bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-LB110 A Phase 2 Evaluation of a Ready-To-Use Liquid Stable Continuous Subcutaneous Glucagon Infusion for the Treatment of Hypoglycemia Associated Autonomic Failure
Authors: Pettus Jeremy H , Nakhle Samer , Ovalle Fernando , Rickels Michael Roehrhoff , Umpierrez Guillermo Enrique , Junaidi Khaled , Close Nicole C , Nguyen Anh
Published: May 2020

OBJECTIVE:A novel, ready-to-use, liquid stable, continuous subcutaneous glucagon infusion (CSGI; Xeris Pharmaceuticals) was evaluated for the treatment of adults with type 1 diabetes (T1D) with documented Hypoglycemia Associated Autonomic Failure (HAAF).

METHOD:This was a Phase 2 prospective, multi-center, randomized, placebo-controlled, double-blind, parallel trial in T1D adults with documented HAAF, defined as Gold Scale Score ≥4. Subjects were randomized in a 1:1:1 ratio to receive 4 weeks of continuous treatment (via Omnipod pump) with high rate CSGI (80mcg/hour), low rate CSGI, (20mcg/hour) or placebo (matched infusion rates for low and high rate CSGI). The primary endpoint evaluated at 4 weeks was the percent change of the epinephrine hormone response after 30 minutes of induced hypoglycemia. Epinephrine levels and hypoglycemia symptoms were recorded following a stepwise hypoglycemia clamp, and results compared between study treatment arms. Following the first four weeks, subjects continued for an additional 24 weeks to assess their epinephrine hormone response to hypoglycemia measured at 3 months post-treatment (16 weeks), and 6 months post-treatment (28 weeks).

RESULTS:Forty-nine subjects were randomized to receive treatment with high rate CSGI (n=15), low rate CSGI (n=18), or matching placebo (n=16). At the end of study treatment, there were no statistically significant differences between the treatment arms for percent change of epinephrine hormone response during a stepwise hypoglycemia clamp (CSGI vs. placebo; p=0.160). As a result, long-term follow-up of the subjects was stopped early. The long-term follow-up data collected to date will be reported separately. The administration of low and high rate CSGI was associated with mild to moderate nausea (5.9%, 20%, respectively) and vomiting (11.8%, 13.3%, respectively) that was self-limited and required no additional intervention. In this 4-week assessment, CSGI was not associated with pain nor significant injection site reactions, and no SAEs related to CSGI were reported.

CONCLUSION:In this proof-of-concept study, CSGI did not demonstrate statistically significant improvements in plasma epinephrine concentration when compared to placebo at 4 weeks. While there were positive epinephrine and improved hypoglycemia awareness responses observed in some subjects, the equivocal efficacy results observed may be explained by the unanticipated and incomplete elimination of hypoglycemia on CSGI therapy, and those on placebo therapy experienced hypoglycemia improvement. CSGI can be safely used with concomitant diabetes medications, and there were no SAEs related to CSGI. The 4-week administration of both low and high rate CSGI was safe and well tolerated.
MON-LB9 Cyclic Progesterone Therapy in Androgenic Polycystic Ovary Syndrome (PCOS) - Person-Related 6-Month Experience Changes
Authors: Shirin Sonia , Murray Faye , Hajjaran Maryam , Goshtasebi Azita , Kalidasan Dharani , Prior Jerilynn C
Published: May 2020

Endometrial cancer1 and oligomenorrhea2 are common risks for women living with androgenic PCOS (WLWP); cyclic progesterone therapy could prevent both. Cyclic oral micronized progesterone therapy (Cyclic OMP; 300 mg at hs/14 days/cycle) also corrects the neuroendocrine origins of PCOS3. Although vaginal progesterone is used in PCOS ovulation induction 4, and short Cyclic OMP decreases LH and/or Testosterone 5,6, no WLWP person-level prospective data with Cyclic OMP therapy are published.

A WLWP, aged 31, BMI 20.1, with heavy flow and slightly irregular ~35-day cycles, was unable to tolerate birth control pills. She was prescribed Cyclic OMP (300 mg/h.s. cycle days 14-27)7. She began keeping the Menstrual Cycle Diary© (Diary), a 19-item tool (scored 0-4), during her 1st Cyclic OMP cycle and took no other therapy. This pilot study was designed to understand Cyclic OMP-related experience changes in WLWP: 1) by documenting experience changes on the 1st to the 6th complete Diary; and 2) by assessing follicular phase changes in baseline data (no Rx) vs. cycles 3 and 6. We entered data from six consecutive Diaries into an SPSS (Version 24) database. Analysis #1 used Wilcoxon Signed Ranks Tests (for within-person ordinal data) and #2 repeated measures ANOVA. Research question: What Cyclic OMP-related experience changes occurred for a WLWP? On Cyclic OMP, she spontaneously reported improvements in aching joints, sleep and GI problems. We assessed selected, potentially E2-related Diary changes: flow, fluid retention, breast tenderness, stretchy cervical mucus and anxiety. Cyclic OMP was associated with shorter cycle lengths of 28.17+/-0.8 days. Fluid retention (P=0.000), mucus (P=0.048), and breast tenderness (P=0.000) all decreased, but anxiety and flow were unchanged. Follicular phase only fluid retention significantly decreased (F (1.2, 14.7) = 6.7, P =0.017).

Although open-label, these prospective analyses suggest that Cyclic OMP, alone, is related to short-term benefits in androgenic PCOS. Prospective studies and controlled comparative trials of this innovative “luteal phase replacement” PCOS therapy are needed. Reference:1Barry J Hum Reprod Update 2014 20:748. 2Azziz R Nat Rev Dis Primers 2016;2:16057. 3Blank S Hum Reprod Update 2006;12:351. 4Montville C Fertil Steril 2010;94:678. 5Livadas S Fertil Steril 2010;94:242. 6Bagis T J Clin Endocr Met 2002;87:4536. 7Prior J https://hellocluecom/articles/cycle-a-z/the-case-for-a-new-pcos-therapy 2018
SAT-LB70 Relationship Between LC-MS/MS Measurements of PTHrP and Calcium in Patients With Compromised Renal Function
Authors: Kroner Grace , Kushnir Mark , Straseski Joely
Published: May 2020

Elevated concentrations of parathyroid hormone related peptide (PTHrP) may indicate hypercalcemia of malignancy and can prompt investigation into potential malignancy. Early studies using PTHrP radioimmunoassays suggested that PTHrP concentrations in normocalcemic renal failure patients were elevated due to assay cross-reactivity with C-terminal fragments present in this population [1]. At our institution, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for PTHrP targeting a peptide in the middle of the PTHrP sequence (to avoid measuring terminal fragments). Given the high specificity of LC-MS/MS, our objective was to revisit the earlier observation that PTHrP concentrations are elevated in renal failure patients. We used retrospective chart review to investigate 1) whether PTHrP concentrations differed between adult patients with and without renal impairment and 2) how PTHrP and calcium concentrations were related in these patients. We excluded patients with cancer; the participants (n=93, 20-90y, 56% female) were categorized based on eGFR using the 2009 CKD-EPI equation following KDIGO guidelines. We focused on patients with healthy kidney function (n=21, 20-73y, 43% female), stage 4 kidney disease (n=40, 23-90y, 63% female), and end stage renal disease (ESRD, n=19, 27-81y, 58% female), 7 of whom were on hemodialysis. When measured by LC-MS/MS, we observed higher PTHrP concentrations in ESRD and stage 4 patients compared to those with healthy kidney function (p<0.0001 for both). Overall, there was a strong negative correlation between eGFR and PTHrP (ρ=-0.768, p<0.0001). In contrast to the previous study documenting elevated C-terminal fragments of PTHrP in normocalcemic patients, we observed that 80% of patients with elevated PTHrP had hypercalcemia, in agreement with the positive association between concentrations of PTHrP and calcium (ρ=0.295, p=0.0178). No statistically significant difference was observed between distributions of PTHrP concentrations in stage 4 and ESRD patients with and without hypercalcemia. Among ESRD patients, higher PTHrP concentrations occurred in patients on dialysis compared to those not on dialysis (p=0.003). Our data suggest that elevated PTHrP concentrations are not solely due to decreased glomerular filtration; otherwise, patients on hemodialysis would have decreased PTHrP concentrations due to clearance. Considering the specificity of the LC-MS/MS method for the central portion of PTHrP, we conclude that elevated PTHrP concentrations may occur in patients with severe renal dysfunction; PTHrP elevations correlate with hypercalcemia in the majority of these patients. Clinicians should be cognizant of the method used to measure PTHrP when evaluating hypercalcemia, particularly in patients with renal insufficiency.

1) Orloff et al., Kidney International. 1993;43:1371-76.
MON-LB101 5-Year Data of an Aggressive Pharmacological Approach to Moderate and Morbid Obesity: Is Prevention of Bariatric Surgery Feasible in the Long Run?
Authors: Cadegiani Flavio
Published: May 2020

Background: Maintenance of weight loss in patients that undergo weight loss interventions is highly challenging, irrespective of the type of approach to obesity (whether surgical, pharmacological, or non-pharmacological). We proposed a protocol of an aggressive clinical treatment for obesity aiming to prevent the need of bariatric surgery, in patients unwilling to undergo this procedure, by proposing a protocol that included the combination of different anti-obesity medications and non-pharmacological modalities, for longer duration, and with an active approach to prevent weight regain. Our initial 2-year data showed that 93% (40 of 43 patients) with moderate and morbid obesity were able to avoid the need of bariatric surgery, with concomitant improvements of the biochemical profile. However, whether these patients would maintain their successful rates after five years was uncertain. Our objective is to describe the efficacy and safety of a long term (5-year data) pharmacological and multi-modal treatment for moderate and severe obesity. Methods: The 40 patients that were successful in the two-year approach in our obesity center (Corpometria Institute, Brasilia, DF, Brazil) were enrolled. A long-term anti-obesity protocol was employed, with continuous or intermittent use of anti-obesity drugs, trimestral body composition analysis, psychotherapy, visit to a nutritionist every four months, and both resistance and endurance exercises at least four times a week. Body weight (BW), total weight excess (TWE), body fat, markers of lipid and glucose metabolism, liver function, and inflammation were analyzed. Subjects that dropped out were considered as weight regain. Therapeutic success for the 5-year follow-up included as the maintenance of >20% loss of the initial BW loss, and no weight regain (or < 20% of the initial weight loss). Results: A total of 27 patients (67.5%) were able to maintain the body weight, seven dropped out, and six regained more than 20% of the initial weight loss. Of these, 21 (77.8%) had significant further increase of muscle mass and decrease of fat loss, while 17 (63.0%) had further weight loss (p < 0.05), compared to the 2-year data. Improvements on the biochemical profile persisted in all 27 patients, and had significant further improvements in 24 (88.9%) of these patients. Conclusion: The risk of weight regain five years after a weight loss treatment for obesity was significantly lower compared to previous literature, and comparable to the long-term outcomes of bariatric procedures. An aggressive, structured, and long-term clinical weight loss approach has been shown to be feasible, even for morbidly obese patients.
SUN-LB122 Sequential Testing to Assess Insulin Resistance in the Course of Participation in a Diabetes Prevention Program (DPP)
Authors: McPhaul Michael John , Larsen Julia A , Brandon Martha M
Published: May 2020

Obesity has become increasingly prevalent in the United States and diabetes prevalence has increased dramatically. It is estimated that diabetes affects more than 30 million Americans (CDC, 2015). Prediabetes, a condition in which blood sugar or HbA1c levels are elevated but not to levels permitting a diagnosis of type 2 diabetes, is even more prevalent. Prediabetes precedes the development of type 2 diabetes and for this reason, has been identified as a condition at which interventions might be targeted and progression to overt diabetes might be interrupted. The publication of the initial results of the Diabetes Prevention Program (Knowler WC, 2002) demonstrated that lifestyle change and medication could substantially reduce progression to type 2 diabetes. These efforts have stimulated the CDC to implement the National Diabetes Prevention Program. Unfortunately, a substantial proportion of individuals adhering to lifestyle change or medication still progress to overt diabetes and the identification of individuals participating in a DPP at continued risk for the development of type 2 diabetes would be valuable. We designed a protocol to determine whether individuals responding appropriately to a DPP might be distinguished from individuals at continued risk for diabetes progression by sequential assessments of insulin resistance. We recently validated a multiplexed mass spectrometry assay for the measurement of intact insulin and C-peptide (Taylor SW, 2016), used this to model insulin resistance in individuals undergoing formal assessment of insulin resistance using Steady State Plasma glucose (SSPG) measurements (Abbasi F, 2018) and defined an Insulin Resistance Score (IRS) based on this data. To explore the use of this IRS in the context of an established an IRB approved protocol (Quest Testing to Assess Insulin Resistance [Q-TAIR]; Western IRB protocol # 20171395), we enrolled three cohorts totaling 40 individuals. In addition to anthropometric measurements, this protocol permitted assessment of laboratory data for fasting glucose, HbA1c, electrolytes, lipids, and the IRS at baseline, 1, 3, and 6 months, and 1 year. Data collection is complete for cohorts 1 and 2; data collection is still ongoing for cohort 3. Subjects enrolled in the individual cohorts were enrolled in individual participating practices and varied widely in the proportion offered enrollment based on laboratory test results. In keeping with expectations for adherent participants in a DPP, patients lost an average of 11 lbs. In cohorts 1 and 2, initial IRS were top or middle tertile risk in 10 of 17 patients. Importantly, normalization or improvement of laboratory test results at the conclusion of the DPP did not reflect the continued elevation of IRS risk observed in 5 of the 17 patients. These findings suggest the potential utility of the IRS in assessing changes in the degree of insulin resistance in DPP participants.
SUN-281 Pituitary Hyperplasia Secondary to Uncontrolled Primary Hypothyroidism
Authors: Betancourt Jessica Lee
Published: May 2020

Background: There are several recognized causes of hyperplasia of the pituitary gland. These may present as sellar masses and be misdiagnosed as pituitary adenomas. Pituitary hyperplasia can occur in the presence of long standing primary hypothyroidism due to the loss of negative feedback caused by decreased secretion of thyroxine (T4) and triiodothyronine (T3) by the thyroid gland, leading to excessive thyrotropin releasing hormone (TRH) production by the hypothalamus causing Thyrotroph pituitary hyperplasia Clinical case: 51 y/o female with a past medical history that includes anxiety & depression, obesity, pre-diabetes and uncontrolled hypothyroidism due to Hashimoto’s, presented to the Endocrinology clinic for recent diagnosis of pituitary macroadenoma. Patient reported tiredness, decrease energy, myalgias, weight gain, abnormal menstrual periods and frontal headaches. On physical exam, she had a body mass index of 37.39kg/m2, blood pressure of 130/85mmHg, heart rate of 91 bpm. There was no thyromegaly noted on exam. No abdominal striae was noted. Overall, exam was unremarkable. Her neurological exam was normal and there were no obvious visual field deficits. Initial laboratory tests revealed a thyroid stimulating hormone (TSH) >150 uIU/mL (0.46–4.7 uIU/mL), free T4 0.3 ng/dL (0.7–1.3 ng/dL) and positive TPO antibodies. Other endocrine work up including ACTH, cortisol, prolactin, FSH, LH and IGF-1, were normal. An MRI of the pituitary revealed a heterogeneous enhancing mass replacing the pituitary gland in the sella that measured 16 x 17 x 11 mm. She was evaluated by Neurosurgery, for presumed diagnosis of pituitary macroadenoma. However, prompt recognition of uncontrolled primary hypothyroidism causing pituitary hyperplasia lead to medical management, first. She was started on weight based (1.6mcg/kg/day) levothyroxine at 175 mcg per day. Six weeks after thyroid replacement therapy laboratory evaluation showed improvement in thyroid function test with a TSH of 0.8mIU/mL, free T4 2.8ng/dL and total T3 307ng/dL. A repeat MRI of the pituitary showed decrease in size of the pituitary gland measuring 15 x 4 x 10 mm. Conclusion: This case illustrates the importance of early recognition of uncontrolled primary hypothyroidism during the evaluation of a pituitary mass. Complete regression of this pituitary gland abnormality can be achieved with thyroid hormone replacement avoiding the irreversible consequences of inappropriate pituitary surgery.
OR08-02 Do OGTT-based Insulin Secretory Response Measures Approximate 1st Phase Insulin Response in Pregnant Women?
Authors: Powe Camille Elise , Gordesky Larraine Huston , Catalano Patrick M
Published: May 2020

Background: We previously showed that 1st phase insulin response increases dramatically in pregnancy, independent of changes in insulin sensitivity. Measurement of 1st phase insulin response requires the use of hyperglycemic clamps or intravenous glucose tolerance tests (IVGTTs) which are rarely performed in pregnant women. Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy.

Methods: In a secondary analysis of a longitudinal study of glucose metabolism in pregnancy, we examined Pearson correlations between OGTT-based insulin secretory response measures and 1st phase insulin response. Forty women were studied pre-pregnancy; 36 returned in early and late pregnancy (12–14 and 34–36 weeks gestation). At each time point, after overnight fasts, an IVGTT and an OGTT were performed on separate days. The 1st phase insulin response was calculated as the incremental area under the curve during the 1st 10 minutes after intravenous administration of a 0.5 g/kg glucose load (or 19g/m2 body surface area if weight >120% ideal body weight). Homeostatic Model Assessment (HOMAB), Insulinogenic index (IGI), Corrected insulin response (CIR), Insulin area under the curve/Glucose area under the curve (AUCins/AUCglu), and the Stumvoll 1st Phase Estimate (Stumvoll) were calculated from insulin and glucose levels measured fasting and 30, 60, 90, 120, and 180 minutes after an oral glucose load (75 grams pre-pregnancy, 100 grams in pregnancy).

Results: The best OGTT-based measure for estimation of 1st phase insulin response differed across study timepoints. In early and late pregnancy, AUCins/AUCglu had the strongest correlation with 1st phase insulin response (early: R=0.79, P<0.0001; late: R=0.69, P<0.0001), but was not associated with 1st phase insulin response pre-pregnancy (R=0.32, P=0.08). IGI had the strongest correlation with first phase insulin response pre-pregnancy (R=0.50, P=0.005) and was correlated with 1st phase insulin response in late (R=0.68, P=0.0001), but not early (R=0.36, P=0.07) pregnancy. Stumvoll was the only OGTT-based measure that was significantly correlated with 1st phase insulin response at all timepoints (pre: R=0.44, P=0.01; early: R=0.67, P=0.0001; late: R=0.67, P=0.0001). HOMAB was the weakest correlate of 1st phase insulin response, though the correlation was significant in early pregnancy (pre: R=-0.04, P=0.82; early: R=0.33, P=0.05; late: R=0.18, P=0.28).

Conclusion: OGTT-based measures of insulin secretion do not have a consistent relationship with 1st phase insulin response across pre-, early, and late pregnancy. Our findings suggest that Stumvoll can be used in OGTT-based longitudinal studies of insulin secretory response that begin prior to pregnancy and span gestation. For cross-sectional studies in pregnancy, AUCins/AUCglu are the best estimates of 1st phase insulin response.
MON-584 Albuminuria and Obesity - Which Are the Associated Factors?
Authors: Costa Cláudia Fernandes , Salazar Cristina Daniela , Ferreira Maria João Silva , Pedro Jorge Pires , Neves João Sérgio , Maia Isabel , Gonçalves Vanessa Guerreiro , Canha Marta , Viana Sara , Silva Maria Manuel , Mendonça Fernando , Cabral Pedro , Lourenço Rita , Meira Patrícia , Belo Sandra , Varela Ana , Lau Eva , Oliveira Joana , Santos Ana Paula , Torres Isabel , Freitas Paula , Carvalho Davide M ,   Grupo AMTCO
Published: May 2020

Introduction

The association between obesity and renal dysfunction has been widely studied. Albuminuria is a cardiovascular risk factor and the most prevalent marker of kidney injury in people with obesity. Despite the higher prevalence of hypertension and diabetes in those patients, other contributing factors are still unknown.

We aimed to explore the factors related to albuminuria in obesity, analyzing its variation after bariatric surgery.

Methods

We evaluated 2518 patients undergoing bariatric surgery, of those, 1243 with preoperative albuminuria measurement were included in this study. Albuminuria was determined by the albumin-creatinine ratio (RAC) in an occasional urine sample (mg/g) or by the 24-hour urine albumin excretion rate (TEA) (mg/24h). Means and medians were compared using Student’s T-test or Mann-Whitney tests, respectively. Spearman correlation was used.

Results Age (ρ = 0.073; p = 0.010), body mass index (BMI) (ρ = 0.139; p <0.001), waist circumference (WC) (ρ = 0.220; p <0.001), glycated hemoglobin (HbA1C) (ρ = 0.221; p <0.001), systolic blood pressure (SBP) (ρ = 0.203; p <0.001), diastolic blood pressure (DBP) (ρ = 0.134; p <0.001), uricemia (ρ = 0.141; p <0.001) and C-reactive protein (CRP) levels (ρ = 0.090; p = 0.017) were positively correlated with albuminuria.Patients with albuminuria (TEA / RAC≥30) had higher BMI (45.0 ± 6.0 vs.43.2 ± 5.6kg / m2; p <0.001), WC (129.3 ± 13.1 vs. 122.0 ± 12.9cm; p <0.001), SBP (142.7 ± 18.0 vs.134.1 ± 16.5mmHg; p <0.001), DBP (88.0 ± 12.6 vs.83, 2 ± 10.3mmHg; p <0.001), uricemia (6.1 ± 1.5 vs.5.4 ± 1.4mg / dL; p <0.001) and CRP (11.3 (16.4) vs.8, 3 (9.6) mg / L; p <0.001).Excluding patients with diabetes and hypertension, BMI and WC remained statistically positively correlated with urinary albumin excretion. After surgery, the decrease of albuminuria was correlated with the reduction of HbA1C (ρ = 0.144; p <0.001) and CRP (ρ = 0.113; p = 0.037).

Conclusion Anthropometric, inflammatory and metabolic factors, namely WC, CRP and uricemia, may be involved in the etiopathogenesis of albuminuria in obese patients. Bariatric surgery is the most effective method to reverse obesity and it has been shown to be a promising therapy on the treatment of associated renal dysfunction.
MON-093 Pleuropulmonary Blastoma and Multinodular Goiter in a 22 Yr Old Male with DICER1 Syndrome
Authors: Lhamu Ugen , Phornphutkul Chanika , Massingham Lauren , Quintos Jose Bernardo
Published: May 2020

Background

DICER1 syndrome is an autosomal dominant condition due to mutations in the DICER1 gene, located on chromosome 14q32.13. Patients are at increased risk for malignant and benign tumors, including pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig cell tumors, multinodular goiter (MNG) and differentiated thyroid cancer (DTC). MNG is very common in patients with DICER1 Syndrome but data on incidence is lacking. MNG is more common in females than males.

Case presentation:

22 year old man who originally presented with pleuropulmonary blastoma, Type 3 at 3 years of age. His treatment included pulmonectomy, radiation of 46.6 Gy to thorax, and alkylating agents including Cisplatin, Ifosphamide and Cytoxan. He developed frontal lobe metastasis over the course of 3 years and was treated with focal cranial radiation. His father and maternal uncle had history of lung cancer.

He was evaluated at the Endocrine clinic at 12 years 10 months for short stature. His height was 132.5 cm (SDS -2.96), weight 29.7 kg (SDS -2.40), and BMI 16.99kg/m² (SDS -0.61). On examination he had normal thyroid exam and Tanner 2 bilateral 4 cc testicles. He was treated with Levothyroxine for subclinical hypothyroidism (TSH: 5.96 uIU/ml (0.35–5.5) and Free T 4: 0.99 ng/dl (0.8–1.80) and growth hormone (GH) for growth hormone deficiency (peak GH was 7.7 ng/ml after Arginine and Clonidine GH stimulation test).

At 14 years 10 month he developed respiratory distress. CT scan of chest showed right lower pole nodule 1.6 x 1.5 x 1.4 cm. Ultrasound of thyroid showed right thyroid solid mid pole isoechoic nodule 1.4 x 1.7 x 1.3 cm with multiple enlarged bilateral cervical nodes, largest left supraclavicular region > 1 cm. Biopsy of the right nodule was negative for malignancy. Over the course of 2 years he developed new right thyroid isoechoic nodule in the lower pole 2.1 x 2.5 x 1.9 cm and new left thyroid isoechoic nodule in the upper pole 1.0 x 0.5 x 0.5 cm. Biopsy was negative for malignancy.

Due to his PPB, MNG and family history of lung cancer he was evaluated at our genetic cancer clinic and tested positive for germline DICER1 pathogenic variant c.4605_4606del (p.Cys1535Trpfs*3)

Conclusion:

Our 22 year old male presented with pleuropulmonary blastoma and over the course of few years developed MNG. Genetic testing was positive for germline DICER1 pathogenic variant c.4605_4606del (p.Cys1535Trpfs*3). Our case illustrates the importance of consideration of: 1) Testing children with PPB for DICER1 Syndrome as there are screening recommendations including regular thyroid ultrasound and examinations to look for MNG or other features concerning for thyroid gland neoplasia. 2) MNG is uncommon in children and detection of this should raise suspicion for consideration of testing for DICER1 Syndrome.
OR29-05 A Natural History Study of Fibrodysplasia Ossificans Progressiva (FOP): 12-Month Outcomes
Authors: Mukaddam Mona Al , Pignolo Robert J , Baujat Geneviève , Brown Matthew A , De Cunto Carmen , Rocco Maja Di , Hsiao Edward C , Keen Richard W , Sang Kim-Hanh Le Quan , Strahs Andrew , Marino Rose , Kaplan Frederick S
Published: May 2020

Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists.

Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study.

Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents <10% involvement, score=1 represents 10–90% involvement, and score=2 represents >90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ.

Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis.

In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year).

Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year).

Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO.

Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.
SAT-143 Missed Pituitary Apoplexy in a HIV Patient
Authors: Tsang Tiffany , Raghuwanshi Maya P
Published: May 2020

Background: Pituitary hemorrhage has a prevalence of up to 25% in macroadenomas. In apoplectic hemorrhage, loss of pituitary function is associated with significant mortality. Sudden hemorrhagic enlargement of a preexisting adenoma compresses surrounding structures; ophthalmoplegia, mydriasis and ptosis occur when cranial nerves in the cavernous sinus are affected. The classic clinical syndrome of headache, visual deficits, altered mental status and hypopituitarism, combined with imaging, confirms the diagnosis of pituitary apoplexy.

Clinical Case: A 73 year-old smoker with a history of transsphenoidal surgery 20 years ago for a pituitary adenoma, HIV (CD4 928), hypertension, diabetes, coronary artery disease presented with two days of altered mental status, lethargy and headaches. Patient was febrile to 104.1°F on arrival. Head CT was done prior to a lumbar puncture, which showed a 1.7 x 2.1 x 2.2 cm pituitary mass. CSF analysis was positive for xanthochromia, and revealed 220 RBCs, 275 WBCs, glucose 143 mg/dL, protein 154 mg/dL and an opening pressure of 9 mm H20. Meropenem and vancomycin were started for presumed meningitis. A hypopituitary state was found on labs: prolactin 1.9 ng/mL (4.6–21.4 ng/mL), ACTH 3.2 pg/mL (7.2–63.3 pg/mL), cortisol 3.6 ug/dL, TSH 0.164 uIU/mL (0.27–4.0 uIU/mL), free T4 0.6 ng/dL (0.7–1.5 ng/dL), T3 0.3 ng/mL (0.6–1.6 ng/mL), IGF-1 33 ng/mL (41–179 ng/mL), total testosterone 4 ng/dL (193–740 ng/dL), LH 0.3 mIU/mL and FSH 1.2 mIU/mL. Subsequent MRI showed a 2.2 x 2.4 x 2.9 cm pituitary macroadenoma extending into the suprasellar region with mass effect on the optic chiasm and lateral displacement of the cavernous sinus segment of internal carotid arteries bilaterally. An ophthalmologic exam could not be performed due to altered mentation. Endocrinology recommended cosyntropin testing to assess for adrenal insufficiency. The following day, the patient developed a fixed and dilated right pupil, and was taken to the OR for emergent decompression. IV dexamethasone and levothyroxine were started post-operatively.

Conclusion: Differential diagnoses of pituitary apoplexy include bacterial meningitis and subarachnoid hemorrhage with aneurysmal rupture. A nonpupil-sparing third nerve palsy suggests a mass lesion. Given his symptoms and xanthochromia, this patient likely presented with pituitary apoplexy that was overlooked on initial scans. Hemorrhage that is iso-dense to normal brain tissue would not have the typical “pituitary ring sign”, a radiographic feature of peripheral enhancement around a non-enhancing infarcted center. Predisposing factors include hypertension, diabetes mellitus, pituitary dynamic testing, bromocriptine, estrogens or radiotherapy. This patient had multiple comorbidities. A lumbar puncture possibly worsened preexisting pituitary apoplexy, acutely expanding the area of hemorrhage and causing compressive symptoms.
SAT-072 A Case of Solitary Hyperfunctioning Thyroid Nodule Harboring Papillary Thyroid Carcinoma in a Pediatric Patient
Authors: Burdea Liliana , Calabrese Mary E , Jo Inha , Mantis Stelios
Published: May 2020

Introduction: Thyroid nodules are less common among children than adults but are more likely to be malignant. Among all the thyroid nodules, autonomous functioning thyroid nodules (AFTN) are generally considered to be a benign entity, with malignancy found in less than 1 %. AFTN are very rare in the pediatric population, and the optimal treatment is not well defined. We present a 14-year-old female patient with an AFTN treated with surgical resection and found to contain papillary thyroid carcinoma, despite a previous biopsy which did not demonstrate malignancy. Case presentation: A 14-year-old girl presented with left-sided palpable thyroid lesion for four months. The patient had no symptoms at that time, and the physical exam was notable for a palpable left thyroid nodule measuring 3x 2.2 cm. Thyroid studies were remarkable for a suppressed thyroid-stimulating hormone (TSH) of 0.056uIU/mL (0.350–4.94), normal free thyroxine (FT4): 1.1 ng/dL (0.7–1.5), and positive anti-thyroglobulin antibodies: 9.0 IU/ml (0.0 - 4.1) with negative anti peroxidase antibodies and negative thyroid-stimulating immunoglobulin. Initial ultrasound (US) showed a left complex cystic and solid nodule measuring 3.4 cm x 1.8 cm x 2.3 cm. Fine needle aspiration (FNA) of the nodule revealed a benign aspirate. An I-123 scan revealed a hyperfunctioning nodule with suppression of uptake in surrounding thyroid parenchyma. The patient was then lost to follow up, presenting to our clinic over a year later due to difficulty breathing when supine and increased nodule size. Thyroid studies were notable for a suppressed TSH of 0.005 and slightly elevated FT4:1.8. Thyroid US showed a mixed cystic and solid nodule measuring 4.7 x3 x 4cm, with no calcification. Given the increased size of the lesion, her age, and difficulty breathing when supine, a decision was made to proceed with left hemithyroidectomy for definitive diagnosis and treatment. Pathology of the specimen revealed an encapsulated papillary thyroid carcinoma with focal capsular invasion. Right hemithyroidectomy was performed three weeks later, followed by I-131 ablation one month after surgery. The patient is currently doing well and euthyroid on thyroid hormone replacement therapy, with no evidence of disease. She is undergoing surveillance with ultrasound imaging and laboratory evaluation. Conclusion: This is a rare case of AFTN harboring papillary thyroid carcinoma. Although the majority of cases of AFTN are benign, an FNA was performed and was negative for malignancy. Due to an increase in size, new symptoms and ultrasound changes, surgery was performed and revealed the final diagnosis. The behavior of thyroid nodules in pediatric patients can be different than adult patients. Even though the majority of AFTN are benign, we should still keep malignancy in our differential when the nodule has a growth pattern, new US findings or patient develops worsening symptoms.
SUN-488 A Coexisting of Two Different Thyroid Malignancies: A Collision Phenomenon
Authors: Pishdad Reza , Boutin Regine , Hajjar Richard , Jaloudi Mohammed , Galan Mark , Cespedes Lissette Maria , Raghuwanshi Maya P
Published: May 2020

A Coexisting of Two Different Thyroid Malignancies: A Collision Phenomenon Introduction: Collision tumors are rare clinical entities wherein two histologically distinct tumor types occur at the same anatomic sites. Simultaneous papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) of the same thyroid is a very rare occurrence with limited clinical information. Herein, we report a case of PTC and FTC of the same thyroid lobe. Clinical case: A 79-year-old man presented to the emergency department for evaluation of left hip pain of 2-month duration. Three days before presentation, he sustained a physical trauma to the left side of his body. X-ray imaging of the left femur revealed a lytic bony lesion measuring approximately 5.2 cm x 4.2 cm at the proximal end of left femur as well as a displaced pathologic fracture of its lesser trochanter. Biopsies of the bone lytic lesion suggested metastatic follicular thyroid carcinoma. CT of the neck revealed an enlarged thyroid with a cystic lesion as well as 2 nodules in the left lobe of thyroid gland. Total thyroidectomy was performed. Histopathology revealed 2 separate primary malignancies of PTC and FTC. Following diagnosis, laboratory test results showed TSH 2.6 uIU/mL (reference range, 0.2–4), anti-thyroglobulin antibody (anti Tg) < 1.0 IU/mL (reference range, 0.0–0.9), calcitonin 8.4 pg/mL (reference range, 0–8.4), and CEA 1.1 ng/mL (reference range, 0.0–3.0). The patient was placed on thyroid hormone replacement therapy and was treated with external beam radiation to his bone metastasis. He was scheduled for later further thyroid ablation. In his follow-up visit, three months later, he reported no pain on ambulation. Discussion: For each type of thyroid malignancy, several genes have been identified. However, to date, no common gene mutation responsible for the pathogenesis of the different tumor types has been determined. For instance, point mutations of the RAS oncogene are found in about 40% of thyroid neoplasms (N-RAS, H-RAS, and K-RAS, in order of decreasing frequency) including both PTC and FTC. No single theory can completely explain the pathogenesis of these tumors in all cases, and so, with the present level of understanding of the disease, a combination of theories must be accepted. Management of collision tumors of the thyroid gland is usually complex owing to the presence of dual pathology in the tumor tissues and given the fact that literature on this condition is scarce. Generally, the treatment needs to be individualized. Conclusion: Most likely, a rare phenomenon of simultaneous mutation of different genes can give birth to contemporary different thyroidal neoplasms. References: Zhu Z, Gandhi M, Nikiforova MN, et al. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003; 120:71.
SAT-282 Hypothalamic Pituitary Adrenal Axis Hyperactivity in Db/db Mice
Authors: Kameda Hiraku , Sekizaki Tomonori , Shibayama Yui , Nomoto Hiroshi , Cho Kyu Yong , Nakamura Akinobu , Miyoshi Hideaki , Atsumi Tatsuya
Published: May 2020

Background: Patients with diabetes present hypercortisolemia, which may exacerbate not only glycemic control but also diabetic complications and fatty liver (1). Blood steroid hormone levels including corticosterone and aldosterone are high in db/db mice (2), although the mechanism is still unclear. Objective: To reveal the mechanism underlying the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in obese and diabetic condition. Method: Total RNA from hypothalamus, pituitary, and adrenal glands in ten-week-old db/db and db/+ mice were extracted and analyzed with DNA microarray and real-time PCR. Experiments were approved by the Institutional Animal Care and Use Committee. Results: Hypothalamic Crh mRNA expression was not changed in db/db mice, although Avp expression was 2.8-fold higher than db/+ mice. Pituitary Crhr1 and Pomc expression were higher (3.0- and 7.0-fold, respectively), and Nr3c1 expression was lower (0.7-fold) in db/db mice than db/+ mice. Adrenal Mc2r, Nr5a1, Cyp11b1, and Cyp11b2 were higher in db/db mice than db/+ mice (1.7-, 1.7-, 2.2-, 1.3-fold, respectively). Conclusion: Increased expression of tropic hormone receptors and abrogated negative feedback system may be responsible for HPA axis hyperactivity in db/db mice. Reference: (1) Chiodini I et al. Diabetes Care. 2007 Jan;30:83–8. (2) Hofmann A et al. Horm Metab Res. 2017 Jan;49:43–49.
OR15-07 Novel Genes Involved in Sex Differentiation Identified by Whole-Exome Sequencing in a Cohort of Children with Disorders of Sex Development
Authors: Rakover Yardena Tenenbaum , Admoni Osnat , Assad Ghadir Elias , London Shira , Barhoum Marie Noufi , Ludar Hana , Almagor Tal , Bertalan Rita , Bashamboo Anu , McElreavey, Prof Kenneth
Published: May 2020

Background: Disorders of sex development (DSD) are classified as a congenital discrepancy between external genitalia, gonadal and chromosomal sex. Despite extensive laboratory and imaging investigations, the etiology of DSD is unknown in more than 50% of patients and the diagnosis is often delayed to the second decade of life. Our objective was to evaluate the etiology of DSD by whole-exome sequencing (WES) in children in whom hormonal and candidate gene approaches had not identified the etiology. Methods: Nine patients diagnosed with DSD (eight 46,XY and one 46,XX) were enrolled. Patients underwent hormonal evaluation, including ACTH, GnRH and hCG tests. Candidate genes were sequenced in accordance with the hormonal results. WES was performed for the probands and their parents. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient with fusion of the labia majora. In six of the nine patients (66%), a pathogenic mutation was identified by WES that explained the phenotype: four known DSD-causing genes—POR, CHD7, HSD17B3 and WT1—and two novel genes—BMP4 and RFXP2. In three patients, variants of unknown significance were found. An 11-y-old boy had a novel de-novo mutation in BMP4. In humans, mutations in this gene, encoding bone morphogenetic protein 4, are associated with autosomal dominant microphthalmia. BMP4 is expressed in the urethral epithelium and has a role in the development of external genitalia and the pituitary. This is the first report of a BMP4 mutation in a child with DSD. A 12-y-old boy had a mutation in RFXP2, encoding insulin-like 3 hormone receptor, which has been previously reported in adult males with cryptorchidism. This is the first case of an RFXP2 mutation in a child with DSD. Conclusions: WES has a crucial role in early diagnosis of the etiology of DSD, making extensive endocrine testing unnecessary, and has important implications for sex of rearing decisions.
SAT-413 Does Dipeptidyl Peptidase-4 Inhibitor Exacerbate Graves’ Disease?
Authors: Sekizaki Tomonori , Kameda Hiraku , Cho Kyu Yong , Akinobu Nakamura , Takahashi Kiyohiko , Wada Norio , Takeuchi Jun , Nagai So , Miyoshi Hideaki , Atsumi Tatsuya
Published: May 2020

Abstract: [Background] Dipeptidyl peptidase-4 (DPP-4) is expressed as CD26 on the surface of immune cells including T cells, suggesting that inhibition of DPP-4 may affect the immune system (1). Actually, DPP-4 inhibitor (DPP-4i)-induced polyarthritis and bullous pemphigoid have been reported (2, 3). It has also been reported that the prevalence of Hashimoto’s thyroiditis was significantly higher in patients on DPP-4i treatment (4). However, relationships between DPP-4i and Graves’ disease has been unclear. [Methods] To investigate the impact of DPP-4i administration on the activity of Graves’ disease, we conducted a multicenter observational trial that included patients with both Graves’ disease and type 2 diabetes mellitus who were administered an oral hypoglycemic agent (OHA) including DPP-4i from December in 2009 to April in 2018. Patients who had systemic diseases affecting thyroid function and those who underwent thyroidectomy or radioiodine treatment within 6 months before or after OHA administration were excluded. Exacerbation of Graves’ disease was defined as an increase in antithyroid drug dose within 6 months after OHA administration. The trial was approved by the institutional review board of Hokkaido University Hospital. [Results] Eighty-three patients were enrolled in the study, and they were divided into an exacerbation group (n = 18) and a non-exacerbation group (n = 65). Comparing baseline characteristics, the percentage of DPP-4i administration was higher in the exacerbation group (83.3%) than in the non-exacerbation group (32.3%) (p = 0.0001). Mean age was also significantly higher in the exacerbation group (p = 0.04), and the duration of Graves’ disease was significantly shorter (p = 0.01). Multivariate logistic regression analysis using factors extracted by comparing baseline characteristics demonstrated a significant association between DPP-4i administration and Graves’ disease exacerbation (odds ratio 5.62, 95% confidence interval 1.16–27.0, p = 0.02). [Conclusion] The current study suggests that DPP-4i administration is associated with exacerbation of Graves’ disease.

Reference: (1) Morimoto C et al., Immunol Rev. 1998 Feb;161:55–70. (2) Yokota K et al., Intern Med. 2012;51(15):2041–4. (3) Yoshiji S et al. J Diabetes Investig. 2018 Mar;9(2):445–447. (4) Kridin K et al. Immunol Res. 2018 Jun;66(3):425–430.
MON-497 Evaluation and Comparison of Ultrasonographic Features According to Histology of Thyroid Nodules
Authors: Ferrinho Cátia , Cunha Clara Valério , Silva Eugénia , Saraiva Catarina , Ferreira Rute Costa , Roque Catarina , Chorão Martinha , Oliveira Manuela , Duarte João Sequeira
Published: May 2020

Introduction: The prevalence of thyroid nodules identified by ultrasonography (US) may be up to 70%, with the majority being incidentalomas. Less than 15% of thyroid nodules will be malignant. Ultrasonography plays a key role in the diagnosis and management of thyroid diseases and US features have been described in way to predict the risk of malignancy. Aim: Evaluate and correlate US features with histological results, in our hospital, from January 2017 to December 2018. Materials and methods: Cross-sectional study. A total of 117 patients were evaluated, 77 had histology of nodular hyperplasia (benign) and 40 had histology of thyroid carcinoma (malign) after partial or total thyroidectomy. We described the size of the nodule (the largest diameter), the US features detailed in the ultrasound report (shape, margins, echogenicity, composition and microcalcifications), the EU-TIRADS score of each nodule and the histology of thyroid. The data were analysed using nonparametric statistical tests. The results are presented as median (interquartile range). The level of significance accepted was p<0.05. Results: Of the 117 patients, 82.1% were female, with a median age of 59.7 (25.0) years, nodule size in benign histology group was 35.0 (14.0) mm and in malign histology group was 20.0 (28.0) mm. Of malignant nodules, 90.0% (n=36) were papillary carcinomas. The prevalence of US features: 76.9% were solid, 35.0% had microcalcifications, 25.6% had irregular margins, 17.9% were markedly hypoechoic and 6.8% were taller-than-wide. Three characteristics were significantly related to malignancy: irregular margins (p=0.001), markedly hypoechoic (p=0.001) and microcalcifications (p=0.015). The taller-than-wide feature had the highest specificity of 94.8%; the marked hypoechogenicity with a specificity of 92.2%, had the highest positive likelihood ratio (LHR+: 4.81 (95% CI: 2.02–11.44)) and the highest diagnostic odds ratio (DOR: 7.10 (95% CI: 2.48–20.30)). The EU-TIRADS 5 category had a significant association with malignancy (p=0.001) and 80.0% of malignant nodules were classified in this category. The specificity was 62.3%, LHR+ was 2.12 (95% CI: 1.53–2.94) and DOR was 6.62 (95% CI: 2.69–16.31). Conclusion: In the evaluation of the US features, marked hypoechogenicity had the highest LHR+ and DOR. It was possible to verify that the EU-TIRADS 5 category was a good predictor of risk to malignancy, which reinforces the importance of categorizing the nodules for selective perform of fine needle aspiration.