bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-918 Familial Paraganglioma: Familiar Case Report
Authors: Ricardo Gustavo Piech , Naldi Murilo Marques , Calasans Camila Ricci , Chang Claudia Veiga , Tirapeli Renata da Cunha Scalco , Bueno Cristina Bellotti Formiga , Scalissi Nilza , Lima Jose Viana
Published: May 2020

Introduction: Pheochromocytomas and Paragangliomas (PGL) are rare tumors originating from chromaffin cells. They may be sporadic or associated with familial inherited genetic syndromes around 50-80%. There are several PGL syndromes, the most common being PGL 1 (SDHD mutations), PGL 2 (SDHAF), PGL 3 (SDHC), PGL 4 (SDHB), PGL 5 (SDHA), PGL 6 (SLC25A11) and PGL 7 (DLST). SDHB mutations generate a higher probability of malignant PGL, as well as risk of renal, GIST and pituitary neoplasms. We report the case of a patient with a positive family history for the autosomal dominant SDHB mutation.Clinical cases: FZR, male, 19 years old, history of headache, sweating, palpitations, and sudden onset tremors associated with hypertensive peaks. Physical examination: Blood Pressure 140x90mmHg lying down, 110x70 standing up. Performed examinations, of which altered, showed: Plasma metanephrines: 82 pg/mL (RV <65), Plasma normetanephrines: 1.488pg/mL (VR <196), Urinary Catecholamines: 1.784mcg/24h (RV: 80-500), Abdomen Resonance showed an expansive, solid, heterogeneous abdomen mass in posterior contact with the left psoas muscle, medial with the aorta, and lateral with jejunum loops, measuring 7x3.5 cm. MIBG scintigraphy: abnormal uptake in left kidney. Family history: uncle diagnosed with cervical paraganglioma with cervical lymph node metastasis, gastric GIST and PCR genetic sequencing identifying mutation in SDHB (Q.137 G > T in exon 2). Asymptomatic second cousin with positive genetic analysis for the same mutation and another deceased first cousin diagnosed with pheochromocytoma with bone metastasis. He underwent tumor resection that identified retroperitoneal paraganglioma with 10% KI67, Protein S-100, Chromogranin-A and Synaptophysin positive. Carried out PCR genetic analysis that identified the same Q.137 G > T mutation in exon 2 of the SDHB gene in heterozygosis.Twenty-six relatives were called for mutation research, of which 5 positive for the SDHB mutation, until now, including the patient’s mother and twin brother, both already investigating related diseases.We await new family members and, subsequently, the result of the mutation analysis to continue the clinical and laboratory follow-up of this family.Conclusion: Although rare, this condition should be remembered as a differential diagnosis of diseases with such clinical symptoms and, once characterized, investigate possible associations with genetic syndromes.
MON-199 Targeting Pheochromocytoma/Paraganglioma with Polyamine Inhibitors
Authors: Ghayee Hans Kumar , Rai Sudhir , Bril Fernando , Hatch Heather , Xu Yiling , Kalavalapalli Srilaxami , Garrett Timothy , Plant Dan , Bose Prodip , Hromas Robert , Cusi Kenneth , Tischler Arthur , Gupta Priyanaka , Bibb James , Beuschlein Felix , Robledo Mercedes , Calsina Bruna , Timmers Henri , Taieb David , Kroiss Matthias , Richter Susan , Eisenhofer Graeme , Bergeron Raymond , Pacak Karel , Tevosian Sergei G
Published: May 2020

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease occurs in about 10% of cases, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease with very little treatment options. To find a new treatment strategy, we utilized a metabolomics approach to identify unique metabolic pathways. A metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 50 human fresh frozen PCC/PGL samples was conducted. Since the polyamine pathway surfaced in the metabolomics analysis, we hypothesized that treatment with polyamine inhibitors would be an effective option for aggressive PCC/PGL tumors. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in xenograft models. Results: Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tumor tissues compared to their SDHB wild-type counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts. Conclusions: This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine inhibitors significantly inhibited hPheo1 cell growth and led to growth inhibition in xenograft mouse models treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL.
SUN-163 Metastatic Spindle Cell Sarcoma Unmasked by Bilateral Adrenal Hemorrhage Resulting in Adrenal Insufficiency
Authors: Mehta Paras Bharatesh , Liu Chienying
Published: May 2020

Introduction:

Adrenal hemorrhage (AH) is rare and can be life-threatening when bilateral AH causes adrenal insufficiency (AI). Risk factors include trauma, stress, sepsis, anticoagulant and antiplatelet use, hematologic disorders, and underlying adrenal tumors. We describe a patient whose bilateral AH led to a diagnosis of an underlying malignancy and caused AI.

Clinical case:

A 71-year-old man with well-controlled HIV presented with fatigue, weight loss, and acute lower abdominal pain.

Four months prior to presentation, he underwent hip arthroplasty. His post-operative course was complicated by multiple pulmonary emboli and a new left 11.6 x 7.3 x 8.9 cm cystic retroperitoneal lesion with a density of 29 Hounsfield units on CT, thought to be a pancreatic pseudocyst or adrenal or retroperitoneal hemorrhage. Since the size remained stable on repeat CT three days later, he was discharged on rivaroxaban. On the day of presentation, he acutely developed severe abdominal and back pain. CT scan revealed a new 8.0 x 7.8 x 7.8 cm right adrenal collection and increased size of the prior left adrenal lesion to 13.1 x 10.6 x 13.0 cm. MRI confirmed bilateral adrenal masses with intralesional AH, as well as numerous peritoneal and retroperitoneal implants not noted on prior imaging.

He remained stable and was managed non-operatively. Sodium (Na) and potassium (K) ranged 134-138 mmol/L (135-145) and 3.7-4.3 mmol/L (3.5-5.1), respectively. On presentation, morning cortisol and ACTH were 11 ug/dL and 27 ng/L (6-50), respectively, with an undetectable aldosterone and PRA 0.65 ng/mL/hr (0.25-5.8). Subsequent ACTH levels were 71 and 102 ng/L, and cortisol levels were 12 and 14 ug/dL. ACTH-stimulated cortisol was 15 ug/dL and free cortisol was 0.88 ug/dL. Plasma metanephrines were normal. Hydrocortisone was started and anticoagulation was held indefinitely. Biopsy of a retroperitoneal implant revealed metastatic spindle cell sarcoma.

Three weeks later, given a persistently low Na of 134 mmol/L and increased K of 4.7 mmol/L, although blood pressure and heart rate were normal, he was empirically started on fludrocortisone. He followed up with oncology and was started on palliative chemotherapy.

Clinical lessons:

AH should prompt evaluation for an underlying etiology. In our patient, we suspect he already had a unilateral adrenal metastasis causing the initial unilateral AH, as he had no other risk factor. Four months later, the subsequent bilateral AH was likely caused by further metastatic spread and exacerbated by anticoagulation therapy.

This case also suggests that AH may preferentially affect the zona fasciculata of the adrenal cortex and cause glucocorticoid deficiency, a phenomenon which has been noted on prior case reports. Our patient only needed hydrocortisone replacement initially, followed by fludrocortisone replacement three weeks later.
MON-626 Frequency and Associated Factors with Multidrug-Resistant Organism Infection in Diabetic Foot Ulcers in a Peruvian Public Hospital
Authors: Yovera-Aldana Marlon Augusto , Sifuentes Liset Paola , Cruz-Estacio Delia , Flores Diana Consuelo , Damas-Casani Lucy Nelly
Published: May 2020

Objective: To determine the frequency and associated factors with multidrug-resistant organism (MDRO) infection among patients with diabetic foot ulcers in a Peruvian Public Hospital.

Materials and methods. Cross-sectional survey was conducted from January 2017 -December 2018 at National Hospital in Lima Perú. Ulcers with clinical signs of infection (erythema, edema, pain, purulent exudate) according Infectious Diseases Society of America clinical practice guideline were included1. Wounds with only skin involvement were excluded. On admission, specimens for culture were obtained after cleansing and debriding of the wound. Samples were promptly sent to the microbiology laboratory for culture using appropriate transport media. Bacterial identification and antibiotic susceptibility testing were performed using the VITEK® 2 automated system (BioMérieux Laboratory, Argentina). Multidrug-resistant organisms were identified according to the recommendations of International Expert Proposal2. Prevalence ratios derived from bivariate analysis are given with their 95% CI, which was performed to study factors associated with the presence of multidrug-resistant bacteria; and a multivariate analysis with a lineal model to associated variables found in the bivariate analysis. This study has the approval of the Research Ethics Committee of the María Auxiliadora Hospital.

Results Among 153 selected subjects, 75% were male, with an average age of 59 yo, 70% had ≥10 years of diabetes duration and only 16% had HbA1C <7%. A frequency of 85% of patients with MDRO infection was found and was associated with minor amputation RP 1.18 (95% CI 1.01-1.44) and with hospitalization time of ≥ 28 days RP 1.21 (95% CI 1.03-1.30).

Conclusion. 6 of 7 patients have MDRO infection among patients with diabetic foot ulcers and are associated with the occurrence of minor amputation and hospitalization time ≥ 28 days.

References

1. Lipsky BA, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-73.

2. Magiorakos AP, et al. Multidrug-resistant, extensively drug-resistant and pandrugresistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-81.
SUN-551 Impaired Vascular Relaxation and Altered eNOS Regulation in Boys with Hypospadias
Authors: Lucas-Herald Angela K , Alves-Lopes Rheure , Haddow Laura , O’Toole Stuart , Flett Martyn , Amjad S Basith , Lee Boma , Steven Mairi , Montezano Augusto C , Ahmed S Faisal , Touyz Rhian
Published: May 2020

Background: Sex hormones influence vascular function. Whether boys with hypospadias who have insufficient androgen exposure during the masculinisation programming window have altered vascular function is unknown. Objective: To investigate whether vascular function is impaired in boys with hypospadias and to explore the putative role of eNOS. Methods: Peripheral arteries from excess foreskin tissue obtained from boys undergoing hypospadias repair (cases) or circumcision (controls) were used. Vascular function was assessed by myography. mRNA expression was measured by qPCR in vascular smooth muscle cells (VSMCs). Nitric oxide (NO) was measured by DAF fluorescence assay and peroxynitrite levels measured via ELISA. Results: 23 boys with hypospadias and 34 age-matched controls were studied. There were 18 (52%) cases of distal, 7 (22%) of midshaft and 9 (26%) of proximal hypospadias and none of them had biochemical evidence of hypogonadism or a variant in AR. Clinical cardiometabolic parameters were similar between groups. Endothelium-dependent relaxation to acetylcholine (ACh) and endothelium-independent relaxation to sodium nitroprusside (SNP) were reduced in arteries from cases vs controls (Emax %U46619: 72.4 vs 1.2, p<0.0001 and Emax %U46619: (42.7 vs 11.8, p<0.01 respectively). Incubation with the NO synthase inhibitor, L-NAME (1x10-5 M) worsened endothelial-dependent relaxation in controls (Emax % U46619: 76.8 vs 1.2, p<0.0001) but had no effect in cases (Emax % U46619:60.6 vs 72.4, p=0.3). Testosterone (1x10-7 M) ameliorated vascular relaxation (p<0.05), whereas17[[Unsupported Character - Symbol Font 𝝱]];-estradiol stimulation (1x10-9 M) did not. In cultured VSMCs, mRNA expression of eNOS and iNOS was reduced whereas that of nNOS was increased in cases versus controls. Nitric oxide production was reduced in cases (5 fold, p<0.01), as was peroxynitrite production (0.5 fold, p<0.05). Testosterone increased expression of eNOS in VSMCs. There was no difference in mRNA expression of the AR and GPRC6A but cases had increased expression of ESR1 (2.71 fold), ESR2 (2.63 fold) and GPR30 (2.86 fold) (p<0.05). Conclusion: Arteries in eugonadal boys with hypospadias show vascular dysfunction which involves impaired NOS/NO regulation effects that are ameliorated with testosterone but not oestrogen. These processes may predispose to long-term cardiovascular disease.
SUN-747 Steroid Hormone Metabolism Mediated Racial Disparity in Men with Benign Prostatic Hyperplasia
Authors: Liu Teresa T , Ricke Emily A , Strand Douglas , Dhir Rajiv , Ricke William Allen
Published: May 2020

Introduction and Objective: Racial disparity in prostate cancer has been well established, with African American (AA) men having higher rates of diagnoses and death from the disease compared to Caucasian American (CA) men. AA men also have a high incidence of benign prostatic hyperplasia (BPH), a disease associated with lower urinary tract symptoms (LUTS) that affect >210 million men worldwide. Furthermore, AA men with BPH have an increased incidence of non-surgical treatment failure, larger prostates at time of surgery, and surgery occurring at a younger age. The use of selective estrogen receptor modulators (SERMs) in the treatment of BPH has been proposed, as an increase in ERα has been associated with disease progression. AA men have higher levels of circulating estrogens as compared to CA leading to an increased prenatal exposure to estrogens. Estrogen exposure has been shown to alter the epigenetic landscape of genes, and this prenatal exposure to estrogens could sensitize the AA men to altered steroid homeostasis leading to an increase susceptibility to BPH and an altered response to treatment. In this study, we examine the prostate expression and localization changes in estrogen receptors (ERα, ERβ) as well as steroid metabolism genes in AA and CA with or without BPH. Methods: To examine the impact of race on BPH, we examined prostate tissue from 66 men. We utilized 21 normal transition zone controls from radical prostatectomies, 8 normal transition zone controls from organ donors, and 37 BPH samples divided between CA and AA men. Using multispectral quantitative multiplex IHC, we examined the steroid hormone related protein expression of ERα, ERβ, CYP7B1, and AKR1C1 on each FFPE tissue section. We quantified the optical density of each protein of interest as well as examined colocalization and coexpression through cell and tissue segmentation. Results: In CA men, there is a dysregulation of ERα:ERβ homeostasis with BPH relative to normal as an increase in ERα and a decrease in ERβ expression was observed. Furthermore, an increase in CYP7B1, an enzyme that degrades ERβ ligands, was also observed. In AA men, we observed no difference between normal and BPH states, however in both normal and BPH prostate tissues, ERα and ERβ were increased relative to CA men. In addition, there is a decrease in AKR1C1, the enzyme that metabolizes DHT to an ERβ ligand. Conclusions: Our study supports the concept that differences in hormone pathways exist between AA and CA men. Understanding how these racial difference in steroid metabolism enzymes as well as ERs between CA and AA men with BPH could enhance treatment strategies for men with BPH.
SAT-195 The Diagnosis and Management of a Functional Paravertebral Paraganglioma
Authors: Findlay Ryan , Rutledge Angela , Payne Sonja , Inculet Richard , Pandey Sachin , Uum Stan Van
Published: May 2020

A 32-year-old male presented with a 4-year history of palpitations, diaphoresis, and orthostatic hypotension. One year prior to presentation, he began experiencing severe, episodic headaches and neck pressure. Neurological work-up included an MRI head, neck, and spine, identifying a left posterior mediastinal lesion adjacent to the T5 vertebral body, approximately 2.4 x 2.0 cm. A community surgical center attempted mass resection via Video -assisted (VATS) approach. Resection was aborted intraoperatively due to a hypertensive crisis following lesion manipulation, with his systolic blood pressure increasing above 325 mmHg.

Subsequent evaluation revealed a 24-hour urine norepinephrine of 6117 nmol/d (normal <575) and normetanephrines of 16.6 umol/d (normal <3.4). An MIBG study showed intense tracer avidity in the left paraspinal lesion and minimal uptake in the adrenal glands.

A functional paravertebral paraganglioma was diagnosed and the patient was initiated on alpha and beta-blockade in preparation for staged combined treatment.

Spinal angiography was performed to define the arterial supply of spinal cord and tumor, which confirmed a hypervascular left thoracic paraspinal tumor. Arterial supply emanated from the left T4 intercostal and left supreme intercostal arteries and a prominent draining vein was present. Trans-arterial particle embolization was performed via both arteries with minimal residual tumor blush present post procedure.

Successful VATS excision of the tumor was completed one week after arterial embolization with minimal blood loss. Pathology of the resected tumor revealed an overall intact tumor that stained diffusely positive with synaptophysin and sustentacular cells highlighted by S100 protein with a few foci of coagulative necrosis.

Episodes of hypertension (maximum BP 210/80) occurred during embolization and surgical resection with vascular manipulation. These were managed with intraoperative nitroprusside and phentolamine. Peri-procedural plasma metanephrine and cathecholamine levels were collected. Normetanephrine levels (normal <=0.89 nmol/L) were 4.66 before embolization, >6.25 after embolization, 3.70 the day after embolization, 4.10 before VATS, and 0.69 after VATS. Norepinephrine levels (normal 0.8–3.4 nmol/L) were 24.3, 111.7, 61.1, 19.6, and 4 respectively. Genetic testing showed no hereditary predisposition.

Discussion:

Functional neuroendocrine tumours may be difficult to diagnose due to the wide variety of clinical presentations and must be considered when investigating a vascular mediastinal tumor. In our case, pre-operative embolization did not normalise plasma catecholamine levels, likely from incomplete arterial embolization, but helped reduce intra-operative surgical bleeding risk. Alpha- and beta-blockade should be continued until surgical resection, with dose adjustment as required.
SUN-658 CHL1 Increases Insulin Secretion&Negatively Regulates the Poliferation of Pancreatic β Cell
Authors: Yang Tao , Fu Qi , Jiang Hemin
Published: May 2020

CHL1 Increases Insulin Secretion & Negatively Regulates The Poliferation Of Pancreatic β Cell

Objective: CHL1 belongs to neural recognition molecules of the immunoglobulin superfamily, is mainly expressed in the nervous system. CHL1 is involved in neuronal migration, axonal growth, and dendritic projection. RNA sequencing of single human islet cells confirmed that CHL1 had an expression difference in β cells of type 2 diabetes and healthy controls. However, whether CHL1 gene regulates islet function remained to be explored.

Methods: PCR and Western Blot were applied to investigate the tissue distribution of CHL1 in wild-type C57BL/6J mice. The islet expression of CHL1 gene was observed in pancreatic islets of NOD mice and high-fat-diet C57BL/6J mice of different ages. MIN6 cells with siRNA to silence CHL1 or with lentivirus to overexpress CHL1 were constructed. Effects of the gene on proliferation, apoptosis, cell cycle and insulin secretion were determined by using CCK8, EdU, TUNEL, AV/PI, GSIS, electron microscopy and flow cytometry.

Results: CHL1 was localized on the cell membrane and expressed in the nervous system, islet of pancreas and gastrointestinal tract. CHL1 was hypoexpressed in the pancreatic islets of obese mice, hyperexpressed in the pancreatic islets of NOD mice and in vitro after treated with cytokines. After silencing CHL1 in MIN6 cells, insulin secretion decreased in 20 mM glucose with down-regulation of INS1, SLC2A2 gene, and transmission electron microscope showed the number of insulin secretary granules <50nm from the cell membrane was significantly reduced. Silencing of CHL1 in MIN6 cells induced cell proliferation, reduced apoptosis rate, prolonged the S phase of cell cycle and shortened the G1 phase with downregulated expression of p21, p53 and up-regulated expression of cyclin D1, opposite results were found in CHL1 over-expressing MIN6 cells. Proliferation induced by silencing of CHL1 was inhibited by ERK inhibitor (PD98059), which indicates that ERK pathway is essential for signaling by these molecules in pancreatic β cell.

Conclusion: The expression of CHL1 gene was significantly decreased in the pancreatic islets of obese mice induced by high-fat diet. The low expression of CHL1 gene promotes the proliferation of MIN6 cells through the ERK pathway and affect cell cycle through the p53 pathway. This may be one of the mechanisms that pancreatic β cells compensatory hyperplasia in the stage of obesity-induced pre-diabetes.
MON-245 Brain Fog: An Important Cue to Neurosarcoidosis and Its Flare-Up?
Authors: Shah Manasi Sanjiv , Oo Yin Htwe
Published: May 2020

Introduction:

Sarcoidosis is a multisystem inflammatory disorder characterized by noncaseating granulomas in various organ systems, mainly the lung and lymphatic system. Neurosarcoidosis (NS) involving central or peripheral nervous system is uncommon and Hypothalamic-pituitary (HP) NS is rarer.

Case:

A 45-years-old African American man presented with a few days’ history of cognitive slowness (brain fog) and a sense of loss of direction. He was discharged a few months ago from another hospital after being admitted for shortness of breath and hypercalcemia of 13 mg/dl, which improved after hydration. CXR showed mediastinal and bilateral hilar enlargement. He was discharged home with outpatient pulmonary appointment but was readmitted to our hospital with altered mental status. Calcium level on this admission was 11.5 mg/dl. CT brain showed a sellar/suprasellar lesion, which was better visualized on MRI as enlargement and enhancement of pituitary gland, pituitary stalk, optic chiasm, left and right optic tract and nerves, and hypothalamus. He had left hemi-temporal field defect. Work up revealed inappropriately high normal 1,25 vitamin D, low PTH, PTrp and vitamin D. He has anterior hypopituitarism and mildly elevated prolactin. EBUS with mediastinal lymph node biopsy was non-diagnostic, however, excisional biopsy of mediastinal node showed non-caseating granuloma. ACE level, flow cytometry, infectious work up and serum IgG4 were normal.

Discussion:

NS may present as cranial nerve palsy, chronic headache with incidental HP mass and endocrine dysfunction such as diabetes insipidus, hyperprolactinemia, and anterior hypopituitarism. Visual deficits from optic atrophy or neuropathy; or change in vision from anterior uveitis are present in 41% of patients. Other non-specific presentations of NS include fatigue, cognitive difficulties (brain fog), such as impaired memory, slowed thinking, diminished attention and concentration. Hypercalcemia in sarcoidosis is due to increased intestinal absorption of calcium from increased 1,25 OH vitamin D. Though definitive diagnosis of NS is based on evidence of non-caseating granulomas from neural tissue, probable diagnosis can be made from clinical and radiologic characteristics, non-caseating granulomas at an extraneural site with no evidence of alternative disease. Steroid is the mainstay of treatment in NS and requires slow tapering. Other immunomodulators can be considered in worsening disease or patients with steroid adverse effect.

Conclusion:

Diagnosis of NS is challenging due to its rarity and difficult access to neural tissue for diagnosis. Though brain fog may not be specific for NS or its flare-up, additional neurological test or imaging should be considered especially in African American patients with hilar lymphadenopathy as 20% of NS patients may simply present with non-specific cognitive or behavioral complaints. ​
MON-178 Cyclical Cushing’s Syndrome in 12 Patients with Ectopic ACTH Secretion
Authors: Zenno Anna , McGlotten Raven , Kargi Atil , Nieman Lynnette
Published: May 2020

Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge.

Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET).

Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment.

Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had biochemical evidence of ACTH-dependent Hi-F. IPSS results suggested EAS in 9 patients, 8 of whom had Hi-F for more than two months, and 1 whose cycles occurred every 5 - 7 days. IPSS was consistent with Cushing’s disease (CD) in 2 patients after Hi-F of only 6 -7 weeks and one with Eu-F on admission, estimated duration < 4 weeks. DST suggested EAS in 9 patients, and CD in the one with recent Eu-F. CRH was consistent with EAS in 10 patients, but suggested CD in 2 with marginal increases in ACTH (34.5%, 38%) but not cortisol. 7 patients had ACTH-secreting tumor on pathology (5 pulmonary, 1 pancreas, 1 appendix NET), and 5 had occult presumed EAS. Time from one Hi-F episode to the next ranged from 1 week to 6 years with Hi-F duration of 3 days to 5 years. 24-hour urine free cortisol (UFC) levels were 17 - 301 times the upper reference range (RR) during Hi-F periods. During Eu-F, lowest UFCs were within RR in 9 patients and subnormal in 3. Hypokalemia occurred in 11 patients with Hi-F; increasing values paralleled movement to Eu-F.

Conclusion: Patients with possible ectopic ACTH-secretion and CCS may pose a diagnostic challenge: clinical and biochemical evidence of hypercortisolemia may not be present, depending on the timing and/or duration of hypercortisolism. Furthermore, test results may inappropriately suggest Cushing’s disease if performed after less than 8 weeks of hypercortisolism, or with recent eucortisolism. Thus, weekly UFC measurement may facilitate diagnosis of cyclical Cushing’s syndrome and determine appropriate timing of dynamic testing such as inferior petrosal sinus sampling. Potassium may be a useful marker to determine when medical treatment can be tapered or stopped.

1. Meinardi JR, et al. Eur J Endocrinol. 157:245, 2007.
MON-917 Carney Complex Due to a Contiguous Gene Deletion Syndrome (17q24.2-17q24.3)
Authors: Flippo Chelsi L , Hannah-Shmouni Fady , Stratakis Constantine
Published: May 2020

Background

While genomic rearrangements of chromosome 17 are not uncommon, deletions of chromosome band 17q24.2-q24.3 are rare, and associated features include cardiac abnormalities, characteristic facial appearance, short stature, obesity, syndactyly, intellectual disability, seizures, delayed dentition, and features of Carney Complex. It has been suggested that the involvement of KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A genes contribute to this phenotype. A case of a child with a 3.7 Mb deletion at chromosome band 17q24.2-q24.3, as well as a 2.1 Mb gain at chromosome 17q22, is described.

Clinical Case

A now 6 year old female was born at 34 weeks gestational age with prenatal course complicated by oligohydramnios and intrauterine growth restriction. Birth weight was at the 9th percentile, and birth length was at the 92nd percentile. She was noted to have a patent ductus arteriosus (PDA), poor suck and swallow, and dysmorphic features. Chromosome microarray revealed a 3.7 Mb deletion at Chromosome 17q24.2-q24.3, involving KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A, as well as a 2.1 Mb gain at Chromosome 17q22, involving C17orf112 and KIP2B.

At 6 years old, she continues to be small for weight (-4.5 SDs), BMI (-4.22 SDs), and height (-2.5 SDs), though with appropriate pre-pubertal linear growth velocity. She is minimally verbal and continues to receive physical, occupational and speech therapies. Examination showed dysmorphic facial features, including triangular face with pointed chin, prominent forehead with low-set ears, retro-micrognathia, almond-shaped eyes with up-slanting palpebral fissures, bulbous nose, thin lips, and irregularly-shaped teeth. She had bilateral 5th digit clinodactyly, tapering of the distal aspects of bilateral first digits of the hands, and syndactyly of bilateral 2nd/3rd digits of the feet. She had scant freckling over the nasal bridge and cheeks, as well as freckles of the left arm, left groin, and back. She had no clinical stigmata of hypercortisolism. Echocardiogram continues to show a PDA with no cardiac myxomas. Thyroid ultrasound was normal. However, she does have mild hypercalcemia, most recently 2.61 mmol/L (2.15-2.55), and mildly elevated alkaline phosphatase of 341 U/L (96-297).

Conclusion

This case highlights a child with many of the previously reported findings associated with 17q24.2-q24.3 deletions. However, she also was noted to have a 2.1 Mb gain at chromosome 17q22 involving C17orf112 and KIP2B genes, which have not yet been associated with a clinical phenotype. It is therefore unclear if her phenotype is partially explained by the chromosomal gain. Clinicians should suspect a contiguous gene deletion syndrome in a patient with Carney Complex and atypical features. Patients with this condition have also been described as “Carney Complex-plus”, a term that we do not recommend be used.
OR31-05 Emergence of Ovarian Hyperandrogenism and Luteal Insufficiency Following ESR1 Knockdown in the Mediobasal Hypothalamus of Adult Female Rhesus Monkeys
Authors: Levine Jon E , Greinwald Emily P , Felton Jesi A , Flowers Matthew T , Willging Molly M , Shapiro Robert A , Keen Kim L , Terasawa Ei , Uhlrich Daniel J , Abbott David Howard
Published: May 2020

Diminished estradiol (E2) negative feedback action by neuronal ESR1 in the arcuate nucleus (ARC) of the mediobasal hypothalamus (MBH) is hypothesized to cause gonadotropin-releasing hormone (GnRH) hypersecretion, and thus LH excess, contributing to ovarian hyperandrogenism in polycystic ovary syndrome (PCOS). In primates, including humans, however, the mediating estrogen receptor is unknown. Thus, to test the hypothesis that diminished E2 action on ARC ESR1 contributes to female primate ovarian hyperandrogenism, eleven, ovary intact, adult female rhesus macaques, pair housed with female peers, received five 12µl MRI-guided MBH infusions into the rostral-to-caudal extent of both right and left ARC. Each infusion comprised gadolinium contrast agent and ~3-4 x 1010 adeno-associated virus 8 (AAV8) particles containing either a shRNA specific for ESR1 (n=6, ERaKD) or scrambled shRNA (n=5, control). Mid-surgery MRI scans identified targeting accuracy. 2-2.5 years following AAV8 infusion, EIA-determined P4 values were obtained from twice weekly serum samples; samples obtained during the follicular phase of menstrual cycles or anovulatory periods were submitted to liquid chromatography, tandem mass spectrometry (LCMS) for additional steroid hormones. LCMS-determined values were also obtained 0 hours (h) and 24 h following an IM injection of 200IU hCG. Both ERaKD (28.5 ± 1.3 days, mean ± SEM) and control (34.0 ± 3.3 days) female groups exhibited comparably regular menstrual cycles. ERaKD exhibited higher circulating levels of LH (2.8 ± 0.2 ng/ml, p=0.03), androstenedione (A4, 0.43 ± 0.03 ng/ml, p=0.03) and testosterone (T, 0.23 ± 0.03 ng/ml, p=0.09), and LH/FSH ratio (1.7 ± 0.2, p=0.05) compared to controls (LH, 2.1 ± 0.4; A4, 0.30 ± 0.05; T, 0.18 ± 0.01 ng/ml; LH/FSH 1.3 ± 0.2). Following an ovarian androgen-stimulating hCG injection, ERaKD 24-h peak levels for T (0.28 ± 0.01 ng/ml) were higher (p=0.03) compared to controls (0.21 ± 0.01 ng/ml). In addition, luteal insufficiency emerged in ERaKD females, with mean (2.4 ± 0.3 ng/ml), peak (3.6 ± 0.4 ng/ml) and area-under-the-curve (AUC, 23.2 ± 4.2 ng/ml/days) P4 values diminished compared to controls (mean, 3.6 ± 0.1, p=0.01; peak 5.7 ± 0.1 ng/ml, p=0.01; AUC, 43.7 ± 6.7 ng/ml/days, p=0.03). Taken together, these results suggest that knockdown of ARC ESR1 disrupts Gn stimulation of ovarian function, contributing to female monkey ovarian hyperandrogenism and menstrual cycle impairment emulating PCOS in women.
MON-508 Clinicopathological Features of Papillary Thyroid Cancer After Fukushima and Chernobyl Accidents
Authors: Drozd Valentina , Branovan Igor , Fridman Mikhail , Shiglik Nikolay , Reiners Christoph
Published: May 2020

The phenomenon of a sharp increase in the incidence of thyroid cancer worldwide is now under debate. Screening activity, diagnostic improvements or real rise in incidence as a result of unknown carcinogens are discussed. Studies in Belarus after Chernobyl showed that the synergistic influence of radiation and nitrates might lead to an increased thyroid cancer (TC) risk in children. For better understanding of the etiology, we compared the published clinical data of pediatric TC patients after the nuclear emergency of Fukushima with the observations we made after the Chernobyl accident.

In a large-scale survey after the Fukushima accident, 300,476 subjects were screened and by September 2018, 191 subjects were diagnosed with thyroid malignancy or suspected malignancy by fine needle aspiration. Mean age of TC patients was 17.8 years at presentation. Mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were detected in 79%, 45%, and 2.1% of all cases, respectively. Only 4.8% TC cases were staged as low risk pT1aN0M0 (Suzuki et al. 2018). For comparison, in Belarus patients mean age was 13.0 years at presentation (1078 cases), mean tumor size 14.4 mm. Lymph node metastases were observed in 74%, pulmonary metastasis in 11% and extra-thyroidal extension in 48.5 - 64.1% (with respect to latency period). The low risk (pT1aN0M0) TC patients were diagnosed in 19.2% cases.

The most of TC cases from Japan and Belarus were clinically significant, not “overdiagnosed” and screened on time. Given that the accidental thyroid doses were very low in Japanese cases, it would be very important to evaluate and compare the exposure to endocrine disruptors as e.g. nitrates and low radiation doses from diagnostic procedures (dental X-ray examination and computed tomography).

Referece:

Suzuki S, Matsumoto Y, Ookouchi C, Nakano K, Iwadate M, Suzuki S, Nakamura I, Fukushima T, Mizunuma H, Yamashita S, Takenoshita S. The clinicopathological features of childhood and adolescent thyroid cancer in Fukushima after the Fukushima Daiichi nuclear power plant accident. Thyroid. 2018; Supplement 1, (Poster 136).
SAT-728 The Regulation of Tumor Suppressor Genes P53, BRCA-2, and Cell Cycle Protein p21 by Bisphenol S (BPS) in MCF-7 and T47-D Breast Cancer Cells
Authors: Parker Jordan , Morse Mia , Benard Paige , Pfiffner Samantha , Romanski Madison , Dinda Sumi
Published: May 2020

Bisphenol A (BPA) is considered to be an endocrine disrupting chemical (EDC), which mimics endogenous hormones and is linked to various cancers. Bisphenol S (BPS) is a BPA analogue, often used in plastics. BPS can leach into food and drink products, exposing humans to these chemicals. Evidence suggests BPS is also an EDC with similar endocrine disrupting effects. Despite hopes for a safer alternative, research has shown BPS possesses estrogenic activity due to its structural similarities with its analogue BPA. Previously we have shown the effects of BPS on estrogen receptor-alpha (ERα) and BRCA-1 in both MCF-7 and T-47D breast cancer cells. The wild-type p53 and BRCA-2 work to prevent cancer by monitoring and repairing DNA damage; however, in breast cancer patients these genes are often mutated. Mutated p53 will induce the cell cycle protein p21 to act as an oncogenic transcription factor. In the present study, we have examined the effects of BPS, alone and in combination with hormones and anti-hormones, on p53, BRCA-2, and p21 in both MCF-7 and T-47D cell lines by utilizing western blot analyses, cellular viability assays, confocal microscopy, apoptosis assay, and RT-qPCR analyses. Western blot studies revealed alterations in the expression of p53, BRCA-2, and p21 related with varying concentrations of BPS (4-20 µM). In comparison to the control, p53 expression increased (65-95%) in the presence of BPS in both MCF-7 and T-47D cells. In addition, BRCA-2 expression revealed a similar increase in both cell lines when treated with BPS. However, p21 expression decreased (approximately 50%) with increasing concentrations in both cell lines. For further evaluation, an optimal concentration of 8 µM BPS was then used in combination with various hormones and anti-hormones. Compared to the control, BPS and E2 were up regulated in a similar fashion to p53. A similar trend in the effects on BRCA-2 expression was depicted in T-47D and MCF-7 cells. However, in p21, BPS and E2 were down regulated in both MCF-7 and T-47D breast cancer cells. In order to determine the influence of BPS on the growth of breast cancer cells, image cytometric analysis with propidium iodide staining was utilized to quantify alterations in T-47D and MCF-7 cell numbers and viability. Upon treatment of BPS concentrations (4-20 µM), an increase in cellular proliferation (12-60% increase) occurred in both cell lines. These cellular proliferative effects of BPS and E2 were sensitive to combination treatments with anti-estrogens. Confocal microscopy was utilized to examine the cytolocalization of p53 upon exposure to BPS alone and in combination with hormones and anti-hormones. The results from this study will yield a greater understanding of the molecular regulation of BPS action via the p53, BRCA-2, and p21 signaling pathways linked with breast cancer.
MON-921 Autonomous Cortisol Secretion Coexisting with Pancreatic Neuroendocrine Tumor: A Rare Presentation
Authors: Faro Fernanda , Karman Gabriela , Dal-Prá Nathalia , Loureiro Jéssica , Feder Cecilia Kauffman Rutenberg , Santomauro Augusto Cezar , Lima Jose Viana , Mascarenhas Bruna , Santomauro Ana Teresa , Cury Adriano Namo
Published: May 2020

Introduction: neuroendocrine tumors (NET) are a very rare and heterogeneous group of malignancies that can be associated with adrenocortical tumors in approximately 20% of the cases, mostly bilateral and non-functioning. Autonomous cortisol secretion occurs in less than 10% of adrenal incidentalomas and the coexistence of pancreatic neuroendocrine neoplasms and autonomous cortisol secretion is not well-described.

Clinical case: a 54-year-old man with previous history of systemic hypertension and type 2 diabetes mellitus, presented with left hypochondrium pain in the last 18 months, associated with abdominal distension, constipation and nausea. Physical examination without abnormalities. Abdominal tomography demonstrated dilatated pancreatic duct and a solid heterogeneous nodule in left adrenal, measuring about 2.7 cm. Ecoendoscopy revealed a heterogeneous, hypoechoic and oval nodular lesion, located at the transition of pancreatic head and uncinate process, measuring 1.5x1.1cm. Biopsy was performed, showing a pattern of neuroendocrine neoplasia, with chromogranin and synaptophysin +, Ki67 1%. Gallium-68 dotatate PET revealed two pancreatic nodular formations, one in proximal neck/body (1.5 cm) and the other in pancreatic tail (1 cm), presenting SUV of 20.4 and 21, respectively. Adrenal nodule presented minimal increase in radiopharmaceutical concentration. To exclude the hypothesis of metastasis, PET FDG was performed, showing physiological uptake in adrenal nodule. Pituitary MRI had no abnormalities.

Chromogranin A and gastrin values were normal. Pheochromocytoma and primary hyperaldosteronism were excluded. Hypercortisolism investigation presented the following results: 23h salivary cortisol 167ng/dl (NR < 100), 24-hour free urinary cortisol 42.1 mcg/24h (NR 4.2-60), post-1mg and 2mg dexamethasone serum cortisol of 10.8 mcg/dl and 3.8 respectively (serum dexamethasone levels of 193 and 780 ng/dl; NR > 130), ACTH 13 and 11 pg/ml.

By these results, coexistence of non-functioning pancreatic neuroendocrine tumor and autonomous cortisol secretion was confirmed. A total pancreatectomy with partial gastrectomy and bileodigestive anastomosis was performed. Pathological anatomical evidence demonstrated a well-differentiated neuroendocrine tumor (NET G1) and immunohistochemistry analyses showed positive chromogranine A, synaptophysine, Ki67 1% and negative ACTH. Clinical follow-up of the adrenal adenoma was preferred.

Conclusion: although most adrenocortical tumors associated with NET are nonfunctional, hypercortisolism should be considered. Adrenal metastasis and ectopic ACTH secretion are differential diagnosis. Clinical follow-up is an option when patient is asymptomatic and comorbidities are well-controlled.
SUN-931 Characterization of an Ovarian Steroid Cell Tumor in a VHL Patient
Authors: Nocito Marta Claudia , Saraithong Prakaimuk , Newman Erika A , Thomas Inas H , Rainey William E , Lerario Antonio M , Heider Amer , Else Tobias
Published: May 2020

Most ovarian steroid cell tumors arise sporadically. However, they can also be observed as a rare manifestation of von Hippel Lindau disease. Here, we present a clinical, pathological and molecular characterization of a steroid cell tumor in a VHL patient. A 14 year old girl with molecularly confirmed diagnosis of VHL developed hirsutism and amenorrhea. Initial clinical hormonal evaluation was notable for elevated 17-OHP of 406ng/dl, androstenedione 275ng/dl, and testosterone 102ng/dl. In order to exclude congenital adrenal hyperplasia as a common cause of hirsutism in adolescents, ACTH stimulation was performed, but no increase in 17-OHP was observed. Anti Muellerian hormone, inhibin (INH) A and INH B were normal. Imaging revealed a bilobed 6cm left adnexal mass. The mass was resected en bloc via a left oophorectomy. Pathological evaluation showed multinodular steroid cell tumor with clear cytoplasm and delicate vascular meshwork. Immunoprofiling demonstrated positivity for inhibin and calretinin; while renal cell carcinoma markers were negative. All laboratory values normalized post-surgery. In addition to clinical measurements pre- and post-surgery, steroid profiles were evaluated by LC-MS/MS. Quantitative RT-PCR analysis showed robust tumor expression of enzymes facilitating the production of androgens, but not estrogens. Further preliminary analysis by exome sequencing confirmed the known germline pathogenic variant in VHL, but no additional obvious somatic driver mutations were identified. Interestingly, the NGS analysis of different specimens from the same tumor revealed multiple different single base pair variants in the VHL gene as a second hit. In summary, hirsutism in VHL patients should raise the suspicion for unusual ovarian tumors. In contrary to the usual theory of a monoclonal expansion after loss of the wt VHL allele, this tumor appeared to be oligoclonal as evidenced by different somatic VHL mutations. This could be either explained by initial parallel occurrence of several clones or that the VHL second hit is not an initial event, but the mutation instead supports tumor expansion following initial steps of tumorigenesis.
SUN-569 The Normalization of Sleep Duratioin as a Factor of Glyhemoglobin Reducing
Authors: Dzherieva Irina , Volkova Natalya , Komurdzhyntcs Maria , Davidenko Ilia , Ganenko Lilia , Plyashkevich Maria
Published: May 2020

Sleep deprivation is an important risk factor of the metabolic disorder. According to the systematic review published in the Circulation there are a lot of data from epidemiological, clinical and experimental researches which confirm this fact. The goal of our research was to assess the level of glycohemoglibin after the normalization of sleep duration. 24 patients with diabetes mellitus type2 (19 females and 7 males, average age 58.7 ±1.3 yer) were included in the research. Diabetes mellitus type 2 duration was 9.5 years. Criteria excluded were myocardial infarction, stroke, sleep apnea, oncological diseases and depression. To exclude depression we used the questionnaires: Center for Epidemiological Studies Depression Scale and The Hospital Anxiety And Depression Scale. To exclude sleep apnea we used questionnaire STOP-Bang score. The sleep duration was assessed by the patients self-reports. Glycohemoglibin was determined by Immunoinhibition Method Cobas 6000, Roche Diagnostics. The sleep duration was corrected by cognitive behavioral therapy. For statistic assess of the results we used the method Wilcoxon F. Results: At the beginning of the treatment the level of glyhemoglobin was 7.8% and the sleep duration was 6.4 hours.The included patients were treated by cognitive behavioral therapy for 6 months without changing other kinds of therapy. The sleep duration significantly(P=-0.35) enlarged until 7.5±0.2 hours and the level of glyhemoglobin was lowered by 0.4% significantly (P=0.47). The improving of sleep duration can successfully reduce the level of glyhemoglobin in diabetes mellitus type 2 without any intervention at glycemia and could contribute to the prevention of diabetes complications.