bluuebunny/crossref_metadata_2025 huggingface dataset:
RF35 | PSAT268 Reversal of Graves’ Disease Associated Facial Volume Expansion and Eyelid Changes Following Teprotumumab Therapy
Authors: Ugradar Shoaib , Douglas Raymond
Published: November 2022

Background

Thyroid eye disease (TED) causes orbital soft tissue expansion. Teprotumumab, a monoclonal antibody to the IGF-1R reduces orbital soft tissue swelling in TED. In this study, we quantified the changes to pan facial soft tissue volumes, following treatment with Teprotumumab.

Methods

In this prospective longitudinal study, all patients presenting at our institution for the treatment of TED were considered for study eligibility. Patients who were currently on any other medical therapy for TED were excluded. Further, patients who had any plans to embark on a weight loss regime, or medications that might cause weight loss were excluded. The primary outcome measure was a change in soft tissue volume of the face from baseline to within 3 weeks of the final infusion. Secondary outcome measures included changes in proptosis, clinical activity score and body weight. All patients had 3D facial imaging using the Vectra H2 (Canfield, USA). The use of this system to quantify volumetric change in facial soft tissue has previously been shown to be reliable and accurate.

We also used the Mimics (Materialise) software to build 3D reconstructions of the face from CT scans, allowing us to calculate the volume of muscle and fat tissue pre and post treatment. Relationships between continuous variables were analyzed using bivariate and multivariate analysis. Intraobserver and Interobserver variability was calculated by two observers doing all calculations twice on two separate days.

Results

Forty-three patients with confirmed euthyroid status at the time of study were included. The mean duration of TED was 30 months (34). Following Teprotumumab therapy, the mean (SD) decrease in volume for each region was 0.74 mL (0.82) in the upper face, 1.9 mL (1.2) in the periorbital region, 0.18 mL (0.6) in the temples, 1.73 mL (2.2) in the midface and 2.84 mL (4.7) in the lower face. The mean (SD) decrease in the volume of the full face was 8.4 mL (8.5) (figure 2). There was a significant correlation between 3D facial imaging and volumetric study using CT scans (p < 0.05). Mean (SD) weight prior to therapy was 75 kg (12) and 69 kg (15) following therapy (p < 0.05). There was no relationship between previous steroid use and total body weight reduction and changes in facial volume.

Conclusion

The results of this study expand the borders of TED, suggesting its sequelae may reach beyond that of the orbit and periorbital tissues, to include changes across the entire face. Teprotumumab significantly reduces these changes.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.
ODP545 Ectopic Cushing's Syndrome in Small Cell Lung Cancer: A Frequently Missed Diagnosis
Authors: Iqbal Qasim , Martinez Valerie
Published: November 2022

A 61-year old woman, heavy smoker (40 pack-years) with a medical history of type 2 diabetes was brought to the hospital with the chief complaint of altered mental status. She had been recently diagnosed with stage IV small cell lung cancer two weeks prior but had not started chemotherapy. Physical examination was consistent with scattered petechiae and violaceous striae in bilateral upper extremities, chest, and trunk. On arrival, the patient had a blood glucose of 506 mg/dl, K 2.5 mmol/L, bicarb 23, pH 7.5, and beta-hydroxybutyrate 5.3. Further workup revealed an AM cortisol >110 and extremely elevated urine and salivary cortisol at 21000 ug/dl and 97200 ug/dl, respectively. Other remarkable labs were ACTH 480 and low TSH (0.288), free T4 (0.53), and free T3 (1.5). MRI abdomen showed bilateral adrenal masses characteristic of metastatic disease. MRI brain did not show signs of pituitary pathology. The patient was started on Ketoconazole 200 mg twice daily, Octreotide 100 mg IV every 6 hours, and Spironolactone 25 mg twice daily. Spironolactone was increased to 50 mg and later to 100 mg due to significant hypokalemia. At the same time, she was also started on urgent inpatient chemotherapy with Cisplatin/Etoposide and completed one cycle. Cortisol levels started to improve and eventually normalized. Her mental status improved as well. Although the patient symptomatically improved, her extensive-stage small cell lung cancer makes her prognosis poor in the long term.

Presentation: No date and time listed
ODP558 Steroid Receptor Coactivators Promote Non-Small Cell Lung Cancer Tumorigenesis by Inhibiting Differentiation Factors, C/EBPα and NF-κB
Authors: Mendelson Carole , Mishra Ritu
Published: November 2022

The steroid receptor coactivator (SRC) family comprises three members, SRC-1 (NCOA1), SRC-2 (NCOA2), and SRC-3 (NCOA3). These SRC family members modulate diverse gene expression programs both by nuclear receptors and other transcription factors to drive physiological and pathophysiological processes. Notably, SRC-1, -2 and -3 also were found to be involved in different aspects of tumorigenesis. SRC-1 and SRC-3 overexpression has been observed in endometrial, ovarian, prostate, colorectal, gastric, lung, pancreatic and liver cancers. SRC-2 expression is elevated in patients with metastatic prostate cancer. This suggests that SRC family members are involved in signaling pathways critical for cancer cell proliferation and tumorigenesis. In the present study, we have begun to elucidate the mechanisms by which SRC members play a role in non-small cell lung cancer (NSCLC). We used the potent small-molecule SRC inhibitor, SI-2, which significantly impedes primary tumor growth in a breast cancer mouse model [1]. SI-2 selectively reduces cellular protein levels of SRC-1, SRC-2 and SRC-3 post transcriptionally. We observed that treatment of the NSCLC lines A549 and H1299 with SI-2 significantly induced protein expression of CCAAT/enhancer-binding protein-α (C/EBPα). C/EBPα is a basic leucine zipper transcription factor that is highly expressed in differentiated fetal lung epithelial cells, where it controls differentiation-dependent gene expression and inhibits cell proliferation. C/EBPα was found to be inactivated in various types of cancers, providing evidence for a possible tumor suppressor function of the C/EBPα (CEBPA) gene. We found that activation of C/EBPα in SI-2 treated NSCLC (A549 and H1299) was associated with a decline in the levels of histone deacetylases, HDAC-2 and-4. This suggests that inhibiting SRC family members in lung cancer cells causes reactivation of the epigenetically suppressed CEBPA gene by inhibiting histone deacetylase expression. We also observed that SI-2 increased expression of nuclear factor-κB (NF-κB) p65 protein in both A549 and H1299 cells. Previously, we found that NF-κB activates signaling pathways leading to enhanced fetal lung epithelial cell differentiation by decreasing HDAC-2 and -4 expression and binding to promoters of differentiation-inducing genes. Overall, we speculate that the SRC inhibitor, SI-2, blocks NSCLC proliferation and tumorigenesis by enhancing histone acetylation and transcriptional activation of putative tumor suppressors, C/EBPα and NF-κB, to increase lung epithelial cell differentiation. References1. Song, X., et al., Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3. Proceedings of the National Academy of Sciences, 2016. 113(18): p. 4970-4975.

Presentation: No date and time listed
RF27 | LBSUN362 Germline CDKN1B Variants Type And Site Are Associated With Specific Phenotype In Multiple Endocrine Neoplasia 4
Authors: Halperin Reut , Tirosh Amit
Published: November 2022

Background

The latest of the multiple endocrine neoplasia (MEN) syndromes described is MEN4, caused by germline CDKN1B tumor suppressor gene mutation. The main clinical manifestations of MEN4 are primary hyperparathyroidism (PHPT), neuroendocrine tumors (NET) and pituitary adenomas (PitAd). CDKN1B codes for the nuclear protein p27, a key regulator of cell cycle. This protein is an intrinsically unstructured protein, that folds upon interacting a putative interactor. It is comprised of two major domains: a kinase inhibitory domain (CDKi) that binds to cyclins and cyclin dependent kinase (CDK), and a scatter domain. p27 acts by inhibiting complexes of cyclins and CDKs, thus preventing the transition between phases of the cell cycle. Less than sixty cases of MEN4 syndrome were described thus far, with clinical manifestations resembling in part to a late onset of MEN1.

Hypothesis

Specific alterations in p27 protein will result in distinct clinical phenotypes.

Methodology Case report

We collected published and unpublished data on all currently known patients with MEN4 worldwide, including newly identified kindreds from our clinic, and performed a thorough genotype-phenotype analysis of the various MEN4 manifestations. Whole exome sequencing was performed, revealing a germline CDKN1B frameshift variant (p.Q107fs*12), that was further verified by Sanger sequencing. A detailed literature review, including requests of unpublished clinical data from past studies was undertaken. Based on the data we performed a time-dependent risk analysis for the three main manifestations of MEN4 by various genotype-related parameters: variant type (single-nucleotide variant vs. indels) and site (variant- and domain-specific analyses). Major results Of 73 cases, 53.4% developed PHPT, 28.8% had PitAD and 19.2% - NET. PitAd developed earlier (age, 34.4±21.4 years) compared with PHPT (50.6±13.9 years) and NET (52.9±13.9 years). The risk to develop PHPT, PitA and NET in patients with MEN4 were 53.4%, 23.2% and 16.2% by age 60 years, respectively.CDKN1B variants clustered in genetic locations, or "hotspots" (i.e., codon 41 frameshift: n=13, codon 107 frameshift: n=11, c.-29-(-26)AGAG deletion: n=4). Although founder effect is relevant, this finding is in contrast to MEN1 genotype. We then performed time-dependent risk analysis for developing clinical manifestation by each gene domain alteration (either point mutation or upstream indel). We found a higher risk to develop PHPT or PitAd with variants affecting codons 94-96 (Log-rank, p values 0.014 and 0.047, respectively), and trend towards higher risk for PHPT for Scatter domain variants (p=0.09). Moreover, indels were associated Conclusions: MEN4 genotype is distinct than MEN1, by the presence of hotspots, and genotype-phenotype association. Further, the risk for PHPT is lower than MEN1, with a lower penetrance, and older age at diagnosis.

Presentation: Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.
PSUN299 GLP-1 Contribution to Insulin Secretory Response to Protein Ingestion and Insulin Kinetics Following Gastric Bypass and Sleeve Gastrectomy
Authors: Rayas Maria , DeFronzo Ralph A , Gastaldelli Amalia , Salehi Marzieh
Published: November 2022

Rapid passage of ingested nutrients to the gut after Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) results in hyperinsulinemia after glucose ingestion, in part due to an enhanced glucagon-like peptide-1 (GLP-1)-induced insulin secretory response (ISR) and reduced metabolic clearance rate of insulin (MCRI). The effect of endogenous GLP-1 on insulin kinetics is unknown, and so is GLP-1 contribution to insulin secretory response to non-glucose nutrient ingestion. In non-surgical subjects, protein ingestion enhances insulin secretion and reduces MCRI. We hypothesized that protein ingestion enhances GLP-1-induced ISR and alters MCRI in proportion to changes in nutrient influx after GB and SG.

To test this hypothesis ISR, β-cell sensitivity to glucose (BGS), MCRI, and oral glucose insulin sensitivity (OGIS) were measured on 3 days during 50 g glucose ingestion as well as 50 g protein ingestion with and without GLP-1R antagonist, exendin (9-39) [Ex-9] infusion. Ten GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN) were enrolled. The 3 non-diabetic groups were matched for age, BMI, fat-free mass, HbA1c; surgical groups were matched for weight loss and time post-surgery.

Fasting glucose, insulin, and ISR were similar among the 3 groups and among the 3 studies but fasting MCRI was greater in surgical groups than CN (p<0.05). Compared to glucose, protein ingestion led to larger BGS in 3 groups despite smaller overall ISR response (AUCISR3h) (p<0.05). Blocking GLP-1R during protein ingestion decreased AUCISR3h only in surgical subjects (p<0.05 for interaction), whereas BGS was reduced similarly in 3 groups during Ex-9 infusion (p<0.05). OGIS was smaller during protein than glucose ingestion in 3 groups (p<0.05). GLP-1R blockade did not affect insulin sensitivity. Following nutrient ingestion in parallel with increase in insulin secretion MCRI was reduced to nadir values at 40 minutes, but then gradually increased approaching premeal values at different pace among surgical and non-surgical subjects (p<0.05). The slope of MCRI: Insulin (0-40 min) was smaller after protein ingestion than glucose, and after protein with Ex-9 infusion than without in 3 groups (p<0.05). Blocking GLP-1R had no effect on MCRI values in the latter phase of protein ingestion when insulin secretion reduced approaching premeal values. There was no association between parameters of insulin sensitivity and insulin clearance during glucose or protein ingestion.

Our findings indicate that the regulation of insulin secretion and clearance during protein ingestion is altered after GB and SG. Further, endogenous GLP-1 contribution to insulin secretory response to protein ingestion after GB and SG is enhanced, but GLP-1 effect on insulin kinetics is trivial.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN305 A Double-Blind, Placebo-Controlled Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HM15136 in Obese or Overweight Subjects with Co-morbidities
Authors: Shin Wonjung , Choi JaeDuk , Yun Hyori , Han OakPil , Cho Hyungjin , Hompesch Marcus , Baek Seungjae
Published: November 2022

HM15136 is a novel long-acting glucagon analogue with an extended half-life. In vivo efficacy studies of HM15136 in animal models showed its therapeutic potential in obesity, and treatment requiring hypoglycemia. We enrolled an obese and overweight subjects without diabetes (study Part 1) and with diabetes (study Part 2) in a randomized, double-blind, placebo-controlled study to assess the safety, pharmacokinetics, and pharmacodynamics of multiple subcutaneous doses of HM15136 for 12 weeks (NCT04167553). In Part 1, a total of 36 non-diabetic subjects randomly received HM15136 or its matching placebo in a ratio of 9: 3 in 3 cohorts (0.02, 0.04, and 0.06 mg/kg). The baseline mean age was 37.5 years, BMI was 33.9 kg/m2, and Fasting Plasma Glucose (FPG) was 92.3 mg/dL. The FPG increased with escalating doses of HM15136. The mean (SD) changes from baseline in FPG at week 12 were -1.0 (13.0) mg/dL for 0.02 mg/kg, 12.0 (10.7) mg/dL for 0.04 mg/kg, 17.9 (16.9) mg/dL for 0.06 mg/kg vs. 0.6 (6.5) mg/dL for placebo group. The FPG had returned to baseline at 3 weeks after study drug discontinuation. The presence of Anti-Drug Antibodies (ADAs) was confirmed in 5 subjects (18.5%) but dose-dependency was not observed. One (1) out of 5 ADA positive subjects had neutralizing ADA activity with no cross reactivity to endogenous glucagon. The most frequent Treatment Related Adverse Event (TRAE) was injection site erythema (11.1%), the frequency of TRAEs was not dose dependent. Throughout Part 1 and Part 2, all TRAEs were mild except for moderate hyperglycemia in patients with diabetes. Part 2 was completed earlier than planned due to the impact of COVID-19 and discontinued subjects due to the hyperglycemia. Part 2 was not included in this presentation because the interpretability of the data was limited. In conclusion, HM15136 was safe and well tolerated in non-diabetic obese subjects during the 12-week treatment at various dose levels. Treatment with HM15136 showed a dose dependent blood glucose increase. These results suggest future development opportunities for the management of treatment requiring hypoglycemia. A phase 2, Proof-of-Concept study in patients with congenital hyperinsulinism is currently ongoing (NCT04732416).

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN314 Severe Insulin Resistance Impacts the Growth Hormone-Insulin-Like Growth Factor-I Axis and Linear Growth
Authors: Okawa Marinna
Published: November 2022

Diabetes and insulin resistance (IR) may impact growth hormone (GH), insulin-like growth factor 1 (IGF-1), and linear growth. Poorly controlled diabetes impairs growth, while high insulin may increase growth.

To understand relationships between diabetes, IR, and growth, we examine height, body mass index (BMI), glucose, GH, and IGF- in patient populations with IR, including (in order of increasing IR): congenital generalized lipodystrophy (CGL), heterozygous pathogenic variants of the insulin receptor INSR (+/-), homozygous INSR variants (INSR-/-), and autoantibodies to the insulin receptor (Type B IR).

Patients with CGL and INSR +/- have less IR, lower glucose, higher BMI, and higher IGF-1 vs patients with INSR -/- and Type B INSR. Patients with INSR -/- have short stature, while those with CGL have tall stature. GH is comparable in all groups. After remission of Type B IR, patients had normalization of insulin resistance, glucose, and IGF-1, supporting the idea that IR or elevated glucose caused low IGF-1.

Our findings suggest that severe IR causes elevated blood glucose with inadequate glucose reaching cells mimicking a starvation state and causing low IGF-1. If this occurs during childhood growth (as in INSR -/-, but not in Type B IR), it leads to short stature.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN330 Patients with Recurrent Hypoglycemia Encounters Across Chicago: Who are they?
Authors: Zhao Lihui , Katz Joshua , Deng Yu , O’Brien Matthew , Furmanchuk A’lona , O’Connor Clare , Rosenman Marc , Kho Abel , Wallia Amisha
Published: November 2022

Hypoglycemia is an acute complication of diabetes management that has been linked to increased morbidity. Although current guidelines have called for treatment changes for avoidance of hypoglycemia, it remains a critical issue. Our goal was to examine the socio-demographic and clinical factors for recurrent hypoglycemic encounters across a large metropolitan area.

CAPriCORN is a research network which brings together merged, de-duplicated, and de-identified electronic medical health record data from 6 institutions across Chicago. Patients with a diabetes diagnosis and hypoglycemic encounters (HEs) between 2011-18 were identified using ICD-9 and 10 codes. HEs were identified using a validated algorithm. Analysis was performed to evaluate the patient characteristic differences between patients with 1 vs 2-3 vs ≥4 HEs utilizing chi-square for categorical variables and ANOVA for continuous variables.

Of 423,643 patients identified with a diagnosis of diabetes, 17,885 (4%) patients had at least one diagnosis of hypoglycemia, which included 30,157 unique encounters (1 HE: 12,886 pts and encounters; 2-3: 3,640 pts and 8,238 encounters, and ≥4: 1,359 pts and 9,033 encounters). The 1,359 patients with ≥4 HEs (8% of all patients with HEs) accounted for over 30% of all HEs.

Older adults (65 years and older) comprised 57% of all patients and 62% of patients with HEs. Older adults comprised 63% of those with 1 HE, 61% of those with 2-3, and 52% of those with ≥ 4 (p< 0.001). Adults 80 years and older represented > 20% of those in each group. Whites (N=7,203, 40%) and Blacks (N=6,511, 36%) accounted for most with HE, and within each category. Overall, among those with 1, 2-3, and ≥ 4 HEs there were also significant differences by race and ethnicity.

Patients with a HE had significant history of complications, including 54% with nephropathy, 24% with neuropathy, and 23% with ophthalmologic complications. However, a history of diabetic ketoacidosis (DKA) was noted in 53% of all patients with a HE, with 49%, 61%, and 66% of patients in 1, 2-3, and ≥4 HEs groups, respectively (p<0.001).

Of those with medication information (n=8,938), patients on insulin-only therapy represented 47% of patients with a HE, and 44%, 52%, and 65% of patients who had 1, 2-3, and ≥4 HEs, respectively (p<0.001). Patients on sulfonylureas or meglitinides represented 28% of patients with a HE, and 31%, 25%, and 15% of patients who had 1, 2-3, ≥4 HEs, respectively (p<0.001). Of those with lab information for HbA1c (n=5,259) there was no significant difference between groups.

Overall, a small diverse group of patients accounted for a large amount of hypoglycemic encounters. Special attention should be paid to subsets of patients, including older adults, those with a history of DKA, and those on high-risk therapy.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN135 Genetic Inactivation of Glutaminase Reduces Amino Acid Induced Alpha Cell Proliferation
Authors: Shou Matthew , Siv Walter , Debo Joshua , Sellick Katelyn , Reuter Austin , Stanley Jade E , Danielle Dean E
Published: November 2022

Glucagon stimulates glycogenolysis and gluconeogenesis in liver resulting in increased hepatic glucose output. Thus, interrupting glucagon signaling in liver reduces blood glucose levels in animal models and individuals with diabetes. However, interrupting glucagon signaling also leads to hyperaminoacidemia and proliferation of glucagon secreting alpha cells, evidence of an endocrine liver-alpha cell axis. Among the high amino acids, we previously identified high glutamine levels are required for alpha cell proliferation. We recently found that glutaminase (GLS) is expressed in alpha cells at much higher levels than any other pancreatic endocrine cells. Additionally, mouse pancreatic islets cultured in high amino acid containing media and treated with the small molecule inhibitor of GLS (CB839) have reduced alpha cell proliferation (Vehicle: 7.6 ± 2.2%, 0.1µM CB839: 0.11 ± 0.05%**, 10µM: 0.02 ± 0.01%**; n=3-4, **p < 0.01). To further characterize the role of glutamine metabolism in glutamine-induced alpha cell proliferation, GLS activity was specifically knocked out in mouse alpha cells by breeding Gcg-CRE ERT2 with Glsflox mice (aGlsKO). Targeted deletion of Gls expression in most alpha cells was confirmed by staining for GLS and glucagon (aGlsWT: 95% GLS+, aGlsKO: 18% GLS+). Mice were treated with a glucagon receptor monoclonal antibody (GCGR mAb/mAb-4) for 10 days or with isotype control IgG. aGlsWT mice treated with GCGR mAb have robust alpha cell proliferation while aGlsKO mice treated with GCGR mAb for 10 days showed a 4.5-fold decrease in alpha cell proliferation and were similar to mice treated with the control IgG (aGlsWT Ab: 15.7 ± 3.6% alpha cell proliferation, aGlsWT IgG: 1.0 ± 0.4%***, aGlsKO Ab: 3.4 ± 0.6%**; n=4-6, ***p < 0.001). In addition, aGlsWT mice treated with GCGR mAb showed a robust activation of mTOR in alpha cells as measured by phospho-S6 expression while this was lost in aGlsKO mice treated with GCGR mAb. Induced expression of the mTOR-dependent glutamine transporter SLC38A5 was also lost (aGlsWT Ab: 25.0 ± 4.8% alpha cell SLC38A5 expression, aGlsWT IgG: 0.40 ± 0.27%***, aGlsKO Ab: 3.7 ± 3.5%***, n= 2-4, ***p < 0.001). Similar results on proliferation and mTOR activation in alpha cells were observed after 4 weeks of GCGR mAb treatment. Together these data suggest a critical role for glutamine metabolism via glutaminase in alpha cell proliferation.

Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF16 | PSUN170 Prevalence of Fournier's Gangrene in T2DM Treated with Oral Antiglycemic Medications
Authors: Engel Ashley , Carroll Ty
Published: November 2022

Introduction

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have become common pharmacotherapies in the treatment of type 2 diabetes mellitus. These agents are well described to increase the risk of genitourinary infections. Fournier's gangrene (FG), is a rare, life-threatening, necrotizing genitourinary infection with risk factors including diabetes, obesity, alcohol abuse, poor hygiene, immune suppression, malignancy, and HIV.1 An increased risk of FG has also been associated with the use of SGLT-2i; however, the exact risk of FG in association with SGLT-2i use is unknown.

Hypothesis

We hypothesized that SGLT-2i therapy did NOT increase the risk of FG when compared to other treatments for type 2 diabetes.

Methodology

We used the TriNetX database tool to search clinical data available within the Froedtert and the Medical College of Wisconsin system. The database was searched to identify patients with a diagnosis of type 2 diabetes and FG. From this data, we identified the number of patients with type 2 diabetes mellitus who developed FG based upon treatment with and without SGLT-2i exposure within 12 months. Patient characteristics including BMI, renal function, glycemic control, age, sex, tobacco use, and alcohol use were compared in both treatment arms.

Results

Data from 1.54 million patients showed that 143,330 (∼9.3%) carry a diagnosis of type 2 diabetes mellitus. Of these patients, 49,950 were treated with a SGLT-2i as part of their therapy while 44,510 patients were treated with oral antiglycemic agents without SGLT-2i exposure. Two hundred sixty of the 143,330 patients with diabetes (0.181%) developed FG. During a period of 12 months, 140 of 49,950 (0.280%) patients treated with a SGLT-2i developed FG. Whereas 120 of 44,510 (0.269%) without SGLT-2i therapy within a 12 month period developed FG. Patients’ characteristics (including sex, age, BMI, renal function, glycemic control, history of tobacco use, and alcohol use) were similar between the SGLT-2i therapy group and the group without SGLT-2i exposure.

Conclusion

We conclude patients treated with oral therapies for type 2 diabetes developed FG with similar frequencies regardless of exposure to SGLT-2i therapy. Patients with FG had similar characteristics and known risk factors regardless of SGLT-2i therapy utilization. Further study is required to determine if the previously noted association of FG and SGLT-2i treatment is due to the increased number of risk factors in the population receiving SGLT-2i therapy rather than the SGLT-2i themselves. References: 1. Bersoff-Matcha SJ, et al. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Annals of Internal Medicine. 2019;170(11): 764-769.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.
ODP439 Characteristics of Long COVID Symptoms and Utility of Serum Antibody Measurement for the Evaluation of Long COVID.
Authors: Sakurada Yasue , Sunada Naruhiko , Honda Hiroyuki , Tokumasu Kazuki , Otsuka Yuki , Hanayama Yoshihisa , Nakano Yasuhiro , Hasegawa Kou , Obika Mikako , Hagiya Hideharu , Otsuka Fumio
Published: November 2022

The pandemic of the new coronavirus infection (COVID-19) has yet not only to be converged, but also new infections continue to occur. At least about one-third of the affected patients suffer from various symptoms even after the acute phase. However, effective treatments for sequelae have not yet been established, and the prognosis and risk factors are still unclear. It is possible that endocrine disruption is involved in the occurrence of long COVID. Okayama University Hospital set up a COVID-19 aftercare (CAC) outpatient clinic on Feb. 15 in 2021 to treat patients suffering from sequelae even one month after COVID-19 infection. In the present study, to extract the key factors that affect the onset and course of sequelae, a retrospective analysis was performed by focusing on changes in the number of symptoms and patient background during the three months from the first outpatient visit. Also, we focused on how various sequelae progress in patients who received continuous medical care for 3 months, in which the relationship between the sequelae and the serum COVID-19 antibody titer measured at the first visit was evaluated. In this study, the data from 65 patients who visited our clinic.

Presentation: No date and time listed
ODP622 A Case of a Rare Steroid Cell Tumor in a Patient with PCOS
Authors: Elsheikh Sahar , Eduafo Augusta
Published: November 2022

Background

Ovarian sex cord-stromal tumors are rare and represent approximately 7% of all primary ovarian tumors. Steroid cell tumors of the ovary are uncommon sex-hormone secreting tumors and are classified as pure stromal tumors. These tumors are known to secrete hormones like androstenedione, alpha-hydroxyprogesterone, and testosterone. Polycystic Ovarian Syndrome (PCOS), a disorder affecting 6% to 10%, is characterized by hyperandrogenism and ovulatory dysfunction. We report a case of a patient with known PCOS who was found to have steroid secreting tumor.

Clinical Case

A 35 years old female presented to our office complaining of worsening hirsutism, amenorrhea and weight gain. Her past medical history was significant for PCOS, hypothyroidism, and obesity. Physical Examination was notable for hirsutism, obesity and clitoromegaly. Initial labs showed elevated testosterone level of 134 ng/dL (normal levels 0-70 ng/dL). Other labs ruled out congenital adrenal hyperplasia (CAH). Pelvic US was consistent with known PCOS but did not revealed additional findings. Endometrial biopsy was unremarkable. Subsequent labs showed continuous significant elevation in testosterone to 382 ng/dL with free testosterone level of 24 ng/dL. CT abdomen and pelvis with and without contrast showed a right solid adnexal mass. Patient underwent staging laparotomy with bilateral salpingo-oophorectomy. Pathology result was significant for well differentiated sex cord-stromal tumor, steroid secreting type. Genetic testing came positive for BRCA 1.

Conclusion

This case illustrates that in the setting of rapid onset of hirsutism and elevated testosterone, an androgen secreting ovarian tumor should be considered and ruled out, even in the setting of known PCOS.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON212 None-surgical sterilization of female dogs
Authors: Ko CheMyong J , Lin Po-Ching , Zhou Sherry , Hess Rex , Park Chanjin
Published: November 2022

Female pet dogs are sterilized by surgically removing their ovaries as a means to eliminate the source of germ cells and sex steroids. Surgical sterilization is inevitably invasive to the animals and costly to their owners, and an alternative method that is non-invasive and affordable has been long sought without success. In this study, a proof-of-concept of sterilizing female dogs by a non-surgical alternative was developed and successfully tested.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF22 | PMON03 Sex-specific Effects of Bisphenol-A and its Analogs on Monoamine Levels in the Paraventricular Nucleus
Authors: Mansi Maryam A , Chuang Yen-Jun , MohanKumar Puliyur , MohanKumar Sheba
Published: November 2022

Bisphenol A (BPA) is known to produce adverse effects on fertility, cardiovascular, and metabolic health. The constraints placed on BPA production led companies to switch to BPA's structural analogs, Bisphenol S (BPS) and Bisphenol F (BPF). These chemicals are used in various equipment, food and drink cans, and paper, permitting widespread exposure. We recently found that prenatal exposure to low levels of these chemicals can increase blood pressure in the offspring. However, the underlying neurobiological mechanism is unclear. We hypothesized that these chemicals could alter the levels of monoamines, specifically in brain regions that regulate cardiovascular function such as the paraventricular nucleus (PVN) of the hypothalamus. Pregnant Sprague Dawley rats were exposed to saline, 5 µg/kg BW of BPA or BPS, or 1 µg/kg BW of BPF from gestation day 6 to 21. Their adult Male and Female offspring were implanted with a radiotelemetry device to measure blood pressure and heart rate levels. Following telemetry, animals were sacrificed, and the brains were collected, frozen and sectioned. The PVN was microdissected, and analyzed for monoamine levels using HPLC-EC. Males exposed to BPA had significant increases in the levels of serotonin (5HT) in the PVN compared to the control group, while a marked increase in 5HT levels were only observed in females exposed to BPF and not BPA (p = 0.0002). No significant changes were observed in Dopamine (DA) or norepinephrine (NE) levels. There were significant sex differences (p<0.0001) and treatment effects (p=0.0003) in the DOPAC/DA turnover ratio with males exposed to BPA, BPS, and BPF having markedly less turnover rates compared to control. No changes in DOPAC/DA turnover was apparent in females. There were significant sex (p<0.0001) and treatment effects (p<0.0001) in the 5HIAA/5HT turnover ratio, with males in the BPA and BPS groups having significantly less turnover compared to controls. In contrast, Females exposed to BPS and BPF had significantly lower 5HIAA/5HT turnover ratios but higher turnover ratios in the groups exposed to BPA. These results indicate that 5-HT production increases markedly in males exposed to BPA and in females exposed to BPF. This is associated with reduced metabolism of 5-HT. This suggests that the significant increases in 5-HT activity in the PVN could possibly contribute to the development of hypertension in these animals.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF22 | PMON06 The Contraceptive Synthetic-Progesterone Levonorgestrel (LNG) Significantly Accelerates Fetal Hypothalamic Neuronal Development (Neuroendogenesis) in the Zebrafish (Danio rerio).
Authors: Hinojosa Gabriella , Ruiz Mia , Garcia Kassandra , Dearth Robert
Published: November 2022

The fetal brain has a known vulnerability to exogenous influences due to its plasticity and high volume of replicating and differentiating cells. It is particularly susceptible to a group of environmental molecules classified as endocrine disrupting chemicals (EDCs). Previous vertebrate studies have provided supportive evidence that steroid mimicking EDCs might stimulate hypothalamic progenitor cell differentiation to neurons (neuroendogenesis). Changing the normal timing of neuroendogenesis could play a role in establishing an alternative developmental timeline leading to disruptions in key endocrine regulated process, like pubertal onset. Levonorgestrel (LNG), a synthetic progestin used in contraceptive pills, has been found at physiologically relevant levels in water sources worldwide. Therefore, we investigated the effect LNG had on neuroendogenesis in zebrafish (Danio rerio), an established comparative neurobiological animal model. Fertilized zebrafish embryos were collected (in-house breeding) and individually placed in 96-well plates. Starting at 3 hours post fertilization (hpf), embryos were exposed to either 5 ng of LNG (previously established physiologically relevant dose), 100ng of estradiol (E2, positive control) or a vehicle control for 5 days (5 dpf); covering the duration of neurogenesis. LNG had no effect on fertilization ratios, hatching or morphology compared to controls. On 5 dpf, larvae were paraffin-processed, slides were serially sectioned at (3-4 um) and prepped for immunohistochemistry (IHC). Brain tissue s were stained with hematoxylin and eosin (H&E) to identify regions of the brain including the hypothalamus and thalamus. Brain sections were also stained for the immunofluorescent (IF) neuronal marker α-HUC and/or estrogen receptor (ER) and imaged on a confocal microscope. The number of total cells, positive stained cells and negative stained cells were counted in the preoptic area (POA), rostral hypothalamus (RH) and thalamus, comparisons were made between groups. Interestingly, LNG significantly (p<0.001) increased the number of positive cells expressing α-HUC in the hypothalamus compared to controls. Similar results were observed in the POA (p< 0.01) and RH (p <0.001) compared to their respective controls. Furthermore, we observed no significant changes in α-HUC expression in the thalamus due to LNG treatment comparted to controls. Our data suggests that LNG selectively targets hypothalamic neuronal development, accelerating neuroendogenesis increasing the number of endocrine-regulating neurons in the brain. This is the first study to show that exposure to low environmentally relevant levels of LNG increases neurons in the hypothalamus, thus, highlighting the possibility that LNG may target the brain to potentiate subsequent health issues later in life.

Presentation: No date and time listed
PMON30 Low-dose Infigratinib, an Oral Selective Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitor, Demonstrates Activity in a Preclinical Model of Hypochondroplasia
Authors: Dambkowski Carl , Demuynck Benoit , Legeai-Mallet Laurence , Loisay Léa
Published: November 2022

Background

Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations play a crucial role in achondroplasia (ACH), thanatophoric dysplasia (TD), and hypochondroplasia (HCH). HCH is a less severe form of dwarfism than ACH, but similarly is caused by gain-of-function mutations in the FGFR3 gene. HCH is characterized by a disproportionate short stature and a growth deficit affecting both endochondral and intramembranous ossification. While multiple therapeutic strategies are being tested for ACH, currently there are no approved therapeutic options for individuals with HCH. We tested the hypothesis that the oral, selective FGFR tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) could improve the HCH phenotype and improve endochondral and intramembranous ossification in a preclinical mouse model of HCH Fgfr3N534K/+.

Methods

The first Hch mouse model studied expresses the most frequent human mutation p.Asn540Lys (Fgfr3Asn534Lys/+), and exhibits a mild dwarfism and most of the hallmarks of the human pathology. Fgfr3N534K/+ mice received subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4–19) or 21 days (PND 3–24), respectively.

Results

Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib every 3 days did not show obvious and significant modification of the dwarf phenotype. In contrast, Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeletal measures. Length of the long bones was statistically significantly increased in Fgfr3N534K/+ mice compared with Fgfr3+/+ mice (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment also modified the skull shape (skull width, skull height, nasal bone length and naso-occipital length), the length of the mandible and skull base, as demonstrated by measurement of the foramen magnum (foramen magnum length +3.72%). Infigratinib treatment modified the cartilage growth plate organization, in particular the hypertrophic chondrocyte area. Finally, the high activation of the MAP kinase pathway due to the HCH missense FGFR3 mutation was reduced by treatment, as revealed by the immunolabelling of phosphorylated Erk1/2 proteins.

Conclusions

Treatment with daily 1 mg/kg infigratinib improved the length and weight of Fgfr3N534K/+ mice and significantly modified the skull and the axial and appendicular skeleton. We demonstrated in Fgfr3N534K/+ mice that infigratinib is able to counteract the constitutive activation of FGFR3 due to the heterozygous N540K mutation localized in the tyrosine kinase 1 domain of the protein. These results provide a rationale for targeting FGFR3 with a specific TKI for the treatment of children with HCH.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF17 | P715 Contribution of Low Muscle Mass and Genetic Factors in NAFLD and Liver Cirrhosis
Authors: Choe Hun Jee , Koo Bo Kyung , Kwak Soo-Heon , Lee DongHo , Lee Hyunsuk
Published: November 2022

Introduction

Both sarcopenia and genetic risk factors are important risk factors for non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the independent effects of low muscle mass and genetic risk factors in the development of NAFLD and liver cirrhosis (LC) in the Korean population.

Method: A prospective community-based cohort consisted of adults with age 40–70 years were followed-up biennially from 2001–2002 to 2017–2018. NAFLD was defined as hepatic steatosis index of ≥36, and liver cirrhosis (LC) was defined as a fibrosis-4 index score of ≥1.3. The subjects were divided into four groups according to body mass index (BMI)-adjusted muscle mass. Cox proportional hazards models incorporating age, sex, BMI≥ 25 kg/m2, metabolic syndrome, and PNPLA3, and TM6SF2 risk alleles were used to assess the independent determinants for the incident NAFLD and development of LC among individuals with NAFLD at baseline.

Results

Among the 4,038 participants without NAFLD at baseline, 920 (22.8%) developed NAFLD during the follow-up. Both the TM6SF2 risk alleles (hazard ratio [HR]. 1.19, [95% confidence interval (CI), 1.00–1.40], P=0.044) and muscle mass index quartiles (Q) (HR per 1 Q, 1.18, 95% CI, 1.11–1.27, P<0.001) were associated with development of NAFLD in the fully adjusted model.

Of the 1,442 patients with NAFLD at baseline, LC was eventually confirmed in 552 (38.3%) patients. Only the PNPLA3 risk variant, but not the TM6SF2 genotype nor muscle mass index, was an independent risk factor for developing LC among NAFLD subjects (HR 1.22, 95% CI 1.08–1.38, P=0.001)

Conclusion

Both the lower muscle mass index and genetic risk variants are important contributors in the development of NAFLD. In patients already diagnosed with NALFD however, PNPLA3 conferred a greater risk for the progression to LC than lower muscle mass.

Presentation: No date and time listed
LBMON135 Diffuse Large B-cell Lymphoma Affecting The Pituitary Gland: A Case Report
Authors: Masumy Misha , Aschemeyer Jayme
Published: November 2022

Introduction

Diffuse large B-cell lymphoma is a common manifestation of non-Hodgkin lymphoma, representing approximately 25% of non-Hodgkin lymphoma cases. Patients typically present with an enlarging lymph node that is painless and associated with constitutional symptoms. For the pituitary to be involved is extremely uncommon with approximately 10 previously reported cases. We present a 51-year-old Caucasian female who initially presented with nausea, vomiting, polyuria, and polydipsia and was found to have a pituitary mass diagnosed as diffuse large B-cell lymphoma upon surgical resection.

Case Presentation

A 51-year-old female presented with nausea, vomiting, polydipsia, and polyuria. She had no history of lithium use. She was found to have an initial serum osmolarity of 324 mOsm/kg (280-300mOsm/kg), urine sodium of <20mmol/L, and urine osmolality of 191 mOsm/kg (390-1,090 mOsm/kg). She was initially diagnosed with primary polydipsia, however, her symptoms did not improve with appropriate treatment. An MRI was performed demonstrating a 13mm lobulated, homogeneously enhancing hypothalamic mass with adjacent thickening of the pituitary stalk and pituitary. Subsequent lab work demonstrated deficiencies in ACTH, TSH, cortisol, FSH, LH, and GH. She was initiated on DDAVP, levothyroxine, and hydrocortisone. A repeat MRI several months later revealed that the pituitary mass had enlarged to 2.4cm×2.3cm×1.5cm. She underwent surgical removal of the mass via right frontal craniotomy, and histopathology demonstrated diffuse large B-cell lymphoma. She underwent chemotherapy with high dose methotrexate and cytarabine for 3 cycles. Subsequent MRIs demonstrated stable intracranial findings. Her pituitary function did not recover, and she remains on hormonal replacement with levothyroxine, hydrocortisone, and desmopressin. The patient continues to follow with endocrinology and oncology in the outpatient setting.

Conclusion

This is a rare instance of diffuse large B-cell lymphoma affecting the pituitary gland. In a patient presenting with symptoms of diabetes insipidus, it is prudent to evaluate for other signs of pituitary involvement. This patient was found to have a pituitary mass on MRI that did not have an appropriate response to medical therapy. Thus, surgical management was performed, and histopathology elucidated the etiology of her symptoms. Reference: Kenchaiah, M., Hyer, S. L. Diffuse large B-cell non Hodgkin's lymphoma in a 65-year-old woman presenting with hypopituitarism and recovering after chemotherapy: a case report. J Med Case Reports 5, 498 (2011). https://doi.org/10.1186/1752-1947-5-498

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON138 Leg Tumeo: Is It Neuroendocrine Tumor?
Authors: Priyadarshini Shista , Lamichhane Bikal , Manas F N U
Published: November 2022

Introduction

Neuroendocrine tumors (NETs) are heterogenous group of epithelial neoplasms often known to produce and secrete peptides and bioamines. The presentation varies from symptomatic functional to non-functional tumors. The functional tumors cause symptoms based on the substance secreted: corticotropin, gastrin, glucagon, insulin, norepinephrine, serotonin, somatostatin, etc. The prognosis ranges from well-differentiated tumors being indolent while the poorly differentiated forms are aggressive. We present a case with an atypical presentation of NET which was noted to secrete an atypical hormone, cortisol.

Case Presentation

A 55-year-old Caucasian man presented with bilateral lower extremity grade 3 pitting edema for past 2 weeks. His past medical history was significant for hypertension. Lower extremity doppler showed no evidence of deep vein thrombosis. Serum potassium was critically low at 1.9mmol/L. Computed tomography of abdomen and pelvis showed a large mass involving the right hepatic lobe, upper pole of right kidney and hypoattenuated lesions in left hepatic lobe. The intrahepatic inferior vena cava appeared to be severely compressed by the mass. MRI abdomen was suggestive of hepatocellular cancer but alfaprotein levels was normal. Biochemical testing for evaluation of hormonal hypersecretion showed elevated cortisol levels (57.2mcg/dl) and markedly elevated dehydroepiandrosterone sulfate (2641mcg/dl). Serum adrenocorticotrophic hormone and aldosterone levels were within normal limits. Low dose dexamethasone suppression test showed no decline in serum cortisol level reflecting adrenal origin. Urinary evaluation showed elevated cortisol but normal metanephrine and catecholamine levels. With concerns for adrenal carcinoma, right adrenal mass biopsy was performed. The biopsy showed poorly differentiated malignant neoplasm with neuroendocrine features. Tumor cells were positive for synaptophysin (a marker for neuroendocrine differentiation) and CD 138. Soon after, he progressed to multisystem organ failure, tumor lysis syndrome and resorted to comfort care. The patient passed away within a week of diagnosis.

Conclusion

NETs usually originate in gastrointestinal tract, pancreas, adrenal, lung and rarely genitourinary tract. The incidence of NETs is on the rise with increased detection by imaging. Adrenal NETs, well-known as pheochromocytoma are mostly benign but small cell adrenal neuroendocrine carcinomas are rare and have a grave prognosis. Flushing, diarrhea are the commonest presentations (75-85%) for gastrointestinal NETs and symptoms are based on the substance secreted. This case highlights a case of adrenal neuroendocrine cancer presenting with lower extremity swelling and secreting an uncommon hormone, cortisol. Increasing awareness among the medical fraternity will help with early diagnosis and better outcomes.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.