bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-641 Identifying Risk Factors Associated with Severe Maternal Morbidity Among Women with Gestational Diabetes Using Common Data Model
Authors: Cho Seo-Ho , Kim Kwangsoo
Published: May 2020

Objective: To identify the risk factors associated with severe maternal morbidity among women with gestational diabetes using common data model

Background: Severe maternal morbidity is an unintended, adverse outcome of the pregnancy or the process of labor and delivery that causes short and long-term consequences to women’s and infants’ health. The prevalence of severe maternal morbidity has been increasing, from 5 to 14 cases per every 1,000 births from 1994 to 2014, and is estimated to increase over time.

Previous studies have shown an association between gestational diabetes and pregnancy complications including hypertension, preeclampsia, and preterm birth. We assessed the association of representative biomarkers with severe maternal morbidity among women with gestational diabetes.

Methods: This cohort study used data collected from common data model database at a single tertiary center in Seoul, Korea during 2004-2019. All patients with indication of gestational diabetes were included in the study. Cases were all women who experienced severe maternal morbidity using the ICD-10 codes identified by the Centers for Disease Control and Prevention. We assessed associations between representative biomarkers and severe maternal morbidity, using t-test and multivariable logistic regression models.

Results: Among 15,096 women who gave birth, the prevalence of gestational diabetes was 9.19% (n=1,388). Among those, 329 (23.7%) developed severe maternal morbidity during pregnancy. HbA1c, triglyceride, and fasting blood sugar were higher among women with severe maternal morbidity (p<0.05) and younger age showed association (p<0.01) with severe maternal morbidity.

Conclusion: This study showed that gestational diabetes was highly associated with severe maternal morbidity. Blood glucose and lipid metabolism were shown to be associated factors with severe maternal morbidity among women with gestational diabetes.
SUN-009 Variable Presentation of Two Patients with Gestational Trophoblastic Disease and Hyperthyroidism
Authors: Chale-Matsau Bettina , Mokoena Samantha , Kemp Tanja , Pillay Tahir S
Published: May 2020

Background: Gestational trophoblastic disease (GTD) represents a group of tumours caused by abnormal proliferation of trophoblastic cells, including molar pregnancy. Elevated β-hCG levels are an established marker for the presence of the disease and useful for monitoring. Due to the shared structural homology of β-hCG and TSH, hyperthyroidism can occur.

Clinical Cases: We present two patients with GTD associated with hyperthyroidisim. Case 1, a 20 year old female (G1P0) presented to the emergency department complaining of vaginal bleeding associated with abdominal pain. She was estimated to be 13 weeks. Laboratory evaluation were β-hCG 648 324 IU/L, TSH 0.06 (0.35 - 4.94 mIU/L, free T4 23.2 (9.0 - 19.0 pmol/L, Hb 8.0 (11.6 - 16.4 g/dL). Ultrasound revealed molar pregnancy. She underwent uterine evacuation, thereafter complicated with thyroid storm (Burch Wartofsky score = 45). Post- operative vitals were BP 192/112, pulse rate 120 bpm and temperature 360C. She was managed in high care on labetolol, carbimazole, lugol’s iodine and hydrocortisone.

She was subsequently referred to Medical Oncology for further management. Histology sample obtained in theatre confirmed complete molar pregnancy.

Her staging CT scan indicated the presence of small lung nodules, suggesting metastatic disease. The patient’s FIGO/WHO score was III: 2. At the time of preparing this study, she had already received 7 weeks of methotrexate intramuscularly and still had detectable β-hCG levels.

Case 2 was a 31 year old female presented similarly. This was her second pregnancy (G2P1), 12 weeks by dates. Her vitals were BP 141/74, pulse rate 110 bpm and temperature 36oC. The Ultrasound revealed larger for gestational age uterus with cystic structures in utero. Her quantitative β-hCG was significantly elevated (> 1 500 000 IU/L) she was thyrotoxic [TSH (<0.1 (0.34 - 4.94 mIU/L) free T4 (47.2 (9.0 - 19.0 pmol/L)], however did not develop thyroid storm (Burch Wartofsky score = 20). This patient also underwent uterine evacuation and did well post operatively. She was treated for her thyrotoxicosis with carbimazole, propranolol and thiamine. Further management was by Medical Oncology. Histological examination was in keeping with a partial mole.

Her staging CT scan showed no metastasis, and had a FIGO/WHO score of 1: 4 due to her pre-treatment hCG of >1.5 million IU/L. She received 7 cycles of intramuscular methotrexate from which she achieved and maintained suppressed β-hCG levels (<1 IU/L).

Conclusions: This study has demonstrated that the β-hCG levels may not always correlate with disease severity and prognosis.

When comparing the two patients Case 1 had lower levels of β-hCG and of free T4 than Case 2, however was clinically more unwell, developed thyroid storm and had metastatic disease. Case 2 had hCG levels almost double those of Case 1, wsa stable and her levels decreased much quicker reaching undetectable levels
OR12-03 Mineralocorticoid and Glucocorticoid Receptors Adopt Distinct Quaternary Structures and Can Form Heteromultimers That Affect Chromatin-Binding Profiles
Authors: de la Rosa Diego Alvarez , Johnson Thomas A , Fettweis Gregory , Hager Gordon L
Published: May 2020

The mineralocorticoid and glucocorticoid receptors (MR and GR) are evolutionarily related nuclear receptors with high sequence conservation and a shared hormone response element (HRE). Both receptors are activated by glucocorticoids, but MR can be selectively activated by aldosterone. Using the imaging technique Number & Brightness (N&B) it has recently been proposed that liganded GR dimers form tetramers upon binding to HREs in live cells. We now show that agonist-bound MR adopts a tetrameric organization in the nucleoplasm and forms complexes with an average of 7 receptor units upon binding an HRE. Interestingly, MR antagonists eplerenone and spironolactone induced intermediate oligomerization arrangements, strongly suggesting that higher order oligomerization is essential for receptor activity. Site-directed mutagenesis and deletion analysis suggest that the N-terminus of MR is a main determinant of higher order oligomerization. Both with corticosterone and aldosterone, GR can incorporate into MR complexes partially displacing MR monomers. Genome-wide chromatin binding studies suggest that the presence of GR in the same cells profoundly change MR interaction with distinct sets of enhancers in a ligand-dependent way, contributing to receptor-specific signaling. Certain genes respond to only one receptor while others respond to both receptors. The interaction of these two closely related receptors has important implications for the mechanisms for glucocorticoid signaling and transcription factors in general.
SAT-725 Alterations in the Phenotype and Epigenomic Landscape of Luminal Breast Cancer Following Long-Term Nanomolar Exposure to Bisphenol a (BPA)
Authors: Liwag Jason Tan , Velarde Michael Cu , Bagamasbad Pia Dano
Published: May 2020

Breast cancer (BCa) is the leading cause of female cancer-related death worldwide. Luminal BCa accounts for at least 70% of all BCa and is characterized by its hormone dependence, particularly to estrogen. Endocrine disruptors may function to exert the pro-tumorigenic effects of estrogen in proxy following environmental exposure. Bisphenol A (BPA) is a ubiquitous endocrine disruptor shown to increase risk towards developing BCa in multiple in vivo mammalian models and in vitro human breast models. Despite this, there is limited information on the phenotypic and epigenetic effects of nanomolar BPA following long-term exposure particularly in the context of BCa stem cell population, which accumulate the ‘cellular insult’ and are likely to pass such information down through epigenetic mechanisms. We hypothesize that BPA affects the epigenome, in part, by altering the regulation of DNA methyltransferases (DNMTs) since BPA disrupts transcriptional and translational regulation of DNMTs in various other tissue types such as the brain, testis and prostate. In this study, MCF7 cells were chronically (>4 weeks) cultured with nanomolar doses of BPA, and subsequently subjected to phenotypic assays and gene expression analysis in monolayer or mammosphere culture. Gene expression analysis revealed a downregulation of DNMT3A and ESR1 following long-term exposure to BPA in mammosphere culture of MCF7 cells, but not in monolayer culture. This is accompanied by alterations in mammosphere morphology, reduction in mammosphere size, an increase in the mammosphere number, and an increase in the CD49f+ population, indicating a positive contribution of BPA to stemness. However, there are no significant changes in proliferation, apoptotic rate, and metastasis in both monolayer and mammosphere culture. Future analysis includes assessment of genome-wide alterations in DNA methylation patterns in these chronically exposed MCF7 mammospheres, as well as identifying estrogen responsiveness, chemotherapeutic response, and self-renewal properties of these cancer cells.
SUN-423 Impact of Hyperthyroidism and Its Treatment on the Outcome of Mental Health, Occupational Functioning and Quality of Life - a Prospective Study
Authors: Chopra Roopa , Kalaria Tejas Kumar , Gherman-Ciolac Carolina , Raghavan Rajeev , Viswanath Ananth , Buch Harit , Kar Nilamadhab
Published: May 2020

Hyperthyroidism is known to be associated with psychiatric symptoms such as anxiety and depression, impartment of functioning and poor quality of life (QOL).

It was intended to study the outcome of anxiety, depression, ability to work and QOL following the treatment of hyperthyroidism in endocrine clinic.

In a prospective study, all newly referred hyperthyroidism patients with fully supressed TSH (<0.004 mIU/L) were followed up three monthly for more than a year. Besides the thyroid status and clinical assessment, they were assessed using Patient Health Questionnaire (PHQ)-9 for depression, Generalised Anxiety Disorder (GAD)-7 questionnaire for anxiety; EuroQoL (ED5D) for QOL and Work and Social Adjustment Scale (WSAS) to measure functional impairment.

There were 177 participants (77.9% females), with a mean age of 50.1±15.6 years (range 16-86). Majority (88.7%) were having Grave’s disease and 11.3% had thyroid nodular disease; 10.2% had recurrent hyperthyroidism. At the baseline, anxiety was considered severe in 27.7%; similarly depression was moderately severe in 13.7% and severe in 14.9%. Although these decreased over time, considerable proportions continued to have these symptoms even after a year of treatment. A little over a quarter (26.6%) had beta-blockers at baseline and 9.0% had antidepressants; these proportions decreased reflecting symptomatic improvement. Proportions not-working changed from 28% to 18.2% within a year. WSAS suggested that the proportion with significant impairment changed from 46.7% to 34.6% (mean score change from 11.6 to 5.1). The EuroQoL mean score was 59.6 at the initial assessment which increased gradually to over 80. Most of these outcome parameters correlated with the improvement in thyroid status; however for many patients, mental health symptoms and functional impairments continued even after the thyroid tests became normal.

Considerable proportion of patients with hyperthyroidism had anxiety, depression, functional impartment and poor quality of life; most of which improved with the course of anti-thyroid treatment; however a considerable proportion continued to have symptoms and impairments even after a year. This suggests the need for additional psychiatric intervention, probably early in the treatment to decrease the morbidity and improve QOL. Use of specific screening measures for psychiatric symptoms in the endocrinology clinics may be useful.

References

(1) Demet et al, Arch Med Res. 2002 Nov-Dec;33(6):552-6.
SAT-191 A Case of Hypoplastic Left Heart Syndrome and Paraganglioma
Authors: Bowes Christa , Subauste Angela
Published: May 2020

INTRODUCTION:

Cyanotic heart disease and paragangliomas are two rare diagnosis. Co-occurrence of congenital cyanotic heart disease and pheochromocytomas/paragangliomas has been described, but the mechanism is unclear. In those patients where immediate cyanosis resulting from the congenital heart disease happens right after birth there is an association with an earlier detection of tumor compared to those with cyanotic heart disease later in life (26.6 years vs 46.3 years respectively) [1]. The objective of this case is to highlight this association, as a high degree of suspicion needs to be had when caring for individuals with cyanotic heart disease to pursue evaluation of these tumors. CASE: A 23-year-old man with a chief complaint of diffuse abdominal pain was found to have a 2.6 x 2.8 cm smoothly marginated soft tissue mass in the right lower quadrant on abdominal computed tomography. Patient had a known history of hypoplastic left heart syndrome (mitral atresia-aortic atresia) who had undergone a three-stage Norwood repair in childhood. In his adulthood was diagnosed with Central Adrenal Insufficiency, and Type 2 Diabetes Mellitus. At the time of presentation patient was short of breath, tachycardic (heart rate 115), and tender to palpation of his right lower quadrant. Plasma normetanephrines were 3.8 nmol/L (normal < 0.9 nmol/L), 24-hour urinary excretion of normetanephrine was 1117 mcg/24h (normal 103-390 mcg/24h). Plasma metanephrine levels were normal. A nuclear medicine whole body scan with metaiodobenzylguanidine (MIBG) scan confirmed a MIBG avid tumor in the right lower quadrant. Preoperative management was initiated with oral doxazosin. He underwent laparoscopic surgery with removal of a 3 cm pelvis mass resected from the retroperitoneal tissue deep to the peritoneum along the gonadal vein and ureter. Final pathology confirmed the diagnosis of a paraganglioma. Postoperatively, plasma normetanephrines were corrected at 0.86 nmol/L. Patient underwent genetic testing that was negative for FH, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and VHL. CONCLUSION: Multidisciplinary approach to these patients is essential given their complex hemodynamics. Long term follow up is necessary to monitor for tumor recurrence, review of case reports may suggest a higher risk of recurrence [1]. Of these case reports there has been no strong genetic association found, the most popular theory is a causal relationship from their cyanotic heart disease. References:

Zhao B, Zhou Y, Zhao Y et al (2018) Co-occurrence of pheochromocytoma-paraganglioma and cyanotic congenital heart disease: A case report and literature review. Front Endocrinol. https://doi.org/10.3389/fendo.2018.00165
SAT-723 Effects of Organohalogenated Endocrine Disrupting Chemicals on Cell Proliferation and Gene Expression in GH3 Somatolactotropes
Authors: Ringrose Sophie , Grammatopoulos Kyriakos , Welch Natalie , Simbi Bigboy , Niessen Stijn J , McGonnell Imelda M , Scudder Christopher J , Fowkes Robert C
Published: May 2020

Endocrine Disrupting Chemicals (EDCs) are substances that have been increasingly implicated in many serious pathologies, such as tumor formation, metabolic, growth and reproductive disorders. The economic and health burden of exposure to these compounds has an annual predicted cost in excess of €150 billion, across the EU regions alone. Of the growing list of compounds that act as EDCs, the organohalogenated compounds (OHCs), polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) have been associated with an increased risk of pituitary disease. We have previously reported that feline patients with hypersomatotropism (acromegaly) are exposed to elevated levels of PBDEs and PCBs in their environment. However, the mechanisms by which these compounds might directly influence somatotroph function have yet to be established. In this study, we use the GH3 rat somatolactotrope cell line to investigate how two PCB congeners - 138 and 153 - influence cell proliferation (using a Crystal Violet assay) and somatotrope gene expression (using a multiplex RT-qPCR approach to examine expression of Esr1, Esr2, Sstr1, Sstr2, Sstr3, Sstr4, Sstr5, Insr, Tshr, Pou1f1, Ghrhr2, Gh). GH3 cells were treated with Phenol Red-free media in the absence or presence of either PCB138 or 153 (-10 to -6 M), or in combination (-10 to -6M) for up to 72h. Treatment with either PCB alone, or in combination, caused significant concentration-dependent, biphasic changes in cell proliferation at each time point, but with a different profile of response on each day (significantly increased at high pM/low nM concentrations); there was no evidence of toxicity at maximum concentrations (-6M). Gene expression changes were determined in GH3 cells treated in the absence or presence of either -8M or -6M PCB138 or 153 for 24h. Differential effects of these compounds were seen on the expression of Sstr3, Sstr4, Sstr5 and Insr; all other gene transcripts were unaffected. These findings reveal that GH3 cells exposed to physiologically relevant concentrations of PCB138 and 153, alone or in combination, show concentration-dependent increases in cell proliferation; furthermore, the expression of genes associated with therapeutic targets for the treatment of acromegaly (i.e. SSTRs) are differentially affected by exposure to PCB138 and 153. Our data indicate a potential mechanism for EDCs in the onset of acromegaly, that require further, in vivo, investigations.
MON-444 The Case of a Rare Anaplastic Thyroid Cancer Variant with Rhabdoid Features
Authors: Foster Jennifer , Diedrich Veronica , Leonard Talayna , Shahlapour Mahmood , Horani Mohamad Hosam
Published: May 2020

Introduction: We present a very rare case of a variant of anaplastic carcinoma, a high-grade thyroid carcinoma with rhabdoid features. Less than 15 cases have been reported in English literature over the last 20 years. The prognosis of thyroid cancer with this variant phenotype is unfortunately very poor with a mean survival time of only 6 months after diagnosis. Treatment includes surgery, often a total thyroidectomy due to the rapid rate of growth of this tumor type. The benefits of chemotherapy and radiation are not yet apparent.

Case presentation: A 49 year old female with history of breast cancer status-post recent chemoradiation therapy presented to the emergency department for a rapidly enlarging, right-sided neck mass. The mass had been present for approximately one month, but it was estimated to have grown from 3cm to 5cm within the two weeks prior. The patient was being followed by her ENT specialist and had a recent outpatient CT scan done. The results of the CT revealed a large thyroid tumor partially obstructing the esophagus and given the rapid progression of symptoms, she was instructed to go straight to the ED for emergent admission. Upon arrival, the patient reported not having consumed any solids or liquids for the past day due to concerns of aspiration and increasing neck pain. She had complaints of worsening dysphagia. Initial lab work revealed low thyroglobulin (1.4 ng/mL), elevated T4 (15.42 nmol/L) presumably due to Tamoxifen exposure, and elevated PTH (96.9 pg/mL), likely primary hyperparathyroidism. She was admitted and endocrine was consulted for further evaluation. The patient underwent a fine-needle aspiration biopsy showing high-grade anaplastic carcinoma with extensive necrosis and rhabdoid features. The tumor was eventually classified as stage 4B with gross extra thyroidal extension to the adventitial layers of the esophagus, thus it was determined to be unresectable. It was recommended at that time she have a percutaneous tracheostomy and feeding tube to protect her airway. However, the patient requested to be discharged so that she could obtain a second opinion regarding treatment options and prognosis. She subsequently underwent a total thyroidectomy at another hospital.

Conclusion: It remains unclear whether this patient’s history of breast cancer treated with chemoradiation therapy played a role in the development of this rare thyroid carcinoma. Some cases of the rhabdoid phenotype are documented to have transformed from papillary thyroid carcinoma, for which radiation therapy is a well-known risk factor. Future studies should use molecular markers, such as BRAF V600E mutations common to papillary and anaplastic thyroid carcinomas, to help differentiate between types of thyroid cancers and avoid delayed treatment options for rapidly metastasizing thyroid tumors.
SUN-695 Should Vitamin B12 Status Monitoring Be Implemented for Patients Taking Metformin?
Authors: Hoskyns Wesley , Shahlapour Mahmood , Brooks Ryan , McNierney Dakota , Kihara Sylvia , Horani Mohamad Hosam
Published: May 2020

Introduction : Cobalamin (vitamin B12) is used in multiple metabolic processes, functioning primarily as a coenzyme with Methylmalonyl-CoA mutase and Methionine synthase in humans. Without functioning enzyme, substrate levels build up which are neurotoxic, leading to neurological debilitation. Lack of enzyme also halts cellular replication processes causing severe anemia. Since numerous studies have found decreased cobalamin levels in patients who regularly take metformin1, then could regular monitoring of cobalamin levels in such patients prevent these outcomes?

Case Presentation : We present a 50-year-old female who reported to the ED with general weakness and shortness of breath after having a seizure. Her medical history included type 2 diabetes mellitus being treated with metformin and a history of seizures controlled by carbamazepine since childhood.

Neurological exam abnormalities consisted of DTRs that were 1/4 on all proximal and distal upper and lower extremities and absent fine sensory and vibratory sensation on ankles and feet bilaterally. Patient was also ataxic. Hgb A1c was 14%. Head CT, chest x-ray, EKG, and cardiac markers found no abnormalities. CBC found a profound pancytopenia with WBC 1.6, RBC 1.27, Hgb 5.2, MCV 119, MCH 40.9, MCHC 34.3, RDW 18.2, and platelets 113. Blood smear was normal. Bone marrow sample showed normochromic macrocytic cells with no other abnormalities. Folate level was normal and cobalamin was found to be low (61.5 pmol/L). Intrinsic factor antibodies were negative. Extensive autoimmune workup was also negative.

Discussion: Our patient’s neurological symptoms and pancytopenia were found to be due to multiple factors. R. Pawlak, found that metformin use had a 2.45 (p < 0.0001) times higher odds of developing B12 deficiency in comparison to non-metformin users1. This was also supported by a systemic review of the impact of metformin

Carbamazepine is known for its effects on decreasing the absorption of folate and has statistically been found to decrease cobalamin significantly as well.

There are several B12 assessment methods available to providers, including serum/plasma B12, Mean Corpuscular Volume (MCV), Homocysteine (Hcy), Holotranscobalamin II (holoTCII), and serum and urinary Methylmalonic Acid (MMA). Urinary MMA has been found to be the most specific and sensitive of these markers when adjusted by kidney function (through serum creatinine levels) and while fasting

Conclusion : Currently, there are no screening guidelines by the U.S.P.S.T.F or American Diabetes Association for cobalamin deficiency. However, neurologic deficits and macrocytic anemia could be prevented through monitoring cobalamin levels in diabetics receiving metformin treatment. This monitoring might be needed more in patients with seizure disorderon Carbamazebin.
MON-643 Diabetes’ Cost to Us Taxpayers: Thirty-Day Readmission and Resource Utilization Among Diabetics Patients Admitted with ST-Elevation Myocardial Infarction: A Propensity Score Match Analysis
Authors: Nasserifar Shabnam , Ho Kam Sing
Published: May 2020

PURPOSE: To determine the relationship between diabetes and thirty-days readmission, mortality, morbidity, and health care resource utilization in patients who were admitted with ST-Elevation Myocardial Infarction (STEMI) in the United States. METHOD: A retrospective study was conducted using the AHRQ-HCUP Nationwide Readmission Database for the year 2014. Adults (≥ 18 years) with a primary diagnosis of STEMI (1), along with a secondary diagnosis of diabetes were identified using ICD-9 codes as described in the literature (2). The primary outcome was the rate of all-cause readmission within 30 days of discharge. Secondary outcomes were reasons for readmission, readmission mortality rate, morbidity, and resource use (length of stay and total hospitalization costs and charges). Propensity score (PS) using the 1:1 nearest neighbor matching without replacement was utilized to adjust for confounders (3). Independent risk factors for readmission were identified using a Cox proportional hazards model (4). RESULTS: In total, 116,124 hospital admissions among adults with a primary diagnosis of STEMI were identified, of which 18.05% were diabetics. 1:1 PS matching was performed based on demographic (age, gender, hospital status, etc.) and clinical characteristics (Charlson comorbidity score. The 30-day rate of readmission among diabetics and non-diabetics with STEMI were 9.31% vs. 6.18% (p <0.001). The most common readmission for both groups was recurrent myocardial infarction. During the index admission for STEMI, the length of stay (LOS) among diabetics and non-diabetics patients were not statistically different (4.74 vs 4.58 days, p=0.12). However, the total hospital cost for the diabetic patients was statistically different ($27,027 vs $24,807, p <0.001). Most importantly, diabetics patients’ in-hospital mortality rate during their index admission was significant higher (10.20% vs 5.92%, p <0.001). Amongst those readmitted, the LOS, total hospital cost, or in-hospital mortality among diabetics were not statistically different when compared to their counterparts during their readmission. Diabetes (HR 1.60, CI 1.27-2.02, p <0.001) was an independent predictor associated with higher risks of readmission. Other independent predictors associated with increased 30-day readmission include acute exacerbation of CHF, acute exacerbation of COPD, acute kidney injury, secondary diagnosis of pneumonia, history of COPD, history of ischemic stroke, history of atrial fibrillation & atrial flutter, history of chronic kidney disease, history of iron deficiency, and use of mechanical ventilator. CONCLUSION: In this study, diabetics patients admitted with STEMI have a higher 30 days of readmission rate, total hospital cost, and in-hospital mortality (p <0.001) than their non-diabetic counterparts.
MON-197 Developing a Research Database About Primary Aldosteronism: Rationale and Baseline Characteristics
Authors: Wang Wen , Ren Yan
Published: May 2020

Introduction There were limited evidence supporting the management of PA, primarily due to lack of high quality of data. Developing a research database through integrate both retrospective and prospective collected data regarding clinical care and outcomes of patients with PA may provide valuable evidence on management of PA. Methods The establishment of PA research database involved two steps. Firstly, patients with confirmation of PA between 1 Jan 2009 to 31 Aug 2019 were identified and data were extracted from EMR. Secondly, patients who have positive confirmatory testing for PA and agree to participant a prospective cohort will be enrolled. Data regarding clinical care and long-term outcomes will be prospectively collected based on the case report forms since 1 Sep 2019. We evaluated the quality of research database through assessment of quality of key variables. Results Totally, 904 patients diagnosed as PA in WCH were identified, of which 507 patients had positive confirmatory testing for PA were finally included into the retrospective database. Among included patients, the mean age was 49.2 years old, and the mean BMI was 24.72 kg/m2. There were 37 (7.3%) patients diagnosed as chronic kidney disease (CKD), 13 (2.6%) as coronary artery disease (CAD), 95 (18.7%) as diabetes mellitus (DM) and 77 (15.2%) as obstructive sleep apnea-hypopnea syndrome (OSA). The mean systolic blood pressure (SBP) was 155.8 mmHg, and the mean diastolic blood pressure (DBP) was 96.2 mmHg. Among included patients, the lowest serum potassium during admission was 2.96 mmol/L, and the mean serum aldosterone was 26.4 ng/dL. Validation of data extracting and linking showed the accuracy were 100%. Evaluation of missing data showed that the completeness of BMI (95.9%), SBP (1%) and DBP (1%) were high. Conclusion Through retrospective and prospective cohort of PA, a research database about PA with high quality and comprehensive data will be established. We anticipate that the research database will provide a high level of feasibility for management of PA in China.
SAT-555 Can Histology Predict the Presence of KCNJ5 Somatic Mutation in Aldosterone-Producing Adenomas?
Authors: Yamazaki Yuto , Gao Xin , Tezuka Yuta , Omata Kei , Ono Yoshikiyo , Morimoto Ryo , Gomez-Sanchez Celso E , Nakamura Yasuhiro , Satoh Fumitoshi , Sasano Hironobu
Published: May 2020

Aldosterone-producing adenoma (APA) is well known to harbor marked intratumoral heterogeneity in terms of morphology and CYP11B2 (aldosterone synthase) localization. In histology, APA is generally characterized by two distinct cell subtypes, namely “clear cells” and “compact cells”. Clear tumor cells harbor abundant lipid droplets in their cytoplasms and compact tumor cells generally featuring small round shape have abundant intracytoplasmic organelles including mitochondria.

Relatively close correlation between these histological characteristics (morphology and CYP11B2 immunohistochemistry) and genotypes of aldosterone-driver gene somatic mutation has been reported. Among them, KCNJ5-mutated APAs have been reported to harbor clear cell predominant features, while APAs with other rare somatic mutations including ATP1A1, ATP2B3 and CACNA1D harbor heterogenous or relatively compact cell predominant morphometry. However, these previous evaluation were based on eyeball analysis with relatively low reproducibility. Therefore, we developed the more quantitative methods using digital image software in order to analyze the widespread area, which can reflect intratumoral heterogeneity, with high reproducibility to analyze the further detailed correlation between histopathological characteristics and genotype in APA. We explored the utility of immunohistochemistry including CYP11B2 and KCNJ5. We further attempted to propose histopathological scoring system to predict the presence of KCNJ5 somatic mutation in APAs.

Results of our present study revealed that KCNJ5 was predominantly immunolocalized in zona glomerulosa among adrenal cortex (vs. ZF, P=0.0002, vs. ZR, P=0.0002), furthermore, predominantly in APCCs than in non-APCCs (P=0.0019). Among the tumors, KCNJ5 immunoreactivity was significantly higher in KCNJ5-wild type APAs than in mutated ones (P=0.0037). KCNJ5-mutated APAs had significantly lower nuclear / cytoplasm ratio and abundant clear cell components than those with wild type, harboring large tumor size. In conclusion, we firstly proposed a novel histopathological predicting scoring system for the presence of KCNJ5 somatic mutation, including the following histopathological findings; N/C ratio, clear cell (%), tumor size, CYP11B2 immunoreactivity and KCNJ5 immunoreactivity. It is true that no single histological factors above could precisely predict the presence of KCNJ5 somatic mutation but this newly developed combined histopathological predicting scoring system could provide relatively high accuracy to predict KCNJ5 somatic mutation in APAs (AUC=96%, sensitivity:100%, specificity:90%, 4 points or more). However, further prospective validation by large number of cases is required for clarification.
SAT-133 Breast Tumor Kinase (Brk/PTK6) Mediates Triple Negative Breast Cancer Cell Migration and Taxol Resistance via SH2 Domain-Dependent Activation of RhoA and AhR
Authors: Dwyer Amy Renee , Kerkvliet Carlos J Perez , Krutilina Raisa , Playa Hilaire , Park Deanna , Thomas Warner , Smeester Branden , Seagroves Tiffany Nicole , Lange Carol A
Published: May 2020

Triple negative breast cancer (TNBC) patients have higher recurrence rates and a worse prognosis relative to patients diagnosed with other breast cancer subtypes. Protein tyrosine kinase 6 (PTK6; also called Brk), a soluble tyrosine kinase, is overexpressed in 86% of breast cancer patients, however its precise function in the context of TNBC is poorly defined. PTK6 expression is elevated in TNBC models in response to both cellular and endocrine stress, coordinated transcriptionally by the Hypoxia-Inducible Factors (HIFs) and glucocorticoid receptor (GR). We showed previously that PTK6 expression, but not its intrinsic kinase activity, is required for breast cancer cell motility. To further delineate the mechanisms of PTK6 signaling, we created kinase-intact domain structure mutants of PTK6 via in frame deletions of the N-terminal SH3 or SH2 domains. MDA-MB-231 cells expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were less responsive to growth factor-stimulated cell motility relative to wild type or kinase dead (KM) controls. To identify signal transduction pathways activated in TNBC cells harboring PTK6 domain mutants, we used a reverse phase protein array (RPPA), which revealed that the SH2 domain of PTK6 mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Moreover, in TNBC cells, including a taxane-refractory TNBC model, addition of AhR or Rho inhibitors to paclitaxel (Taxol) enhanced cytotoxicity. Together, these studies reveal that the SH2-domain of PTK6 is an effector of advanced cancer phenotypes in GR+ TNBC cells and identify RhoA and AhR as novel therapeutic targets in PTK6+ tumors.
SAT-431 Insulin Resistance, Lipid Profile and High-Sensitivity C-Reactive Protein in Patients with Autoimmune Thyroiditis
Authors: Neves Celestino , Neves João Sérgio , Pereira Miguel , Oliveira Ana , Medina José Luís , Delgado Luís , Carvalho Davide
Published: May 2020

Introduction: Thyroid function and autoimmunity has been associated with cardiovascular events in patients with autoimmune thyroiditis. Objectives: To evaluate the association between thyroid function, antithyroid antibodies levels, insulin resistance and markers of cardiovascular risk in patients with autoimmune thyroiditis. Methods: We evaluated 228 patients with autoimmune thyroiditis, 93.9 % female, with a mean age of 47.06 ± 15.35 years. We analyzed thyroid function, anti-thyroglobulin antibodies (anti-Tg), anti-thyroid peroxidase antibodies (anti-TPO), HOMA-IR, HOMA-B, QUICKI, HISI (Hepatic Insulin Sensitivity Index), WBISI (Whole-Body Insulin Sensitivity Index), the levels of lipid profile, high-sensitivity C-reactive protein (hs-CRP), homocysteine, folic acid, and vitamin B12. We defined 3 groups based on TSH levels: TSH between 0.35-2.49 µUI/ml, (n = 166), TSH between 2.50-4.94 µUI/ml, (n = 43) and TSH over 4.95 µUI/ml, (n = 19), and normal levels of free T4 and free T3. A 75-g OGTT was performed in the morning and blood samples were obtained every 30 min for 120 min for measurements of plasma glucose, insulin, and C-peptide. For the statistical analysis we used the Mann-Whitney test and Spearman correlations. Results are expressed as means ± SD or percentages. A two-tailed p<0.05 was considered statistically significant. Results: There were no significant differences regarding median age or median BMI between groups. We did not find any significant differences comparing group with TSH 0.35-2.49 and group with TSH 2.50-4.94, in all parameters evaluated. Group with TSH 2.50-4.94 had higher indexes of QUICKI (0.69 ± 0.39 vs 0.48 ± 0.13; p = 0.02) and HISI (79.83 ± 63.72 vs 41.73 ± 29.02; p = 0.01) than group with TSH over 4.95. The group with TSH over 4.95 demonstrated a higher index of HOMA-IR than group with TSH 2.50-4.94 (3.77 ± 2.93 vs 1.95 ± 1.24; p = 0.01). In the TSH 0.35-2.49 group we found significant correlations between TSH and HOMA-IR (r= 0.18; p = 0.01), total cholesterol and anti-TPO (r =0.23; p = 0.002), anti-Tg and HDL-cholesterol (r= -0.17; p=0.002), anti-Tg and triglycerides (r=0.34; p < 0.001), and anti-Tg and LDL-cholesterol (r=0.16; p=0.03). In the TSH 2.50-4.94 group we observed positive correlation between Apo A1 and HOMA-B (r=0.58; p<0.001), HOMA-IR and LDL-cholesterol (r=0.34; p=0.02) and WBISI and HDL-cholesterol (r=0.34; p=0.02). In the TSH over 4.95 group we observed a correlation between TSH and triglycerides (r=0.70; p<0.001) and between anti-Tg and hs-CRP (r=0.64; p=0.004). Conclusions: The association among TSH, lipid profile, insulin resistance, hs-CRP and antithyroid antibodies in patients with autoimmune thyroiditis may contribute to an increased cardiovascular risk, not only in patients with subclinical hypothyroidism but also in those classified as euthyroid.
SAT-595 Early Weight Gain Impact onto the Arcuate Leptin Receptor Expressing Neurons Activity During Development
Authors: Zampieri Thais T , Bohlen Tabata M , Donato j Jose , Frazao Renata
Published: May 2020

The arcuate nucleus (ARH) is considered the main mediator of the effects of leptin on energy homeostasis, as well, part of the hypothalamic circuitry through which the sex steroids mediate the ovulatory cycle and therefore reproduction. While it is known that aging influences synaptic plasticity of ARH neurons, the effects of increased weight gain early in life onto in the activity of ARH neurons are still poorly understood. In order to demonstrate whether prepubertal adiposity gain is able to modulate the synaptic transmission in leptin receptor (LepR)-expressing cells of the ARH, we employed a postnatal over-nutrition model by raising mice in small litters (SL), while control mice were maintained in regular litters (6-8 pups per litter). The spontaneous currents of LepR-expressing neurons in the ARH were measured by whole-cell patch-clamp recordings in hypothalamic slices obtained from prepubertal, pubertal and adult female LepR-reporter mice. As expected, mice raised in SL exhibited increased body weight compared to control mice at prepubertal and pubertal stage (prepubertal, t(59) = 6.9, P < 0.001; pubertal, t(59) = 5.3, P < 0.001), despite no difference at adult age (t(59) = 1.5, P = 0.4). By evaluating ARH neuronal activity we observed an increased average of excitatory and inhibitory currents frequency during development, in both control females (sEPSC: F(2, 46)= 17.76, P< 0.0001, sIPSC: F(2, 21)= 4.064, P= 0.0322) and in mice raised in SL (sEPSC: F(2, 49)= 27.76, P< 0.0001, sIPSC: F(2, 19)= 6.714, P= 0.0062). However, SL and control mice exhibited similar sEPSC amplitudes at all stages of development. A significant interaction between litter size and excitatory transmission frequency onto LepR-expressing cells were noted at the pubertal and adult stages (F(2, 95)= 3.164, P= 0.046), despite no changes in the amplitudes of these signals (interaction: F(2, 95) = 0.1516, P= 0.8596; age: F(2, 95) = 0.9961, P= 0.3731; litter size: F(1, 95) = 0.076, P= 0.7832). By evaluating the inhibitory transmission to ARH LepR-expressing neurons, no significant interaction between litter size and inhibitory transmission frequency were observed (F(2, 40) = 0.09271, P= 0.9117). However, the average sIPSC amplitude were significantly reduced in the ARH cells recorded from mice raised in SL, when compared to the control group (F(2, 42) = 22.86, P< 0.0001), despite no identifiable interaction between litter size and inhibitory transmission (F(2, 42) = 0.6619, P= 0.5212). Taken together our results suggest that early weight gain influences the excitatory transmission pattern in LepR-expressing neurons by increasing presynaptic excitatory inputs and suppressing postsynaptically transmission to ARH neurons.
SUN-198 Metastatic Progression of Adrenocortical Carcinoma: Phenotypic Transformation to ACTH-Independent Cushing’s Syndrome
Authors: Ocampo Javier , Luzuriaga Maria Gracia , Ayala Alejandro Raul
Published: May 2020

Background: Adrenocortical carcinoma (ACC) is a rare malignancy. Around 60% of adrenal carcinomas are functioning tumors and may present with distinctive phenotypes (1). Very rarely, as the disease progresses, changes in secretory patterns may be observed.

Clinical Case: A 39-year-old female presented to the hospital with a 1-month history of abdominal pain associated with hirsutism, weight gain, acne, and amenorrhea. Computed tomography of the abdomen showed a 7 cm left adrenal mass with areas of necrosis as well as presumptive metastatic disease involving the liver and lungs. Biopsy of the adrenal mass confirmed the diagnosis of adrenocortical carcinoma. Initial laboratories were compatible with hyperandrogenemia (increased 24-hour urine 17-ketosteroid level of 106.3 mg/24 hr (n 6.0-15.0) and mildly elevated testosterone of 65 ng/dL (n<45)). Aldosterone, renin, and metanephrines levels were normal. The patient underwent adrenalectomy after 1 month and was placed on hydrocortisone replacement. Follow-up biochemical testing showed a decrease in 17-ketosteroids level to 24.7 mg/24hr. DHEAS and testosterone were persistently elevated. Following discontinuation of hydrocortisone, her 24-hour urine cortisol was normal at 18 ug/24hr, (n 6-24) and ACTH was suppressed at 1.8 pg/mL (n 7-63). She was started on mitotane therapy shortly after.

Three months after initiation of treatment, she was admitted for a pulmonary embolism. At that time, she had clear signs of hypercortisolism, such as weight gain, hyperglycemia, easy bruising as well as purple striae. Progressive metastatic disease with enlarged lung and liver masses was observed in imaging. On this occasion, her morning cortisol was elevated at 35 ug/dL and ACTH was suppressed at 1 pg/mL. Th hyperandrogenemia was more evident this time with DHEAS of 778 ug/dl. Steroid supplementation was discontinued, and ketoconazole was started. An elevated 24-hour urinary cortisol (2085 ug/24hr) confirmed the diagnosis of Cushing Syndrome. Given the progression of disease while on mitotane, the patient was started on chemotherapy with etoposide, doxorubicin, and cisplatin.

Conclusion: This case represents an unusual example of the phenotypic transformation of adrenal cancer resulting in new-onset ACTH-independent Cushing’s syndrome while the patient was on treatment. Awareness of such changes in secretory pattern are important to guide therapy and minimize morbidity associated with hypercortisolism.

Reference: (1) Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical Carcinoma with Hypercortisolism. Endocrinol Metab Clin North Am. 2018 Jun;47(2):395-407.
SAT-059 Congenital Craniopharyngioma: A Rare and Challenging Disease
Authors: Lopes Fernanda Sousa Cardoso , Oliveira Renata Santarem , Braz Délia Oliveira , Pacheco Nayla Samia Silva , de Castro Luiz Claudio Goncalves
Published: May 2020

Introduction: Congenital central nervous system tumors are seldomly seen, with just few reported cases of neonatal craniopharyngioma (NCP). Albeit being a benign tumor arising from epithelial vestiges along the adenohypophysis migration, NCP may have an aggressive behavior due to its location.Case Report: We report a two-month-old female infant referred to the Pediatric ward due to recurrent sepsis episodes, uncontrollable crying, large fontanelle and signs of adrenal insufficiency. Laboratory evaluation showed low serum cortisol 0.11 μg/dL(REF: 6.2-19.4 μg/dL), ACTH 6.66 pg/mL(REF: 7.2-63.3pg/mL) and Na 133 mEq/L(REF: 136-145mEq/L), normal Free T4 1.01 ng/dL(REF: 0.93-1.7 ng/dL) and a slightly elevated prolactin 59.43 ng/mL(REF: 4.79-23.3ng/mL). A transfontanelar ultrasound demonstrated a cystic and calcified sellar/suprasellar tumor. Encephalus Magnetic Resonance Imaging described a 36x42x33 mm multicystic sellar/suprasellar mass extending to the middle line and occupying all sellar space, leading to a deformed and compressed third ventricle, and displacing the mesencephalus, the cerebral pedunculus and the optic chiasm. Imaging evaluation suggested a craniopharyngioma. She started hydrocortisone therapy due to hypercortisolism and was submitted to transsphenoidal surgery, but just a partial resection of the tumor was possible. She needed levothyroxine and desmopressin replacement after surgery. On the 10th post-operative day she died due to infectious complications. The histological analysis of the tumor diagnosed an adamantinomatous-type grade I craniopharyngioma.Comments: Central nervous system tumors developing in the first 60 days of life are considered congenital. Besides being a rare condition, NCP are challenging and life-threatening. Although for some groups the complete resection of the tumor is considered the gold standard approach to those patients, sometimes it cannot be performed due to limitations intrinsic to the tumor biology and due to the patient’s age, worsening the prognosis of the infant. Multihormonal deficits and shortened survival of this patient were consequences of the tumor characteristics, delayed diagnosis of craniopharyngioma and the poor results during and after the surgical intervention.
SAT-553 Use of Optimal Cutting Temperature Compound (OCT)-Embedded Adrenal Tumor Tissue for Intratumoral Steroid Hormone Profiling
Authors: Garber Scott R
Published: May 2020

Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for 5-8% of all hypertension. PA is most commonly attributed to an aldosterone-producing adenoma (APA) or to bilateral hyperaldosteronism (BHA). Mutations in the inward-rectifying K+ channel (mKCNJ5), which increase autonomous aldosterone production, are most frequently detected in APAs. APAs with mKCNJ5 display aberrant expression of aldosterone synthase (CYP11B2) and 17α-hydroxylase (CYP17A1), which are involved in aldosterone and cortisol synthesis, respectively. Co-expression of these enzymes results in the production of a set of “hybrid” steroids, which have been proposed as serum biomarkers. The relative production of hybrid steroids in adrenal tumors vs. adjacent normal adrenal (NA) tissue has not been investigated. Objectives: To determine the utility of OCT-embedded adrenal tumor tissue for steroid profiling. To use immunohistochemistry (IHC)-guided OCT tumor capture for intratumoral hybrid steroid profiling in mKCNJ5 APA and NA tissue. Methods: OCT-embedded adrenal tissue from 9 patients (8 women, Age 45.9 ± 3.3 years) with APAs harboring known KCNJ5 mutations were used for the study. Where available OCT-embedded normal adrenal (NA) tissue adjacent to APAs were used as controls (n=4). IHC was performed for CYP11B2 and CYP17A1 on OCT tissue allowing guided APA capture from serial sections. Steroids were extracted from APA and adjacent NA tissue, and quantified by liquid chromatography/tandem mass spectrometry. Steroids measured were normalized to the protein content of the extracted tissue. Results: Compared to NA, APA tissue demonstrated 23-, 5.6- and 6.4-fold higher levels of aldosterone, 11-deoxycorticosterone, and 18-hydroxycorticosterone, respectively (P<0.05). In addition, the “hybrid” steroid products, 18-oxocortisol and 18-hydroxycortisol, were significantly elevated in APA vs. NA (P<0.01). Conversely, the adrenal androgens dehydroepiandrosterone and 11-hydroxyandrostenedione were lower in APA as compared with NA (P<0.05). All mKCNJ5 APAs were also found to co-express CYP11B2 and CYP17A1. Conclusion: IHC-guided mKCNJ5 APA capture and steroid extraction identified a distinct intratumoral hybrid steroid signature that associated with co-expression of CYP11B2 and CYP17A1.These findings also demonstrate that OCT-embedded tissue can be used to accurately define intra-tissue steroid profiles, which will have application for steroid-producing and steroid-responsive tumors.