bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-426 The Impact from AJCC 8Th Edition Staging System on Thyroid Cancer Outcomes by Race And Ethnicity
Authors: Santamaria-Barria Juan Antonio , Graff-Baker Amanda N , Chang Shu-Ching , Khader Adam , Scholer Anthony J , Kledzik-Garland Mary , Goldfarb Melanie
Published: May 2020

Background. Previous studies have demonstrated racial and ethnic outcome disparities among differentiated thyroid cancer (DTC) patients. However, the impact of the 8th edition of the American Joint Committee on Cancer staging system (AJCC8) on these disparities is unknown.

Methods. DTC patients with sufficient tumor and survival data were identified in the National Cancer Database from 2004-2013. The 7th edition of the staging system (AJCC7) and AJCC8 criteria were compared. Multivariable logistic regression was used to evaluate the association between AJCC7 to AJCC8 staging change and race and ethnicity. Cox-proportional hazards regression was then used to evaluate the association between AJCC7 to AJCC8 staging change and overall survival.

Results. Of 33,323 DTC patients, 76.7% were White/Non-Hispanics, 7.6% Blacks, 6.7% Hispanics, 5.4% Asian/Pacific-Islanders, and 3.6% Native-American/Other. Most were female (77%) with papillary DTC (90%). After adjusting for demographic, tumor, and treatment characteristics, Hispanics and Asian/Pacific-Islanders were 27% and 12% less likely to be AJCC7 to AJCC8 downstaged than White/Non-Hispanics (OR=0.73, 95%CI: 0.66-0.81; and OR=0.88, 95%CI: 0.79-0.99, respectively); Blacks had no significant downstaging difference compared to White/Non-Hispanics (OR=0.99, 95% CI: 0.90-1.09, p=0.79). Although AJCC8 was a better survival prognosticator than AJCC7, Cox-proportional hazards regression showed that all AJCC7 to AJCC8 downstaged patients had an increased risk of death compared to patients with unchanged staging, regardless of race and ethnicity: White/Non-Hispanics (HR=2.64, 95%CI: 2.34-2.98), Blacks (HR=1.77, 95%CI: 1.23-2.54), Hispanic (HR=3.27, 95%CI: 2.05-5.22), Asian/Pacific-Islanders (HR=2.31, 95%CI: 1.35-3.98), and Native-American/Other (HR=5.26, 95%CI: 2.10-13.19). However, based on two way interaction, the magnitude of negative change in survival from downstaging was only different between White/Non-Hispanics and Blacks (HR=2.64 vs. HR=1.77, respectively; p=0.04).

Conclusions. Racial and ethnic outcome disparities persist with AJCC8. The proportion of downstaged DTC patients with AJCC8 varies by race and ethnicity, with the least impact found in Hispanics and Asian/Pacific-Islanders. Downstaged patients across all racial and ethnic groups had a decreased survival than those with unchanged stage, with the least impact in Blacks. These disparities should be taken into account when counseling patients about their prognosis with the new AJCC8.
MON-677 A Neuro-Radiological Stroke Mimicker: Non-Ketotic Hyperglycemia Induced Occipital Lobe Hyperdensity Presenting with Seizures
Authors: Pansare Rahul Shashikant , Castillo Mariana Marrero , Scrogin Andrew
Published: May 2020

Background: Acute hyperglycemia in absence of DKA or HHS is a common cause for hospitalization and is termed as Non-Ketotic Hyperglycemia (NKH). NKH-related occipital lobe seizure activity is a rare entity and it’s neuroradiological findings can be confused for acute stroke. We describe a case of NKH-related seizure activity presenting with distinct MRI findings.

Clinical Case: 19-year-old male with DM-1 presented with complaints of burning and numbness involving the left side of face, left upper and lower extremity. These lasted for a few hours and had resolved upon arrival to the ER. At the time of presentation, vitals were stable. Physical examination was significant for flat affect with delayed response to questions without any focal deficits. History obtained from his father revealed that he has had similar episodes of decreased responsiveness during periods of acute hyperglycemia. Laboratory values were significant for glucose of 779mg/dl and sodium of 126mMol/L. Absence of ketones or acidosis ruled out DKA. Normal serum osmolality of 295 ruled out HHS. HbA1c >15% confirmed his non-compliance to insulin use. UDS was negative. Patient was admitted and started on insulin basal/bolus regimen. On the second day of hospitalisation, rapid response was called for seizure-like activity characterised by twitching of left side of face, staring into space and deviation of eyes to left upper corner. This resolved with IV lorazepam without any residual focal deficits. Glucose at the time of seizure was 425mg/dl. He was started on levetiracetam and EEG thereafter revealed no seizure-like activity. CT head and CT angiogram of the head and neck were negative. However MRI showed T2 hyperintensity and restricted diffusion with edema throughout the right occipital lobe. Neurology suspected stroke. However, extensive stroke workup for infectious, autoimmune and hypercoagulable states remained negative. Glucose control was achieved and patient was subsequently discharged on a strict insulin regimen and outpatient follow up with an endocrinologist.

Conclusion: NKH is known to manifest as seizure activity and thus, should be considered an endocrine emergency requiring prompt diabetic management. The suggested pathophysiology for seizures is prolonged hyperglycemia leading to oxidative stress and cellular edema. Furthermore, this may contribute to the unique MRI findings and should not be confused for an acute stroke.

References: Hung WL1, Hsieh PF, Lee YC, Chang MH. Occipital lobe seizures related to marked elevation of hemoglobin A1C: report of two cases.Seizure. 2010 Jul;19(6):359-62. doi: 10.1016/j.seizure.2010.05.006. Epub 2010 Jun 16.
SAT-545 Diabetes Mellitus Is the Risk Factor of Cardiovascular and Cerebrovascular Events in Primary Aldosteronism
Authors: Otsuki Michio , Saiki Aya , Tamada Daisuke , Kitamura Tetsuhiro , Shimomura Iichiro , Naruse Mitsuhide
Published: May 2020

The prevalence of diabetes mellitus (DM) in primary aldosteronism (PA) patients is higher than essential hypertension patients and general population. Though both DM and PA play an important role in the progression of cardiovascular and cerebrovascular (CCV) diseases, the relationship between DM and these diseases in PA patients have not been evaluated.The aim of this study was to investigate whether DM was involved in the risk of CCV events and the progression of renal disorder in PA patients. This study was conducted as a part of the Japan Primary Aldosteronism Study/ Japan Rare Intractable Adrenal Diseases Study (JPAS/JRAS) study and retrospective cross-sectional analysis. The nationwide PA registry in Japan was established at 29 centers, including 15 university hospitals and 14 city hospitals. Patients, who were diagnosed PA between January 2006 and October 2016 and had available data of CCV events and DM, were enrolled (n=2,524). Logistic and liner-regression analysis for CCV events and renal parameters were performed. DM significantly increased the odds ratio of CCV events (OR 1.59, 95% CI: 1.05-2.41). DM also significantly increased the odds ratio of proteinuria (OR 2.25, 95% CI: 1.59-3.16) and had significant positive correlation with declines in eGFR (β=0.05, p=0.02). In conclusion, DM is an independent risk factor for CCV events and proteinuria in PA patients. We should pay attention to whether DM coexists with PA and treat both DM and PA to prevent the exacerbation of CCV diseases and kidney disease. (Supported by AMED grants No. JP17ek0109112/ JP19ek0109352; National Center for Global Health and Medicine, Japan (27-1402/ 30-1008)).
MON-123 Underdiagnosis of Primary Hyperparathyroidism in the Outpatient Setting of an Academic Health Care System
Authors: Dawood Nardeen , Nguyen Dalena , Tseng Chi-Hong , Livhits Masha Jean , Leung Angela M , Yeh Michael W
Published: May 2020

Background: Primary hyperparathyroidism (PHPT) is the leading cause of hypercalcemia in the outpatient population and is associated with nephrolithiasis, osteoporosis, and further end-organ effects. When indicated, parathyroidectomy is an effective intervention. The aim of this study was to assess the prevalence of patients with hypercalcemia resulting from undiagnosed PHPT within a large, urban, academic healthcare system.

Methods: The study population comprised all patients within UCLA Health. The electronic medical record was queried between 01/01/2016-12/31/2018 to include patients with at least two elevated serum total calcium concentrations (>10.4 mg/dL) within a six-month period in the outpatient setting. Causes of secondary and tertiary PHPT were excluded. In concordance with the PHPT diagnostic criteria outlined by the Fourth International Workshop, we evaluated the proportion of patients with hypercalcemia who were further assessed with a serum intact parathyroid hormone (iPTH) test. The study identified cases of PHPT as defined by confirmed elevated serum total calcium concentrations and elevated or inappropriately normal iPTH concentrations.

Results: There were 7102 patients with a single elevated serum total calcium result who never received a repeat assessment within the study period. Although there were 5617 patients with confirmed hypercalcemia, only 2773 (51%) had an iPTH level assessed within six months of the repeated calcium measurement. Of those who underwent iPTH testing, 1931 (69%) were biochemically confirmed to have classic (34.2%) or normohormonal (35.4%) PHPT; the remaining 31% had an appropriately suppressed iPTH concentration relative to the hypercalcemia.

Conclusions: In a large, academic, tertiary healthcare center, over half of the ambulatory patients with confirmed hypercalcemia did not receive further work-up to assess for possible PHPT. Efforts to improve diagnosis of PHPT and expand curative treatment have the potential to decrease the prevalence of nephrolithiasis, bone loss, and further end-organ effects associated with the disease.
SUN-494 A Case of Hyperthyroidism with Multiple Recurrences of Neutropenia After Stopping Methimazole
Authors: Gil Susana Mallea , Sankowicz Silvina , Aparicio Marta , Latorre-Villacorta Laura , Palazzo Adriana , Sosa Maria de los Angeles , Ballarino Carolina
Published: May 2020

Background: The adverse effects of methimazole usually occur in the first 6 months of treatment and they usually are dose dependent. The most severe ones are hepatotoxicity and agranulocytosis, the frequency of the latter is 0.1-0.5% and with a high mortality rate.

Clinical case: A 15-year-old female patient was sent to Endocrinology in May 2017 because of a 4-month history of tremor, palpitations and heat intolerance. Lab tests: WBC: 6,800, neutrophils: 36% (2,448/l), TSH: < 0.06 uU/ml (0.27- 4.7), T4: > 25 ug/dl (4.5 -12), FT4: >7.7 ng/dl (0.93 -1.7), TPO >1,000 UI/ml (<10), TRAb > 40 UI/L (<1.75) which confirmed Graves’ disease. Propranolol 80 mg/day and methimazole 30 mg/day were prescribed. Two months later methimazole dose was increased to 40 mg/d, hematologic lab test was normal. Seven months after starting methimazole the patient presented with febrile neutropenia, methimazole was stopped, methylprednisolone 20 mg/d was prescribed and we increased propranolol to 120 mg/d, neutropenia improved. A month after the first episode of neutropenia, she presented a second episode with a pharyngeal infection, WBC: 6,300, neutrophils: 1%. In December 2017 radioiodine therapy was performed: 15 mCi. Hyperthyroidism was not resolved, she continued with methylprednisolone 20 mg/d and propranolol 120 mg/d, and 6 drops/d of Lugol solution was prescribed. From December 2017 to July 2018, the patient presented 9 episodes of febrile neutropenia, she had a good response to Granulocyte-colony stimulating factor. Serology tests for CMV, VDRL, HIV, Epstein Barr, Toxoplasmosis, hepatitis B and C were all negative. Lab tests for rheumatologic diseases: rheumatoid factor, C3 and C4, electrophoretic proteinogram, antiestreptolysin O, anti-DNA, ANA, anti-Ro/SSA, anti-La/SSB were all negative, and immunoglobulins were normal. Bone marrow aspiration was normal. We could not perform flow cytometry of anti-neutrophil cytoplasmic antibodies (C-ANCA). Hyperthyroidism persisted and a second I-131 treatment was performed (20 mCi) in June 2018. A month later she presented hypothyroidism, levothyroxine was indicated. She continued with episodes of febrile neutropenia until March 2019, 23 months after the diagnosis of hyperthyroidism, 16 months after stopping methimazole and 8 months after having initiated levothyroxine treatment and having normal thyroid levels.

Conclusion: We presented a young female patient with persistent and recurrent neutropenia despite having stopped methimazole, and regardless of her thyroid hormone levels. Although neutropenia usually appears in the first months of treatment, it seldom occurs much later and almost never after stopping the drug. We could not reach an etiological diagnosis of neutropenia, but it is probable that methimazole had triggered an immune-hematological illness associated to Graves’ disease.
MON-924 Susceptibility Genetic Testing and Functional Imaging Modalities in the Management of Bladder Paragangliomas
Authors: Anandappa Samantha , Joshi Mamta , Breen Louise A , Thurairaja Ramesh , Christodoulou Dimitra , Jacques Audrey , McGowan Barbara Maria Cristina , Izatt Louise , Velusamy Anand , Carroll Paul V
Published: May 2020

Introduction: Bladder Paragangliomas (PGLs) are rare neuroendocrine tumors derived from sympathetic paraganglionic tissue within the bladder wall, accounting for <1% of all Pheochromocytomas and Paragangliomas (PPGLs). >40% of PPGLs are associated with inherited syndromes through mutations affecting citric acid cycle enzymes (commonly SDH). Susceptibility gene identification has important implications for long-term care and facilitates targeted cascade genetic screening. Functional imaging using MIBG, Gallium DOTATATE and FDG-PET have become important tools in both diagnosis and treatment (Peptide Receptor Radionuclide Therapy).

Clinical Cases: We report the demographics, clinical characteristics and novel features of 7 patients with bladder PGLs. The series includes 2 females and 5 males, median age 38 years (range 14-68). 5 presented with hematuria and 2 were detected incidentally (1 found on radiological imaging and the other during cystoscopy surveillance). Other symptoms reported were headaches, sweating and palpitations which were relieved by urination. Only 1/7 had a known family history of PGLs. 5/7 patients had elevated plasma normetadrenaline levels and 2 had non-elevated catecholamine metabolites (these 2 patients were asymptomatic).

6/7 patients had genetic testing performed and pathogenic variants were identified in 4 (Fumarate hydratase (FH), SDHA, SDHB*2 genes) and no pathogenic variant identified in 2 patients in our genetic panel of 10 PPGL genes. All primary tumors demonstrated MIBG avidity and in 2 patients assessed there was PGL FDG-PET avidity. Metastatic disease was present in 2 patients (2 SDHB mutations; with 1 MIBG avid bone and 1 FDG-PET avid nodal metastasis). SDHB immunostaining on resected histology was available for 3 cases - absent SDHB immunostaining in the patient with SDHA mutation and strongly positivity in 2 patients (1 with no genetic mutation and in 1 with FH mutation).

Conclusions: The majority (>65%) of patients with bladder PGL have a germ line mutation in a susceptibility gene involving the citric acid cycle. An extended gene panel should be performed in all patients diagnosed with bladder PGLs including SDHA and FH gene mutations. SDH immunostaining of tumour can indicate SDHx gene defects but can be normal in FH mutations. SDHB is associated with increased risk of malignant/metastatic behavior. All 3 modalities of functional imaging (Ga DOTATATE, FDG PET, & MIBG) have a role in the assessment and treatment decision making in the management of bladder PGLs.
SUN-518 Graves’ Disease Newly Diagnosed in the Setting of Hypokalemic Periodic Paralysis in an HIV+ Patient
Authors: Nosova Emily V , Japp Emily , Brown Sheldon T , Cohen Alan J , Greenberg Pietra D
Published: May 2020

Relevance: A rare yet distinct cause of sudden onset paralysis is severe hypokalemia associated with thyrotoxicosis. This is thought to be associated with mutations in genes encoding cellular potassium channels. We report a case of acute onset paralysis with profound hypokalemia and a new diagnosis of Graves’ thyrotoxicosis in a previously asymptomatic African American, HIV+ man on highly active antiretroviral therapy (HAART) for over 8 years.

Clinical case: A 49-year-old man with hypertension and HIV presented with acute paralysis of his bilateral upper and lower extremities. His initial potassium was 1.8 mEq/L (3.5-5.0). Prior to sudden onset loss of motor strength, he denied any preceding palpitations, tremor, anxiety, diaphoresis, hyper-defecation, weight loss, heat or cold intolerance, neck pain, increase in neck girth or difficulty swallowing, proptosis or other ocular symptoms. He has no family history of thyroid disease. He had an enlarged palpable thyroid without nodules and no audible bruit. There was no periorbital edema or proptosis, and no signs of dermopathy. A thyroid ultrasound showed a hyperemic and diffusely enlarged thyroid gland without nodules. Labs included a TSH of 0.007 mCU/mL (0.43-3.8), Free T4 2.1 ng/dL (0.71-1.85), Total T3 229.6 ng/dL (58-194), and thyrotropin receptor antibody 2.6 IU/L (0-1.75). The CD4+ count was 146 in 2010 with a slow gradual rise to 673 in 2019, and HIV viral load was undetectable. There were no offending medications or supplements identified. With aggressive potassium repletion, the serum potassium improved to 4.6 mEq/L and he regained normal strength within several hours. He was started on Methimazole 10mg daily and propranolol 10mg TID. At one month, the thyroid function tests normalized. Methimazole 10mg daily was continued and propranolol was tapered off. He remains euthyroid. Genetic testing is pending.

Conclusions: Graves’ disease is the most common thyroid disease triggered by immune reconstitution in HIV + individuals on HAART. The incidence of thyroid disease in HIV patients on HAART is higher in women and Africans with a 1.5-2 fold increase compared with the general population [Muller et. al, Eur Thyroid J 2019;8:173-185]. Despite a higher incidence of hyperthyroidism in women, over 95% of cases of hypokalemic periodic paralysis have been reported in men, with a 10-fold higher incidence among Asians compared to Westerners. There has been one prior case report of Thyrotoxic Periodic Paralysis in an HIV + patient and this was in a Polynesian male (Brown JD et al. Hawaii Med J 2007). To our knowledge, this is the first case report of an African American HIV+ patient with this disorder. An association with mutations in the Kir2.6 gene (encodes a potassium channel, is expressed in skeletal muscle, and is transcriptionally regulated by thyroid hormone) has been proposed [Ryan et. al, Cell 2010 January 8; 140(1):88-98].
OR19-07 Metformin Inhibits Activation of the Melanocortin Receptor 2 and 3 in Vitro, a Possible Mechanism for Its Anti-Androgenic and Weight Balancing Effects in Vivo
Authors: Flueck Christa E , Parween Shaheena
Published: May 2020

Metformin is recommended as one of the first-line drugs for the treatment of type 2 diabetes and the metabolic syndrome. In addition to its insulin sensitizing effects, it has been shown to attenuate androgen excess in women with polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), as well as to ameliorate obesity. The mechanisms of metformin action seem manifold. Preclinical studies suggest that it inhibits the cellular stress response at the level of the mitochondrial OXPHOS system and through AMPK dependent and independent mechanisms. Recent studies have shown that metformin decreases ACTH secretion from pituitary and reduces ACTH-stimulated adrenal secretion. In this study we investigated the effect of metformin through its specific melanocortin receptor 2 (MC2R) on signaling targeting adrenal steroidogenesis. To assess this effect, we used mouse adrenal OS3 cells, which do not express the MC2R. Cells were transfected with the human melanocortin receptor 2 and stimulated by ACTH. Downstream cyclic AMP production was then assessed by a co-transfected cAMP-responsive vector producing luciferase that was measured by a dual luciferase assay. The amount of luciferase produced in this assay corresponds to the amount of receptor activation with varying amount of ACTH. The effect of metformin was then tested in this system. We found a significant inhibition of ACTH induced MC2R activation and signaling with 10 mM metformin. The ACTH concentration response curve (CRC) was half-log shifted indicating antagonism. This effect was dose dependent with an IC50 of 4.2 mM. Metformin did not affect cell viability and basal cAMP level under used conditions. We also tested the effect of metformin on homologous receptors (MCRs). No significant effect was found on MC1R and MC4R activity. However, a 2-log shift in ACTH EC50 was observed with MC3R. In conclusion, metformin seems to act on MC2R and MC3R signaling directly. The role of MC2R for steroidogenesis is well established. MC3R is involved in energy balance and seems to act as a rheostat when the metabolism is challenged. Our study may explain how metformin attenuates the excess response to ACTH and helps in weight loss and improving androgen excess in PCOS and CAH.
MON-473 Evaluating Conflicting Thyroid Function Tests in New Admissions: Discordance of TSH, FreeT4 and Clinical Status: A Clinical Challenge!
Authors: Patel Sabah , Krutilova Petra , Gilden Janice L , Barsano Charles P
Published: May 2020

Background: It is not uncommon to encounter patients whose thyroid function tests (TFTs) seem mutually inconsistent or inconsistent with a patient’s clinical status, At times, the simplest reconciliation of the findings invokes a rare disorder that we are hesitant to accept. In this case, a clinically euthyroid patient presents with elevated TSH and Free T4 (FT4) suggestive of a TSH-producing tumor or of Thyroid Hormone Resistance.

Clinical Case: A 72 yr-old man with cardiomyopathy on amiodarone is admitted to the Medical Service for treatment of anasarca. He had no symptoms or signs of thyroid dysfunction and was not taking L-T4, amphetamines or propranolol. Findings on exam included normal VS, runs of atrial tachycardia, and edema from feet to scrotum. Thyroid exam was normal. Serum creatinine was 2.24 mg/dl (NL: 0.67-1.17). Bili was 2.7 mg/dl (NL: 0.67-1.17); AST and ALT were normal, Chest x-ray revealed cardiomegaly with clear lung fields. Thyroid ultrasound revealed a normal size gland containing a few sub-centimetric nodules. On Day 2 The serum FT4, by analog assay, was elevated at 1.66 ng/dl (NL: 0.76-1.46) and TSH was elevated at 9.06 mIU/L (NL: 0.35-3.74), Anti-peroxidase and anti-thyroglobulin antibodies were negative. The Medical Service’ diagnosis was “amiodarone-induced thyroiditis.” The amiodarone was discontinued and diuresis was induced with bumetanide, Endocrinology consultation was requested On Day 4 the FT4 and TSH were still elevated at 1.62 and 10.1, respectively. FT4 by dialysis was not elevated at 1.62 ng/dl (NL: 0.9-2.2). The FT3 was 2.34 pg/ml (NL: 2.18-3.98). On Day 5 Anti-thyroxine antibodies and Thyroid Stimulating Immunoglobulins (TSI) were negative. Paired TSH samples with and without neutralization of Human Anti-Mouse Antibodies (HAMA) were identical: both elevated at 8.30 mIU/L (NL: 0.4-4.50). Serum Iodine was markedly elevated at 2288 mcg/L (NL: 52-109).

The FT4 levels by analog assay therefore appear to have been falsely elevated (as indicated by the dialysis assay) though not by recognized factors such as thyroxine antibodies, amphetamines or propranolol. Continued observation is necessary to further assess the transience of the post-admission TFTs.

Conclusion: In patients admitted to Acute Medical or Psychiatric Services, most combinations of high or low TSH and FT4 have been reported as well other aberrations of “non-thyroidal illnesses.” In patients with conflicting TFTs at admission, especially those who are clinically euthyroid, it is generally better to allocate a few weeks for observation and monitoring than to immediately launch into searches for rare disorders. This is especially important when multiple potentially thyro-active clinical states exist, such as renal and hepatic compromise, amiodarone use, and highly elevated iodine levels.
SUN-482 A Very Rare Case of Thyroid Cancer
Authors: Lokshin Vladimir , Soni Lina , Luis Milay , Hope Lisel
Published: May 2020

Background: Cribriform-Morular variant of Papillary Thyroid Cancer (PTC-CMV) is an exceedingly rare subtype of thyroid cancer that predominantly affects younger females. As the name implies, it is a papillary thyroid carcinoma with predominantly cribriform and morular pattern of carcinoma cells on cytopathology. While completion thyroidectomy is usually recommended for larger and higher-risk Papillary Thyroid Cancer (PTC), surveillance may be acceptable with PTC-CMV, which tends to be a less aggressive malignancy. Clinical Case: A 46-year-old Guyanese woman presented with a three week history of an enlarging right-sided neck mass associated with a globus sensation while swallowing food. She denied any history of radiation exposure. Her exam findings were positive for a tender, right-sided neck mass. CT neck without contrast revealed a 4.1 x 4.0 x 5.9cm heterogeneous mass within the right thyroid lobe causing mild tracheal deviation to the left. Ultrasound of thyroid gland showed a solid heterogeneous hypoechoic 4.22 x 2.39 x 2.46cm right lobe nodule with no microcalcifications, border irregularity or taller-than-wider morphology. Fine Needle Aspiration of the nodule came back as Atypia of Undetermined Significance. The patient then underwent a core needle biopsy. The resultant pathology was negative for thyroid carcinoma or medullary thyroid carcinoma but was suggestive of a bronchial cleft cyst versus bronchogenic cyst with atypical glandular proliferation. She subsequently underwent a right hemithyroidectomy which revealed a final pathological diagnosis of a 3.5cm PTC-CMV. Such pathology warranted the patient to undergo a colonoscopy which was negative for Familial Adenomatous Polyposis (FAP). Given her negative GI workup and non-contributory family history for colonic polyposis or carcinoma the decision was made to continue surveillance rather than performing completion thyroidectomy as the disease was presumed to be sporadic. Discussion: PTC-CMV accounts for 0.2% of all PTC. It is associated with FAP in more than 50% of cases but can also occur sporadically. This subtype of PTC generally follows a less aggressive course. Review of current literature revealed several case series of CMV-PTC patients. In the largest one, 32 cases were observed over a 19 year period and only two out of twelve patients with FAP-associated PTC-CMV initially treated with hemithyroidectomy developed recurrence to the contralateral lobe. Interestingly, none of the remaining patients with the sporadic type developed recurrence suggesting that completion thyroidectomy may not be mandatory in this group. It is, therefore, critical to identify these patients and screen them with a colonoscopy to avoid the potentially unnecessary resection of the contralateral lobe and the consequent need for thyroid hormone replacement.
SUN-032 Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism
Authors: Cho Yun Kyung , Kim Sang-Wook
Published: May 2020

Background: Normosmic congenital hypogonadotropic hypogonadism denotes Kallmann syndrome not associated with anosmia or hyposmia. Over the past few years, the availability of next-generation sequencing has started to unravel the complex molecular basis of congenital hypogonadotrophic hypogonadism including digenic or oligogenic pathogenecity in addition to classic monogenic causality (1).

Clinical Case: A 22-year-old male patient was referred to the endocrine clinic in 2018 with recent -onset hyperglycemia. His weight was 82.2 kg with a height of 180 cm (BMI of 25.3 kg/m2). Physical examination revealed small testes, micropenis, and no axillary and pubic terminal hair. His smell sense was intact. His hormonal test reveals low testosterone (0.10 ng/mL) and low free testosterone (0.65 pg/mL) levels with inappropriately low gonadotrophins levels. Secretion of LH and FSH increased 2-fold after GnRH stimulation. His bone age was 13-years 6-months old, and brain magnetic resonance imaging showed the presence of olfactory bulbs, and unremarkable findings except for small size of the pituitary gland. There were no signs associated with CHARGE syndrome (coloboma ocular, heart defects, atresia or stenosis of the choanae, retardation of growth and/or development, genitourinary anomalies, and ear abnormalities). Biochemical investigation demonstrated high serum glucose level and high HbA1c (13.8%). To identify variants to cause the phenotype of the proband, we adopted trio-based whole exome sequencing (WES) and candidate gene approach. Candidate genes was listed from the orphanet (https://www.orpha.net). WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C>T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G>A, p.Arg80Gln, rs1799904). The missense variants were predicted to have a damaging effect on the encoded protein, by SIFT and PolyPhen-2 analyses. Genetic analyses of his family revealed that his father had the same heterozygote missense mutations of the CHD7 gene, but wild type of PCSK1. Proband’s mother had the same heterozygote missense mutations of PCSK1, but wild type of CHD7. Furthermore, the proband had homozygote missense mutation of PAX4 (c.575G>A, p.Arg192His, rs2233580) known as maturity-onset diabetes of the young (MODY) 9 gene. Both parents have the same but heterozygous mutation of PAX4 p.Arg192His, and pre-diabetic range of hyperglycemia.

Conclusion: This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male.

Reference: (1) Maione L, et al. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55-R80.
SUN-744 Phosphorylation Site S122 in Estrogen Receptor α Has a Tissue-Dependent Role in Female Mice
Authors: Gustafsson Karin L , Farman Helen H , Henning Petra , Lionikaite Vikte , Movérare-Skrtic Sofia , Sjogren Klara , Andersson Annica , Islander Ulrika , Bernardi Angelina I , Chambon Pierre , Ohlsson Claes , Lagerquist Marie K
Published: May 2020

Estrogen treatment increases bone mass and reduces fat mass but is associated with adverse effects in postmenopausal women. Knowledge regarding tissue-specific estrogen signaling is important to aid the development of new tissue-specific treatments. We hypothesized that the posttranslational modification phosphorylation in estrogen receptor alpha (ERα) may modulate ERα transcriptional activity in a tissue-dependent manner. Phosphorylation of site S122 in ERα has been shown in vitro to affect ERα activity, but the tissue-specific role in vivo is unknown. We herein developed and phenotyped a novel mouse model with a point mutation at the phosphorylation site 122 in ERα (S122A). Female S122A mice had increased fat mass and serum insulin levels but unchanged serum sex steroid levels, uterus weight, bone mass, thymus weight, and lymphocyte maturation compared to WT mice. In conclusion, phosphorylation of ERα S122 has a tissue-dependent role with an impact specifically on fat mass in female mice. This study is the first to demonstrate in vivo that phosphorylation of a transactivation domain in a nuclear steroid receptor modulates its activity in a tissue-dependent manner.
SAT-661 The Lesser Evil: Pembrolizumab Induced Remission of Metastatic Melanoma with Autoimmune Diabetes, Hypothyroidism, and Colitis
Authors: Harris Asaf , Andres Kayla , Kawji Mohammad
Published: May 2020

Background: Immune checkpoint inhibitors (ICI) are a new class of immunotherapy agents that empower the innate immune system to destroy cancer cells by overcoming checkpoints against autoimmunity and self-tolerance. ICI use against certain cancers has yielded impressive results. Pembrolizumab, an ICI approved by the FDA in 2014 for treatment of metastatic melanoma, is a monoclonal antibody which binds the programmed cell death protein 1 (PD1) receptor, blocking it’s activation. Recent case reports have demonstrated a link between pembrolizumab and severe immunotherapy related adverse events including the incidence of autoimmune disorders.

Clinical Case: A 68-year-old male with hypertension and a past medical history of cutaneous melanoma treated fifteen years earlier with tumor resection was started on pembrolizumab after identification of new metastases to the lung and bones. After 3 cycles of therapy he began to experience dizziness, lightheadedness, and vision changes with diarrhea. Outpatient labs demonstrated hyperkalemia with hyponatremia. He was directed to the emergency department by his oncologist for presumed adrenal insufficiency, where he received one dose of IV dexamethasone (4 mg). Repeat labs demonstrated severe diabetic ketoacidosis with elevated blood glucose 981 (70-99 mg/dL), pH 7.19 (7.32-7.42), anion gap of 37 (4-15 mmol/L), and betahydroxybutyrate > 9.00 (0.00-0.40 mmol/L). Following endocrinology consultation steroids were discontinued in favor of iv insulin and fluid resuscitation, with admission to the medical intensive care unit. Further lab testing demonstrated low C-peptide levels and positive IA-2 and GAD-65 antibodies, confirming autoimmune diabetes. Endoscopic biopsy was also consistent with autoimmune colitis, and TSH one month after discharge was 123.70 (0.30-5.00 mcIU/mL) with free T4 < 0.1 (0.6-1.6 ng/dL).

Despite early discontinuation of anti-PD1 therapy the melanoma has remained in remission for three years, suggesting a sustained immune response. He continues to require insulin and thyroid hormone replacement, though the autoimmune colitis has resolved.

Conclusion: This case demonstrates the overall benefit of immune checkpoint inhibitor therapy in the treatment of metastatic melanoma, while highlighting a potentially lethal therapy complication with the concurrent onset of multiple autoimmune processes affecting separate organ systems. Increased awareness of the potential for DKA in patients not previously diagnosed with diabetes is needed to avoid delays in care and improve outcomes. This case also suggests a potential benefit to integrating routine blood glucose monitoring in immune checkpoint inhibitor treatment protocols, the utility of which should be further investigated.
MON-302 The Prevalence of Acromegaly in the Sleep Apnoea Clinic
Authors: Lynch Julie Marie , Kyriakakis Nikolaos , Elliott Mark , Baldwin Lisa , James Anneli , Seejore Khyatisha , Ghosh Dipansu , Watts Sue , Sathyapalan Thozhukat , Murray Robert Douglas
Published: May 2020

Introduction: The prevalence of acromegaly in the general population ranges 4-14/100,000. 45-80% of acromegaly patients have obstructive sleep apnoea (OSA). The OSA population might represent a target group for earlier detection of acromegaly, thereby reducing associated long-term morbidity.

Methods: Patients attending the sleep service (11/2014-04/2018) were recruited in a prospective multicentre cohort study. All had serum IGF-1 measurement and completed a screening questionnaire for five key symptoms associated with acromegaly. Those with raised age-specific IGF-1 underwent further biochemical assessment to investigate for acromegaly.

Results: 1080 participants (73% male, mean age 55.6±12.0yrs) with confirmed OSA were recruited across two sites. Forty-three patients (4%) reported at least 4/5 acromegaly-related symptoms. There was no correlation between serum IGF-1 and symptom score. Sixty-one patients (5.7%) had elevated IGF-1 level on initial assessment. Fifty-one had repeat IGF-1 testing, while one had growth hormone measurement of <1µg/L. Nine patients were lost to follow-up, including one death.

Of the repeat IGF-1 tests, results were normal in 24 cases and no further investigation was undertaken. Repeat IGF-1 results were unavailable in 3 cases. In the remaining 24 patients with persistently raised IGF-1, 11 had GH <1µg/L, suggesting that acromegaly was unlikely. The remainder (n=13), as well as the 3 individuals with unavailable IGF-1 results, had an oral glucose tolerance test. One patient (BMI of 23.7kg/m2) was diagnosed with acromegaly, was diagnosed with severe OSA and reported 4/5 acromegaly-related symptoms during screening.

Conclusion: Our study identified a single case of acromegaly within the OSA population that may represent a higher prevalence than in the background population, however is based on a single case. As a consequence of the significant number of patients with elevated serum IGF-1 measurements requiring further investigation, IGF-I is not currently a cost-effective screening tool for early detection of acromegaly in OSA patients.

Funding: Ipsen UK
SAT-377 Case Series of Ectopic Parathyroid Gland
Authors: Rajoo Subashini , Kuan Yueh Chien , Tong Chin Voon
Published: May 2020

The prevalence of mediastinal parathyroid adenoma is unknown. Embryological origin and more extensive aberrant migration of the parathyroid glands result in ectopic glands found in the mediastinum. We report herein 4 cases of ectopic parathyroid adenoma causing primary hyperparathyroidism from three public hospitals in MalaysiaCase 1.A 70 year old lady with underlying diabetes mellitus, hypertension, chronic immune thrombocytopenic purpura and liver cirrhosis presented with incidental asymptomatic hypercalcemia during an admission for pneumonia. Her blood results revealed high corrected calcium of 2.93 mmol/L (2.02-2.60) and a low phosphate of 0.66 (0.81-1.45) mmol/L with an unsuppressed intact parathyroid hormone (iPTH) of 14.56 pmol/L (1.6-6.9). She had an equivocal urinary calcium excretion ratio of 0.01. Her bone mineral density confirmed severe osteoporosis at distal radius and neck of femur with a Tscore of -3.6 and -3.1 respectively. A hyperfunctioning ectopic parathyroid gland was seen in the Technetium Sestamibi scan which corelates with a mediastinal lymphadenopathy on CECT. The largest node measured 1.6 x 1.2 cm. Parathyroid gland was confirmed on HPE of the video-assisted-thoracoscopic surgical (VATS) excision of the mediastinal mass. Intraoperative iPTH (ioPTH) serially reduced from 8.87 to 1.94 to 1.03 pmol/L and she maintained a serum calcium levels of 2.4 mmol/L post surgery. She did not require any calcium or vitamin D supplementation. Case 2. A 36 year old male presented with generalized body weakness secondary to hypokalemia. His calcium was 3.07 mmol/l, phosphate 0.64 mmol/l and iPTH 11.53 pmol/L. Increase Technetium uptake seen at mediastinum. Post operatively, calcium normalized and remained stable 1 year later. Case 3.47 year old female presented with acute gallstone pancreatitis complicated with a pancreatic pseudocyst. She was found to have hypercalcemia of 2.77 mmol/L, phosphate 0.70 mmol/l and iPTH 21.87 pmol/L. Sestamibi scan revealed hyperfunctiong parathyroid tissue posterior to the left thyroid lobe and in the mediastinum. She is awaiting surgery. Case 4.Another asymptomatic 47 year old male who has history of post Radioactive-iodine hypothyroidism had an incidental finding of serum calcium of 2.69-2.84 mmol/L, phosphate 0.71-0.91 mmol/L and iPTH 9.89 pmol/L with urinary calcium excretion ratio of 0.019. His Sestamibi scan showed uptake at the superior mediastinum. Ectopic parathyroid gland is rarely encountered. With the advent of Technetium-Sestamibi scintigraphy, ectopic parathyroid adenoma can be localized easily. However, surgery poses a challenge due the location of the adenoma which may occasionally be near large vascular structures in the mediastinum. The availability of intraoperative PTH aids the decision for surgical exploration and completion.
OR06-02 TBR-760, a Chimeric Somatostatin-Dopamine Compound, Arrests Aggressive Non-Functioning Pituitary Adenoma Growth In Vivo
Authors: Halem Heather A , Hochgeschwender Ute , Thiagalingam Arunthi , Culler Michael D
Published: May 2020

TBR-760 is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R; EC50 0.064nM) and SST type 2 (SSTR2; EC50 1.2nM) receptors. Prior studies have demonstrated that the chimeric DA-SST compounds are more potent and effective than either individual or combinations of individual DA and/or SST analogs in inhibiting secretion from pituitary adenomas. Non-functioning pituitary adenomas (NFPA) express high levels of D2R as well as lower levels of SSTRs, including the type 2 receptor (1), and thus have an appropriate receptor profile to respond to TBR-760. The present study examines the ability of TBR-760 to inhibit tumor growth in a mouse model of aggressive NFPA. Heterozygous and null mutant mice lacking one or both copies, respectively, of the pro-opiomelanocortin (POMC) gene (POMC-KO mice)(2) spontaneously develop aggressive, non-secreting pituitary adenomas (3). The POMC-KO mouse tumors have been shown to express D2R and SSTR2 at a similar level as human NFPAs (4). In addition, merging of microarray data (Affymetrix, U133 plus_2.0 and Mouse Genome 430 2.0 arrays), reveals 154 common gene signatures between human NFPAs and the POMC-KO mouse tumors. In an initial study, heterozygous POMC-KO mice with an established pituitary tumor of approx. 10mm3 (mean volume 8.9±0.3), as determined by MRI, were treated with a range of TBR-760 doses (0.125 to 12.5mg/kg, sc, QD) for 60 days. During that time, tumors in vehicle-treated mice increased in size by 890±0.7%, whereas all doses of TBR-760 tested resulted in a nearly complete inhibition of tumor growth from treatment initiation. We then compared the effect of the TBR-760 chimera with that of its individual SST agonist (SSTA) and DA agonist (DAA) components on tumor growth in the POMC-KO mice. As in the earlier study, TBR-760 treatment (1mg/kg, sc, QD), initiated when the mice had an established tumor of approx. 10mm3, completely arrested tumor growth during the 8 weeks of treatment (final mean tumor volume of 8.5±1.3mm3 vs. 54.61±10.6mm3 in vehicle-treated mice). Treatment with equimolar or 10x-higher doses of the individual SSTA or DAA, either alone or in combination, had no significant effect on tumor growth, except in the lower dose DAA group where a modest suppression of tumor growth was observed. These data demonstrate that only the dual DA-SST chimeric compound, TBR-760, completely arrested tumor growth in the POMC-KO mouse model of NFPA. Further, despite the highly aggressive nature of the POMC-KO tumors, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a medical therapy to prevent or arrest the growth of NFPAs and, potentially, to induce NFPA shrinkage. References: (1) Florio et al., 2008 Endocr Relat Cancer; 15: 583-596. (2) Yaswen et al., 1999 Nat Med; 9:1066-70 (3) Karpac J et al., 2006 Cell Mol Biol; 52: 47-52.
MON-492 Should Isthmic Thyroid Nodule Be Included in ACR TI-RADS Points in Predicting Thyroid Cancer?
Authors: Jasim Sina , Baranski Thomas J , Teefey Sharlene , Middleton William
Published: May 2020

Background: Thyroid nodules are routinely evaluated with ultrasound. Isthmic nodules carry higher risk of malignancy (in press). Surgical studies suggest higher risk of metastasis from thyroid cancer located in isthmus region. In this study, we evaluate how adding an extra point for isthmic location to current ACR-TIRADS will affect the sensitivity and specificity to predict thyroid cancer.

Methods: We performed a subanalysis of isthmic nodules contained in a retrospectively created database of 3313 adult patients from six referral centers with confirmed benign or malignant nodules. Sensitivity and specificity were calculated using the current ACR TI-RADS scoring system and compared to a system that would add an extra point based on nodule location in the isthmus.

Results: There were 195 nodules in the isthmus (34 malignant). If a recommendation for FNA was considered a positive test result, the sensitivity and specificity would be 50% (17/34) and 61% (99/161) respectively using current ACR TI-RADS scoring. If an additional point was added the sensitivity and specificity would be 62% (21/34) and 36% (58/161) respectively. Adding the additional point would lead to detection of 4 additional malignant nodules at the cost of biopsying 41 additional benign nodules. If a recommendation for either FNA or follow-up ultrasound for 5 years was considered a positive test result, the sensitivity and specificity would be 82% (28/34) and 35% (56/161) respectively using current ACR TI-RADS scoring. If an additional point was added the sensitivity and specificity would be 94% (32/34) and 15% (24/161) respectively. Adding the additional point would lead to detection of 4 additional malignant nodules at the cost of either biopsying or following 32 additional benign nodules.

Conclusions: Isthmic nodules are more likely to be malignant than nodules in other locations. When using the ACR TI-RADS, adding a point for isthmic nodules improves detection of cancer with a moderate increase in the rate of FNA and follow-up of benign nodules. Given the higher risk of extra thyroidal extension and nodal metastases for isthmic cancers, this tradeoff between sensitivity and specificity may be acceptable and should be considered when dealing with nodules in the isthmus.

Keywords: thyroid nodule, ACR TI-RADS, location, isthmus, thyroid cancer