bluuebunny/crossref_metadata_2025_split huggingface dataset:
MON-201 Effects of Incretins on Catecholamine Synthesis by Rat Pheochromocytoma PC12 Cells
Authors: Komatsubara Motoshi , Fujisawa Satoshi , Nada Takahiro , Iwata Nahoko , Otsuka Fumio 
Published: May 2020

Abstract
Incretins, such as gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are metabolic hormones secreted from the intestine to stimulate insulin secretion from the pancreatic β cells. Dipeptidyl peptidase-4 (DPP-4) inhibitors, as anti-diabetic agents, increase the bioavailability of both GIP and GLP-1. Since the receptor expressions of GIP and GLP-1 are detected in various organs, incretins have been suggested to affect many kinds of tissues and organs in addition to their insulinotropic effects. For instance, GIP and GLP-1 have been reported to regulate ovarian steroidogenesis and hypothalamic-pituitary-adrenal axis including secretions of adrenocorticotropin from the pituitary and cortisol from the adrenal cortex. However, the roles of GIP and GLP-1 in the adrenal medulla have not been recognized. Here we focused on the activity of bone morphogenetic protein (BMP)-4, which is expressed in the adrenal medulla and is functionally involved in the control of catecholamine synthesis. We earlier reported that BMP-4 treatment decreased catecholamine synthesis via smad1/5/9 phosphorylation and regulated catecholamine synthesis by cooperating with glucocorticoid and melatonin in rat pheochromocytoma PC12 cells. In the present study, roles of GIP and GLP-1 in the regulation of catecholamine production were studied using PC12 cells by focusing on interaction with BMP-4 and adrenocortical steroids. Both of GIP receptor and GLP-1 receptor expressions were detected in PC12 cells. Of note, treatments with GIP, but not with GLP-1, increased dopamine synthesis and the mRNA levels of catecholamine synthetic enzymes including tyrosine hydroxylase (TH), which is a rate-limiting enzyme for catecholamine synthesis, DOPA decarboxylase (DDC), and dopamine β-hydroxylase (DBH), by PC12 cells. Treatments with GIP enhanced glucocorticoid- and aldosterone-induced TH mRNA levels by upregulating the expressions of glucocorticoid receptor (GR) as well as mineralocorticoid receptor (MR). However, treatment with GLP-1 had no effect on corticosteroid-induced TH mRNA levels or GR/MR expression. On the other hand, treatment with GIP attenuated the inhibitory effect of BMP-4 that enables to decrease TH mRNA levels by suppressing BMP-induced Smad1/5/9 phosphorylation and Id-1 transcription. Furthermore, GIP treatment upregulated the expression of inhibitory Smad7, possibly leading to the suppression of BMP-4 signaling by PC12 cells. Collectively, it was revealed that incretins, in particular, GIP has an inducing effect on catecholamine synthesis through inhibiting BMP activities as well as enhancing corticosteroid actions in adrenomedullar cells.
SUN-693 What Else Should Be Done in Patients with Uncontrolled Type 2 Diabetes and Severe Insulin Allergy?
Authors: Elshimy Ghada , Correa Ricardo Rafael , Techathaveewat Pawarid , Vinales Karyne Lima , Harman Sherman Mitchell 
Published: May 2020

Abstract
Introduction: Insulin allergy in patients with diabetes mellitus is a very rare condition. The immediate vital implications for the patient call for prompt diagnosis and management of insulin allergy. We present a case of a patient that was unable to tolerate the insulin desensitization process, however; he was successfully treated with antidiabetics’ medications following the AACE guidelines for the management of type 2 diabetes (T2DM).Case description:31 years old obese Caucasian male with a BMI of 35, a history of T2DM and insulin allergy who was admitted to the hospital with hyperglycemia and osteomyelitis of the right foot. Endocrinology was consulted for the management of diabetes. Laboratory results showed hemoglobin A1C 11.1%, C peptide level 2.79 with blood glucose 283 mg/dl with negative insulin specific IgG level and elevated Ig E levels. The patient was actually diagnosed with T2DM in 2001, then started on metformin, glyburide initially. Given uncontrolled diabetes he was started on insulin in 2007 however, he developed an allergic reaction to different types of insulin (including anaphylactic reaction) so he was referred to allergy and immunology for further testing and possible desensitization. He had an allergy to human, bovine and porcine insulin. Exclusion of other causes of allergy including latex, protamine, and zinc was performed by the immunologist. Trial of insulin desensitization (using NPH and regular Insulin) failed. He also developed an allergic reaction to different medications including sulfonylurea, SGLT2 inhibitors, DDP4 inhibitors, and alpha-glucosidase inhibitors. During the inpatient setting in 2019, we assessed the patient and considered different options available; bromocriptine versus amylin products versus fish insulin versus IGF1 (as of last resort). Other options were another desensitization process in the ICU setting with transitioning to an insulin pump, however, the patient refused that option. We started the patient on bromocriptine mesylate(cyclocet) with pioglitazone and the A1C improved in the next 3 months from 11.1%--&gt;9.8%. The patient is still following up with us and plans for desensitization once the osteomyelitis of the foot is controlled. Discussion and conclusion: Insulin allergy is a rare but severe condition that calls for immediate work-up. It can be managed well in close cooperation between the endocrinologist and the immunologist. Our patient developed IgE-mediated symptoms occurring immediately after insulin injection and confirmed by intradermal skin testing. Specific immunotherapy has been reported in case reports in the literature and should be considered for these patients Following AACE guidelines for the management of T2DM with the addition of bromocriptine mesylate until desensitization was a beneficial option for our patient.
SUN-621 Body Weight and Body Composition in Patients with Chronic Pancreatitis Are Associated with Islet Function After Total Pancreatectomy and Islet Cell Transplantation
Authors: Harindhanavudhi Tasma , Yang Yi , Hodges Jim , Bellin Melena Dawn 
Published: May 2020

Abstract
Background: Total pancreatectomy with islet autotransplant (TPIAT) is done in patients with chronic pancreatitis to treat intractable pain. In TPIAT, islets are isolated after pancreatectomy and infused into the liver via the portal vein to mitigate post-operative diabetes. Outcomes vary, with ≥60% needing exogenous insulin supplementation to maintain normoglycemia. The current study’s aim was to determine if pre-surgical body composition is associated with islet function and insulin sensitivity after TPIAT.
Methods: We characterized body weight and composition as related to insulin sensitivity and dependence and diabetes outcome in 88 adults who underwent TPIAT for chronic pancreatitis at the University of Minnesota. At baseline, 12 and 18 months after TPIAT, insulin independence was assessed; metabolic testing used mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Body composition was measured by Dual X-ray absorptiometry (DXA). Statistical analyses used linear and logistic regression.
Results: At baseline, mean age was 39.9 (SD 11.1) years. 9.1% were underweight (BMI&lt;18.5 kg/m2), 45.5% normal weight (BMI=18.5–24.9), 22.7% overweight (BMI=25–29.9) and 22.7% obese (BMI≥30). Islet equivalent per kg did not differ between body weight categories (p=0.17). Overweight/obese patients had higher peak and AUC c-peptide and lower insulin sensitivity index, as expected. Compared to baseline, android to gynoid fat ratio was lower at 12 (0.80 vs 0.88; p=0.012) and 18 months (0.81 vs 0.88; p=0.041), and lean mass was lower at 18 months (38848 vs 42338 kg; p=0.029). Baseline body weight was positively associated with acute insulin response to glucose (AIRg) at 12 months (effect size 38.5, SE 17.1 mU/L/min; p=0.029) and 18 months (38.3, SE 18.5 mU/L/min; p=0.045), while baseline lean mass was inversely associated with AIRg at 12 (p=0.01) and 18 months (p=0.033). Baseline body weight was positively associated, and fat mass inversely associated with disposition index (Di; islets’ ability to secrete insulin normalized to insulin resistance) at 18 months (p=0.019 for both).
Percent body fat and percent gynoid fat predicted Sg (glucose effectiveness index, i.e., ability of glucose to promote its own disposal and inhibit hepatic glucose production absent an incremental insulin effect) at 18 months (p=0.042 and p=0.019, respectively). Insulin independence at 12 and 18 months was not significantly associated with baseline body weight or body composition.
Conclusions: Overweight/obesity is common in patients with chronic pancreatitis. After TPIAT, patients had lower muscle mass and A/G ratio. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT surgery.
SAT-154 Clinical Presentations and Outcomes of Adrenal Metastases Vary Based on Etiology
Authors: Mao Jimmy , Bancos Irina 
Published: May 2020

Abstract
Background: Adrenal metastases occur in 1–8% of patients with an adrenal mass. Recognizing patterns in the presentation of adrenal metastases is critical in dictating management.
Objective: To describe the presentation of patients with adrenal metastases and identify baseline characteristics predicting the etiology.
Methods: A retrospective analysis of adult patients diagnosed with adrenal metastases between 2000–2019 at a single institution tertiary center was performed. Partial cohort analysis is presented.
Results: In 327 patients (127 (39%) women, median age at diagnosis of 67 years (range 25–92)), median tumor size was 2.7 cm (range 0.5–15), and 99 (30%) had bilateral tumors. While most patients (188, 57%) were found to have an adrenal mass during cancer staging, 117 (36%) were found incidentally and 22 (7%) based on symptoms. Adrenal metastases originated from the lung (118, 36%), genitourinary (GU) (100, 31%), gastrointestinal (GI) (47, 14%), and other (43, 13%) organ systems. Unknown primary malignancies were diagnosed in 19 (5.8%) patients.
Male predominance was observed in GU (72%) and lung (62%) metastases, but equal gender distributions were noted for all other metastases, p=0.01. Patients with GI and lung metastases were diagnosed with smaller tumors (median 2.1 and 2.6 cm, respectively) compared to those with GU (median 3.5 cm) and other (median 4 cm) metastases, p=0.0008. Bilateral metastases were more frequently found in patients with lung (37%) and other (38%) metastases compared to those with GI (17%) and GU (24%) metastases, p=0.01. Of 99 (30%) patients with bilateral metastases, 23% developed primary adrenal insufficiency (PAI), most commonly in those with lung (36%) and GU (30%) malignancies.
Only 123 (38%) patients were evaluated by an endocrinologist. Pheochromocytoma work-up was more often pursued if seen by an endocrinologist (71% vs. 15%, p&lt;0.0001) in 118 (36%) patients. Adrenalectomy was performed in 94 (29%) patients, most frequently in those with GU metastases (57%), compared to only 10% of those with lung metastases.
Patients were followed for a median time of 14 months (range 0.1–181), and 222 (68%) died. GU metastases carried the best prognosis with a mortality rate (MR) of 43%, as opposed to a MR of &gt;70% in all other metastases, with lung metastases carrying the worst prognosis (MR of 85%). Multivariate analysis revealed that mortality was associated with increasing age (OR 1.3 (95% CI 1.04–1.6) for each decade) and metastasis subgroup (lung vs. GU: OR 7.2 (95% CI 3.7–14)).
Conclusion: Adrenal metastases most commonly originated from lung, GU and GI malignancies, with a third of patients discovered incidentally. Bilateral metastases occurred in 30% of patients, where 1 in 4 developed PAI. Only a minority were evaluated by an endocrinologist or had work up for pheochromocytoma. Mortality was highest in those with adrenal metastases originating from the lung.
SAT-416 Novel Autoantibodies for Thyroid-Specific Transcriptional Factors in Patients with Immune-Related Adverse Events Involving the Thyroid Gland
Authors: Yamauchi Ichiro , Yasoda Akihiro , Yamashita Takafumi , Ueda Yohei , Fujii Toshihito , Taura Daisuke , Sone Masakatsu , Inagaki Nobuya 
Published: May 2020

Abstract
Background: Immune-related adverse events by immune checkpoint inhibitors often involve several endocrine-related organs. PD-1 pathway blockade therapy by anti-PD-1 antibodies including nivolumab frequently causes thyroid dysfunction (thyroid irAE). Thyroid irAE seems to be distinctive compared to conventional painless thyroiditis in terms of a clinical course: transient thyrotoxicosis and subsequent persistent hypothyroidism [1]. Our retrospective cohort study regarding nivolumab provided several suggestions [2]. The thyroid irAE (+) group had a longer median overall survival than the thyroid irAE (−) group in patients with lung cancer, but this observation was not seen in patients with malignant melanoma: In addition, 5 of 17 patients tested at the point of thyroid dysfunction development were double negative for TPOAbs and TgAbs, known thyroid autoantibodies. From these findings, we set a hypothesis that antibodies for unknown antigens mediate prognostic effects of thyroid irAEs if tumor tissues express the same antigens. Methods: We performed co-immunoprecipitation using Protein G beads, sera of three patients with thyroid irAEs, and lysates of HEK293T cells overexpressing candidate proteins tagged with FLAG and HiBit (NKX2-1, PAX8, FOXE1, and HHEX). The pellets were analyzed by western blot. Results: FOXE1 bands were augmented in patient 1 with lung cancer, a PAX8 band in patient 2 with malignant melanoma, and bands of FOXE1, PAX8, and HHEX in patient 3 with renal cell carcinoma, compared to a control sample of a normal subject. We performed subcutaneous injections of purified IgG fraction from the serum of patient 3 to C57BL/6 mice every 2 weeks. The mice were sacrificed after 4 weeks, but no significant changes were observed in their thyroid glands and thyroid function. Conclusions: We identified novel autoantibodies for FOXE1, PAX8, and HHEX, thyroid-specific transcriptional factors. In our experiments, the pathogenicity of antibodies were not suggested. Considering our previous observation that the thyroid gland expresses both PD-L1 and PD-L2, ligands of PD-1 receptor [1], PD-1 pathway blockade may particularly disrupt immune tolerance of the thyroid gland, resulting in autoantibody production. Because thyroid irAEs have been revealed to be a prognostic factor, these novel autoantibodies are candidate biomarkers for PD-1 pathway blockade therapy. References: 1. Yamauchi et al. Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. Thyroid. 2017; 27(7): 894–901. 2. Yamauchi et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS One. 2019; 14(5): e0216954.
MON-525 ATA and ACR TIRADS Classification Systems as Additional Predictors of Malignancy in Afirma GSC Suspicious Thyroid Nodules
Authors: Azaryan Irina , Endo Mayumi 
Published: May 2020

Abstract
Objective: Evaluation and management of thyroid nodules with cytologically indeterminate results remain challenging in clinical practice. Despite the implementation of molecular testing in an attempt to avoid surgical intervention, diagnostic thyroidectomy still occurs due to the relatively low positive predictive value of these molecular testing. We conducted a study to analyze whether combining US characteristics and results of molecular testing would better elucidate predicting true positive results.
Methods: We retrospectively reviewed thyroid ultrasound images of 172 nodules in 162 patients (mean age, 55 years +/- 14) with indeterminate cytology results (Bethesda III and IV) that underwent Afirma Gene Sequencing Classifier (GSC) testing at a single academic medical center between 2017–2019. All nodules were classified according to 2015 American Thyroid Association (ATA) and 2017 American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS).
Results: A total of 172 with subsequent Afirma GSC molecular testing were included in the study. There were 127 nodules with Bethesda III (AUS/FLUS) (73.8%), and 45 nodules with Bethesda IV (SFN/HCN) (26.2%) results. The mean nodule volume was 5.4 +/- 10 cm3. Afirma GSC identified 129 nodules (75%) as benign and 43 nodules (25%) as suspicious. Per ATA classification, 10.4% (18) of nodules were classified as very low risk, 40.7% (70) as low risk, 36.5% (62) as intermediate and 12.8% (22) as high risk for malignancy. There was a significant association between ATA classification and Afirma benign nodules (P=0.002). All nodules were also classified per TIRADS system with the following distribution: 5 (1.16%) TIRADS 1, 7 (4%) TIRADS 2, 54 (31%) TIRADS 3, 90 (52%) TIRADS 4, and 16 (9.3%) TIRADS 5. We did not observe the similar association between TIRADS system and benign nodules as we did with ATA classification (P=0.4).
35 patients (79.5%) with Afirma suspicious results underwent surgery, of which 18 (51.4%) surgical pathology were malignant. 8 patients with Afirma suspicious results decided to proceed with ultrasound surveillance. The malignancy rates of nodules with low, intermediate and high suspicion for malignancy classified by the ATA guidelines were 44% (9 of 18), 33% (56 of 18) and 22% (4 of 18). The malignancy rates of TIRADS category 3, 4 and 5 nodules were 44% (8 of 18 nodules), 44% (8 of 18 nodules) and 11% (2 of 18 nodules). Subset analysis of surgical pathology benign and cancerous nodules did not show significant association between ATA (P=0.5) or TIRADS (P=0.4) classification systems.
Conclusion: Our study showed that Afirma benign nodules were associated with a lower risk of malignancy per ATA classification but not with TIRADS system. We did not find a significant association between pathology proven cancer cases and high-risk ATA or TIRADS ultrasound classification systems.
OR06-01 The Role of Germline Defects in Cushing’s Disease
Authors: Hernández-Ramírez Laura C , Pankratz Nathan , Lane John , Faucz Fabio R , Chittiboina Prashant , Denise Kay M , Mills James L , Stratakis Constantine A 
Published: May 2020

Abstract
J.L.M. and C.A.S. contributed equally. Introduction: Cushing’s Disease (CD) has been described as a component of a number of familial genetic syndromes. Yet, such cases may go largely unrecognized due to phenotypic variability, incomplete penetrance, and the rarity of the disease. We determined the frequency and type of germline genetic causes of CD and characterized their clinical phenotype in a large cohort of CD patients. Methods: We studied 245 unrelated CD patients (139 females, 60.4%), referred to our Center between 1997–2018, including 230 pediatric (≤18 years at disease onset, 93.9%) and 15 adult patients (6.1%). Germline genetic causes were identified by whole exome sequencing in 184 patients and by Sanger sequencing of specific genes in 39 patients; 22 patients did not undergo genetic testing, due to low quality or insufficient DNA. When available (n=66), corticotropinoma DNA was screened for USP8 hotspot variants using Sanger sequencing. Results: Eighteen patients (7.3%) had positive family history: nine presented as FIPA with unknown genetic cause, eight presented as MEN1 (seven had confirmed MEN1 variants), and one had a family history of pheochromocytoma/paraganglioma and pituitary adenoma with unknown genetic cause. Among the 227 sporadic patients (92.7%), 13 (5.7%) simplex cases had putative pathogenic variants in the following genes: CDKN1B (n=5), CABLES1 (n=3), AIP (n=1), PRKAR1A (n=1),TP53 (n=1),TSC2 (n=1), and USP8 (n=1). Altogether, cases with potentially inheritable genetic causes(familial and simplex) accounted for 12.7% (31/245) of all patients. There were no statistically significant differences in age at disease onset, age at diagnosis or tumor diameter between patients with potentially inheritable genetic defects and the rest of the cohort. In the pediatric subset, however, there was a non-significant higher frequency of macroadenomas among familial and simplex patients (21.4%), compared with sporadic patients (12.4%, P=0.19). Somatic USP8 hotspot mutations were found in 33.3% (12/36) of sporadic patients, but only in 3.3% (1/30) of familial and simplex (e.g. patients with a disease-associated germline defect, but no affected relatives) cases (P=0.0038). The global frequency of USP8 defects was 19.7% (13/66). Conclusions: Potentially inheritable cases of CD accounted for one-eighth of the patients in our cohort: 64.5% (20/31) of them are associated with defects in genes with a known involvement in CD. Patients with germline genetic causes of CD might present as apparently sporadic cases, due variability in disease penetrance. Unlike sporadic cases, somatic USP8 hotspot mutations are rare in those with inheritable causes of CD, suggesting different drivers for tumorigenesis in each group. Identifying the genetic causes of CD should lead to a more precise genetic testing and counselling and might aid in developing targeted therapeutic strategies.