bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-394 Concordant Parathyroid Imaging; Frequency and Predictors of Concordance and Its Impacts on Cure
Authors: Khine Aye Aye , Muhamad Hatta Sharifah Faradila Wan , Buch Harit , Yousuf Quratulain , Vydianath Sanjay , Strouhal Peter , Garnham Andrew
Published: May 2020

Introduction: Accurate pre-operative imaging of a parathyroid adenoma facilitates minimally invasive surgery for primary hyperparathyroidism, increases cure rate and reduces perioperative complications. The two most commonly deployed preoperative localization studies are ultrasonography (US) and parathyroid scintigraphy using 99m-techentium sestamibi (RN). Patients who have concordant results between the two studies (most studies report concordance rate of 60%) usually undergo minimally invasive surgery whilst those with non-concordance scan results often need bilateral open neck surgery.Objectives: We did a retrospective assessment of the clinical, biochemical and imaging parameters of patients who had parathyroid surgery in our hospital to assess (a) the sensitivity and positive predictive value (PPV) of US and RN scans (b) the frequency of concordance between the two imaging studies (c) the clinical and laboratory predictors of concordance and (d) the impact of concordance on the cure rate.Method: 155 patients who were operated for PHPT between January 2011 and January 2019 were included. All patients underwent preoperative localization with US and RN imaging. The sensitivity and PPV of the 2 imaging procedures in detecting a parathyroid adenoma were determined by correlating the imaging findings of both scans with the composite information obtained from surgical findings and post-operative biochemical results to indicate cure. The patients with concordant and non-concordant imaging findings were compared for surgical cure rate, serum calcium and parathormone level, and the volume and weight of the adenoma.Results: The sensitivity and PPV of US were 80.9% and 82.8% and for RN scan 78.7% and 87.8% respectively. There was no statistically significant difference in the accuracy between the two modalities. 93(60%) patients had concordant and 62(40%) patients had non-concordant scan results, which included true discordance and non-localization by one or both scans. Cure rate in concordant and non-concordant scans were 96.8% and 83.7% respectively (p=0.02, chi-square). In comparison to patients with non-concordant imaging, patients with concordant imaging had higher level of serum calcium (mean 3.02 vs 2.86, p=0.04), the resected adenoma was larger in volume (mean 3109mm3 vs 2083mm3, p=0.05) and was heavier (mean 1.59 vs 1.10 p=ns). However there was no difference in the age or serum PTH level between the 2 groups of patients.Conclusion: Both US and RN imaging have similarly high sensitivity and PPV in identifying a parathyroid adenoma and our figures were comparable to the published literature. When the two studies are concordant a significantly higher surgical success rate is obtained. Patients with higher serum calcium and larger adenomas are more likely to demonstrate concordant imaging.
SUN-216 Investigating the Role of the Liver X Receptor in Potentiating Mitotane Therapy in Adrenocortical Carcinoma
Authors: Warde Kate , Shoenmakers Erik , Leonard Maeve , Maunsells Rebecca , Hantel Constanze , Gurnell Mark , Dennedy Michael Conall
Published: May 2020

Introduction: Adrenocortical Carcinoma is a rare aggressive cancer which carries a poor prognosis. Adjuvant mitotane improves survival but is limited by a narrow therapeutic window and severe adverse effects. Liver X receptors (LXRs), part of the nuclear receptor superfamily are highly expressed in adrenal tissue and mediate transcellular and intracellular cholesterol homeostasis. We hypothesise that LXRα inhibition increases toxic lipid accumulation in adrenocortical cancer cells and potentiates the adrenolytic effect of mitotane. Methodology: ATCC-H295R and MUC1 ACC cells and were pre-treated with the LXRα inverse agonist SR9243 5µM and antagonist GSK2033 5µM followed by mitotane treatment (20, 40, 50μΜ) for 6 hours. Cholesterol-methyl-β-cyclodextrin treatment was carried out 1hr prior to mitotane. H295R cells were transfected with a LXR⍺ dominant negative construct using lipofectamine. Cell death was assessed using annexin/PI staining and proliferation using MTT assay. Free cholesterol (FC) levels were assayed using filipin staining and lipid droplets via BODIPY® and analysed on the Amnis ImageStream® imaging cytometer. Downstream targets ABCA1 and ABCG1 were evaluated by qRT-PCR. Lipid droplet associated proteins PLIN 1-4 and hormone sensitive lipase (HSL) expression were evaluated using western blotting. Results: Downstream reduction of ABCA1 and ABCG1 expression confirmed LXRα blockade. Mitotane effectively induced dose-dependent H295R apoptotic cell death which was potentiated pharmacologically and genetically by LXR⍺ inhibition. In line with these findings, cholesterol-methyl-β-cyclodextrin treatment increased cell death in H295R and MUC1 cells. In addition to inducing cell death, LXR⍺ inhibition decreased proliferation of both cell lines. An increase in FC and a decrease in cholesterol esters was observed following mitotane treatment in H295R cells. This was accompanied by decreased lipid droplet numbers confirmed by lower expression of lipid droplet associated proteins, PLIN1-3. These effects were potentiated when mitotane was combined with LXRα inhibition. We demonstrate increased HSL activity, which was associated with higher SOAT-1 expression and increasing toxic FC accumulation. Investigation of lipid droplet content BODIPY® of both cell lines showed H295R cells preferentially store cholesterol esters and MUC1 cells store triacylglycerides.Conclusion: We propose a mechanism for enhancing mitotane’s efficacy as an adrenolytic through increased free cholesterol via LXR⍺inhibition. Targeting the LXRα, its putative ligands, or associated lipid mediators may present a novel therapeutic approach in the setting of primary and metastatic ACC.
SUN-252 Rescue of Function of Inactivating Mutations in Human GPCRs in the Reproductive Hypothalamic-Pituitary-Gonadal Axis
Authors: Millar Robert Peter
Published: May 2020

Inactivating mutations have been described for human GPCRs at all levels of the reproductive hypothalamic-pituitary-gonadal (HPG) axis which results in reproductive incompetence. The majority of the mutations in GPCRs give rise to misfolding and a failure to traffick to the cell surface. We have interrogated data bases for cell-permeant small molecules which bind to and stabilise the GPCR as it emerges from the endoplasmic reticulum and hence facilitate trafficking of the mutant GPCR to the cell membrane and restoration of function. In this way we have successfully ‘rescued’ function of mutant Neurokinin B, GnRH, LH and FSH receptors using small molecule antagonists which bind orthosterically or agonists which bind allosterically. These discoveries represent an advance towards novel personalized medicine for GPCR deficiencies in the human HPG axis.
SAT-148 Ectopic ACTH Secretion Has Varied Presentation and Requires Individualized Treatment - One Size Does Not Fit All
Authors: Francis-Emmanuel Patrice , Siddique Rana , Soong Elaine , Clark John , Majeed Joohi , Wijenaike Nishan , Marath Haris , Brahma Anupam , Tauni Rahat
Published: May 2020

Ectopic ACTH secretion (EAS) presents in myriad ways. We present five cases of EAS to highlight similarities and differences in presentation and treatment. The first woman with known metastatic lung neuroendocrine tumour (NET) for two years presented with facial fullness, proximal weakness, worsening hypertension and hypokalaemia. Random cortisol of 2742nmol/L (99.39mcg/dL), with adrenocorticotrophic hormone (ACTH) of 201ng/L (5-50), was in keeping with EAS. She received medical treatment followed by bilateral adrenalectomy with EAS resolution and development of adrenal insufficiency. She is doing well. The second woman with proximal weakness was evaluated by neurologists. All neurological tests were normal but facial fullness and easy bruising was noted. Random cortisol was 875nmol/L (31.71mcg/dL) and ACTH was 90 ng/L. Imaging revealed metastatic liver disease with unknown primary and biopsy confirmed NET. Cortisol rose despite medical treatment and she died within fifteen months. The third woman with significant smoking history presented with haemoptysis and breathlessness. A right lung mass was suspected on chest X-ray and confirmed with CT. Endobronchial ultrasound-guided biopsy revealed small cell lung cancer (SCLC). She developed generalised weakness and severe hypokalaemia. Random cortisol of 1645nmol/L (59.63mcg/dL) with ACTH of 282ng/L suggested EAS. Despite medical treatment, she died within two weeks. The fourth woman presented with confusion, hypertension and severe hypokalaemia. Morning cortisol of 8557nmol/L (310.19mcg/dL) and random ACTH of 73ng/L were suggestive of EAS. CT demonstrated left lung mass with widespread metastases. She deteriorated and died within 2 weeks. Our only man had incidentally discovered metastatic liver lesions on ultrasound. Further imaging revealed prostatic mass and biopsy showed small cell neuroendocrine cancer. He presented with severe hypokalaemia. Random cortisol was 1065nmol/L (38.61mcg/dL) and ACTH was 188ng/L. He was commenced on medical treatment but declined rapidly and died.

All our patients had profound hypokalaemia and metastatic disease at presentation. Many patients do not exhibit classical cushingoid features as EAS tends to develop acutely and underlying malignancy drives weight loss. A high index of suspicion is required to make a diagnosis. EAS should be considered in patients with proximal myopathy, pigmentation, resistant or severe hypokalaemia or hypertension and known or suspected malignancy. Early and quick control of cortisol excess is essential to minimise cardiometabolic abnormalities, severe infections and thromboembolic complications. Prognosis depends upon age, frailty, comorbidity, nature of neoplasm and extent of hypercortisolaemia. Adrenolytics with or without bilateral adrenalectomy, reduction in tumour burden and management of complications are the mainstay of treatment.
MON-697 Necrotising Fasciitis- Importance of Glycemic Control
Authors: Kasireddy Amulya Reddy , Farooq Umer
Published: May 2020

Introduction:

Necrotising fasciitis is an infection of the deep soft tissues characterised by fulminant tissue destruction, systemic toxicity and high mortality. We report a case where accurate diagnosis, timely surgical intervention and antibiotic therapy along with strict glycemic control resulted in a favourable outcome.

Case:

A 74 year old woman with a history of type 2 diabetes mellitus, hypertension and end stage renal disease(ESRD) on peritoneal dialysis(PD) presented to the emergency department with the complaint of pain in the right lower quadrant of abdomen, right pelvis and right groin since 4 days which acutely worsened overnight. Of note the patient has Peritoneal catheter for dialysis and was last dialysed last night without any difficulty. Other associated symptoms were chills, nausea. The patient denied fever, skin changes in the affected area.

On physical examination, the patient was awake, alert and oriented, in moderate distress. Abdomen was soft, non distended, PD catheter was in place with no surrounding skin erythema or tenderness. Genitourinary examination showed swelling of Mons Pubis with overlying erythema on the right side with extension to the right labia majora, exquisitely tender to palpation, no crepitus, no pustules, no palpable abscesses or visible wounds.

Initial labs showed elevated WBC count(36.4K/UL; n<10.5K/UL) and Blood glucose of 361mg/dl(n 70-100mg/dl). CT scan of the abdomen and pelvis showed right anterior pelvic wall subcutaneous infiltration extending inferiorly into the mons pubis and right labial regions suspicious for cellulitis with no abscess. Broad spectrum intravenous antibiotics Meropenem, Vancomycin and Fluconazole were started and patient was taken to the operative room for debridement and approximately 25 cm long and 15 cm wide and 8 cm large abscess originating in the right labia extending up into her right groin was found along with necrotic skin, subcutaneous tissue and fat which was sharply excised. Peritoneal dialysis catheter site looked non infected and was left in place and fluid cultures were sent. Patient was switched to Hemodialysis while awaiting PD catheter fluid cultures. Hospital course was complicated by multiple debridements, severe septic shock requiring upto 4 pressors and intubation. She was started on insulin drip for glycemic control as the blood sugars were constantly ranging 300mg/dl(n 70-100mg/dl). HbA1C was 10.9% (n 5.7-6.4%). After 10days she was extubated and off pressors and was stable to be transferred to subacute rehab facility for diligent wound care for the next few weeks before she could go home.

Conclusion:

In patients with uncontrolled diabetes mellitus who present with critical illness like necrotising fasciitis, strict glycemic control with insulin drip yield favourable outcomes.
SUN-056 Long Term Outcomes in Patients with Disorders of Sex Development in Lucknow, North India
Authors: Bhatia Vijayalakshmi , Dominc Nibu
Published: May 2020

Due to the deviant genitalia and infertility, the ill effects of DSD are on sexual and psychosocial life. Our aim was to assess the self-reported psychosocial and sexual quality of life in older individuals who are living with a DSD. Quality of life in 31 patients with a DSD (age >16 years, median [IQR] 23 [19-27] years, 16 males) was compared with age, sex and socioeconomic status matched normal (n = 46) and chronic disease controls (type 1 diabetes patients, n = 43) using SF-36v2 Health Survey. Another structured questionnaire was administered touching upon domains of sexual and psychosocial life. Eighteen patients reported history of persistent teasing, with no difference in prevalence between males and females. Eighteen reported suicidal thoughts (no association with being teased), 6 having attempted suicide. Gender identity (GI) of 30 patients was identical with their given sex of rearing, which had been decided by the caregiver in 19 families (including one who had gender change suggested by the parents at 4 years of age), and with physician assistance in 11. One patient had spontaneous change of GI at 16 years age. Sexual orientation was heterosexual in 25 of 29 who responded to this question, homosexual in 1 and bisexual in 3, including the 2 who had gender change. Romantic relationship was reported by 12 patients, sexual activity by 7, aversion to sex (due to fear of rejection) by 11 and abuse by 4. Seventeen patients thought the timing of genital surgery should be before age 5 years and another 10 before age 10 years. Only 2 of 31 patients thought decision for the timing and choice of surgery should rest with themselves, the remainder preferring a decision by parents in 25% and by the physician in 67%. The physical and mental quality of life scores (QOLS) were not different between patients and the controls. Mental QOLS were significantly lower for those with history of teasing. Physical QOLS in males correlated with external masculinisation score (r=0.55, p=0.04). Conclusion: Serious psychological stress is common in patients with DSD in our region. Despite early sex assignment, the absence of prominent gender dysphoria in adulthood, along with their stated preference for corrective genital surgery at an early age, favour an early sex assignment and genital reconstruction before the age of romantic relationships.
MON-474 Coexistence of Thyroid Dysgenesis and Premature Ovarian Failure: A Case Report
Authors: Calma Catherine P , Naranjo May U , Lima Valerie U , Tarongoy Jeannine Erika M
Published: May 2020

Background. Congenital hypothyroidism (CH) secondary to thyroid dysgenesis is rare. It may present with ascites and short stature. Primary ovarian failure (POF) is most commonly associated with autoimmune thyroid diseases1. However, there is no report of the association of POF with congenital hypothyroidism.

Clinical case. A 30 year old female presented with increasing abdominal girth, short stature and arrest of menstruation at 27 years old. Newborn screening was not done. Developmental milestones were at par. She had a low timber voice and was slow to respond. Her skin was rough and dry. Her hair was sparse, and she had thin eyebrows. Her tongue was not enlarged. Her abdomen was globular with a positive fluid wave test and shifting dullness. Initial tests indicated a hypothyroid state: elevated TSH (50.40 IU/mL, N=0.35-4.94 IU/mL), low FT4 (0 pmol/L, N=12-22 pmol/L). Ultrasound of the thyroid suggests thyroid dysgenesis (small right thyroid gland measuring 1.4 x 0.2 x 0.4 cm and an absent left thyroid gland). Karyotyping was 46, XX and insulin growth factor 1 was normal. Unexpectedly, further tests were consistent with a concomitant primary ovarian failure: low estradiol (5 pg/mL, N=12.4-233 pg/mL), high FSH (112.7 mIU/mL, N=3.5-12.5 mIU/mL) and LH (61.9 mIU/mL, N = 2.4-12.6 mIU/mL). Chest radiography showed left pleural effusion. Abdominal CT scan showed marked ascites with normal reproductive organs. Anti-TPO antibodies were normal (4.87 IU/mL, N=0-25 IU/mL). The patient was treated with Levothyroxine 50 mcg daily then gradually increased to 100 mcg daily. She was given Spironolactone 50 mg daily and paracentesis was also done to address ascites. The patient had improvement of symptoms after a month of treatment. However, the etiology of POF remains to be further elucidated.

Conclusion. This case report emphasizes the importance of the early detection of congenital hypothyroidism through newborn screening. Severe hypothyroidism is rarely seen due to the wide availability of the TSH assay and its diagnosis should instigate further work-up for its etiology. Concomitant premature ovarian failure in the absence of an autoimmune thyroid disorder should prompt further investigation for another etiology since premature ovarian failure is not commonly associated with congenital hypothyroidism.

Reference: (1) Ayesha, Jha V, Goswami D. Premature Ovarian Failure: An Association with Autoimmune Diseases. J Clin Diagn Res. 2016;10(10):QC10-QC12.
SUN-128 Impaired Fasting Glucose Is Associated with Insulin Resistance in Patients with Germline Mutations in the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene
Authors: Bansal Rashika , Armiyaw Latif , Lee Maya , Tepede Aisha , James Welch , Agarwal Sunita Kishore , Simonds William F , Weinstein Lee Scott , Muniyappa Ranganath , Blau Jenny
Published: May 2020

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by hyperparathyroidism, pituitary adenomas, and gastro-entero-pancreatic neuroendocrine tumors. Patients with MEN1 mutations have impaired glucose homeostasis, but the role of insulin resistance and beta-cell function is unclear.

METHODS: Using a case-control study design, a retrospective analysis of germline mutation-positive MEN 1 patients (n=289) seen at our institution between 1991-2019 was performed. Patients with diabetes and/or insulinoma were excluded. Subjects were age, BMI, sex and race matched 1:1 to unrelated, healthy controls. Fasting glucose, insulin, c-peptide, calcium, PTH, 25-OH vitamin D, cholesterol, LDL, HDL and triglycerides (TG) were compared between two groups. Homeostasis model assessment (HOMA-IR) and HOMA-beta cell function (HOMA-b) were used as surrogate measures of insulin resistance and beta-cell function, respectively. Data is presented as mean ± SD.

RESULTS: MEN1 subjects (n=40; age 41±11 years; BMI 29.2±7.2 kg/m2) were matched to healthy controls (age 41±11 years; BMI 29.1±7.5 kg/m2). Only 3 MEN1 patients had no evidence of pancreatic neuroendocrine tumors. Impaired fasting glucose was more prevalent in MEN1 compared with controls (53% vs 10%, p<0.0001). HOMA-IR was positively associated with BMI, but not age, sex, calcium or vitamin D levels in either cohort. HOMA-IR adjusted for age, BMI, and sex was higher in patients with MEN1 compared with controls (4.01 vs. 2.44, adjusted ratio of means 1.54, 95% CI [1.14, 2.07], p=0.005). HOMA-b was not significantly different between the groups (177 vs. 129, adjusted ratio of means 1.17, 95% CI [0.86, 1.58], p=0.23). There were no significant differences in total cholesterol, LDL, HDL, and TG between the groups.

CONCLUSION: Lower insulin sensitivity, but not impaired beta cell function may contribute to the higher prevalence of impaired fasting glucose in MEN1 patients compared with controls. Mechanistic studies into the role of menin loss in glucose homeostasis are warranted.
SAT-185 Primary Adrenal Lymphoma Presenting with Symptomatic Hypercalcaemia
Authors: Forde Hannah Elizabeth , Noble Jane , Gibbons David , Holian John , Gerard Connaghan Daniel , Crowley Rachel K
Published: May 2020

Introduction: Primary adrenal lymphoma (PAL) is a rare cause of adrenal enlargement with approximately 200 cases reported in the literature to date. It tends to affect elderly men and has a high incidence of bilateral involvement at diagnosis. We report the case of a 66 year old man, whose PAL manifested with symptomatic hypercalcaemia.

A 66 year old male, originally from the Philippines, was referred to the emergency department with nausea, vomiting, weight loss and right flank pain. His past medical history was significant for hypertension, gout and stage 3b chronic kidney disease. His medications were amlodipine, losartan and febuxostat. His family history was significant for hypertension. On examination he was hypertensive (blood pressure, 160/100 mmHg) and hyperpigmented. His laboratory investigations revealed; corrected calcium of 3.79 mmol/l, undetectable PTH, vitamin D 49 nmol/l. He was treated with intravenous (IV) 0.9% saline and IV zoledronic acid and his calcium levels improved.

To investigate causes of non-PTH mediated hypercalcaemia, computerised tomography of the thorax, abdomen and pelvis (CT TAP) as well as a positron emission tomography (PET) scan were performed. These demonstrated bilateral, large, metabolically active adrenal masses with no evidence of extra-adrenal disease. Differential diagnosis at this point included bilateral adrenal hyperplasia, metastases, lymphoma or adrenal TB. There were no radiological features of adrenocortical carcinoma (ACC) or phaeochromocytoma and subsequent biochemical investigations confirmed no evidence of cortisol, androgen or catecholamine excess. Adrenocorticotrophic hormone (ACTH) levels were elevated however, and a synacthen test revealed inadequate adrenal reserve (peak cortisol 214 nmol/l). The patient was commenced on maintenance steroids and with stress dose steroid cover, proceeded to adrenal biopsy. Histology confirmed diffuse large B cell non-Hodgkin’s lymphoma. Haematology became involved in his care and he commenced polychemotherapy in the form of R-CHOP, 1 week post confirmation of the diagnosis. His treatment is ongoing and he has tolerated it well with minimal side effects, except a flare of gout.

Learning points: PAL should be considered in the differential diagnosis in patients with bilateral adrenal masses. Image guided adrenal biopsy is the gold standard for diagnosis, though caution must be exercised and an ACC or phaeochromocytoma should be excluded prior to biopsy. The prognosis of PAL is poor and therefore early diagnosis and prompt initiation of treatment are required to improve outcomes.
SUN-141 Altitude as the Second Hit on the Appearance of Paragangliomas
Authors: Arcos Oscar , Zambrano Maria , Valenzuela Alex , Omehara Miguel , Muniere Jaqueline , Sanchez Gabriel , Lizcano Fernando
Published: May 2020

Paragangliomas are rare neuroendocrine tumors with a high degree of inheritance. These neoplasms arise from the extra-adrenal autonomic paraganglion and can secrete catecholamines. Many patients debut with symptoms of hypertensive crisis, tachycardia, dyspnea, headache and intense sweating. However, many tumors that are derived from the parasympathetic system are asymptomatic. Supported on the genetic basis are classified into two conglomerates: conglomerate I are those that have mutations and alter the response to hypoxia. Cluster II has a more syndromatic component, with alteration in the function of complex signaling pathways. A study based on histopathological diagnoses was carried out between 2007 and 2017 at a hospital in Bogotá (Colombia) 2600 meters above sea level, which documented 108 cases of paragangliomas that were predominantly located at the carotid level (76%), with a 4.7:1 ratio between women and men. 93.2% of the patients came from geographical locations with heights above 2,500m above sea level. Most of the tumors were asymptomatic. We draw attention to the fact that paragangliomas are probably more frequent than clinically diagnosed and the influence of the environment on the development of these tumors is highlighted, with a special contribution of oxygen pressure as a second event that contributes to the formation of the tumor.
SUN-926 Malignant Transformation of a Benign Glucagonoma After 13 Years
Authors: Shakir Mohamed K M , Usman Aqueel , Bauer Elizabeth M , Hoang Thanh Duc
Published: May 2020

Glucagonoma are rare neuroendocrine tumors arising solely in the pancreas and approximately 25 % of glucagonoma cases start in a benign form. We hereby report a 76 -year-old male who was initially diagnosed with asymptomatic benign glucagonoma. Follow-up surveillance 13 years later shows that the tumor has undergone differentiation into a malignant form. Case Report: A 63-year-old man was referred for evaluation of an enhancing lesion (2.7 cm) at the pancreatic tail. He was completely asymptomatic with normal physical exam. Initial labs: normal except for elevated serum glucagon level (206 pg/mL, ref 0–60). A 2-hour oral GTT confirmed the autonomy of glucagon secretion by the tumor. Somatostatin and other tumor markers were normal. PET scan showed abnormal uptake at the distal pancreatic tail, correlating with the CT scan findings. The patient underwent laparoscopic distal pancreatectomy, with removal of a 2.8cm mass which predominantly expressed glucagon. Plasma glucagon level in the peripheral venous blood and intraoperative splenic vein dropped to <50 pg/mL immediately after the surgical resection. Following surgery patient remained completely asymptomatic for the next 13 years with normal blood glucose, glucagon, insulin, chromogranin levels, complete blood count and liver functions. Additionally patient continued to have normal surveillance MRIs of the abdomen. 13 years following removal of pancreatic mass, an elevated glucagon serum level (230 pg/mL) was noted on routine surveillance screening. At this time patient also remained asymptomatic. Abdominal MRI and PET scan revealed a 4-cm pancreatic mass with hepatic metastases. Biopsy of the hepatic lesion confirmed glucagonoma. Patient was treated with Lanreotide which has normalized the serum glucagon levels and the tumor size remained stable for the 12 months of follow up. Discussion: In our patient the glucagon secreting tumor without any classic presenting symptoms was found incidentally and the asymptomatic glucagonoma treated surgically presumably at an earlier stage. It is known that some glucagonomas are associated with serum levels of the peptide in the “physiologically elevated” range, even in the presence of necrolytic migratory erythema. The complete remission without any treatment lasting for more than 13 years confirmed the benign nature of the tumor. It is also reported that gluconomas less than 2 cm in size has less potential for metastasis. The usual recommendation is to monitor these patients post-resection to a maximum of 10 years although in our patient the malignant nature of the tumor was expressed 13 years after initial resection. The reason for malignant transformation after this prolonged period remains unknown. This case highlights the importance of continuous monitoring neuroendocrine tumors even beyond 10 years after surgery.
SUN-255 The Synthetic Progestin, 17-alpha-hydroxyprogesterone Caproate, Used in Human Pregnancy Alters Prefrontal Cortical Development in Rats
Authors: Lolier Melanie L , Wagner Christine K
Published: May 2020

17-alpha-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestin commonly prescribed for the prevention of recurrent preterm birth. Treatment with 17-OHPC in high-risk pregnant women begins between gestational weeks 16-20, and continues through week 36 1. Recent studies suggest that 17-OHPC is not an effective treatment for reducing rates of preterm delivery 2,3. Most concerning is the timing of 17-OHPC administration, which coincides with critical periods of mesocortical dopamine pathway development in the fetus 4. Regulating behaviors of executive function, the mesocortical pathway originates in dopaminergic neurons of the ventral tegmental area (VTA) that innervate the medial prefrontal cortex (mPFC). Disruptions in mesocortical dopamine pathway development are believed to underlie deficits in cognitive functioning 5,6.

In rodent models of cortical development, the developing mesocortical dopamine pathway is sensitive to progestins. There is transient expression of nuclear progesterone receptors (PR) in both the VTA and mPFC 7. PR are powerful transcription factors that can alter gene expression and fundamentally alter neural development 8,9. When rodents are treated with 17-OHPC during mesocortical dopamine pathway development, there are significant sex-specific alterations in dopaminergic innervation of the mPFC and deficits in cognitive behaviors in adulthood 10. Microglia, the resident immune cells of the central nervous system, play a critical role in establishing dopaminergic circuitry of the forebrain 11. The following experiment tested the hypothesis that 17-OHPC alters microglia activity in a sex-specific manner. Our results reveal that there is an innate sex difference in the number of reactive microglia, where control group females had significantly more than males. Treatment with 17-OHPC abolishes this sex difference by reducing the number of reactive microglia in 17-OHPC treated females to male-like levels in both the prelimbic (PL) and infralimbic (IL) mPFC. There is also a significant reduction in the percentage of reactive microglia in 17-OHPC treated animals compared to controls. These results suggest that early 17-OHPC exposure may decrease functional microglial activity during critical periods of cortical development, and that females are more vulnerable than males. Consideration should be given to the potential effects of 17-OHPC on neural and cognitive development in children.
SUN-739 Next Generation AR Antagonists Increase Systemic Active Glucocorticoid Exposure by Altering Glucocorticoid Metabolism
Authors: Alyamani Mohammad , Sharifi Nima , Li Jianbo , Patel Mona , Berk Michael , Taylor Susan , Przybycin Christopher , Posadas Edwin M , Madan Ravi , Gulley James L , Rini Brian I , Garcia Jorgi A , Klein Eric A
Published: May 2020

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Despite the increased survival benefits of these agents, resistance normally occurs and the disease transitions to its lethal form. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations and increased ratio of active to inactive glucocorticoids. We measured cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) in serum using mass spectrometry before and 1 month on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide (n=25) 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer (n=54) and 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer (n=38 patients). Progression-free survival (PFS) was determined in the metastatic CRPC study of enzalutamide +/- PROSTVAC for those with glucocorticoid changes above and below the median. A statistically significant rise in cortisol concentration and cortisol/cortisone ratio with AR antagonist treatment occurred uniformly across all 3 clinical trials. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p < 0.001), 36/54 (67%) patients (p < 0.001), and 30/38 (79%) patients (p = 0.051), in the 3 respective trials. In the trial of enzalutamide +/- PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved PSA progression-free survival and radiographic progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. In conclusion, treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. These findings have potential consequences for immune suppression and the efficacy of treatment combinations using next-generation AR antagonists. On-treatment, glucocorticoid changes might serve as a pharmacodynamic biomarker.
MON-663 Prandial Insulin Dosing Based on Carbohydrate Content Does Not Significantly Improve Glycemic Control in Hospitalized Patients with Diabetes
Authors: Goel Heenam , Dojki Farheen K , Davis Dawn Belt
Published: May 2020

Introduction: Diabetes mellitus (DM) is a highly prevalent concern in hospital medicine. In-hospital hyperglycemia and hypoglycemia are common. Hospitalized patients have variable and unpredictable amounts of carbohydrate content in their meals. We hypothesized that order sets that allow for flexible dosing of prandial insulin using an insulin to carbohydrate ratio (ICR) would provide superior blood glucose control in the complex hospital environment. Methods: We performed a retrospective review of electronic medical records from a single university hospital. The hospital implemented new order sets allowing prandial insulin dosing based on an ICR and inpatient nursing staff received necessary training. We compared glucose levels over the first three days after admission in hospitalized patients prescribed prandial insulin either as a fixed dose or based on an ICR. Patients on fixed dose insulin were selected from a time 3 months prior to the implementation of ICR order sets, to avoid any bias in patient selection. Patients on ICR dosing were selected from 3 months after implementation of ICR order sets, to allow adequate time for initial implementation. Our inclusion criteria included patients admitted to both medicine and surgery services, with Type 1 or Type 2 DM, age between 18-80. Exclusion criteria included transplant patients, patients on insulin infusion, pregnancy, steroid use and dialysis. 65 patients were included in each group. Outcome measures included average blood glucose over 72 hours, fasting and postprandial hypoglycemia (<70 mg/dL) and hyperglycemia incidence (>180 mg/dL). Results: Average glucose over 3 days was 167 +/- 39 mg/dL and 162 +/- 33 mg/dL and did not differ between groups. However, a higher percentage of glucose values were in target range (70-180 mg/dL) in the fixed dosing group (67.9%) compared to ICR (62.5%, p=0.018). The incidence of hypoglycemia was low and did not differ between groups (1.2% in both). However, patients had more overall hyperglycemia with ICR dosing (36% vs 31%, p=0.018), particularly pre-lunch hyperglycemia (52% vs. 38%, p=0.007). Fasting glucose was similar between groups.

Conclusions: In conclusion, our study demonstrated that prandial insulin administered based on ICR did not improve overall glycemic control or reduce incidence of hypoglycemia in hospitalized patients with diabetes. In fact, overall and post-meal rates of hyperglycemia were generally higher with ICR dosing. This could be related to inaccurate counting of carbohydrates or delayed timing of insulin administration as it was given after the food was consumed. Additional studies are needed to further evaluate the effectiveness of flexible meal dosing and the impact on patient satisfaction and staff workload.
SUN-639 Secretagogin Levels Are Unrelated to Gestational Diabetes Mellitus in a Cohort of Pregnant Women
Authors: Deischinger Carola , Harreiter Jürgen , Wagner Ludwig , Baumgartner-Parzer Sabina , Kautzky-Willer Alexandra
Published: May 2020

Introduction

Secretagogin (SCGN) is a calcium binding protein related to insulin release in the pancreas. Although SCGN is not co-released with insulin, plasma concentrations have been found to be increased in type 2 diabetes mellitus patients.1,2,3 Up to this day, no study on SCGN levels in patients with gestational diabetes mellitus (GDM) has been published.

Patients and Methods

In 138 women of a high-risk population for GDM at the Medical University of Vienna, secretagogin levels of GDM patients were compared to women with a normal glucose tolerance (NGT). Glucose tolerance, insulin resistance and secretion were assessed with an oral glucose tolerance test (oGTT) performed before 20 weeks gestation. The women with GDM (39.1%) were further divided into GDM types depending on insulin sensitivity or secretion defects defined as below the 25th percentile in the oGTT of the NGT controls.

Results

Compared to women with NGT (mean SCGN= 52.7 ng/dl), there was no statistically significant difference in SCGN in patients with GDM (mean value 53.9 ng/dl, p=0.857). After splitting into secretion defect and insulin resistance subtypes, SCGN remained unrelated to GDM in our study population. However, Secretagogin was found to be significantly higher in postpartum visits (mean= 62.9 ng/dl) than during pregnancy (mean value= 48.5 ng/dl; p= 0.047). Furthermore, SCGN was positively correlated with BMI (p=0.006) in the present analysis.

Conclusion

Unlike in studies conducted on type 2 diabetes,1,2,3 a relationship between GDM and Secretagogin levels could not be demonstrated in this study. However, lower levels during pregnancy point towards physiological changes in SCGN levels unrelated to (gestational) diabetes mellitus. Further research, ideally including before-pregnancy levels, is paramount to assess possible roles of SCGN during pregnancy.

1. Maj M, Wagner L, Tretter V, et al. A TRPV1-to-secretagogin regulatory axis controls pancreatic β-cell survival by modulating protein turnover. EMBO J. 2017;36(14):2107-2125. doi:10.15252/embj.201695347

2. Yang C, Qu H, Zhao X, et al. Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation. Exp Clin Endocrinol Diabetes. 2019:0-4. doi:10.1055/a-1001-2244

3. Maj M, Wagner L, Tretter V. 20 Years of Secretagogin: Exocytosis and Beyond. Front Mol Neurosci. 2019;12(February):1-10. doi:10.3389/fnmol.2019.00029
SUN-266 Protein Induced Pancreatic Hormone Secretion Is Modulated by Vagal CaSR
Authors: Norton Mariana , Cork Simon C , Alonso Aldara Martin , Roberts Anna G , Patel Yateen S , Cheng Sijing , Hansford Robert , Cao Ye , Salem Victoria , Hanyaloglu Aylin Carla , Chang Wenhan , Murphy Kevin Graeme
Published: May 2020

The existence of a vago-vagal entero-pancreatic pathway, where sensory information from the gut can signal via vagal afferents to the brain to mediate changes in pancreatic function, has been recognised for over a century, and investigated extensively with regards to pancreatic exocrine secretions. However, the role of such pathways in pancreatic endocrine secretions has received less attention.

The secretion of insulin and glucagon in response to protein and amino acids is conserved across species. This effect is thought to promote amino acid uptake into tissues without concomitant hypoglycaemia. We found that the essential amino acid L-Phenylalanine potently stimulates glucagon secretion, even when administered directly into the gut at small doses unlikely to significantly raise systematic levels. Administration of L-Phenylalanine also increased neuronal activation in the rat and mouse dorsal vagal complex, the central nervous system region directly innervated by vagal afferents.

L-Phenylalanine modulates the activity of the calcium sensing receptor (CaSR), a nutrient sensor more commonly known for its role in calcium homeostasis, but which is thought to also act as a sensor of aromatic amino acids. Interestingly, the CaSR is one of the few nutrient sensors expressed in vagal afferents and in vitro calcium imaging revealed CaSR synthetic agonists activate subpopulations of vagal afferents.

The role of CaSR in vivo was investigated further by selectively knocking down the CaSR in vagal afferents. Briefly, CaSR floxed mice were bilaterally injected directly into the nodose ganglion, where the cell bodies of vagal afferents are located, with a cre expressing adeno-associated virus. CaSR knockdown did not interfere with normal food intake, nor the vagal-dependent anorectic effects of cholecystokinin, or of L-Phenylalanine. However, it did blunt protein-induced glucagon secretion, suggesting involvement of the CaSR in the vagus nerve in protein sensing and glucose homeostasis.

Future studies are required to determine the importance of vagal CaSR in protein induced pancreatic endocrine secretions, and the possibility of exploiting this circuit to develop new anti-diabetic therapies.
MON-705 Islet Auto-Transplantation Following Partial Pancreatectomy Improves Glycemic Outcomes and Reduces Length of Hospital Stay: Multi-Center, Case-Control Study
Authors: Chaidarun Sushela S , elmunzer Joe B , kerrington Smith D , Gardner Timothy B
Published: May 2020

Introduction: Islet auto-transplantation (IAT) is increasingly being performed to prevent brittle diabetes following pancreatic resection in patients with benign pancreatic diseases. While patients undergoing total or completion pancreatectomy clearly benefit from IAT, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine if IAT improved glycemic outcomes in patients undergoing partial pancreatectomy for benign pancreatic diseases. Methods: We performed a multicenter, retrospective case-control study of patients who underwent partial pancreatic resection with IAT at two tertiary care centers. Case patients were compared to controls who underwent partial pancreatic resection without IAT at one center prior to offering IAT. The primary outcome was the mean change in pre vs. post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Results: 9 patients requiring partial pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups including age, etiology of pancreatitis, the presence of diabetes and pre-operative HgA1c (5.7 vs. 5.2, p=0.448). With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs. post-operative HgA1c (0.42 vs 2.83, p=0.004) and one case patient (14.3%) vs. three control patients (23.1%) developed new post-operative diabetes (p=0.581). Patients who underwent IAT had a shorter length of stay (6 days vs 11 days, p=0.039) compared to control patients. Conclusions: Patients undergoing partial pancreatic resection for benign pancreatic disease should be considered for IAT, as long-term glycemic outcomes are improved in those undergoing transplant. The shorter length of hospital stay is likely related to less brittle glucose control after the surgery with some endogenous insulin production by auto-islet graft function.
SUN-475 Thyroid Extranodal Diffuse Large B-Cell Lymphoma in Setting of Gastric Large B-Cell Lymphoma
Authors: Russell Yan , Schwartz Benjamin , Ventura Ana , Oprea Mihaela , Khokhar Jatinder , Guber Helena Abby
Published: May 2020

Background: We report a case of concomitant thyroid and gastric diffuse large B-cell lymphoma (DLBCL). Clinical Case: A 73 year-old man presented with melena of 2 days duration. EGD revealed a 1.5 x 0.7 cm gastric ulcer. Biopsy revealed marked chronic active gastritis with glandular atypia, positive for H. pylori. Repeat biopsy of the same ulcer post H. pylori treatment demonstrated high-grade B-cell lymphoma. Immunostains were positive for CD20, CD10, BCL6, cyclin D and negative for CD 23 and CD 30. More than 95% of tumor cells expressed Ki-67, while 10% expressed MUM-1 and BCL2. Benign T cells stained positive for CD3 and CD5. FISH was negative for gene rearrangement involving BCL-6/BCL-2 and C-MYC. Staging PET/CT showed hypermetabolic regions involving the stomach wall, large left neck mass and right lung focus. The neck focus had a max SUV 48.5 (8 fold greater than the other sites), that localized to a soft tissue mass measuring 4.9 x 2.7 cm. FNA of the left-sided thyroid mass showed diffuse large B-cell lymphoma with immunostain positive for CD20 and negative for cytokeratin AE1-3, PAX8, and CD 10. The morphology was similar to that of abnormal lymphoid cells in the gastric biopsy. Patient had normal thyroid function tests but positive autoimmune thyroid disease markers (TPO and anti-TG antibody). Treatment with R-CHOP resulted in shrinkage of neck mass. Conclusion: Hypermetabolic regions revealed by PET/CT at distant sites from primary tumor require further evaluation including biopsy as indicated. Clinical correlation and response to chemotherapy can provide supplemental information in the overall assessment of the disease process.
MON-196 A Single-Center Experience of Patients with Metastatic Pheochromocytoma/Paraganglioma Treated with 177Lu-DOTATATE
Authors: Roslyakova Anna , Beltsevich Dmitry , Plotkin Michail , Rumyantsev Pavel , Ladygina Daria
Published: May 2020

The prevalence of metastatic pheochromocytoma/paraganglioma (PPGL) is reported to be 3% to 36% of all the cases. The five-year overall survival rate of such patients ranges from 40 to 77%. The management of metastatic PPGL is challenging taking into account the fact that the optimal strategies for clinical care beyond surgical resection are not guided yet. Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues is effective in other neuroendocrine tumours, can be indicated in patients with positive scans for the respective radiopharmaceuticals.

We report preliminary data of the prospective study aimed to assess the safety and efficacy outcomes of 177Lu-DOTATATE for 6 patients with histologically confirmed PPGLs with metastatic progression after the complete PPGL surgery. The mean age of our cohort was 53 years (range 14–73); an equal number of male and female patients was included. Two of them had germline mutations in RET and SDHB genes, respectively. Radiological response utilized RECIST 1.1 criteria; toxicity was graded according to common terminology criteria for adverse events version 4. PPRT scheme varied between three and four cycles. Partial response (PR) was achieved in one and stable disease (SD) in four 4 patients. One patient had treatment refractory with disease progression and dramatic increase of chromogranin A concentration (+268%). Biochemical response (>50% decrease) of chromogranin A was found in 1/6 patients and of catecholamines in 2/6 patients. No hematological or kidney toxicity grade 3–4 was registered.

Median overall survival and median progression-free survival rate will be reported after the end of the study.

To date, about 250 PPGL patients have been treated with PRRT. PRRT using 177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control in the setting of retrospective small case reports or case series. However, more well-designed prospective studies are required to confirm these findings.