bluuebunny/crossref_metadata_2025_split huggingface dataset:
OR06-03 Serotonin Regulates Corticotroph Tumor Cell Proliferation and ACTH Secretion
Authors: Zhang Dongyun , Bergsneider Marvin , Wang Marilene B , Kim Won , Heaney Anthony P 
Published: May 2020

Abstract
Serotonin (5-HT) is an important hormonal modulator and neurotransmitter, and 5-HT has been demonstrated in pituitary tissue from several species. Previous responses to 5-HT antagonists have been reported in some patients with Cushing disease although this effect was unsustained, and ACTH and cortisol levels actually increased in some patients. To better understand the role of serotonin in the regulation of corticotroph tumor growth and ACTH secretion, we first measured serotonin levels in supernatants (SNs) derived from murine corticotroph tumor AtT20 cells. We demonstrated that AtT20 cells secrete serotonin (2±0.05ng/105cells/24h) which was ~50% of the levels secreted by the serotonin secreting mid-gut carcinoid BON-1 cell-line (4.2±0.05ng/105cells/24h). In contrast, serotonin secretion was not detected in rat pituitary tumor lactotroph (GH3) or human embryonic kidney (HEK293) cell SNs, or in our Ham’s F12 medium control. Immunocytochemical staining using serotonin specific antibodies demonstrated that serotonin was diffusively present in AtT20 cell cytoplasm, suggesting that serotonin was endogenously generated in the AtT20 cells. Using real-time PCR, we demonstrated that both serotonin synthesis enzymes, tyrosine hydroxylase-1 (THP1) and -2 (THP2) are expressed in AtT20 cells with higher relative THP1 expression, confirming endogenous corticotroph pituitary tumor serotonin production. We further demonstrated that the synthetic glucocorticoid Dexamethasone (100nM x 24h) suppressed TPH1 expression and inhibited corticotroph tumor serotonin secretion. We next evaluated the actions of serotonin and various serotonin antagonists on corticotroph tumor cell proliferation and ACTH secretion. Ritanserin (10-5M) inhibited murine corticotroph tumor proliferation by 5% and inhibited ACTH secretion by ~25%. In contrast, metergoline (10-5M) and the orally administered TPH inhibitor, telotristat etiprate (10-5M for 1-3 days), inhibited ACTH secretion by 50% and 30% respectively but did not reduce cell proliferation, suggesting that Metergoline and telotristat may regulate ACTH secretion independently of their anti-proliferative effect. Addition of serotonin (10-4~10-5M) to corticotroph tumor cells cultured in reduced serum (OptiMEM) or no serum conditions, resulted in an 80% increase in cell proliferation but had little effect on ACTH secretion with a 1-4% increase. In summary, we have demonstrated that serotonin is synthesized in and secreted from corticotroph tumor cells and that serotonin plays a role in regulation of corticotroph tumor proliferation and ACTH secretion in vitro. Our findings using inhibitors of serotonin action indicate potential for targeting this pathway as a novel treatment for patients with CD.
SAT-358 Hypercalcemia-Induced Altered Mental Status as the Primary Manifestation of Classic Hodgkin Lymphoma
Authors: Modarressi Taher , Shah Megha 
Published: May 2020

Abstract
Hodgkin lymphomas (HL) are lymphoid neoplasms formed by a conglomerate of malignant Hodgkin/Reed-Sternberg cells with heterogeneous non-neoplastic inflammatory cells. Classic HL (cHL), one of two major subtypes, comprises 90% of all cases. HL typically presents as asymptomatic adenopathy or mass on chest imaging; constitutional symptoms (unintentional weight loss, night sweats, fever) occur in approximately 40% of cases. Though hypercalcemia is not uncommon in HL due to increased production of 1,25(OH)2D or, less commonly, direct bony involvement, it is unusual for severe hypercalcemia and its related symptoms to be the primary reason for presentation such as in our case below.
An 87-year-old man was admitted to our institution with three days of increasing agitation and confusion in the context of several weeks of forgetfulness and decline in his daily activities. He previously lived robustly independently. His past medical history included atrial fibrillation, hyperlipidemia, and benign prostatic hyperplasia. His home medications included metoprolol, apixaban, atorvastatin, tamsulosin, finasteride and a multivitamin.
Laboratory evaluation revealed serum calcium 17.5 mg/dL and serum creatinine 3.0 mg/dL (eGFR 20 mL/min/1.73m2). Complete blood count, phosphate, magnesium and alkaline phosphatase were normal. Intravenous fluids and later pamidronate improved his calcium to the 11–13 mg/dL range. Endocrinological workup revealed PTH 7 pg/mL (nl 15–65 pg/mL), 25(OH)D 15 ng/mL (nl 20–80 ng/mL), PTHrP 0.8 pmol/L (nl &lt;2.0 pmol/L) and 1,25(OH)2D 57 pg/mL (nl 18–64 pg/mL). Serum protein electrophoresis showed no abnormalities and lactate dehydrogenase was 230 U/L (nl 125–250 U/L)
Computed tomography (CT) of his abdomen revealed non-specific prominent mesenteric lymph nodes. Neck CT did not show any abnormal cervical or supraclavicular lymphadenopathy. Chest CT did not show any mediastinal masses, abnormal lymphadenopathy, or findings consistent with silicosis (he had a 15-year history of masonry and brick-laying). Bone scan showed asymmetric uptake in two areas of his femurs, with xrays revealing subcortical scleroic lesions. Patient declined inpatient bone marrow biopsy, and was empirically started on prednisone, with rapid improvement in calcium to 9.6 mg/dL and return to his baseline mental status. He eventually accepted and underwent bone marrow biopsy as an outpatient, which revealed marrow involvement by classic Hodgkin lymphoma. The patient was started on a regimen of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, with excellent clinical response.
This case illustrates an atypical, hypercalcemia-driven initial presentation of Hodgkin’s lymphoma. It also exhibits the hallmark “inappropriate normal” 1,25(OH)2D which, in the context of hypercalcemia and low PTH, suggests extrarenal (i.e. PTH-independent) production of 1,25(OH)2D.
SAT-620 Left Ventricular Myocardial Deformation in T2DM Is Associated with Chronic Hyperglycemia but Not Myocardial Perfusion: A Study Based on Magnetic Resonance Imaging
Authors: Zhou Fangli , Deng Mingyan , Xie Linjun , Guo Yingkun , Ren Yan 
Published: May 2020

Abstract
Background: Diabetic cardiomyopathy is accompanied by left ventricular diastolic dysfunction. Abnormal glucose metabolism plays an important role in the pathogenesis of diabetic cardiomyopathy. However, it’s still not clear whether the influence of hyperglycemia on LV dysfunction is directly affects cardiomyocytes or is related to impaired myocardial perfusion. In this work, we focus on investigating the association between HbA1c and myocardial dysfunction, and if it is independent of myocardial perfusion reserve.
Materials and Methods: 64 type 2 diabetic patients were recruited at the endocrine clinic. They are divided into two group, well blood glucose-controlled group (HbA1c&lt;7) and poor glucose-controlled group (HbA1c≥7) T2DM group, according to their HbA1c level. All of the T2DM patients and age-matched healthy volunteers (normal glucose metabolism group, NGM group) underwent CMR to acquire normal values for myocardial strain and perfusion reserve.
Results: Well blood glucose-controlled group owned lower global circumferential PSSR than NGM group (p=0.037). Global circumferential PS (p=0.011), global longitudinal PS (p=0.004), global radial PDSR (p=0.005), circumferential PDSR (p=0.001), longitudinal PDSR (p=0.001), global circumferential PSSR (p=0.049), longitudinal PSSR (p=0.041) were significantly lower in the poor glucose-controlled group compared to the NGM group. In the multivariable linear regression analysis, HbA1c existed in all equations except the global circumferential PSSR equation and p&lt;0.05, and Slope, Max SI and Tpeak did not show dependent association with longitudinal and circumferential strain parameters.
Conclusion: In subclinical cardiac dysfunction T2DM patients, diastolic dysfunction is more common, but systolic dysfunction is still exist. Poor blood glucose control which is defined as HbA1c ≥ 7% is an independent risk factor for LV deformation for T2DM patients. Subclinical myocardial dysfunction is not triggered by myocardial perfusion reserve.
SAT-209 Treatment-Resistant Hypertension in a Post-Transplant Patient with Cystic Fibrosis: A Rare Case of Pheochromocytoma
Authors: Tansey David Joseph , Hatunic Mensud , Conneely John , Murray Michelle 
Published: May 2020

Abstract
Background: Pheochromocytoma is a rare catecholamine-producing tumor with an estimated incidence of less than 0.1% in the global population. We present the case of a pheochromocytoma in a 25-year-old man with a background history of a double-lung transplant for Cystic Fibrosis, carried out 5 years earlier. Clinical Case: A 25 year old, with a background history of Cystic Fibrosis and a Double Lung transplant in 2012 presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with Distal Intestinal Obstruction syndrome (DIOS) for which he was admitted for rehydration and laxatives. Contrast-enhanced computed tomography (CT) imaging of the abdomen and pelvis which showed a 3.4 cm right adrenal lesion, which was confirmed by a subsequent MRI Adrenals and an Endocrinology review was requested. On review, the patient was noted to be hypertensive with a blood pressure averaging 170/90 despite treatment with 3 different anti-hypertensive medications - namely amlodipine, telmisartan and doxazosin. On review of his medical notes, it was clear that he had been persistently hypertensive over the last 3 years. On further questioning, he noted increasingly frequent sweating episodes over the last number of months but denied any palpitations, headache or back pain. Laboratory analysis showed an elevated plasma normetanephrines (NMN) of 3167 pmol/L (182-867) as well as elevated metanephrines (MN) of 793 pmol/L (61-377) and high 3-MT of 257 pmol/L (&lt;185). His MIBG scan showed only a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary meeting and given the suggestive laboratory and radiologic findings, a presumptive diagnosis of pheochromocytoma was made. After controlling blood pressure with an alpha-blocker and beta-blocker for a week, the patient was hydrated and scheduled for an elective right adrenalectomy. The histopathology of the excised adrenal gland was consistent with a 3cm pheochromocytoma with none of the adverse features associated with malignant potential. The patient recovered well post-op, his blood pressure normalised and he was discharged home well for follow-up at the Endocrine and Transplant clinics. Conclusion: We describe a rare case of a right adrenal pheochromocytoma in a young man with multiple co-morbidities, who completely recovered after tumor resection. This case highlights the crucial importance of investigating secondary causes of hypertension, especially in younger patients. This is the first documented case in the literature of a case of pheochromocytoma in a post-transplant patient with Cystic Fibrosis. References: 1. Farrugia FA, Marikos G et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. Endocrine Regulation, Volume 51, Issue 3, 30th August 2017.
OR03-06 NAD+ Availability Modulates 11β-HSD1-Mediated Glucocorticoid Regeneration in Mouse Skeletal Muscle
Authors: Elhassan Yasir S , Kabli Ali , Nielsen Thomas , Fletcher Rachel , Oakey Lucy , Cartwright David , Chubanava Sabina , Garten Antje , Doig Craig , Treebak Jonas Thue , Lavery Gareth Geoffrey 
Published: May 2020

Abstract
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependant reductase located in the sarcoplasmic reticulum (SR) lumen of skeletal muscle. It generates active glucocorticoids to regulate permissive and adaptive metabolism and contributes to the development of the Cushing’s syndrome phenotype in mice receiving oral corticosterone. The SR enzyme hexose-6-phosphate dehydrogenase (H6PDH) generates NADPH which supports 11β-HSD1 activity. H6PDH depletion disrupts the SR NADPH/NADP ratio leading 11β-HSD1 to assume glucocorticoid-inactivating dehydrogenase activity. Little is understood regarding routes to NAD(P)(H) biosynthesis and metabolism in the SR. Here we asked whether modulating cellular nicotinamide adenine dinucleotide (NAD+) availability (the parent molecule of NAD(P)(H)) would influence muscle 11β-HSD1 activity given its sensitivity to the SR NADPH/NADP ratio. We used FK866 to inhibit nicotinamide phospho-ribosyltransferase (NAMPT, rate-limiting enzyme in NAD+ biosynthesis) to deplete NAD(P)(H) in wild type mouse primary myotubes. FK866 treatment for 48h impaired cellular energetic status, reducing NAD+ (&gt;90%), NADP+ (&gt;50%) and ATP (&gt;30%) without limiting cell viability. 11β-HSD1 reductase activity was decreased to 30% that of untreated cells (152±18 vs. 512±44 pmol/mg protein/h respectively, p&lt;0.005). Employing H6PD knockout myotubes, NADP+-dependent 11β-HSD1 dehydrogenase activity was also impaired following NAMPT inhibition. The NAD+ precursor nicotinamide riboside (NR, 0.5mM), which bypasses NAMPT inhibition through the NR kinase pathway restored NAD+ levels and rapidly rescued 11β-HSD1 reductase activity in wild type and dehydrogenase activity in H6PD knockout myotubes. To assess this in vivo, we examined 11β-HSD1 reductase activity in muscle explants of inducible muscle-specific NAMPT knockout mice in which NAD+ levels are reduced by 90%, and show 40% lower activity compared to wild type explants (114±14 vs. 67±10 pmol/mg protein/h, p=0.04). These data suggest a novel level of redox-regulated 11β-HSD1-mediated glucocorticoid metabolism in skeletal muscle. These data also imply a pathway by which NAD+ status is communicated between the cytosol and the SR, which is contrary to the current belief that the pyridine nucleotide pool in these compartments is separate. NAMPT inhibition is being studied as a potential anti-cancer therapy and these data reveal hitherto unanticipated effects this therapy may have in a range of tissues.
MON-220 Real World Performance of Urinary and Plasma Metanephrine Assays in Diagnosing Phaeochromocytoma/Paraganglioma
Authors: Deyab Eithar , Saleh Dina , Menon Ravi Kumar 
Published: May 2020

Abstract
Introduction:
Diagnosis of pheochromocytoma/paraganglioma (PPGL) can be challenging. Plasma metanephrines have highest sensitivity (96-99%) yet lowest specificity (85%)1 whereas 24-hour urinary metanephrines have 87.5% sensitivity and 99.7% specificity. Diagnostic accuracy depends on factors such as patient positioning and medications, questioning its potential value in a hospital setting.
Methods:
The audit was performed in a hospital which caters to a population of 400,000. Data was collected retrospectively on patients who had a request for plasma or urine metanephrines from March 2018 – September 2018.
Results:
A total of 85 patient order requests (58% male, 42% female) were reviewed; only 2 patients were ultimately diagnosed with a pheochromocytoma.
The mean age of patients was 48 years. The most common indication for requests was hypertension (64 patients).
Locations of order requests included 42% from outpatient clinics, 32% inpatient requests, 18% from Ambulatory Care, 6% by A&E and 2% by GP. Of the 27 (32%) inpatient requests, 10 had positive results: 1 diagnosed with primary aldosteronism, 1 with hypercortisolism and the others had no definite diagnosis. 8/10 patients with positive results did not have a repeat test.
Focusing on plasma metanephrines, 52% plasma metanephrines samples were negative, 22% were positive and 26% were not processed due to laboratory error. From the 19 positive plasma metanephrines, adrenal adenoma was present in 7 patients (from this group, 1 was referred for surgery with confirmed diagnosis of pheochromocytoma), 1 patient’s MIBG scan was negative and 1 diagnosis of stress-related raised metanephrines was made. The remaining 10 patients did not undergo an adrenal scan.
9 out of 18 cases with positive urine metanephrines had an adrenal adenoma. In 7/9, plasma metanephrines were positive, the remaining 2 had negative plasma metanephrines.
34 cases with initial negative test still had another urine/plasma metanephrines performed with similar negative result. Furthermore &lt;50% of the positive urine or plasma metanephrines were referred to and reviewed by the Endocrine team.
Discussion:
This audit highlights the potential pitfalls of investigating PPGL with plasma and urinary metanephrines, and in fact raises the question of its accuracy as an inpatient diagnostic tool as none of the positive inpatient tests resulted in a diagnosis of PPGL. Inappropriate urine and plasma metanephrines requests cause financial burden and patient anxiety. Even with outpatient requests, few positive results led to a PPGL diagnosis. Patient selection and conditions of testing must be more rigorously scrutinised and threshold for positive result must be raised for specificity of the test to be improved in ‘real world’ conditions.
References:
1. Lenders JW al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002.
OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors
Authors: castellnou Solene , Vasiljevic Alexandre , Lapras veronique , Raverot Veronique , Alix Eudeline , Borson-Chazot Francoise , Jouanneau Emmanuel , Lasolle Hélene , Raverot Gerald 
Published: May 2020

Abstract
Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas.
Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients.
Design. Retrospective cohort study.
Setting. University hospitals of Lyon.
Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017.
Intervention. None.
Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS&gt;1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors.
Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p&lt;0.001), smaller (7 vs 19mm; p=0.001) and less invasive (15.4% vs 44.4%; p=0.03).
USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p&lt;0.001).
Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4).
Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.
MON-177 CAH-X Syndrome in a German Cohort of Patients with Congenital Adrenal Hyperplasia
Authors: Sappl Andrea , Lottspeich Christian , Vill Katharina , Morak Monika , Bidlingmaier Martin , Reisch Nicole 
Published: May 2020

Abstract
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is encoded by the CYP21A2 gene. The CYP21A2 gene is flanked and partially overlapped by the TNXB gene encoding an extracellular matrix protein called Tenascin-X. Deficiency of Tenascin X can cause the Ehlers-Danlos Syndrome (EDS). Deletions of CYP21A2 extending into TNXB rarely cause CAH combined with EDS. Heterozygosity of TNXB mutations causing haploinsufficiency of TNX, however, have been described in about 5-7% in a patient cohort from the US and has been named CAH-X syndrome, CAH associated with mild hypermobility form of EDS.
We genetically investigated a cohort of 81 adult patients (31 males, mean age 37,8 years +/- 9,8) with classic CAH for CAH-X. Patients genetically positive for CAH-X and unaffected CAH control patients matched for sex, age and BMI underwent a thorough clinical investigation including joint examination by Beighton 9-point scale, skin and neurological examination, by a standardised protocol of thransthoracic echocardiography and muscle ultrasound. In addition serum tenascin-X has been measured.
In our cohort we identified one patient with CAH and EDS and 4 patients with CAH-X syndrome. All CAH-X patients had serum concentrations of tenascin-X below the normal range, however, not different from 35 unaffected CAH patients with regard to serum concentration. All 4 patients with CAH-X syndrome showed some associated clinical symptoms. Two had joint hypermobility detected by Beighton 9-point score. Two of four CAH-X patients showed cardiac abnormalities (mild mitral regurgitation in one patient and a surgically corrected common arterial trunk type I A in the other patient). The patient with CAH and EDS showed cardiac abnormalities in addition to typical EDS symptomatology. All 5 affected patients complained about back pain and showed foot malposition. Profound changes in muscle ultrasound were found in 60 % of patients with CAH-X syndrome (3/5) and in none of the controls (0/5).
In conclusion, our data confirm the previously described prevalence of CAH-X. Beighton-score seems to be a quick and cheap screening instrument for CAH-X and should be performed in all patients with classic CAH, since protein level in serum cannot be used for screening for CAH-X-Syndrome. A stronger focus needs to be made on back pain and foot malposition as symptoms of CAH-X and echocardiography should be performed in all CAH-X patients. Therapy should depend on clinical symptoms in patients.