sign of benign nature.

Clinical Case: A 50-year-old African-American woman presented to Endocrinology for resistant hypertension since age 30 and an enlarging right adrenal nodule. She was obese, weighing 138.8 kg with a BMI of 55.97 kg/m2, without clinical Cushingoid features. At her first visit she was taking the following antihypertensives: amlodipine, losartan, hydrochlorothiazide, and clonidine patch. She took no other prescription medications. Her baseline metabolic blood profile was normal. Further testing revealed a profile consistent with possible primary hyperaldosteronism and subclinical Cushing’s syndrome: plasma aldosterone 17 ng/dl, plasma renin activity 0.232 ng/ml/hour, ACTH 10 pg/ml, AM cortisol 8.3 mcg/dl, DHEAS 30 mcg/dl, and 1mg dexamethasone suppression test resulted in cortisol of 7.6 mcg/dl (normal < 1.8 mcg /dl) with a simultaneous dexamethasone level of 357 ng/dl (140 – 295 ng/dl). However, 24-hour urinary free cortisol and urinary metanephrines were within reference ranges. Further confirmatory tests were not performed due to her imaging findings, as described below.

The earliest abdominal imaging was a CT abdomen with contrast in 2005 which measured a 2.1 cm right adrenal mass. For various reasons she had repeat CT contrast imaging in 2006, 2007, 2012, and 2014 demonstrating no changes in the dimensions of her adrenal nodule, noting all the studies were performed with contrast only and without Hounsfield unit (HU) measurements. In 2017, a CT abdomen with adrenal protocol demonstrated a right adrenal mass measuring 4 cm x 3.5 cm (increased from 2.1 X 1.2 cm in 2014), characterized by 43 HU pre-contrast, 71 HU post-contrast, and an absolute washout of 29%. Due to high suspicion for malignancy, a PET-CT was performed with FDG, which revealed high uptake in the right adrenal mass.

She was referred for a right adrenalectomy and pathology showed adrenocortical carcinoma with some infiltration into adipose tissue. There was a high mitotic index (42 per 50 high powered fields) and Ki67 of 35%, classified as Stage III pT3NxM0. She was referred to oncology and treated with external radiation to the adrenal bed along with initiation of mitotane.

Conclusion: This case infers that long-term size stability of an adrenal nodule does not confer full confidence of a benign process. Compared with previous reports in the literature describing long latencies for ACC, this is one of the longest records of size stability over 9 years followed by a size increase 3 years later.
SAT-402 Investigating Analogues of Parathyroid Hormone (PTH) and PTH-Related Peptide (PTHrP) to Improve Anabolic: Catabolic Response Ratios Using UMR106-01 Osteocytic Cells
Authors: Oladapo Oladipo Posi , Sugamori Kim S , Mitchell Jane
Published: May 2020

Osteoporosis, the most common bone disease in humans, is characterised by decreased bone mass and increased fracture risk1. Osteoporosis development is associated with an imbalance of bone resorption and deposition mediated by all three bone cell types; osteoblasts, osteocytes and osteoclasts2. Current treatments for osteoporosis either prevent further bone resorption (Bisphosphonates and anti-RANKL) or increase bone deposition through anabolism (Teriparatide and Abaloparatide)3. The two anabolic treatments are truncated analogues of endogenous peptides; parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), respectively. Both are administered intermittently, act on PTH1R receptors on osteoblasts and osteocytes leading to an increase in bone mineral density and bone strength. However, both treatments also have side-effects of hypercalcemia and cortical bone porosity caused by osteoclast stimulation. We therefore compared an array of PTH and PTHrP analogues for potential stimulation of catabolic side effects and desired anabolic effects. Screening assays used are UMR106-01 osteocytic cells that have high levels of PTH1R to measure mRNAs involved in anabolic responses (suppression of WNT inhibitors SOST and Dkk1) and catabolic responses (stimulation of RANKL/OPG, IL6). Peptides were also analysed by real-time cellular impedance assays (xCELLigence) to measure unbiased receptor stimulation. xCELLigence assays showed PTH1-34, PTHrP1-34 and Abaloparatide had the highest potencies (3.7 nM,1.4 nM,1.7nM respectively) while Tyr1PTH1-34 and PTH2-34 had significantly decreased potencies (64nM and 130nM), the β-arrestin biased agonist, D-Trp12Tyr34PTH7–34, had no effect. PTH1-34 potently inhibited SOST (IC50 0.29nM), and catabolic genes (RANK/OPG EC50 0.5nM, IL6 EC50 2.5nM). PTHrP1-34 provided higher potencies for anabolic (inhibited SOST IC50 0.08nM) and catabolic (RANKL/OPG EC50 0.3nM, IL6 EC50 1nM) genes. Altering the first amino acid to Tyrosine; Tyr1PTH1-34 caused potent anabolic responses (SOST IC50 0.97nM) yet showed decreased potency for catabolic responses (RANKL/OPG EC50 20nM, IL6 EC50 > 100nM). Removing the first amino acid of PTH to PTH2-34 drastically decreases the effectiveness of the peptide (OPG, SOST and RANKL IC50 – no effect, IL6 EC50 > 100nM). These results indicate the importance of the N-terminal amino acid for PTH affinity and efficacy and suggest that Tyr1PTH1-34 may offer the best combination of bone stimulation without causing hypercalcemia.

References

1 A.Gupta, L. March. (2016) Treating osteoporosis, Aust Prescr

2 Chen X, et al. (2018) Osteoblast–osteoclast interactions. Connect. Tissue Res

3 Tu KN, et al. (2018) Osteoporosis: A review of treatment options. P T
SAT-352 Severe Primary Hyperparathyroidism, Hypercalcemic Crisis, Acute Pancreatitis and Fatality: Complications of Atypical Parathyroid Adenoma, a Case Report
Authors: Hashem Sherin , Lin Grace , Vavinskaya Vera , Fadare Oluwole
Published: May 2020

BACKGROUND: Atypical parathyroid adenomas (APAs) are a controversial and rare entity. These tumors show some features of carcinomas including adherence to adjacent structures, banding fibrosis, mitotic activity, and tumor cells trapped within capsule; however, they lack definitive capsular, vascular, or perineural invasion. Patients are often asymptomatic, or have vague symptoms such as fatigue. Studies and literature have reported that the elevation in parathyroid hormone (PTH) and calcium levels in APAs are intermediate between those of adenomas and carcinomas, and that the clinical course is generally benign. Clinical Case: A 41-year old woman with diabetes mellitus, Hashimoto’s thyroiditis, and obesity was noted to have mild asymptomatic hypercalcemia during routine tests performed at an outside hospital several months prior to presentation. A few weeks prior to presentation, she started complaining of anorexia, nausea, vomiting and abdominal pain. At the time of presentation, she was critically-ill with a picture of severe acute pancreatitis. Laboratory tests showed hypercalcemia (13.9 mg/dL, normal 8.5-10.6 mg/dL) and elevated lipase (1134 U/L, normal 13-60 U/L); however, a magnetic resonance cholangiopancreatography showed no biliary obstruction. Further testing revealed markedly elevated PTH (>5000 pg/ml, normal 15-65 pg/ml), and subsequent neck ultrasound showed a solitary mass on the left side of the neck. Despite maximum medical treatment, the patient continued to rapidly decompensate and passed away rapidly. Autopsy examination revealed a picture of severe acute pancreatitis including a markedly enlarged necrotic pancreas (360 grams, normal: 60-100 grams), extensive omental fat necrosis, ascites, and dusky discoloration of the abdominal organs. A well-circumscribed mass (6.6 x 3.5 x 1.5 cm) was found on the superior aspect of the left thyroid lobe. The tumor showed parathyroid cell proliferation admixed with banding fibrosis, no unequivocal invasion into the surrounding capsule, blood vessels or perineural spaces, and no evidence of lymph node involvement or distant metastasis, consistent with a diagnosis of APA. Her cause of death was the left neck APA and its associated sequelae of significant hypercalcemia and acute pancreatitis. Conclusion: This patient had asymptomatic hypercalcemia for months prior to presentation with PTH/hypercalcemic crisis, highlighting the importance of ruling out primary hyperparathyroidism in the assessment of patients with asymptomatic hypercalcemia. While it’s generally appreciated that parathyroid carcinomas usually cause more profound hypercalcemia and are more likely to cause fatality from metabolic complications, and that APAs follow a generally more benign course, this case shows that APAs can grow into significantly large lesions and could follow a severe and abrupt clinical course if not surgically removed.
SAT-604 The Role of the Focal Adhesion Kinase Family in Leptin Receptor Signaling
Authors: Hadley Colleen , Cakir Isin , Cone Roger D
Published: May 2020

Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modulate food intake and energy expenditure. As such, neurons within the hypothalamus expressing the long isoform of leptin receptor (LepRb), a type I cytokine receptor, are primarily responsible for mediating the effects of leptin, which signal predominantly through the JAK2-STAT3 transduction mechanism. STAT3 is a latent transcription factor activated upon phosphorylation, which triggers its homodimerization and nuclear translocation. Evidence, however, for JAK2-independent, STAT3-dependent leptin receptor signaling mechanisms exist. FAK (focal adhesion kinase, Ptk2) and Pyk2 (protein tyrosine kinase 2b, Ptk2b) are a subset of nonreceptor protein tyrosine kinases and comprise the focal adhesion kinase family. FAK and Pyk2 are implicated in the regulation of cytokine receptor signaling. Furthermore, Pyk2 knockout mice have an obesity prone phenotype. Here, we studied the role of the focal adhesion kinases in leptin receptor signaling using genetic and pharmacological approaches. We found that overexpression of Pyk2 or FAK increased STAT3 phosphorylation (activation). Overexpression of a FAK or Pyk2 construct with impaired kinase activity, however, attenuated STAT3 phosphorylation, suggesting the increase in STAT3 phosphorylation is largely dependent upon kinase activity of FAK/Pyk2. Treatment of cells with a small molecule dual inhibitor of FAK and Pyk2 (PF431396) attenuated leptin-induced STAT3 phosphorylation in a mouse hypothalamic cell line. Importantly, this effect is independent of JAK2, as PF treatment of two independent JAK2-deficient cell lines exhibited similar attenuation of leptin-induced STAT3 phosphorylation. To assess the physiological relevance of FAK/Pyk2 in leptin receptor signaling in vivo, we administered PF compound to the lateral ventricle of 24-hour fasted lean wild-type mice followed by peripheral leptin administration. Intracerebroventricular (ICV) administration of PF suppressed the anorectic effect of leptin as evidenced by impaired inhibition of food intake upon refeeding. Accordingly, analysis of total hypothalamic lysates from these mice showed ICV PF impaired leptin-induced STAT3 phosphorylation. Taken together, these data suggest that Pyk2 and/or FAK play a role in leptin signal transduction.
MON-164 Determinants of Quality of Life in Primary and Secondary Adrenal Insufficiency from Two Large Tertiary Care Centers in the United States
Authors: Li Dingfeng , Genere Natalia , Xhikola Majlinda , Behnken Emma , Abbondanza Tiffany , Vaidya Anand , Bancos Irina
Published: May 2020

Background: Patients with primary adrenal insufficiency (PAI) and secondary adrenal insufficiency (SAI) report impaired quality of life. Predictors of adverse outcomes include duration of disease, supraphysiologic glucocorticoid (GC) use, and presence of other comorbidities. There is limited evidence to suggest that quality of life is disproportionately affected in one subtype of adrenal insufficiency.

Objective: To identify determinants of quality of life in patients with PAI vs SAI.

Method: Survey study of patients with the diagnosis of AI between 2015 and 2019 was evaluated at two large tertiary medical centers in the United States. Collected variables included data on circumstances of AI diagnosis, symptoms, management, burden of disease, and overall well-being. Patients with AI due to exogenous glucocorticoid use were excluded.

Results: Patients with PAI (n=310, 65% women) were diagnosed at a younger age (37 ± 19 vs 48 ± 16 years, p<.01) than patients with SAI (n=255, 57% women). Patients with SAI were more likely not to understand their diagnosis (13% vs 4% in PAI, p<.01), or to report a discordant diagnosis (16% vs 9% in PAI, p=.02). Patients with PAI were on a higher dose of daily GC (23.8 mg vs 18.5 mg hydrocortisone (HC) equivalent, p <.01), with higher number of patients on HC> 25 mg/day (33% vs 15%, p<.01). Patients with PAI reported a higher compliance with wearing medical alert ID (79% vs 64%, p=.01) and higher availability of injectable GC (74% vs 58%, p<.01). Patients with PAI reported a higher frequency of at least one adrenal crisis within the last 12 months that required self- injectable GC (32% vs 16%, p<.01), or prompted ER visits (56% vs 29%, p<.01) compared to those with SAI. Nevertheless, patients with PAI were more likely to report good general health (78% vs 65% in SAI, p<.01). When adjusted for current age, sex, duration of disease, supraphysiologic GC use, number of current symptoms and recent adrenal crises, patients with SAI had HR of 2.6 (CI 95% 1.5-4.3) for poor health, 1.6 (CI 95% 0.95-2.8) for physical limitations, 1.7 (CI 95% 1.1-2.7) for fatigue, and 2.7 (CI 95% 1.5-4.9) for social limitations compared to those with PAI.

Conclusions: Patients with PAI receive higher daily GC and experience a higher number of adrenal crises when compared to patients with SAI. However, patients with PAI report a better general perception of health, possibly due to a more robust knowledge of their disease and higher comfort level managing AI. More effort is needed to ensure patients with AI are appropriately educated regarding their medical condition and therapy.
SUN-276 Pembrolizumab-Induced Secondary Adrenal Insufficiency Presenting as Severe Hyponatremia in an 80-Year-Old Male
Authors: Kawaji Leslie Daphne R , Villanueva Mary Grace M , Villa Michael L
Published: May 2020

Background

Pembrolizumab is an anti-programmed death 1 (PD-1) antibody designed to incite an immune response against malignant cells. By virtue of this mechanism of action, its use has given rise to immune-related adverse events including those affecting the endocrine system. Adrenal insufficiency can occur rarely with anti-PD-1 therapy, and symptoms are usually non-specific.

Clinical Case

An 80-year-old male, known case of non-small cell lung cancer stage IV presented with a 2-week history of progressive body weakness with anorexia, shortness of breath and low-grade fever. He had just received the 4th cycle of pembrolizumab prior to the onset of symptoms. Past medical history was significant for hypertension and type 2 diabetes mellitus which were both controlled, and pulmonary tuberculosis with completed treatment.

On physical examination, he was drowsy but oriented. He was normotensive (110/70 mmHg) and tachypneic (28 cpm) with rales on both lung fields. Baseline capillary glucose level was 107 mg/dL. Chest radiograph showed hazy opacities in the right upper to middle region. Blood chemistry revealed severe hyponatremia (114 mmol/L, NV 135-145 mmol/L) and low serum osmolality (247 mOsm/kg, NV 280-300 mOsm/kg). Random (taken 1230H) ACTH and cortisol were <5.00 pg/mL (NV <46 pg/mL) and 2.00 μg/dL (NV 4.30-22.40 μg/dL), respectively. Such levels were judged to be low in the background of an acute illness. Thyroid function tests were normal – TSH 0.993 μIU/mL (NV 0.55-4.78 uIU/mL), FT3 3.890 pg/mL (2.30-4.20 pg/mL), FT4 1.450 ng/dL (0.89-1.76 ng/dL). Magnetic resonance imaging of the pituitary gland did not show abnormal parenchymal enhancement or enlargement.

Pembrolizumab-induced secondary adrenal insufficiency was the most probable cause of the hyponatremia. He was started on IV hydrocortisone, as well as piperacillin-tazobactam for pneumonia. Oxygen support via nasal cannula was given. Feeding via nasogastric tube was decided to ensure nutrition and prevent aspiration. He was transferred to the intensive care unit for careful monitoring. Serum sodium level was corrected gradually, with marked clinical improvement thereafter. Within 48 hours, he was transferred to regular room and oral feeding commenced. Hydrocortisone was shifted to prednisone on discharge, with steroid tapering schedule and close follow-up with endocrinologist advised.

Conclusion

We presented a case of secondary adrenal insufficiency which likely resulted from hypophysitis induced by pembrolizumab. Hypophysitis following anti-PD1 treatment occurs in <1% of patients on immunotherapy. In such cases, ACTH deficiency is usually isolated and pituitary imaging is frequently normal. Since more patients are being placed on immune-checkpoint inhibition, clinicians should be vigilant for these adverse events, particularly the endocrinopathies which may have non-specific symptoms and may be irreversible.
MON-619 Predictors of Complications with Fasting the Holy Month of Ramadan in Patients with Diabetes
Authors: Al Qarni Ali Ahmed , Alamoudi Reem Mohammad , Al-Aidarous Salwa , Alshahrani Awad Saad , Abuhelalah Munir , Ahmed Gasmelseed
Published: May 2020

Background: For a whole month, every year Muslims fast daily from dawn to sunset. Those with health conditions that put them at risk are exempted from fasting, yet most of patients with diabetes choose to fast. Clinical and metabolic complications of diabetes during this month are issues of concern for patients and their managing physicians. This study is designed to evaluate the impact of fasting Ramadan on safety of patients.

Methods: A multicentercross-sectional survey was conducted in four hospitals under the Ministry of National Guard Health Affairs; King Abdulaziz Hospital,Al-Ahsa, Imam Abdulrahman bin Faisal Hospital, Dammam, King Abdulaziz Medicalcities, Riyadh and Jeddah. All patients with diabetes followed in the diabetes clinics of all four centers who fulfilled the study inclusion and exclusion criteria were approached within three months post Ramadan and consented for participation in the survey, then filled a self-administered validated questionnaire that consisted of 15 items.

Results: Socio-demographic,clinical, and laboratory characteristics of 1438 patients with diabetes were analyzed. The majority 1207 (83.9%) had type II diabetes, and 828 (57.6%) were females.The mean age was 57.9 ± 14.9 years, and mean BMI 25.25 ± 5.39.The majority 1060 (73.7%) had concomitant diseases. 36 (2.5%)were on diet therapy alone, 147 (10.2%) on metformin monotherapy, and 261 (18.2%) on insulin therapy alone. The remaining 994 (69.1%) were on combination of insulin and oral agents. Health education was received on average by 688 (57.8%) of patients. Out of the 1191 (82.8%) who fasted the full month, 497 (41.7%) experienced acute glycemic complications. Multivariate analyses revealed that significant predictors for unsafe fasting were: type I diabetes [OR 1.8 (95%CI 1.2 - 2.8), p-value 0.007], insulin therapy [OR 1.8 (95% CI 1.4 - 2.3), p-value0.0001], previous history of breaking fast for glycemic reasons [OR 2.1 (95% CI1.5 - 2.9), p-value 0.0001], and not receiving health education [OR 1.6 (95% CI1.2 - 2.0), p-value 0.0006]. Blood sugar control, presence of concomitant diseases, and history of diabetes related hospitalization were not statistically significant predictors [(OR 1.25, 95% CI, 0.9 - 1.7, p-value 0.15),(1.3, 95% CI, 0.9 - 1.8, p-value 0.14), (1.1, 95% CI, 0.8 - 1.6, p-value 0.45)] respectively.

Conclusion: A significant proportion of patients with diabetes do not receive specific education pertinent to fasting Ramadan. Lack of health education, in addition to; type I diabetes, insulin therapy, and previous experience of complications are predictors for unsafe fasting. This highlights the need for better structured educational programs and further research in the field.
SAT-146 A Rare Combination of Severe Ectopic Cushing’s Syndrome and Graves Hyperthyroidism: A Case Report
Authors: Violago Janelle , Hasan Farhad
Published: May 2020

BACKGROUND: Ectopic ACTH secretion (EAS) is a rare cause of Cushing’s syndrome. Olfactory neuroblastoma (ONB) is a malignant tumor derived from the olfactory epithelium and can rarely be a source of ectopic hormone production. There are only 19 reported cases of EAS from ONB. We report a case of severe ectopic Cushing’s due to ONB. Interestingly, the patient also presented with Graves disease, which is an unusual pathophysiologic combination since supraphysiologic levels of glucocorticoids suppress the immune system, thereby ameliorating autoimmune processes. Remarkably, Graves disease improved following the removal of the source of ectopic ACTH. CASE PRESENTATION: A 41year old male presented with epistaxis, anosmia, and headaches. He also reported recent weight gain, muscle weakness, and new onset hypertension. Cross-sectional imaging revealed a right nasal cavity mass with intracranial extension. Endonasal biopsy was consistent with a diagnosis of ONB. Biochemical evaluation demonstrated hypokalemic alkalosis, hyperglycemia, and severe hypercortisolism [ACTH 734 (9-46 pg/ml), am cortisol 110 (2-15 ug/ml), late night salivary cortisol 9.8 and 22.53 (<0.09 ug/dl), 24 hour UFC 41,337.3 (4-50 mcg) and non-suppressed cortisol 110 (1.8 mcg/dl) by 1 mg dexamethasone]. Pituitary MRI showed no sellar pathology. Following a period of cortisol suppression with Ketoconazole then with Etomidate infusion, the patient underwent resection of the ONB, followed by chemo- and radiotherapy, which resulted in improvement of severe hypercortisolism. Histopathology showed positive ACTH immunostaining. Pre-operative evaluation also demonstrated hyperthyroidism: TSH <0.010 (0.3-5uIu/ml), FT4 3.11 (0.89-1.76 ng/dl), normal TT3 0.81 (0.6-1.81 ng/ml). Thyroid auto-antibodies were negative; however, radioiodine scan and uptake demonstrated diffusely increased uptake in the enlarged thyroid gland. Pre-operative euthyroidism was achieved with a combination of methimazole, SSKI and cholestyramine. After 6 months of methimazole therapy the patient presented with hypothyroidism (TSH 72.37, FT4 0.1). Methimazole was discontinued and he achieved euthyroidism on subsequent evaluations. CONCLUSION: EAS due to ONB is a very rare cause of Cushing’s syndrome. To our knowledge, this is the first reported case of a male presenting with EAS and concurrent Graves hyperthyroidism. An extensive review of the literature and seeking expert opinion did not provide a convincing pathophysiologic explanation to this unusual concurrence. We therefore hypothesize that, while the two endocrine conditions were simultaneous, they were likely unrelated.
SAT-405 Trabecular Bone Score (TBS) in Primary Hyperparathyroidism (PHP): A Useful Tool?
Authors: Santos Lívia Marcela , Ohe Monique Nakayama , Pallone Sthefanie Giovanna , Kunii Ilda Sizue , Silva Renata Elen Costa , Sakane Eliane Naomi , Vieira Jose Gilberto , Lazaretti-Castro Marise
Published: May 2020

Background: PHP is a common disorder, and regardless of being an asymptomatic entity, often leads to bone loss and osteoporosis. TBS is a software-based assessment method of trabecular bone structure of the spine based on the analysis of pixels in dual energy x-ray absorptiometry (DXA) images. The aim of this study was to evaluate TBS measurements in combination with DXA values by searching for more accurate bone fragility risk assessment among PHP patients.

Methods: From June/2017 to January/2019, all patients who met the criteria for PHP diagnosis prior to surgery were selected to take part in this study. Control group was composed by non-family related healthy volunteers. Bone mineral density (BMD) by DXA (DXA; Hologic QDR 4500) at the lumbar spine, total hip, femoral neck, distal third of the non-dominant radius and TBS values by InSight were determined in 64 PHP patients and 63 controls. Total and ionized calcium, PTH, 25-hydroxyvitamin D (25(OH)D), creatinine, alkaline phosphatase, P1NP and CTX were measured in all patients and control group.

Results: Primary hyperparathyroidism patients presented significant lower BMD values in all evaluated sites compared to controls. TBS measurements were also statistically different among PHP patients and controls (mean TBS PHP=1233 vs TBS controls= 1280, p=0.044). Patients and controls didn’t differ in age, sex, menopausal state or BMI (body mass index). Osteoporosis diagnosis by DXA analysis was observed in 50% of PHP patients and in 26.6% of controls. Self-reported or image-diagnosed fracture occurred in 15 PHP (23.4%) patients and in 11 (17.5%) controls. Among these fractures, vertebral fracture account for 9 (14%) in PHP group and 4 (6.3%) in controls. ROC curve analysis showed that the TBS value < 1187 is associated to significant high risk of vertebral fracture (sensibility 87.5%, specificity 67.3%) among PHP patients.

Conclusion: TBS, used as a complement to DXA measurements, is a useful tool to better assess fragility risk among PHP patients.
MON-003 Uterine Contractility in Pregnancies Complicated by Obesity: The Effects of Adipokines on the in Vitro Functional Contractility of Isolated Uterine Samples
Authors: Mustafa Hiba J , Upchurch Weston , Vogel Rachel , Iaizzo Paul , Lisa Gill
Published: May 2020

Objectives: The onset of parturition in pregnant women with obesity is frequently delayed. Without induction, these women are nearly twice as likely as normal-weight to have prolonged pregnancy (≥41 weeks gestation) which is concerning because of associated two-fold increased risk of third-trimester stillbirth. Data from vascular studies have shown that different adipokines have different effects on smooth muscle contractility; either as relaxants or constrictors. However, only few studies have investigated their role in uterine contractility, a relationship that we sought to investigate. Materials and Methods: Total of 22 pregnant women scheduled for term cesarean delivery (CD) were recruited. Strips from the first two participants were used to identify dose response effects for each adipokine, and 20 participants’ data were included in the final analysis. Study groups consisted of normal-weight (N=10) and women with obesity (N=10). Myometrial strips were obtained from the hysterotomy incision at the time of the CD. Muscle strips were mounted within experimental recording baths. Both spontaneous and oxytocin induced contractions were recorded by a custom-build data acquisition software. Adipokines of interest included adiponectin, TNFα, resistin, and omentin. Adipokines were added to the muscle baths after muscle equilibration was achieved. Contractions outcomes of interest included forces, durations, and frequencies. Data comparisons were conducted using Wilcoxon Rank-Sum tests; medians and ranges are presented. Results: Forces of contractions in normal-weight participants were double those studied from participants with obesity (13.9 [9.3-34.3] vs. 8.9 [4.8-23.6], p=0.05). There were no statistically significant differences between contractility outcomes of interest after adding adiponectin, TNFα, and resistin to the muscle baths within and between the study groups. In participants with obesity, compared to baseline, omentin significantly reduced the force of spontaneous induced contractions (p=0.002) and prolonged the period between contractions (p=0.01). Importantly, that effect was not seen in normal-weight participants or in oxytocin induced contractions. Omentin also significantly reduced the forces of spontaneous induced contractions (2.9 [2.2-4.6] vs. 14.4 [4.8-33.6]; p=0.01) and prolonged the period (790.6 [753.0-832.0] vs. 611.4 [128.3-702.7]; p=0.04) in participants with obesity compared to normal-weight participants. Differences were no longer observed after adding oxytocin. Conclusion: In vitro, uterine contractions were reduced in muscle samples prepared from pregnant women with obesity compared to normal-weight counterparts. Omentin may have a role in reduced uterine contractility in pregnant women with obesity and that effect may be corrected by oxytocin administration.