bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-239 Combination of Immune Check Point Inhibitors Causing Hypopituitarism
Authors: Dhillon Puneet , Grover Harshwant , Slusser Jonathan , Gopisetti Neethu , Patel Tirth 
Published: May 2020

Abstract
Introduction: Immune Check Point inhibitors (ICI) have been associated with immune related adverse events including a wide array of Endocrinopathies particularly when a combination of ICIs is used. We present a case of Hypopituitarism secondary to CTLA-4 inhibitor Iplimumab and PD-1 inhibitor Pembrulizumab in a patient with Vulvar Melanoma.
Case Description: 49-year-old female with past medical history of Type 2 Diabetes and Vulvar Melanoma presented with nausea, vomiting and fatigue. The patient had surgical excision of Vulvular Melanoma and had been on chemotherapy with Pembrolizumab and Ipilimumab for 1 month. She was found to be hypotensive in the ER, but blood pressure improved after fluid resuscitation. Her blood sugar levels were 76 MG/DL. She denied using any insulin in the last 24 hours. AM Cortisol was &lt;1 UG/ML. TSH was 0.205 UIU/ML with free T4 at 0.74 NG/DL. FSH was 2.5 MIU/ML. LH was 0.5 MIU/ML. Prolactin was 90.2 NG/ML. ACTH was less than 9 PG/ML. MRI of the brain showed mildly enlarged pituitary gland with suprasellar extension, measuring 10.5 mm in craniocaudal height and normal homogeneous enhancement. A diagnosis of Hypopituitarism secondary Ipilimumab and Pembrolizumab was made. She was started on steroids and thyroid replacement. The patient’s symptoms resolved, and she was discharged home in a stable condition with outpatient Endocrinology follow up.
Discussion: Immune checkpoint inhibitors (ICI) includes PD1(Programmed cell death receptor 1) inhibitors like Pembrolizumab and CTLA-4 (Cytotoxic T Lymphocyte Antigen-4) inhibitors like Ipilimumab. CTLA-4 inhibitors have more frequently been associated with Hypophysitis leading to particularly ACTH and TSH deficiencies and causing secondary adrenal insufficiency and secondary hypothyroidism. Posterior Pituitary involvement is less common. MRI usually shows mild to moderate enlargement of the pituitary gland. ICI therapy usually does not need to be stopped. Patients commonly require long term glucocorticoid and thyroid replacement.
SUN-573 Use of PCSK9 Inhibitors Post-Transplant
Authors: Matthews Juliana , Donald Dustin , Carranza-Leon Barbara Gisella 
Published: May 2020

Abstract
Background:
Dyslipidemia is common in patients after transplant. While statins are the mainstay of therapy, interactions with immunosuppressants such as calcineurin inhibitors (CNIs) can limit dose titration or lead to intolerance of this important drug class. Withdrawal of statin therapy can precipitate hyperlipidemia and potentially accelerate cardiovascular disease in transplant recipients, including coronary allograft vasculopathy (CAV) in heart transplant (HT) patients. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) may provide a safe, effective option for such patients. PCSK9i profoundly reduce low-density lipoprotein (LDL) and subsequently the risk of cardiovascular events in nontransplant patients. Further, these novel agents have no known interactions with CNIs. There is a paucity of data describing PSCK9i use post-transplant, with only a few small case series reported in HT recipients. Here, we summarize our experience along with available literature on this topic.
Methods:
In this retrospective case series we investigated adult recipients of heart transplant who were treated with PCSK9 inhibitors from July 2015 to 2019 because of statin intolerance or refractory hyperlipidemia. We compared the data of patients at baseline and after various durations of therapy with the PSCK9i evolocumab and alirocumab using the median and interquartile range (IQR). Specifically, we evaluated PCSK9i efficacy, effect on immunosuppressant levels, cardiac function and adverse events.
Results:
Five patients (4 men; median age 54, IQR 52-60) underwent heart transplant an average of 7.4 years ago. Median treatment duration of evolocumab or alirocumab was 12 months (IQR 7-17). This led to a reduction of total cholesterol by 94 mg/dl (p=0.04) (47% decrease) and LDL cholesterol by 83 mg/dl (p=0.04) (69% decrease). No statistically significant difference in HDL cholesterol, triglycerides or liver function tests (LFTs) were observed. There were no episodes of rejection. Immunosuppressant levels remained at goal. One patient noted a few days of fatigue after alirocumab injections but otherwise no side effects were reported.
Conclusion:
The PCSK9 inhibitors evolocumab and alirocumab are promising alternatives to statin therapy in transplant recipients with statin intolerance or refractory hyperlipidemia. Our study showed their potential to significantly reduce LDL cholesterol in heart transplant patients without altering IST levels. No episodes of transplant rejection were noted. Further long-term studies to establish the safety and efficacy of PSCK9 inhibitors post-transplant are needed.
MON-448 Detection of Thyroid Cancer Recurrence in Patients with Positive Thyroglobulin Antibody Receiving Immunoglobulin Therapy
Authors: Taiwo Adeyinka , Dokun Ayotunde 
Published: May 2020

Abstract
Introduction: Differentiated thyroid cancers such as papillary and follicular thyroid cancer make up more than 90% of all thyroid cancers. The presence of thyroglobulin autoantibodies makes interpretation of the thyroglobulin level unreliable, as it could be falsely low or falsely high. Studies have shown that rising thyroglobulin antibody levels, could be used to monitor for disease recurrence in patients with negative thyroglobulin and imaging studies. However, there are challenges in detecting recurrence in patients with normal thyroglobulin level and thyroid imaging studies, who are on lifelong immunoglobulin therapy and who have increasing thyroglobulin antibody levels.
Clinical case: A 63 yr old female was found to have an incidental left thyroid nodule at age 48yrs from a carotid ultrasound. She underwent US guided FNA of the thyroid nodule and was found to have papillary thyroid cancer. She had total thyroidectomy a month later, with removal of a 1.4cm primary, with no evidence of extrathyroidal extension, clear margins and no evidence of lymphovascular invasion – Stage T1bN0M0. There was left level 6 neck dissection with no carcinoma identified in the 2 lymph nodes removed. She received 105.3 mCi radioactive iodine (RAI) and whole body thyroid scan done 7 days later revealed, increased uptake involving the thyroid bed likely residual thyroid tissue. Activity was noted inferolateral to the right thyroid bed which most likely represents a lymph node. There was no evidence of distant metastasis.
She was commenced on levothyroxine post operatively. Her other past medical history is significant for idiopathic urticaria and angioedema, immune deficiency disorder with low IgG and IgM and asthma. She was commenced on monthly IV immunoglobulins 5yrs post RAI therapy, due to recurrent sinusitis, rhinitis and chronic diarrhea. She was later transitioned to weekly SQ immune globulin – Hizentra which she is on till date.
Over the past 15 years, serial neck ultrasounds post radioiodine ablation have been negative for recurrence. Her TSH ranged 14.91 to 0.04 (ref 0.27-4.2 uiu/ml) and thyroglobulin (Tg) titer remains &lt;0.1 (ref &lt;0.1). Her thyroglobulin antibody titers have trended up from &lt;0.2 (ref &lt;2.0) 5yrs post RAI therapy to 49 (ref &lt;4 iu/ml)) on her most recent test this year. She is currently undergoing further work up to rule out recurrence of her cancer. In our review of the literature we found one report that showed use of Liquid Chromatography–Mass Spectrometry (LC-MS) was able to differentiate thyroid cancer recurrence in an individual with positive antithyroglobulin antibody receiving immunoglobulin therapy.
Conclusion: In patients with negative Tg levels, but elevated thyroglobulin antibody while receiving immune globulin therapy, thyroglobulin antibody levels may not be a reliable indicator of thyroid cancer recurrence. Measurement of Tg levels using a LC-MS may provide some clarity.
SAT-491 Transient Thyrotoxicosis with Immune Checkpoint Inhibitors Therapy: The Importance of Endocrine Evaluation
Authors: Martins Diana Cruz , Guelho Daniela , Vicente Nuno , Ventura Mara , Vieira Alexandra 
Published: May 2020

Abstract
Introduction
The immune checkpoint-blocking antibody nivolumab is recognized as having a crucial role in different malignancies by blocking programmed death-1 (PD-1) receptor immune cells. Besides its benefits, nivolumab may cause endocrine immuno-related adverse events (irAEs), including thyroid dysfunction (TD).
Clinical case
A 71-year-old man, with an uneventful past medical history, was diagnosed with stage IIIB (T4N2M0), epithelial-growth-factor-receptor (EGFR) wild type, lung adenocarcinoma.
The patient underwent 4 cycles of first line chemotherapy with cisplatin/vinorelbine and then radiotherapy, obtaining a partial response.
After 4 months, tumor progression was identified, as assessed by whole-body 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) scan, showing pleural and nodal metastasis. Nivolumab, 3 mg/kg every 2 weeks, was started at this point.
While pre-nivolumab thyroid function was normal, 3 months after starting the therapy, a low serum TSH level of 0.04 mUI/mL (0.38-5.33) was found, associated with a normal level of FT4, of 10.8 pmol/L (7.9-14.4). Thyroid antibody (Ab) tests, including TSH-receptor Ab, were negative. At ultrasound examination, thyroid gland parenchyma was normo-echoic, demonstrating an isoechoic thyroid nodule in the right lobe, with regular margins, measuring 14mm diameter. Previous medical history was negative for thyroid disease.
One week after the referred thyroid function tests, nivolumab was discontinued due to progressive disease as assessed by abdominal magnetic resonance, demonstrating right adrenal metastasis and patient started cisplatin/permetrexed chemotherapy. One month after nivolumab suspension, patient had already normalized thyroid tests, with TSH 2.27 mUI/mL and FT4 9.1 pmol/L. More recently (6 months after nivolumab discontinuation), thyroid function tests continued stable, with TSH 1.05 mUI/ml and T4L 9.4 mmol/l. At this point, patient was receiving permetrexed maintenance therapy.
Conclusions
Immune checkpoint molecules as nivolumab, play a crucial role in anti-tumor immunity evasion. Besides its benefits, it may cause irAEs, including TD.
We believe it’s essential to perform thyroid function tests at baseline and before the administration of each nivolumab dose, if possible. Additionally, large prospective studies are required in order to assess, the impact of autoimmunity on the development of TD induced by nivolumab, and its potential effect on overall survival and specific cancer survival data.
MON-005 Inhibition of Glucocorticoid Signaling in SRC-1/-2 Double-Deficient Mice Results in Impaired Lung Maturation and Delayed Parturition
Authors: Mishra Ritu , Chen Jingfei , Gao Lu , Mendelson Carole R 
Published: May 2020

Abstract
The mechanisms that lead to the initiation of parturition are incompletely defined. Parturition timing is mediated by signals from both mother and fetus. Our previous findings using mice that were double-deficient in steroid receptor coactivators (Src)1 and 2 (Src-1/-2d/d) suggest that the fetus signals its mother when it is ready to be born through fetal lung production of surfactant components, surfactant protein A (SP-A) and platelet-activating factor (PAF). Notably, mice that are double knockout for Src-1/-2 die at birth of respiratory distress, due to decreased surfactant lipoprotein production. Intriguingly, we observed that wild-type (WT) mothers carrying Src-1/-2d/d fetuses manifested a ~38 h delay in parturition compared to WT mothers carrying WT fetuses. This was associated with decreased production of SP-A and PAF by the Src-1/-2d/d fetal lungs. Our findings suggested that these effects of Src-1/-2d/d were caused by impaired glucocorticoid receptor (GR) transcriptional activity in fetal lung cells. To identify other genes in fetal lung that were affected by Src-1/-2d/d, we conducted RNA-seq analysis of lungs from 18.5 days post-coitum Src-1/-2d/dvs. WT fetuses. We observed that one of the genes most highly downregulated in Src-1/-2d/d fetal lungs was 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 catalyzes the conversion of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, which are ligands for the glucocorticoid receptor (GR). We validated the RNA-seq results by RT-qPCR and immunoblotting and observed a striking reduction of 11β-HSD1 mRNA and protein in lungs of Src-1/2d/d fetuses, compared to WT. Others observed that glucocorticoids potently increased 11β-HSD1 expression in various cell types via activation of transcription factors C/EBPα and C/EBPβ, providing a potential positive feed-forward loop. Notably, we observed that C/EBPα and C/EBPβ mRNA and protein were markedly reduced in Src-1/-2d/d fetal lungs, compared to WT. Deletion of the Cebpa gene in respiratory epithelium of fetal mice caused respiratory failure at birth due to surfactant lipid and protein deficiency. This was associated with increased expression of TGF-β2, which inhibits fetal lung maturation. Notably, we observed that expression of TGF-β2 and TGF-β3 were increased in Src-1/-2d/d fetal lungs. Thus, impaired lung development, surfactant synthesis and delayed parturition in Src-1/-2d/d fetuses are likely caused by decreased 11β-HSD1 and GR signaling, resulting in decreased C/EBPα/β expression and increased TGF-β signaling.
SAT-598 Shared Signaling Profile Between Human MRAPα-Induced Human MC4R Constitutive Activity and Obesity-Associated Human MC4R Constitutive Activity
Authors: Botha Rikus , Kumar Shree S , Grimsey Natasha , Kay Emma I , Mountjoy Kathleen Grace 
Published: May 2020

Abstract
The human melanocortin 4 receptor (hMC4R) plays a critical role in the regulation of energy balance with more than 150 distinct human obesity-associated mutations. Most exhibit defective MC4R functionality but six have been reported to associate with constitutive activity. This represents a conundrum since a lean phenotype is expected for enhanced MC4R signaling. Human melanocortin 2 receptor accessory protein alpha (hMRAPα) induces hMC4R constitutive activity in transfected HEK293 cells (1,2). We do not know whether the hMRAPα-induced gain-in-function for hMC4R would cause, or prevent, obesity because of this conundrum. Here, we hypothesize that wild-type hMC4R, obesity-associated constitutively active hMC4R and hMRAPα-induced constitutive active hMC4R can exist in distinct conformational states and elicit distinct signaling profiles. To test this, we compared transiently expressed HA-hMC4R in HEK293 cells for basal and agonist activation for adenylyl cyclase, Cre driven β-galactosidase reporter transcription, and receptor protein expression. Six previously reported obesity-associated hMC4R constitutively active variants were compared with two hMC4R constitutively active mutations not associated with obesity, two hMC4R variants associated with protection from development of obesity, five non-constitutively active hMC4R mutations associated with obesity, hMRAPα co-expressed with hMC4R, and wild-type hMC4R. Our data confirm hMC4R constitutive activity coupling to both adenylyl cyclase and Cre β-galactosidase reporter for only two hMC4R variants associated with obesity (H76R & L250Q), one hMC4R mutation (H158R) not associated with obesity, and hMRAPα co-expressed with hMC4R. We show α-MSH stimulated concentration curves for wild-type hMC4R, H76R, L250Q & H158R hMC4R variants and hMRAPα co-expressed with hMC4R coupling to adenylyl cyclase. Surprisingly, out of these, only wild-type hMC4R and H158R hMC4R variant exhibited α-MSH-stimulated Cre β-galactosidase reporter concentration curves. Western blotting and ELISA showed ~70% reduced cell surface and total receptor protein expression for hMC4R co-expressed with hMRAPα and obesity-associated constitutively active hMC4R variants, compared to wild-type hMC4R. To summarize, two constitutively active hMC4R variants (H76R and L250Q) associated with obesity, and hMC4R co-expressed with hMRAPα, share a signaling profile comprising protein expression and α-MSH stimulated functional coupling to adenylyl cyclase and Cre-reporter gene expression. We conclude (1) if hMC4R is co-expressed with hMRAPα in vivo it would likely contribute to human obesity, and (2) obesity-associated constitutively active hMC4R variants exhibit a signaling anomaly that may underpin development of anti-obesity therapeutics.
1. Kay EI, et al. J Mol Endocrinol. 2013;50:203-215.
2. Kay EI, et al. PLoS ONE. 2015;10(10):e0140320.
SAT-558 A Dedicated Endocrine Hypertension Service Increases the Timely Diagnosis of Primary Aldosteronism
Authors: Yang Jun , Lim Yin Y , Libianto Renata , Shen Jimmy , Young Morag Jennifer , Fuller Peter J 
Published: May 2020

Abstract
Background: Primary aldosteronism (PA) accounts for 3.2-12.7% of hypertension in primary care but is often diagnosed late, if at all. A delayed or missed diagnosis leads to poor blood pressure control and greater cardiovascular risk that could be averted with targeted treatment. An Endocrine Hypertension Service (EHS), encompassing an education program, streamlined diagnostic tests and dedicated PA clinic, was developed to address this issue.
Aims: To analyse the impact of Victoria’s first dedicated EHS on the pattern of PA diagnoses.
Methods: Socio-demographic and clinical data from all patients who attended the EHS since July 2016 (N=267) was collected prospectively. Patients were divided into Year 1 (Y1), Year 2 (Y2), and Year 3 (Y3), based on their first visit.
Results: The proportion of referrals from primary care increased (20% in Y1 to 52% in Y3) with more referrals being made for treatment-naive hypertension (3% in Y1 to 19% in Y3). Patients with a hypertension diagnosis of 5 years or less at the time of referral to EHS increased from 34% in Y1 to 45% in Y3 whilst the percentage of patients with a hypertension diagnosis of more than 10 years decreased from 50% in Y1 to 35% in Y3. Consistent with an earlier presentation, the proportion of patients with end-organ damage at the time of referral decreased from 44% in Y1 to 29% in Y3. Almost a third of the PA patients had unilateral disease; all of those who underwent adrenalectomy had biochemical cure. Patients with bilateral PA were treated with spironolactone. Their systolic/diastolic blood pressure decreased by 15/12 mmHg in Y1, 17/13 mmHg in Y2 and 23/11 mmHg in Y3; while the mean number of antihypertensive medications decreased from 2.9 to 1.8 in Y1, 2.7 to 2.0 in Y2 and 2.2 to 1.6 in Y3
Conclusion: The EHS has facilitated an increase in referrals for PA screening from primary care, resulting in the earlier diagnosis of PA, when less complications are present, and optimised patient outcomes. A broader uptake of such a clinical service, integrated with education outreach, will bridge the gap between the reported high prevalence of PA and the actual low diagnostic rates.
SAT-218 Metastatic Non Seminomatous Germ Cell Tumor Masquerading as Bilateral Adrenal Masses
Authors: Baral Neelam , Bansal Rashika , Basyal Binaya , Lee Wen , Kantorovich Vitaly , Sharma Meeta B 
Published: May 2020

Abstract
Context: Adrenal incidentalomas are commonly nonfunctional and can be diagnosed with imaging and biochemical testing. However, detection of rare causes of adrenal incidentalomas like metastatic adrenal tumors can makes its’ diagnosis very challenging due to vast majority of uncommon primary tumors. Consideration of biopsy for diagnosis and the awareness of rare primary tumors that can metastasize to adrenals is essential to prevent unnecessary adrenalectomies. Our case illustrates one such rare case where bilateral adrenal mass was the initial presentation of obscure retroperitoneal primary NSGCT (Non seminomatous germ cell tumor). Case Description: We present a case of a 34-year-old male with acute abdominal pain found to have huge bilateral adrenal masses. The left adrenal gland was markedly enlarged to 11 x 9 x 5 cm and the right adrenal gland was 6.5 x 3.4 x 7.7 cm. Multiple enlarged and centrally necrotic retroperitoneal lymph nodes (maximum 2.6 x 4.2 x 5.4 cm) along with iliac and inguinal lymphadenopathy were noted. The incidentalomas were proven to be biochemically nonfunctional and extensive imaging and further lab work up ruled out lymphoma, mycobacterial or fungal infection, infiltrative diseases. He then underwent a core biopsy of the left adrenal mass which showed predominantly necrotic tissue, acute inflammatory cells with histiocytes, and rare atypical cells without evidence of malignancy. Repeat core biopsy of left adrenal mass was unrevealing. He finally underwent a core biopsy of a large 4cm retroperitoneal lymph node which ultimately revealed NSGCT. Scrotal ultrasound showed testicular microlithiasis without any testicular mass. He had a very low testosterone level of 21 (241-827 ng/dL) and an a mildly elevated b-hCG (beta human chorionic gonadotropin) of 134 (0-1mIU/ml). A retroperitoneal primary NSGCT with metastasis to the adrenal glands was the most likely diagnosis (visceral metastasis) - Stage III (pTxN3M1S1). He was started on bleomycin, etoposide and cisplatin (BEP) chemotherapy. Conclusion: Rapidly progressing adrenal masses in young males should prompt consideration for metastatic germ cell tumors as a possible cause, even with near normal tumor markers such as alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (B-HCG). Confirmation of the metastatic tumor, via histopathology, is required to avoid unnecessary adrenalectomy.
SUN-034 Combined CNV, Haplotyping and Whole Exome Sequencing Implicates Inherited Novel SRY Mutations Not Account for Familial 46,XY Sex Reversal
Authors: Qiao Jie , Wang Nan , Zhu Wenjiao , Han Bing , Zhao Shuangxia , Song Huai-Dong 
Published: May 2020

Abstract
SRY is one of the important genes involved in the process of human sex determination. The disturbed sex determination caused by SRY mutation accounts for 10-15% cases with complete gonadal dysplasia (CGD), also known as 46, XY sex reversal. Recently, three distal enhancers are disclosed in the upstream of SOX9 gene. In an inherited 46, XY sex reversal pedigree with 5 patients, p.Arg76Leu mutation of SRY and p.G212S mutation of NR5A1were identified from the proband who present with primary amenorrhea and lack of puberty development. The missense mutation of NR5A1was found to be derived from the mother. Interestingly, the paternal inherited p.Arg76Leu mutation of SRY was revealed from other 2 CGD patients, as well as from apparent normal male family members with fertility. P.Arg76Leu variation was found have no effect to the transcriptional activity of target gene SOX9, neither alteration of the nuclear translocation of SRY. Whole exome sequencing also found SRY mutation, FGF10 mutation, GJB4 gene mutation, etc. with no segregation in the family, which suggested SNVs are not main cause of the disease in this pedigree. By copy number variation and SNP haplotype analysis, SOX9 gene far upstream deletion of 68kb was disclosed from the 3 patients in this family, containing one of the enhancers of SOX9. Real-time PCR confirmed that the heterozygous deletion of the region result in loss of SR-XY, but not eSR-B and eALDI. Therefore, single nucleotide variation (SNV) of SRY and NR5A1 are not main causes of severe phenotype of CGD, the enhancers of SOX9 should be investigated carefully in such patients.