bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-125 A Tough NUT (Midline Carcinoma) to Crack
Authors: Lavelle Kristen , Kirkeby Kjersti
Published: May 2020

Introduction

NUT midline carcinoma (NMC) is a rare, highly aggressive cancer with poor prognosis. To date, there is no established therapeutic strategy; further studies are necessary to compare treatment modalities as well as investigate novel immunotherapeutic agents.

Case presentation

A 39-year-old female presented with a rapidly enlarging right neck mass and a recent 40-lb weight loss and was found to have a 5 cm poorly defined infiltrative hypoattenuating mass on CT scan concerning initially for anaplastic thyroid malignancy. Endocrinology and ENT were consulted and the patient underwent thyroid biopsy, which was positive for NMC. PET scan demonstrated hypermetabolic lymphadenopathy in the bilateral neck and mediastinum, but no distant metastases were identified. She then underwent total thyroidectomy with extensive dissection of the bilateral neck; pathology revealed one positive lymph node. On endobronchial biopsy, the mediastinal lymph nodes were benign. Immunohistochemistry revealed PD-L1 expression and gene assay showed an NSD3-NUTM1 fusion of the NUT gene. Oncology advised systemic treatment with carboplatin/taxol and considered Pembrolizimab, an anti-PD-L1 immunotherapy agent.

Discussion

The prognosis of NMC is less than 1 year and only 20-30 cases are reported per year in the USA. NMC is a poorly differentiated subtype of squamous carcinoma characterized by a chromosomal rearrangement of the NUT gene, involving molecular translocation with the BRD4 gene in 70% of cases. It remains challenging to treat NMC, as metastasis is present on diagnosis in most cases and there is currently no established approach. In a report of 40 patients from the NUT Midline Carcinoma Registry, surgical resection correlated with significantly improved survival in contrast to initial radiation or chemotherapy. Recently, BET domain inhibitors have emerged as a promising class of targeted agents for tumors with BRD4-NUT fusions. Their efficacy is unknown for other NUTM1 fusions. Both BET domain and histone deacetylase inhibitors are in clinical trials, and next-generation BET and CDK9 inhibitors have shown preclinical activity. Our patient likely benefited from early intervention with surgical therapy. Her PET scan findings suggest that re-sampling her mediastinal tissue would be prudent. Given her lack of BDR4-NUTM1 fusion, it is unknown if she would benefit from BET inhibitor.

Conclusion

NMC is an underrepresented cancer that warrants further investigation into treatment modalities and novel immunotherapies.

References

Bauer, DE et al (2012). Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clinical cancer research,18(20),5773–5779.

Liu S, et al (2018). NUT carcinoma: a rare and devastating neoplasm. Case Reports.

Napolitano, M et al (2019). NUT midline carcinoma of the head and neck: current perspectives. OncoTargets and therapy,12,3235–3244.
SUN-506 Hyperthyroidism Induced Hepatic Apoptosis
Authors: Ahmed Sabreen , David Julia , Melendez-Ramirez Lydia Yvonne
Published: May 2020

Background:

Graves’ disease is commonly associated with abnormal liver function tests, most frequently ALP, but the exact mechanism is not fully understood. In vitro and in vivo animal studies have shown elevated T3 activity can induce hepatocyte apoptosis via a mitochondrial-mediated pathway. This case demonstrates a patient with elevated aminotransferases and hepatic apoptosis most likely secondary to severe hyperthyroidism.

Clinical Case:

50 year old female with a past medical history of migraines was seen by primary care for fatigue and 15 lb weight loss in one month. She was found to be hyperthyroid with TSH < 0.1 uIU/L (n=0.34-5.6), free T4 3.48 ng/dL (n=0.58-1.64) and mildly elevated aminotransferases of AST 77 IU/L (n=15-41), ALT 144 IU/L (n=12-63), which increased within a week to 159 IU/L and 309 IU/L respectively. ALP and bilirubin were within normal range. She was started on methimazole 20 mg twice daily by her PCP. The patient developed vomiting and stopped taking methimazole after 3-4 days. Upon initial presentation to endocrine clinic, found to be clinically hyperthyroid and as LFTs were improved but still elevated, she was re-challenged with methimazole at a lower dose as well as started on a beta blocker and cholestyramine. TT3 checked was elevated at 2.10 ng/mL (n 0.87-1.78). Graves’ disease was confirmed with elevated TSI as well as RAI uptake and scan showing increased homogenous uptake.

She had extensive workup for another etiology by hepatology including autoimmune, which were negative. Her fibrosis score was stage F1-F2 (n=F0) and necroinflammatory activity grade A3 indicating severe activity (n=grade A0). Core needle biopsy of the liver showed focal lytic necrosis/apoptosis and abundant pigment-laden Kupffer cells signifying recent hepatocellular injury. Her AST and ALT down trended and normalized with repeat fibrosis score of F1 and necroinflammatory activity grade A0. She eventually had definitive therapy with RAI treatment.

Conclusion: In most cases of hyperthyroid induced liver dysfunction, liver histology showed fatty infiltration, cytoplasmic vacuolization, nuclear irregularity and hyperchromatism.

This case, without any other known causes that could explain her hepatic injury, indicates the possible role of hyperthyroidism in hepatic apoptosis.
MON-263 Renal Cell Cancer Metastasis to the Pituitary Masquerading as a Non-Functioning Adenoma
Authors: Vedere Tarunya , Vance Mary Lee
Published: May 2020

A 47 yr. old male with history of RCC and hypertension was seen in pituitary clinic for management of a pituitary mass. He initially presented to an outside hospital with persistent headaches, unintentional weight loss, severe fatigue, dizziness, cold intolerance, low libido and difficulty with erections. CT head showed a pituitary mass. Lab work revealed pan-hypopituitarism with adrenal insufficiency [random cortisol 0.7 ug/dL (4- 19 ug/dL); ACTH 13 pg/mL (7-63 pg/mL)], hypothyroidism [T4 0.52 ng/dL (0.7-1.5 ng/dL); TSH 0.1 mIU/L (0.45-4.5 mIU/L)] and hypogonadism [total testosterone 15 ng/dL (200-1000 ng/dL); LH of 0.6 mIU/mL (1.5-9.3 mIU/mL); FSH of 3.5 mIU/mL (1.6- 8.0 mIU/mL)]. Prolactin was slightly elevated at 34 ng/mL (2- 18 ng/mL) from stalk compression. IGF-1 was 78 ng/mL (Z score -1.2).

When we saw him, he was already on hormone replacement with significant improvement in symptoms. He had no visual field defects or symptoms of diabetes insipidus (DI). As for his history of RCC, he underwent a partial left nephrectomy in 2015, followed by a completion nephrectomy shortly after. Pathology was consistent with clear cell RCC. He did not receive any adjuvant therapy; Follow up imaging studies were reportedly negative for recurrence. Pituitary MRI showed a 1.6 X 1.4 X 1.5 cm enhancing sellar and suprasellar mass without compression of optic chiasm. He was thought to have a presumed non-functioning adenoma, and chose to proceed with trans-spenoidal surgery (TSS). Intra operatively, a very vascular tumor was encountered, which could only be debulked safely. Pathology was consistent with metastatic clear cell RCC. A follow up CT showed innumerable lung nodules and a 3.2 cm right adrenal nodule consistent with metastases. He completed stereotactic radiation to the sella and is currently on Ipilimumab and Nivolumab for immunotherapy.

MP is uncommon, and seen in 1-4% of patients with cancer in autopsy studies. Breast (40%) and Lung cancer (25%) are the most common tumors causing MP in women and men respectively, with very few case reports of RCC MP (2.6%). DI is the most common symptom of MP, which is thought to be due to direct vascular supply from hypophyseal arteries to the posterior pituitary. Interestingly in RCC MP, anterior pituitary dysfunction is more prevalent (90%) compared to DI (24%). There is also a tendency for suprasellar extension, causing vision loss. Radiologic features that could help distinguish MP from an adenoma include a rapidly enhancing sellar mass, erosion of sellar floor or posterior clinoid process, infundibular thickening, and the presence of intra-tumoral vascular flow voids. There reportedly is no benefit to using FDG- PET to diagnose MP from RCC. There are no standardized treatment guidelines and the choice of treatment is also influenced by the extent of systemic disease.
SUN-486 Unusual Presentation of Metastatic Follicular Thyroid Cancer
Authors: Proudan Nikoletta , Andre Kersthine
Published: May 2020

Distant metastasis of follicular thyroid cancer to the bone has been well documented. However, spinal cord compression as the initial presentation of metastatic follicular thyroid cancer without any thyroid symptoms is relatively rare. Here we discuss such a case. A 78-year-old female with history of HTN and melanoma presented to the ED with a 1-month history of middle back pain that progressed to lower extremity weakness, numbness, and inability to ambulate. MRI showed a T7 vertebral mass with cord compression and edema. Metastatic work up was unremarkable except for incidental bilateral thyroid nodules, the largest on the right lobe, at 1.6 cm, with peripheral calcifications. The patient underwent T6-T7 laminectomy with vertebral decompression, partial colpectomy, and T4-T10 fusion. Pathology of the thoracic vertebral mass was positive for CAM 5.2, cytokeran 7, TTF-1, and PAX8 consistent with either metastatic pulmonary adenocarcinoma or thyroid carcinoma. The patient denied shortness of breath, dysphagia, hoarseness, or neck tenderness. She had no personal history of hyperthyroidism or hypothyroidism, or radiation exposure. She also did not have any family history of thyroid cancer. Laboratory work up was significant for TSH of 3.71 mcU/mL (0.4-4.0 mcU/mL), Free T4 1.56 ng/dL (0.7-1.9 ng/dL), thyroglobulin (Tg) 6940 ng/mL (1.6-55.0 ng/mL), and thyroglobulin antibody (Tg Ab) 20 IU/mL (0-115 IU/mL). FNA of the right thyroid nodule showed follicular neoplasm with very similar morphological features to the epidural pathology, favoring a follicular carcinoma. She underwent total thyroidectomy. Pathology showed a 1.6 x 1.1 cm follicular carcinoma with capsular and angiolymphatic invasion, but with uninvolved margins of resection. TNM staging was pT1b, pNx, pM1. She was ablated with 109 mCi of I-131 after withdrawal therapy. Whole body scan after treatment revealed radioiodine avid metastatic disease at T7 and activity in the thyroid bed compatible with residual thyroid tissue. Patient completed 10 fractions of external beam radiotherapy to the spine for a total of 30 Gy. Three months follow up lab work showed Tg 580 ng/mL and negative Tg Ab with a suppressed TSH. Thyroid bed ultrasound did not show any residual tissue or abnormal lymph nodes. Ten-year survival rates in patients with bony metastatic differentiated thyroid cancer range from 13-21% (1). Metastatic thyroid carcinoma should be considered in the differential diagnosis of every patient with new onset bony metastasis and thyroglobulin should be considered as a tumor marker in the initial work up. Research shows increased survival with I-131 avidity and complete bone metastasis resection (1). 1. Ramadan, Sami et al. “Spinal metastasis in thyroid cancer.” Head & neck oncology vol. 4 39. 25 Jun. 2012, doi:10.1186/1758-3284-4-39
SUN-100 Mice Lacking Paternally Expressed DLK1 Reach Puberty at a Lower Body Weight Than Littermate Controls
Authors: Macedo Delanie B , Abreu Ana Paula , Tellez Silvia L , Naule Lydie , Kim Han Kyeol , Capo-Battaglia Athena , Song Yong Bhum , Roberts Stephanie , Latronico Ana Claudia , Carroll Rona Stephanie , Kaiser Ursula B
Published: May 2020

Body fat content along with a variety of genetic, environmental and psychosocial factors are responsible for the development and maintenance of reproductive function, especially in females. Epidemiologic studies indicate a relationship between increased body mass index and earlier puberty in girls. In contrast, a significant delay in puberty and menarche is seen in girls who are very physically active and have markedly diminished body fat. This link between reproduction and metabolism was reinforced with the recent report of loss-of-function mutations in the Delta-like homolog 1 (DLK1) gene in girls with central precocious puberty (CPP) and increased body fat. DLK1 is a paternally expressed gene located on chromosome 14q32.2 in a locus associated with Temple syndrome (TS), an imprinting disorder caused mainly by maternal parental disomy (mUPD). Dlk1 knockout mice display pre- and postnatal growth retardation, a phenotype that overlaps with human mUPD14. However, precocious puberty, a common finding associated with TS, was not carefully characterized in these mice. We used a Dlk1 deficient mouse model to determine the effects of Dlk1 on pubertal maturation. We confirmed by RT-qPCR that Dlk1 mRNA was undetectable in the mediobasal hypothalamus, where kisspeptin and other regulators of puberty are expressed, of Dlk+/p- mice (which inherited the mutant allele from their father) whereas it was present in Dlk+/+ mice. As reported previously, body weight was significantly lower in juvenile male and female Dlk+/p- mice, compared to wild-type littermate controls. Interestingly, mutant and control female mice achieved vaginal opening, a marker of puberty onset, at a similar age (Dlk+/p-: 29.8 ± 1.5 days, n=11 vs. Dlk+/+: 29.1 ± 0.7 days, n=15, p=0.6) despite a considerably lower body weight in the Dlk1 deficient mice at the time of vaginal opening (Dlk+/p-: 10.1 ± 0.8 g vs. Dlk+/+: 14.3 ± 0.3 g, p<0.0001). Similarly, in the Dlk+/p- males, preputial separation occurred at a lower body weight than in controls (Dlk+/p-: 12.4 ± 0.3 g, n=9 vs. Dlk+/+: 14.1 ± 0.2 g, n=19, p<0.0001). We hypothesize that the lack of Dlk1 at the hypothalamic level may be attenuating the effect of the low body weight on determining pubertal onset. These findings suggest that DLK1 is an important link between body weight and pubertal development in mice, as has been shown in humans.
SAT-543 Human Hair Aldosterone Measurements for Evaluation of Primary Aldosteronism
Authors: Demidowich Andrew Paul , Camacho Jancarlos , Sierra Maria de la Luz , Belyavskaya Elena , Lysikatos Charalampos , Kamilaris Crystal , Suzuki Mari , Zilbermint Mihail , Hannah-Shmouni Fady , Stratakis Constantine A
Published: May 2020

Background: Primary Aldosteronism (PA) is the most common cause of endocrine hypertension in US. Diagnostic techniques such as a 24 hour urine collection or saline suppression test (SST) can be laborious for both patients and staff. Our group previously showed that human hair cortisol measurements correlated with urine and serum cortisol levels in patients with endogenous cortisol excess. In this study, we explored whether human hair aldosterone correlated with other measures of aldosterone production. Methods: 41 adult subjects were evaluated at the NIH Clinical Center for adrenal disorders. A pencil-width of hair near the occiput was removed, and the 1cm segment closest to the scalp was analyzed by enzyme immunoassay for aldosterone, reported as pg aldosterone/mg dry hair. Not all subjects underwent complete workup for PA. Data were transformed as necessary to maintain assumptions of normality. Student’s t-test and Pearson correlations were used for statistical analysis.

Results: Of the evaluated subjects, 18 were diagnosed with PA, 22 subjects did not have PA, and 1 subject was indeterminate. The mean hair weight was 33.0±13.7mg. For hair samples weighing greater than 10mg, hair weight was not correlated with hair aldosterone concentration (p=0.40). There was no difference in measured hair aldosterone between the subjects with and without PA (2.01±1.09 vs. 2.52±2.45 pg/mg; p=0.82). Among all subjects, hair aldosterone did not correlate with serum aldosterone (p=0.92), aldosterone-to-renin ratio (ARR; p=0.94), 24 hour urine aldosterone (Ualdo; p=0.85), or the serum aldosterone at the 4 hour time point of a SST (4hrAldo; p=0.98). Serum aldosterone, ARR, Ualdo, and 4hrAldo all correlated highly amongst each other (all p’s<0.001).

Conclusions: Hair aldosterone levels do not correlate with other markers of PA. Further work is needed to understand whether optimization of study conditions could improve the usefulness of hair aldosterone measurements in the evaluation of PA.
MON-907 Silent Presentation of Urinary Bladder Paraganglioma: A Case Report
Authors: Kirupakaran Johnathan , Rodriguez Giovanna , Bahtiyar Gul
Published: May 2020

Background: Paraganglioma is a rare extraadrenal, neuroendocrine tumor of the sympathetic or parasympathetic ganglia (1). Bladder paraganglioma accounts for 1% of all paragangliomas and 0.05% of all bladder tumors (1,2). Characteristic presentation of this tumor includes hypertensive crisis and postmicturition syncope (3).

Clinical Case: 35 year old Middle Eastern man with no pertinent past medical history presented with gross hematuria associated with dysuria, purulent penile discharge, urinary frequency, suprapubic pain, and bilateral flank pain for eight months for which he was given a course of an unknown antibiotic in his home country. Social history revealed smoking half a pack of cigarettes/day for 7 years. Has no family history of cancer. On physical exam he had normal blood pressure with mild tenderness to palpation in suprapubic region. U/A was remarkable for hematuria. Patient was treated for UTI with a course ciprofloxacin without resolution of symptoms. Culture returned negative.

CT abdomen/pelvis yielded an approximately 1.9 cm enhancing mural nodule involving the anterior aspect of the bladder. Free metanephrine, nor-metanephrine, plasma catecholamine, and urine vanillylmandelic acid were within normal limits. Cystoscopy and transurethral resection of the tumor (TURBT) was completed; a 5-6mm tumor was visualized and resected. Surgical pathology demonstrated tumor growth into the lamina propria and muscularis propria. Neoplastic cells in the sample were diffusely positive for synaptophysin and chromogranin. S100 protein immunostain highlighted sustentacular cells. The diagnosis of paraganglioma was made based on surgical pathology. Post TURP MRI yielded an approximately 1.7 x 0.9 cm transmural hypervascular enhancing mass lesion involving the anterior aspect of the bladder. Given transmural extension of the tumor, an open partial cystectomy was performed. The tumor was resected successfully with resolution of symptoms.

Conclusion: This is an exceedingly rare example of a hormonally silent paraganglioma, mimicking the presentation of a UTI. This case may present the unique consideration of tobacco specific carcinogens as a potential risk factor for the development of bladder paraganglioma.

References

1. Benn, DE, Robinson, BG, & Clifton-Bligh, RJ. (2015). “Clinical Manifestations of Paraganglioma Syndromes Types 1-5”. Endocrine-Related Cancer, vol. 22, T91-T103.

2. Loveys, FW, Pushpanathan, C, & Jackman, S. Urinary Bladder Paraganglioma: AIRP Best Cases in Radiologic-Pathologic Correlation”. RadioGraphics, vol 35, no. 5, 1433-1438.

3. Priyadarshi, V, & Pal DK (2015). “Paraganglioma of Urinary Bladder”. Urology Annals, vol 7, no. 3, 402-404.
OR13-03 Understanding Why Older People with Low Trauma Fractures Die Prematurely
Authors: Tran Thach , Bliuc Dana , O’Donoghue Sean , Hansen Louise , Abrahamsen Bo , Bergh Joop van den , Geel Tineke van , Geusens Piet , Vestergaard Peter , Nguyen Tuan V , Eisman John A , Center Jacqueline
Published: May 2020

There is increasing evidence that all proximal and not just hip fractures are associated with increased mortality risk. However, the cause of this increased mortality is unknown. We sought to determine the post-fracture trajectories of subsequent hospital admissions and mortality to develop an understanding of why patients with non-hip fractures die prematurely.

This nationwide Danish population-based study included all individuals aged 50+ years who sustained an incident fragility fracture between 2001 and 2014. High-trauma fractures or individuals with fracture prior to 2001 were excluded. Fracture patients were matched 1:4 by sex, age and comorbidity status with non-fracture subjects alive at the time of fracture. Comorbidities included 33 unique medical conditions of the Charlson or Elixhauser comorbidity index. We modelled the contribution of specific fractures on the risk of subsequent admissions or death within the following 2 years.

There were 212,498 women and 95,372 men with fracture followed by 30,677 and 19,519 deaths, respectively over 163,482 and 384,995 person-years of follow up. Mean age at fracture was 72± 11 for women and 75± 11 for men. Proximal fractures including hip, femur, pelvis, rib, clavicle and humerus had increased mortality compared with their matched non-fracture counterparts with HRs ranging from 1.5-4.0, while distal fractures such as ankle, forearm, hand or foot fractures had similar or lower mortality risk.

Almost 75% of men and 60% of women had ≥1 comorbidity. For every additional comorbidity, risk of mortality increased for all fracture types. However, only for proximal fractures did the fracture itself independently increase mortality risk over and above co-morbidity status.

The 2-yr post fracture admission and mortality patterns differed between proximal and distal fractures. Proximal, but not distal fracture subjects had greater risk of any major hospital admission (including cardiovascular disease, cancer, stroke, diabetes, pneumonia and pulmonary disease) within 2 years compared with their non-fracture counterparts. Distal fractures in general had similar admission patterns as their non-fractured matched counterparts.

Furthermore, 2 year mortality risk was increased for proximal fractures whether or not they were admitted to hospital post fracture. By contrast, mortality risk was similar or reduced for distal fractures compared with non-fracture controls.

This study has not only confirmed the increased mortality following proximal fractures but has demonstrated differing clinical trajectories between proximal and distal fractures that contribute to this increased mortality. These findings provide important insights as to why proximal fracture subjects die prematurely that may lead to specific avenues for intervention.
MON-436 Cribriform-morular Variant of Papillary Thyroid Carcinoma: A Case Report
Authors: Shaheen Zainab , BenHamed Nesreen Aburrahman , Elhamdani Rawan Mehiar
Published: May 2020

Background:

Cribriform - morular variant is a rare variant of papillary cancer with 1–2 % prevalence. There are no established guidelines to screen for thyroid cancer in patients with APC gene mutations and FAP. We present a case of a young female with APC gene mutation and thyroid cancer.

Case:

Female, 25 years-old, without anemia, underwent colonoscopy at age 22 and multiple polyps were seen. One polyp showed intramucosal carcinoma with high-grade dysplasia. She was diagnosed with FAP. She was found to have APC gene mutation on genetic analysis. No family history of FAP was reported.

Chest and abdominal CT showed multiple thyroid nodules.

Thyroid ultrasound showed 3 nodules. The largest is in the mid R lobe, measuring 1 cm, and is isoechoic to hypoechoic, containing some small central cystic areas. The nodules in the left lobe measure 0.6 and 0.7 cm.

FNA of the right thyroid nodule showed follicular neoplasm. Afirma was suspicious.

She underwent total thyroidectomy.

Pathology report showed multifocal tumor in both right (0.8 cm) and left lobe (0.5 cm). Histologic type was Papillary carcinoma, cribriform - morular variant. All surgical margins were negative. No angio-lymphatic invasion or extra thyroidal extension was identified.

Pathologic stage classification was m pT1a pN0 pM0.

Patient did not receive RAI ablation.

Patient doing well and no further recurrence of thyroid cancer is noted.

Discussion:

Patients with FAP have a greatly increased risk for colorectal cancer and also have an elevated risk for other cancers including thyroid cancer (1%-2% compared to 1% in general population). According to ACG guidelines of 2015, annual thyroid screening by ultrasound should be recommended to individuals affected with FAP. Additionally, thyroid cancer found in unscreened patients with FAP was more advanced as compared to patients screened for cancer requiring less aggressive approaches. On ultrasonography, most nodules had benign-looking features (well-defined, hypoechoic, oval to round shapes without calcification), but some nodules had capsular invasion and larger height: width shape. In preoperative FNA, they were diagnosed as CMV-PTC/PTC but could also present as follicular neoplasm or PTC-follicular variant. Compared to conventional PTC, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patient mortality rates (2%). Physical exam and clinical history is not sufficient to screen for cancer.

In patients with APC gene mutations and FAP, there should be high suspicion for diagnosing thyroid cancer as the nodules are usually benign looking and small in size. As noted in the case, nodules were found incidentally, and tumor size was small with benign looking nodules. Additionally, screening should be focused more on young females below the age of 35 because of the high prevalence of cancer.
SAT-748 Advantages and Limitations of an Integrative Measurement for All Serum Androgens and Anti-Androgens
Authors: Schaufele Fred J , Mody Armaiti , Huddleston Heather Gibson
Published: May 2020

Background: Analytic measurements of a hormone in bodily fluids are a cornerstone of clinical evaluation. However, clinical presentation may be affected also by currently unmeasured modulators of hormonal function. An alternative could be to measure the cumulative effect of all factors present in a bodily fluid on the function of a hormone receptor. Prior studies showed an androgen receptor (AR) BioAssay to accurately measure urine androgens in males undergoing testosterone (T) supplementation (1). The factors integrated by the AR BioAssay include androgens, anti-androgens and, in serum, androgen binding proteins affecting ligand availability.

Methods: The AR BioAssay was exposed to male and female serum samples obtained from the CDC’s Hormone Standardization (HoSt) Program, and to female serum samples from the UCSF PCOS Tissue Bank registry. AR activity was quantified against a testosterone standard curve and recorded as ‘T-equivalent’ (‘T-eq’) androgen activity units.

Results: In 40 CDC HoSt sera added directly (no extraction) to AR BioAssay cells, androgen activities ranged from 2.57 to 298 ng ‘T-eq’/dl. In the 20 ‘male’ CDC HoSt sera (T>150 ng/dl), the androgen activity measurements were uniformly less (0.35 ± 0.10) that of the T-measurement. By contrast, in the 20 ‘female’ CDC HoSt sera, in which T concentrations are typically lower than the affinity of T for sex hormone binding globulins such that more of the T is available to the AR BioAssay, the measured androgen levels were on average 1.45-fold higher than the T concentration. This androgen to T comparison showed high variability in females with 5 of 20 CDC HoSt samples having androgen concentrations more than double that of T (maximum, 6.1-fold). In female serum samples from the PCOS registry, androgens were higher in patients with a PCOS diagnosis (57.7 +/-17.6 ng ‘T-eq’/dl; n = 23) compared to women not meeting formal PCOS criteria (38.1 +/-10.8 ng ‘T-eq’/dl; n = 4); androgen values again averaged 1.40-fold (maximum, 4.9-fold) that of the T measurements, regardless of PCOS diagnosis.

Conclusions: Androgen-binding globulins appear to most influence androgen activity levels in male serum. In females, the lower T concentrations may minimize the impact of androgen-binding proteins and permit the impact of non-T androgens to be more pronounced with possible clinical consequence. Further investigations are needed to determine whether functional androgen measurements may improve clinical diagnosis of certain conditions.

Reference: (1) Bailey et al (2016) PLoS One11(3):e0151860
MON-157 The Effect of Exogenous Cushing’s Syndrome on All-Cause and Cause-Specific Mortality: A Systematic Review
Authors: Limumpornpetch Padiporn , Morgan Ann W , Tiganescu Ana , Stewart Paul Michael , Pujades-Rodriguez Mar D M
Published: May 2020

Chronic oral glucocorticoid (GC) exposure from therapeutic anti-inflammatory or immunosuppressive use is the most common cause of Cushing’s syndrome (CS). Previous studies of glucocorticoid therapy and mortality have produced inconsistent results and systematic reviews have only focused on endogenous CS. This is the first study that aimed to investigate all-cause and cause-specific mortality in association with exogenous CS from chronic oral GC therapy. The protocol was designed according to the principles of the PRISMA statement and registered in PROSPERO reference CRD42017067530. A literature review was performed in PubMed/MEDLINE (1966 to 31 Mar 2019), EMBASE (1974 to 31 Mar 2019), web of science (1900 to 31 Mar 2019), CINAHL (1981 to 31 Mar 2019) and reference lists within selected articles. Of 104,064 studies, 127 met the inclusion criteria, encompassing 51,380 patients. The Risk Of Bias In Non-randomized Studies of Interventions (ROBIN-I) tool was chosen and modified for evaluation of quality. The weighted percentage mortality by 5 groups of diseases including vasculitis, connective tissue diseases, inflammatory diseases, haematologic diseases and respiratory tract diseases, was 18.1, 12.7, 16.1, 28.2 and 5.7, respectively. The leading causes of death were cardiovascular disease (25.6%), malignancy (15.6 %), infection (13.4) and respiratory failure (10.8%). Although these studies showed high mortality in patients exposed to GC, estimates were not adjusted for known confounders and available data do not allow disentangling the relative contribution of CS vs. the underlying disease or non-GC immunosuppressive therapies. More extensive, high quality, prospective studies are needed to evaluate these associations and to identify modifiable risk factors.
MON-509 RET Mutations in the MEN1 Syndrome: Is It an Innocent Bystander?
Authors: Rais Nadeem M , Kumar Anshul , Jain Swetha , Mathur Sandeep Kumar , Scaria Vinod , Prakash Savinitha , Joshi Apoorva
Published: May 2020

Introduction

MENIN and RET mutations in MEN1 families, are rare, and, when they co-exist either mutation may predominate the clinical picture.

We report a family, with both mutations, and, suspect that the RET mutation may not be an innocent bystander.

Clinical Cases

GM (36M): 2009: Presented with skin lesions and a lactotroph adenoma causing chiasmal compression. Treatment: Hypophysectomy and Cabergoline. This resulted in restoration of sexual function and fertility.

2013: Developed hyperparathyroidism [Calcium 10.6mg% (8.5-10.5); PTH 610pg/ml (10-65); MIBG Scan: parathyroid adenomas]. Treatment: Subtotal parathyroidectomy with allotransplant.

2015: Developed Zollinger-Ellison Syndrome [multiple gastric ulcers; S Gastrin: 516pg/ml; (0-180)]. Treatment: Pantoprazole.

MRI Abdomen: Calcific atrophic pancreas and bilateral non-functioning adrenal adenomas.

HM (32M): 2008: Skin lesions and Lactotroph adenoma. Treatment with Cabergoline resulted in restoration of sexual function and a reduction in breast and tumour size.

2013: Hyperparathyroidism [Calcium 10.9mg%; PTH: 166pg/ml; Calcium excretion: 1160mg/24hrs (100-250); BMD: Osteopenia. MIBG 123 Scan: Avid uptake in Right Inferior parathyroid gland]. He underwent a subtotal parathyroidectomy with allotransplant.

2015: Recurrent Hyperparathyroidism (Calcium 10.7mg%; PTH: 116pg/ml; MIBG 123 scan: Hyperfunction of the transplanted gland). Stable on treatment with Cinacalcet.

Their mother, AM (42F): 1980: Detected to have a lactotroph adenoma when investigated for primary infertility and galactorrhoea. She was treated with Bromocriptine and delivered the boys in 1980 and 1984 respectively. She had recurrent renal calculi and hydronephrosis (? hyperparathyroidism). She succumbed to renal failure following surgery for a benign pancreatic cystadenoma in 1990.

Discussion

Whole exome sequencing of GM and HM showed pathogenic mutations of both, MENIN and RET gene. The precise mutation was a stop gain mutation at exon 3 MENIN.C511T:p.Q171X . They (GM/HM) also harboured a mutation in the RET gene at exon 14 c. G2492T: p.G831V; g. chr10. This may be the first family in which the rare combination of these two mutations has been reported.

The genomics and the clinical presentation suggest that the MENIN mutation predominates in the family, but the presence of bilateral adrenal adenomas in GM are significant on account of RET mutation. The latter may be a harbinger of serious disease in the future. The situation is further compounded by the recurrence of hyperparathyroidism in the allograft of HM. This may be caused due to chance or an unknown genetic/ epigenetic phenomenon in the two MEN mutated genes and RNA sequencing of the tumour tissue may explain the genetic phenomenon. The latter two events suggest that the RET mutations in MEN1 may not be an innocent bystander.
SAT-663 The Impact of Anxiety on the Successful Management of a Type I Diabetic Patient
Authors: Janakiram Nikhila
Published: May 2020

Background: Patients with both type 1 diabetes mellitus (T1DM) and generalized anxiety disorder (GAD) are known to be at increased risk for hypoglycemic events, long-term hyperglycemia, weight gain and vascular disease. However, little research has been conducted regarding management of anxiety in patients with T1DM.

Clinical case: A 27 year old female with T1DM (controlled on an insulin pump), GAD, PTSD, and history of benzodiazepine abuse presented to the emergency department after experiencing multiple panic attacks the day of admission. Recently, patient had multiple bouts of emesis in addition to decreased oral intake. On admission, blood sugar was 54, which increased to 164 after administration of 1 amp of dextrose-50. Patient was obtunded and unable to provide much history. Overnight, insulin was not given due to patient’s poor oral intake. The following morning, patient had one cup of juice for breakfast. Accu-check shortly after revealed a blood glucose level over 500 and patient developed diabetic ketoacidosis (DKA) and was admitted to the ICU on our hospital DKA protocol. Once anion gap closed, patient was transferred out of the ICU for continued management of her diabetes. Patient went on to have multiple panic attacks for the duration of her hospitalization which were controlled with scheduled diazepam, valproic acid, lorazepam and quetiapine. Psychiatry was consulted and found that a major contributing factor to her developing recurrent DKA was her struggle with anxiety surrounding the responsibilities of managing her diabetes and its associated complications including gastroparesis and neuropathy. Further conversation revealed that her psychiatrist had passed away a few months prior to admission and that she had not established care with a new psychiatrist yet.

Discussion: Given the life changing nature of T1DM, it is not uncommon for these patients to have difficulty coping with the daily challenges required to optimally treat their condition. It can be frustrating when the slightest shift in caloric intake or exogenous insulin leads to life-threatening situations such as DKA. The above case sheds light on the profound medical consequences and setbacks that poorly controlled anxiety can have on diabetic patients. Therefore, recognizing the impact of anxiety on our patients with diabetes is critical in preventing further complications, especially microvascular, macrovascular and potentially other life-threatening events.
MON-537 Primary Adrenal Insufficiency During Tyrosine Kinase Inhibitors Treatment in Advanced Thyroid Cancer Patients
Authors: Valerio Laura , Matrone Antonio , Agate Laura , Bottici Valeria , Viola David , Cappagli Virginia , Giani Carlotta , Molinaro Eleonora , Elisei Rossella
Published: May 2020

Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI).

Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts.

Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation.

Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (<12 months) or late (>36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.
SAT-107 Improved Adult Height in Brazilian Turner Syndrome Patients Treated with Growth Hormone
Authors: Scalco Renata Da Cunha , Braz Adriana Farrant , Malaquias Alexsandra C , Antonini Sonir Roberto Rauber , Guerra-Junior Gil , Mendonca Berenice Bilharinho , Jorge Alexander A L
Published: May 2020

Background: Short stature is the most frequent clinical manifestation in Turner syndrome (TS), occurring in 98% of these patients. Growth hormone was shown to improve adult height in TS patients from diverse genetic backgrounds. However, there are few studies on adult height in TS patients from developing countries, where the diagnosis is frequently delayed.

Objective: To compare adult height between GH-treated and untreated TS patients.

Patients and methods: 120 GH-treated and 109 GH-untreated TS patients from 3 referral hospitals in Brazil were evaluated. The most common reasons for not treating TS patients with GH were late diagnosis or GH unavailability. Data on karyotype, parents’ height, puberty development and GH treatment were obtained from their medical records. Adult height was determined when growth velocity was inferior to 1cm/year during a minimum follow-up period of 12 months.

Results: The frequency of 45,X karyotype was similar between the groups (48.7% vs. 41.9% in GH-treated vs. GH-untreated TS patients, respectively, P= 0.639). GH-treated TS patients started GH therapy at a chronological age (CA) of 11.2 ± 3.7 yr, bone age of 9.3 ± 3.1 yr, height SDS (British 1965 standards) -3.1 ± 1.1. GH mean dose was 48µg/kg.d and GH treatment duration was 5.4 ± 3.0 yr. Estrogen replacement was started late, at CA of 14.3 ± 2.0 yr in GH-treated and at 14.9 ± 1.9 yr in GH-untreated patients, and the rate of spontaneous puberty was similar between the groups (GH-treated 16.8% vs. GH-untreated 22,8%, P=0.304). Adult height was significantly higher after GH treatment (150.1 ± 5.8 cm vs. 143.3 ± 7.2 cm in GH-treated vs. untreated TS patients, respectively, P < 0.001), even with a small but significant difference in target height between the groups (158.2 ± 4.8 vs. 159.8± 4.5 cm in GH-treated vs. untreated TS patients, respectively, P= 0.015). More than half of the TS GH-treated patients reached normal adult height (equal or higher than 150.2 cm), whereas only 15.6% of GH-untreated patients reached it.

Conclusion: Despite the delayed diagnosis of TS patients in our cohort, GH treatment was associated with a significant height gain, and the TS GH-treated group was around 7 cm taller than the GH-untreated group.
OR24-01 Mutational Study of the GPR119 Receptor Binding Site
Authors: Rosales Matthew D , Dean Frank , Kotsikorou Evangelia
Published: May 2020

The GPR119 receptor, a class A G-protein coupled receptor located in the pancreatic β cells, induces insulin production when activated. Due to its specific activity, the pharmaceutical industry has identified GPR119 as a target for the treatment for type 2 diabetes. The lack of a GRP119 crystal structure has hindered the study of the receptor so our laboratory developed GPR119 active and inactive homology models. Docking studies with the inactive receptor model indicated that two leucine residues facing the binding pocket, L5.43(169) and L6.52(242), may be involved in ligand activation. Additionally, a serine at the extracellular end of the pocket, S1.32(4), may help orient of the ligand in the binding pocket via hydrogen bonding. To gain further insight into the role of these residues and the receptor activation mechanism, molecular dynamics (MD) simulations and in vitro cAMP assays of the wild type and mutant receptors were employed. The software NAMD employing the CHARMM force field was used to carry out MD simulations of the active receptor model bound with the agonist AR231453 embedded in a hydrated lipid bilayer. Preliminary results indicate that L6.52(242), located on transmembrane helix (TMH) 6, does not face directly into the binding site and does not interact with the ligand, while L5.43(169), located on TMH5, does face into the binding site, potentially interacting directly with the ligand. Also, S1.32(4), because of its extracellular location, is solvated instead of interacting with the ligand. The in vitro studies overall support the MD simulations. The mutations L6.52(242)M and L6.52(242)A appear to have minimal to no effect on agonist-induced cAMP production, compared to the wild type. In contrast, the L5.43(169)M and L5.43(169)A mutations decrease the potency of activation by AR231453, indicating that L5.43(169) changes the shape of the binding pocket, affecting ligand binding and activation. Finally, the cAMP assays show that the S1.32(4)A mutant also shows decreased activity compared to the wild type, implying that the ligand may be losing a hydrogen bonding interaction when S1.32(4) is mutated to alanine.
SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
Authors: Nakayama Akitoshi , Yokoyama Masataka , Nagano Hidekazu , Sakuma Ikki , Hashimoto Naoko , Higuchi Seiichiro , Yamagata Kazuyuki , Tanaka Tomoaki
Published: May 2020

p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breast cancer cell lines for p53 using CRISPR/Cas9 system, and then performed a three-dimensional culture model. We found that the introduction of mutant p53 was solely able to mediate the transformation to poor architectural structure. Interestingly, our findings in statin-effect along with cholesterol synthesis pathway, especially isoprenoid dependency, revealed that this pathway is necessary and sufficient for the regulation of malignant architecture in SREBP2-dependent manner with cooperatively being controlled by mutant p53 on 3D-cultured breast cancer. Furthermore, in accordance with the malignancy progresses, SREBP2 was accumulated in nuclear and nuclear membrane portion with enhancement in malignant formation. In addition, we found that mutant p53 interacts with SREBP2, and consistently mutant p53 was associated with DHCR7 promoter in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the mutant p53, a gain of function, and its linkage to poor architectural structure in 3D-cultured breast cancer cells via SREBP2-dependent isoprenoids regulation as potential therapeutic targets.
SAT-166 Advantage and Trustworthy of Cortisol and Dexamethasone Evaluation in Different Biological Matrices in Patients with Adrenal Masses
Authors: Lionetto Luana , Maggio Roberta , Lardo Pina , Bernardini Donatella De , Cipolla Fabiola , Capi Matilde , Simmaco Maurizio , Petrangeli Elisa , Toscano Vincenzo , Pugliese Giuseppe , Stigliano Antonio
Published: May 2020

Biochemical function of adrenal masses is currently based on 1mg post-overnight dexamethasone suppression test (pDST). Several approaches are recently developed, in order to reduce false positive/negative samples, only in retrospective series. They are based on the correlation of some different parameters, i.e. late-night salivary cortisol (LNSC) vs serum and salivary cortisol pDST; LNSC vs serum and salivary cortisol and serum dexamethasone pDST; LNSC and cortisone vs serum cortisol and salivary cortisol and cortisone pDST. Although these findings offer a better diagnostic performance, several conditions are still disappointed. No information is traceable about the harvest time of diurnal salivary and serum samples and no study include neither the levels of salivary nor urinary dexamethasone pDST. Aim of our study is to combine all these strategies in order to avoid the underestimated biases and obtain more precise information about the true “cortisol condition” of the patients.

To reach this purpose we assess both cortisol and dexamethasone concentrations in several samples: saliva at 11PM before the drug administration, diurnal saliva and serum at 8AM and also the urine collection from 11PM to 8AM. Analytes levels are measured using a validated liquid chromatography-tandem mass spectrometry method. In this study we included 20 subjects without morphological adrenal alteration (MRI assessment), dyslipidemia, hypertension and impaired glucose tolerance (healthy controls) and 20 patients with adrenal incidentaloma showing different cortisol levels ranging from normal to ACTH-independent hypercortisolism. In both series, LNSC were similar to salivary cortisol pDST, even if they were greater in the patients with adrenal incidentalomas and subclinical cortisol secretion. Serum dexamethasone levels were in reference ranges, while salivary and urinary dexamethasone found in these matrices require additional sample numbers in order to establish appropriate cut-offs. Our preliminary results suggest that the combination of these findings could represent an improvement to assess the individual cortisol status.