bluuebunny/crossref_metadata_2025 huggingface dataset:
RF23 | PSAT240 Suboptimal Thyroid Hormone Replacement is Associated with Worse Hospital Outcomes
Authors: Bianco Antonio C , Ettleson Matthew , Laiteerapong Neda , Wan Wen
Published: November 2022

Introduction

Many patients in the US with hypothyroidism receive suboptimal treatment with thyroid hormone. Sustained off-target TSH levels have been shown to cause serious harm to patients, including increased risk of cardiovascular disease and excess mortality over time. Suboptimal treatment may also impact hospital outcomes. The primary objective of the study was to identify differences in hospital outcomes between patients with and without hypothyroidism.

Methods

This is a retrospective cohort study that utilized the propensity score-based fine stratification method to balance covariates. Patient data was extracted from a large, US-based, IBM MarketScan® Commercial Claims and Encounters Database from January 1, 2008 to December 31, 2015. Participants included patients 64 years and younger who had commercial insurance and a thyrotropin (TSH) level collected prior to a medical or surgical hospital admission. Covariates included age, sex, US region, type of admission (medical vs surgical), year of admission, and co-morbidities. The primary exposure was defined as clinical hypothyroidism, which was divided into 4 subgroups based on pre-hospitalization TSH level: low (TSH <0.40 mIU/L), normal (TSH 0.40–4.50 mIU/L), intermediate (TSH 4.51–10.00 mIU/L), and high (TSH >10.00 mIU/L). Non-hypothyroidism was the non-exposure (control). The primary outcomes were length of stay (LOS), in-hospital mortality, and readmission outcomes following medical and surgical admission.

Results

A total of 46,235 patients were included in the final study population, of whom 9,394 had a diagnosis of hypothyroidism. Those with a high pre-hospitalization TSH level had a LOS that was 1.2 days longer (95% CI [1.1–1.3]; p = 0.001), a 41% higher risk of 30-day readmission (RR 1.41, 95% CI [1.13–1.75]; p = 0.002), and 33% higher rate of 90-day readmission (RR 1.33, 95% CI [1.13–1.56]; p <0.001) compared to balanced controls. Patients with intermediate TSH levels exhibited increased likelihood of 30-day readmission (RR 1.20, 95% CI [1.01–1.43]; p = 0.04). Conversely, those with a normal pre-hospitalization TSH level had a decreased risk of in-hospital mortality (RR 0.55, 95% CI [0.34–0.89]; p = 0.02) and 90-day readmission (RR 0.91, 95% CI [0.85–0.99]; p = 0.02).

Conclusions

Suboptimal treatment of hypothyroidism appears to be associated with worse hospital outcomes, including longer LOS and higher rate of readmission. Public health strategies designed to deliver appropriate, consistent outpatient treatment of hypothyroidism are needed to improve hospital outcomes in those patients with off-target TSH levels.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m.
RF23 | PSAT259 Comparable Bioavailability of a Novel Levothyroxine Solution when Administered with Coffee
Authors: Washington Kris , Baron Michelle , Vandse Sunil
Published: November 2022

Levothyroxine (LT4) is the treatment of choice for hypothyroidism and the second most prescribed medication in the United States. Despite its established efficacy and widespread availability, approximately 40% of patients treated with LT4 fail to achieve thyroid stimulating hormone (TSH) levels within the normal range. Current LT4 product guidelines recommend administration in the fasting state 30-60 minutes before breakfast to avoid a food interaction leading to reduced intestinal absorption of LT4. This recommendation may impact compliance, as over 50% of adult Americans drink coffee every day, 65% of which is consumed during breakfast.While the majority of patients receive LT4 tablets, there is evidence that liquid formulations that bypass the gastric dissolution phase may mitigate the interference with coffee. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility in a variety of clinical scenarios. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered with coffee compared to administration under fasting conditions in an open label, randomized, two-period, two-treatment, two-sequence, crossover, single dose bioavailability study in 40 healthy adults. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered 5 minutes before drinking 8 ounces of American coffee (without milk or sweeteners) or under fasting conditions in each study period. Blood samples were collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals (CI) were calculated from the exponential of the difference between the LT4 solution administration 5 minutes prior to coffee and administration under fasting condition for AUC0-48 and Cmax. An absence of a food effect would be concluded if the baseline corrected 90% CIs of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy adults participated in the trial. There were no serious adverse events (AE) or discontinuations due to AEs. The geometric LS mean ratio of AUC0-48 and Cmax for baseline-adjusted LT4 were 93.98% (90.06-98.07%) and 95.99% (92.64- 99.45%) respectively. The corresponding 90% CIs were included within the acceptance range for bioequivalence.This study demonstrated comparable bioavailability of a single oral 600 μg dose of Thyquidity oral solution administered, 5 minutes prior to coffee or under fasting conditions. These results are consistent with earlier evidence that liquid LT4 overcomes the interference from coffee seen with LT4 tablets and may offer additional flexibility for patients.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.
LBODP070 A Rare Neuroendocrine Tumor-Insulinoma
Authors: Sekhon Navharsh , Medina Dionardo
Published: November 2022

Introduction

Insulinoma is a rare neuroendocrine tumor, which presents sporadically or as a complex of multiple endocrine neoplasia type 1 syndrome (MEN-1). Most Insulinoma cases present with fasting hypoglycemia and some with both fasting and postprandial hypoglycemia.

Case Report

A 48-year-old male with no significant past medical or surgical history presented for an evaluation of hypoglycemia. He was recently seen in the Emergency Room after having a transient ischemic attack-like episode. The patient reported that he was at a family gathering where he was found confused and his blood glucose was checked by a family member with diabetes, which was noted to be 39 mg/ dl. He reported having other such episodes of lesser severity, occurring once or twice a month for many years. His symptoms would typically wake him from sleep, especially during early mornings with diaphoresis. He would take a snack to resolve his symptoms. Except for being overweight, no other abnormal findings were detected on physical examination. Fasting blood work revealed glucose of 42 with elevated insulin, C-peptide, proinsulin levels, and negative beta-hydroxybutyrate and insulin antibodies. An MRI abdomen with contrast demonstrated a 1.2 cm pancreatic lesion in the uncinate process, suspicious for a neuroendocrine tumor. Endoscopic Ultrasound staged the mass in the uncinate process of the pancreas as T1 N0 M0. FNAC showed a few atypical monomorphic cells suggestive of neuroendocrine origin. Immunohistochemical stains on the sample were positive for CD45 while CAM5.2, synaptophysin, and Ki65 were negative. The patient ultimately underwent exploratory laparotomy and resection of the neuroendocrine tumor with partial pancreatectomy.

Discussion

The symptoms of hypoglycemia are classified into sympathoadrenal (palpitation, diaphoresis, tremulousness) or neuroglycopenic (confusion, blurry vision, change in behavior, seizures, and amnesia of hypoglycemic episode). The neuroglycopenic symptoms of hypoglycemia mimic transient ischemic attack (TIA). The diagnosis of insulinoma needs biochemical proof of endogenous hyperinsulinemia and localization of the tumor. Surgery is the treatment of choice in resectable tumors.

Conclusion

This case highlights insulinoma as a rare cause of hypoglycemia and shows the importance of detailed history taking and appropriate investigations in its diagnosis. References: 1. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M, Hanazaki K. Diagnosis and management of insulinoma. World J Gastroenterol. 2013 Feb 14;19(6): 829-37. doi: 10.3748/wjg. v19. i6.829.2. Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. 2009 Oct;89(5): 1105-21. doi: 10.1016/j. suc.2009. 06. 009.3. huo F, Anastasopoulou C. Insulinoma. [Updated 2021 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Presentation: No date and time listed
ODP553 Hypoglycemia after sleeve gastrectomy: a rare case of an insulinoma
Authors: Ferreira-Hermosillo Aldo , Lobaton-Ginsberg Miry , del Pilar Sotelo-Gonzãlez María , Ramírez-Rentería Claudia , Juãrez-Aguilar Fany Gabriela
Published: November 2022

Background

The obesity pandemic has become a great topic of interest due its implications for quality of life, comorbidities, increasing mortality and the economic impact on health services worldwide(1). Laparoscopic sleeve gastrectomy (LSG) has been proposed as an effective and durable treatment for severe obesity and glucose metabolism disorders, achieving weight loss due to its restrictive and humoral effects (2). Its prevalence has increased from 5 to 37% since 2008 (3). One common complication after bariatric surgery (BS) is the postprandial hyperinsulinemic hypoglycemic state (4). While rare, insulinomas can cause it, where symptoms are more common during the fasting state; thus, evaluation of insulin secretion is needed to exclude dumping syndrome or nesidioblastosis. Until now, this is the first report of insulinoma after LSG.

Clinical Case

We here present 43-year-old women who was referred to the Obesity Clinic two years after LSG was performed. She had symptoms of hypoglycemia predominantly in the fasting state with a documented glycemic level of less than 30 mg/dl, compatible with Whipple's Triad. Initially, we suspected dumping syndrome but after documentation of a second low fasting plasma glucose, we decided to perform a 72-hour fasting test, which tested positive. Computed tomography and endoscopic ultrasound were performed, identifying the presence of a homogeneous hypoechoic semioval tumoral lesion in the pancreas. The diagnosis was compatible with insulinoma. A laparoscopic enucleation of insulinoma was performed, and after that, the hypoglycemic symptoms and blood sugar levels improved, remaining asymptomatic until now. The histopathological report described a well-differentiated grade 2 neuroendocrine tumor with positive chromogranin and synaptophysin and Ki67 immunopositivity in 4% of the neoplastic cells.

Conclusion

This is the first case of insulinoma after sleeve gastrectomy, the suggested physiopathology is due to a combination of increased plasma concentrations of incretins, mainly glucagon-like peptide 1 (GLP-1), and an accelerated release of nutrients in the proximal duodenum (5). Although this is a very rare case condition, clinicians must be aware of it, especially if the patient has hypoglycemic symptoms during the fasting state. References: 1) Rev Med Inst Mex Seguro Soc. 2016;54(2): 118–23; 2) J Clin Gastroenterol. 2021;55(7): 551–76; 3) Obes Surg. 2017;27(12): 3179–86; 4) HHS Public Access. 2017;10(1): 1–14; 5) Diabetes Metab. 2011;37(4): 274–81.

Presentation: No date and time listed
ODP554 insulinoma with a delayed diagnosis of 25 years
Authors: Boharoon Hessa , Caplin Martyn , Grossman Ashly
Published: November 2022

Introduction

Most insulinomas are rare pancreatic neuroendocrine tumours that are typically sporadic, solitary, with the great majority less than 2cm in diameter at presentation 1; fewer than 5% of insulinomas are larger than 3cm, and in such cases are not infrequently malignant. The median duration of symptoms before diagnosis is variable, but is usually brief, often just 12–18months, although longer durations are occasionally reported. We report the case of a benign insulinoma whose diagnosis was delayed for 25 years, and who eventually presented with a relatively large but benign tumour >4cm in diameter.

Case presentation

The patient was a50year-old male who presented to our service with a history of hypoglycaemia episodes dating back 25 years. The first, whilst living in Pakistan, he became unwell on his wedding day and was found to have an unspecified but very low blood glucose, confirmed at his local hospital. Since that time, he reported that he had "learned to live with the symptoms" by eating frequent small carbohydrate-rich meals, although missing a meal led to typical hypoglycaemic symptoms. He continued this regimen on moving to the UK, but over a recent period of three months he reported a substantial deterioration in his symptoms(confusion, disorientation, slurred speech, generalised weakness, tachycardia and palpitations), and indeed collapsed on two occasions. He had a fasting glucose of 2.9 mmol/L with grossly elevated and inappropriate insulin and C-peptide level, with a normal cortisol response to Cosyntropin. MRI demonstrated asingle4.1cm lesion in the body of the pancreas, however 68 Gallium-DOTATATE-PET scanning showed no uptake at any site. Accordingly, he was started on diazoxide 50mg tds and referred to the surgical team for distal pancreatectomy: histopathology revealed a 4.4 cm well-differentiated pancreatic neuroendocrine neoplasm of intermediate grade (NET G2, 2017 WHO Pancreatic-NET classification) which immunostained positive for insulin. Post-operatively, his hypoglycaemic episodes have ceased and he remains under active surveillance.

Conclusion

The great majority of insulinomas are small benign tumours, with a short history, with large tumours often indicating malignancy. Our case demonstrates that untreated and without specific therapy, such tumours may continue to grow and attain a large size without this indicating malignant potential. 68 Gallium-DOTATATE-PET is negative in more than 50% of benign insulinomas. We believe that this represents the longest survival, 25 years, of a patient with a benign insulinoma in the absence of treatment.

Presentation: No date and time listed
ODP561 Unilateral Vestibular Schwannoma as the Presentation and Aggravation to be Severe Primary Hyperparathyroidism
Authors: Kiatpanabhikul Phatharaporn
Published: November 2022

Background

A rare benign and slow-growing tumor as vestibular schwannoma (acoustic neuroma) usually presents with asymptomatic/unilateral hearing loss or tinnitus and loss of balance between the ages of 49 to 60 years. 90% of vestibular schwannoma are unilateral and not specifically grown in patients with neurofibromatosis type2 (NF2) (1). The association of schwannoma and parathyroid adenoma has been published not much but consistently until now. However, those were not mention to the relationship between pre- and post-treatment of schwannoma with parathyroid hormone level. Clinical case: A 65-year-old woman, previously healthy, presented with progressive fatigue and loss of balance for 1 month. She developed hearing loss, dysarthria and facial palsy within 1 week. At her first visited, she looked drowsiness and had slow verbal and motor response with right facial palsy, lower motor neuron type. She lost only her right facial sensation by pinprick and hyperreflexia without significant other neurological deficits and abnormal skin lesions. She denied family history of NF2. Severe hypercalcemia (17.66 mg/dL) with markedly elevated parathyroid hormone (PTH 1,115.1 pg/mL; 15-68.3) levels and mild elevation of serum creatine (Cr 1.32 mg/dL) was revealed. MRI brain showed an extra-axial enhancing mass at right CPA-IAC region size 3.7×4.2×2.9 cm possible vestibular schwannoma, this mass causing pressure effect to right sided of pons, medulla, cerebellar hemisphere and fourth ventricle. After treatment with saline hydration, her serum creatinine was recovered to normal range with slightly high normal serum calcium (11.85 mg/dL) but not being well. She came back to hospital again with fatigue and polyuria for 3 days. Her serum calcium rose up to 21.3 mg/dL with very high PTH level; 1,643 pg/mL and elevation of serum creatine (Cr 1.71 mg/dL). Again, she was treated with saline hydration for 3 days before receiving zoledronate 4 mg intravenously. After that her serum calcium and creatinine returned to normal level (Ca 10.32 mg/dL, Cr 1. 08 mg/dL) with being better. She was undergone surgery for removal right vestibular tumor and proved to be schwannoma in pathology. During further investigation of hyperparathyroidism, she had normocalcemia and her PTH level dropped to about 400 pg/mL.

Conclusion

Our patient showed the contribution of vestibular schwannoma to rise up the level of PTH as same level as parathyroid carcinoma. There could be some relationships of mechanism between there two diseases that should be explored further. Reference: 1. Carlson ML, Link MJ. Vestibular Schwannomas. Review article. N Engl J Med 384;14,Apr 8, 2021.

Presentation: No date and time listed
ODP562 ZnT5 Involvement in EMT in Breast Cancer
Authors: Miki Yasuhiro , Iwabuchi Erina , Xu Junyao , Ishida Takanori , Sasano Hironobu
Published: November 2022

The zinc levels in breast cancer tissue are reportedly higher than in normal tissue. In addition, the expression levels of zinc transporters, including ZnT5 and ZnT6, in breast cancer tissue are higher than in normal breast tissue. Moreover, ZnT5 and ZnT6 contribute to the formation of heterodimers and are involved in different biological functions. In vitro studies using chicken DT40 cells showed that ZnT5 and ZnT6 heterodimers are required to activate several proteins that play important roles in tumorigenesis, infiltration, and metastasis. However, the functions of ZnT5 and ZnT6 heterodimers in breast cancer remain unknown. Therefore, in this study, we first immunolocalized ZnT5 and ZnT6 in 113 pathological specimens of breast cancer. We then analyzed the interaction between ZnT5 and ZnT6 in breast cancer tissue using proximity ligation assay (PLA). Further, we evaluated cell migration and the expression of epithelial mesenchymal transition (EMT) markers as well as vimentin and E-cadherin in ZnT5 knockdown MCF-7 cells using siRNA. Next, we utilized human phosphorylation multipathway profiling array to explore the underlying mechanism of ZnT5 knockdown-induced cell migration. Immunohistochemical analysis revealed that the number of ZnT5-positive breast cancer cells was significantly higher in patients with a low pathologic N factor, and the number of ZnT6-positive breast cancer cells was significantly higher in patients with a low histological grade. The number of ZnT5 and ZnT6 double-positive breast cancer cells was significantly higher in patients with low Ki-67 expression than those with ZnT5-positive and ZnT6-negative breast cancer cells. In addition, ZnT5 and ZnT6 heterodimers were detected using PLA in breast cancer tissues with high expression of both ZnT5 and ZnT6. Treatment with 100 µM ZnCl 2 inhibited migration of MCF-7 cells, but ZnT5 knockdown promoted cell migration. ZnT5 knockdown induced higher levels of vimentin and lower levels of E-cadherin and activated SMAD1 in the presence of 100 µM ZnCl 2 . These results indicate that the involvement of ZnT5 in the inhibition of EMT through SMAD1 inactivation. These results also indicate that the role of ZnT5 and ZnT6 heterodimers differs from that of the ZnT5 homodimer in cell proliferation. However, further studies are required to clarify the role of zinc transporters and zinc signaling in breast cancer.

Presentation: No date and time listed
ODP647 Nuclear ERα and NAMPT Crosstalk in Metastatic Breast Tumors
Authors: Mogol Ayca , Chien Christine , Zuo Qianying , Singareeka Raghavendra Akshara , Tripathy Debu , Landesman Yosef , Madak-Erdogan Zeynep
Published: November 2022

Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing a potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis, with a 5-year relative overall survival rate of just 24% for patients with metastatic disease. Previously, we described an increased reliance on NAD+ metabolism in metastatic breast cancer (MBC) cells, which are driven by clonal selection from monotherapy resistance and the metastatic organ microenvironment. In the current study, we investigated if inhibition of NAMPT to block NAD+ production would synergize with standard of care therapies for ER+ MBC. Combination therapy of the NAMPT Inhibitor, KPT9274 and the ERα agonist Fulvestrant (Fulv) synergistically reduced tumor burden in liver metastasis in vitro (combination index < 1 in cell viability assays) and in vivo in mouse xenograft models. A synergistic effect was not observed when KPT-9274 was combined with Palbociclib or Tamoxifen, nor Fulv with other metabolic inhibitors. RNA-Seq analysis showed that NAMPT inhibition restored antiestrogenic activity of Fulv. Metabolomics analysis showed that NAMPT inhibition reduced abundance of metabolites associated with glucose and lipid metabolism. Mechanistically, chromatin immunoprecipitation showed that NAMPT is recruited to ERα binding sites in MBC xenografts and PDX tumors. Targeting metabolic adaptations in endocrine-resistant metastatic breast tumors is a novel approach that could lead to new combined therapies that reduce mortality.

Presentation: No date and time listed
OR16-1 How Strong and Sustained Activation of the Estrogen Receptor-mediated Anticipatory Unfolded Protein Response Kills Breast and Ovarian Cancer Cells
Authors: Boudreau Matthew , Duraki Darjan , Hergenrother Paul , Kim Ji Eun , Livezey Mara , Nelson Erik , Park Ben H , Shapiro David , Yang Rachel , Ghosh Santanu
Published: November 2022

In orthotopic xenografts and a PDX, our anticancer drug ErSO eradicates primary and metastatic therapy-resistant estrogen receptor alpha (ERα) positive breast cancer, and induces near-complete regression of ovarian cancer. The mechanism by which ErSO induces necrosis and kills ER positive cancer cells was unknown. From genome-wide CRISPR-Cas9 screens in MCF-7 and T47D cells with negative selection against first-generation BHPI and second-generation ErSO, and follow-on experiments, we identified the Ca2+ activated, plasma membrane Na+ channel TRPM4 as the executioner protein that BHPI and ErSO use to induce necrosis. Notably, in 6 ERα+ breast and ovarian cancer cell lines, knockout of TRPM4 completely abolished the ability of ErSO to induce death of cancer cells. Moreover, TRPM4 mRNA and protein were dramatically down-regulated in breast cancer cells selected for resistance to BHPI and ErSO. Furthermore, in a mouse xenograft, while ErSO induced near complete regression of orthotopic MCF-7-ERY537S-luciferase tumors, ErSO had no effect on the TRPM4 knockout tumors, which continued their robust growth. Since necrosis, but not most other death pathways, activates immune cells, inducing immunogenic cell death, this provides a new avenue for enhancing cancer immunotherapy. Importantly, medium from ErSO-treated wild type MCF-7 cells, but not medium from TRPM4 knockout cells, robustly activates human THP-1 monocytes and greatly increases their migration. BHPI and ErSO-induced initial anticipatory unfolded protein response (a-UPR) activation results in elevated cytosolic Ca2+, opening the plasma membrane TRPM4 channel, eliciting a rapid influx of external Na+, accompanying Cl- to balance the charge, and water to maintain osmolality. This swells the cells, causing osmotic stress. Importantly, it is the osmotic stress that sustains UPR hyperactivation, leading to ATP depletion, which contributes to membrane rupture and rapid necrotic cell death and to near complete inhibition of protein synthesis that ultimately kills any surviving cancer cells . Suggesting a broad role of TRPM4 in the actions of necrosis inducing anticancer drugs, TRPM4 knockout also inhibited necrosis induced by unrelated anticancer therapies, the mitochondrial targeting oncolytic peptide, LTX-315 and the Ca2+ channel targeting agent, Englerin A. Since increasing expression TRPM4 by viral transduction results in progressively increased sensitivity of ER positive breast cancer cells to killing by ErSO, this enables identification of breast cancer patients whose elevated TRPM4 levels make them most likely to benefit from this novel therapy. The TRPM4 pathway is a new mechanism for sustained lethal activation of the UPR and for targeting ER positive breast and ovarian cancer.

Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 p.m.
OR30-4 Role of ABCA1 in Myeloid Cell Function and Breast Cancer Progression
Authors: Cho Wonhwa , Krawczynska Natalia , Nelson Erik R , Singaram Indira , Bendre Shruti
Published: November 2022

Breast cancer is the second leading cause of cancer related deaths in women in the United States, with most mortalities associated with recurrent metastasis. Interestingly, high cholesterol levels are associated with an increased risk of breast cancer recurrence and poor prognosis, while therapies that lower cholesterol concentrations are associated with a good prognosis. Previous work has identified a metabolite of cholesterol, 27-Hydroxycholesterol (27HC), as being able to promote the progression and metastasis of breast cancer. 27HC does so by acting on myeloid immune cells. Within the tumor microenvironment, macrophages are abundant cells in the myeloid lineage. When macrophages were treated with 27HC, their ability to activate T cells was impaired. Those T cells that were activated, had a decreased anti-cancer cytotoxic response. Subsequent work has identified the Liver×Receptor (LXR) as mediating the immune-suppressive effects of 27HC. However, the mechanism by which LXR activity within myeloid cells inhibits subsequent T cell activity is unknown.ABCA1 is a classic target gene of LXR and is known to facilitate cholesterol efflux from the cell. Our analysis of publicly available transcriptome indicates that ABCA1 expression within breast tumors is associated with good prognosis. These somewhat paradoxical observations suggest that ABCA1 exhibits a pro-immune and anti-cancer effect – opposite to what we would expect for LXR activation. Therefore, the goal of the current work is to determine the effect of manipulation of ABCA1 within macrophages and its consequent effect on T cells in vitro and in context to breast cancer metastasis. Our results to date indicate that knocking down ABCA1 using siRNA by targeting the 3' UTR decreased the expression of genes associated with macrophage function and interaction with T cells. Importantly, many of those effects were rescued by over- expression of ABCA1.In summary, our results indicate that although ABCA1 is a target gene of LXR, the induction of ABCA1 by LXR may be compensatory rather than driving the immunosuppressive effects of 27HC. Thus, we hypothesize that ABCA1 plays a pro-immune function and could be a potential therapeutic target to boost the immune system.

Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.
PSUN347 A Novel Mechanism-based Inhibitor of Ribonucleotide Reductase is Highly Effective in Preclinical Models of Endocrine Therapy-Resistant Breast Cancer
Authors: Dealwis Chris , Keri Ruth , Weber-Bonk Kristen , Baker Taylor
Published: November 2022

Approximately 70% of breast cancers express Estrogen Receptor (ER), and patients with ER+ disease benefit from first-line targeted anti-hormone therapies (e. g. tamoxifen). However, at least 30% of patients develop therapeutic resistance. Second-line therapy includes CDK4/6 inhibitors, yet patients nearly uniformly develop resistance to these drugs as well, highlighting the need to identify additional targets in resistant tumors. In this regard, tamoxifen-resistant breast cancer cells and tumors display increased expression of several key cell cycle and chromosomal maintenance-related genes. This includes elevated expression of genes in the Chromosomal Instability (CIN70) signature, comprising of 70 genes that promote CIN and facilitate tumor progression. RRM2 is one such gene that encodes the small subunit of Ribonucleotide Reductase (RNR). In public RNA-seq data, RRM2 was one of the most differentially expressed CIN70 genes in tamoxifen-resistant cells and tumors, and increased expression is associated with poor patient outcomes. We hypothesized that elevated RRM2 drives CIN and subsequent tamoxifen resistance, and that targeting RRM2 or RNR activity will exacerbate CIN to intolerable levels, leading to drug-resensitization and cell death. We confirmed that RRM2 expression is elevated in multiple tamoxifen-resistant ER+ breast cancer cell lines compared to their parental counterparts. Moreover, we found that tamoxifen-resistant cells also exhibit increased CIN phenotypes as indicated by nuclear defects (micro-, multi-, and dysmorphic nuclei). As a model of intrinsic resistance to endocrine therapy, we examined RRM2 expression in triple-negative breast cancer (TNBC) cells that lack ER and found that these cells also have elevated RRM2 compared to ER+ cells. These data affirm the utility of targeting RNR for treating aggressive disease. While there are five currently approved RNR inhibitors, they cause significant patient toxicities due to their chelator mechanism of action. To address this limitation, we developed a novel mechanism-based inhibitor of the catalytic activity of RNR (RRM127) that is less toxic in mouse models. We demonstrate that RRM127 induces excessive CIN in breast cancer cell lines with high RRM2 expression. Most importantly, we have found that RRM127 suppresses growth of both cell line and patient-derived TNBC xenografts in mice. Together, these results indicate that elevated RRM2 and its associated RNR activity promote CIN and that catalytic inhibition with RRM127 has strong efficacy in preclinical models of breast cancer. Current studies are focused on identifying the mechanisms by which RRM127 blocks breast cancer cell growth.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN378 A Turducken Phenomenon: A Case of Papillary Thyroid Carcinoma Arising Within Struma Ovarii Associated With a Large Mucinous Cystadenoma
Authors: Ali Israa , Khan-Atif Sara , Shah Nisarg
Published: November 2022

Introduction

Struma Ovarii (SO) is one of the types of mature teratoma accounting for up to 3% of all ovarian tumors, with predominant thyroid tissue (>50%). Most cases are reported in middle-aged women. We are presenting a case of asymptomatic papillary thyroid cancer (PTC) presented in SO that was incidentally found and treated successfully

Case presentation

A 72-year-old Hispanic female with a history of hysterectomy, tobacco smoking was found to have a suspicious lung nodule on screening with CT scan of Chest. A subsequent PET/CT Scan revealed incidental findings of left adnexal lesion of 12×12 cm with no FDG uptake and had a minimal uptake in lung nodule favoring a hamartoma. At the gynecology clinic, patient denied having vaginal bleeding, bowel dysfunction, abdominal pain or weight loss. She did report urinary incontinence. Pelvic exam demonstrated a mobile left adnexal mass without tenderness. MRI of Pelvis revealed a 15 cm multi-cystic, left ovarian mass compressing the urinary bladder without any lymphadenopathy.

Tumor markers of CEA and CA-125 were normal. The patient underwent bilateral salpingo-oophorectomy with extensive adhesolysis. Entire ovarian mass was removed intact. Surgical Pathology revealed a 1.2 cm Unifocal PTC arising in 3 cm SO associated with mucinous cystadenoma without lympho-vascular invasion and extra-ovarian extension. No malignant cells were identified in peritoneal washing. This was staged according to AJCC 8th edition as pT1aNxMna. Immunostaining of TTF-1 and TG were positive, which additionally supported above diagnosis. Mutational testing of BRAF, K-RAS and N-RAS were negative.

Post-operatively, at the Endocrine clinic, her TSH and Free T4 were normal. No nodules were detected on the thyroid ultrasound. She was deemed low risk for recurrence and no further treatment was advised except serial monitoring of Thyroglobulin levels and goal TSH < 2.5 mIU/L.

Discussion

In general, SO can be diagnosed only on a histopathological specimen and no specific radiological or biomarkers are available. Most patients are euthyroid and remain asymptomatic like our patient. Thyrotoxicosis occurs in only 5–15% of patients. SO is mostly benign. Its malignant transformation occurs in only 5% of all cases. The most widespread malignant forms of SO are papillary and follicular carcinomas.

There are no well-established guidelines for optimal management of malignant SO. After undergoing oophorectomy, the decision to perform a prophylactic thyroidectomy and administration of 131I-Radioiodine is typically reserved for presence of metastatic disease or high risk of recurrence (>4 cm tumor size, gross extra-ovarian extension, BRAF positivity or histology other than papillary type).

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN365 Insulinoma: A Case Report of a Rare Functioning Neuroendocrine Tumor
Authors: Pescador Antonio , Rosario Michael
Published: November 2022

Insulinoma is a rare functional neuroendocrine tumor that causes inappropriate release of insulin, resulting in symptoms of hypoglycemia which would resolve promptly following glucose administraton. Its incidence is 1 to 3 per 1,000,000 population per year.

Case presentation

This study reports on a 64 year old female with no known co-morbidities who was seen in the endocrinology clinic due to episodes of blurring of vision, lightheadedness and shakiness. Glucose levels as low as 40mg/dL were detected with glucometer during these episodes. Symptom would improve after eating carbohydrate rich food. Symptom onset was 4 years prior to consult. Patient also reported weight gain as she would over-eat to treat her symptoms. The patient came in for evaluation and management of Hypoglycemia. Blood tests revealed high insulin (146.60 uU/mL; reference range: 5.00–10.00 uU/mL) and C-peptide level (7.45 ng/mL; reference range: 0.78–5.19 ng/mL) despite low plasma glucose level (36 mg/dL). Dynamic CT scan of the pancreas revealed an arterially enhancing nodule with intralesional calcification in the distal pancreatic body for which an insulinoma is considered. She underwent distal pancreatectomy and her symptoms showed complete resolution. Surgical pathology was consistent with well differentiated Neuroendocrine tumor.

Conclusion

Clinicians should have a high index of suspicion for Insulinoma in patients with history of recurrent episodes of blurring of vision, lightheadedness and shakiness, particularly if these symptoms would resolve after food intake. Such condition entails proper and timely diagnosis, localization of the tumor and treatment and involves several specialties.

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.
RF07 | PSUN350 Estradiol Effects on Polymorphonuclear Cell Production and Actions Contribute to Estrogen-mediated Lymphangioleiomyomatosis (LAM) Progression
Authors: Minor Briaunna , LeMoine Dana , Seger Christina , Gibbons Erin , Koudouvoh Jules , Hammes Stephen
Published: November 2022

Lymphangioleiomyomatosis (LAM) is a rare lung disease seen almost exclusively in female sexed individuals and characterized by slowly growing, metastatic smooth muscle cell-like adenomas that cause cyst formation in the lung parenchyma and irreversible loss of pulmonary function. Given the female specificity of disease manifestation, metastatic nature, and estrogen sensitivity of LAM cells, we previously proposed that LAM cells originate in the myometrium. Our subsequent reports showed that inactivation of TSC2 in the mouse uterus results in notable LAM features in the setting of primary myometrial tumors. Additionally, we established that estrogen is required to maintain LAM-like tumor progression in a uterine-specific Tsc2-knockout murine model. However, the observed estrogen sensitivity in vivo is more markedly pronounced than that of our estrogen receptor-positive TSC2-null cells when stimulated with estradiol in vitro, suggesting that estradiol may act elsewhere in vivo to promote LAM progression. Recent immunophenotyping of LAM-like TSC2-null uterine tumors revealed preferential increase in polymorphonuclear cell (PMNs) numbers of the tumor microenvironment; we also determined that PMNs are important regulators of tumor growth. Therefore, we hypothesize that, in addition to direct effects of estrogen on tumor cells, estrogen might also stimulate tumor growth by promoting PMN production in the bone marrow and actions in the tumor microenvironment. Here, we show that estrogen availability influences PMN mobilization in naïve and tumor-burdened mice. Using bone marrow cultures and CFC assay, we demonstrate that estradiol is a potent inducer of PMN production in chronic inflammatory conditions. Employing both pharmacologic agents and estrogen receptor (ER)-null bone marrow, we showed that ERα is necessary for promoting induction of PMN fate for myeloid progenitors. While we see that the migratory, invasive, and proliferative capacities of TSC2-null cell lines are not augmented when stimulated with E2 directly, experiments are underway to assess the extent to which estrogen promotes the pro-tumorigenic function of PMNs co-cultured with TSC2-null cell lines. Together these data provide insight into the robust effect of in vivo estrogen stimulation as estradiol may be a dual effector in LAM tumor progression and great target for anti-LAM therapeutic strategy.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSAT018 Management of Pheochromocytoma in the Setting of a Patient with Multiple Vasculopathies
Authors: Khan Abdul , Lightell James , Majors Corey , Alls William
Published: November 2022

A 66-year-old male with history of Type 2 diabetes and adrenal incidentaloma presented to the hospital with significant left lower limb edema and was found to have severe peripheral vascular disease. CT surgery was consulted and performed an angiogram as well as an angioplasty; however, the patient had severe stenosis and stenting was not possible. Femoral popliteal bypass was planned. Due to the patient's acute kidney injury from renovacular hypertension, preoperative evaluation included a MRI abdomen w/wo contrast which showed a 1.4 cm right adrenal nodule with early contrast enhancement which appeared fairly avid and uniform. This nodule had been previously noted by CT scan three years prior. Previous outpatient labs showed elevated metanephrines of 543 pg/mL, which determined the adrenal nodule to be consistent with a pheochromocytoma. Subsequently, femoral popliteal bypass was postponed and the patient was started on an alpha blocker, doxazosin. Urology was consulted and right laproscopic adrenalectomy was planned. Preoperatively, patient developed chest pain due to ventricular tachycardia and NSTEMI was diagnosed by EKG. Patient then underwent a LHC which revealed severe left main 3 vessel coronary artery disease, postponing planned adrenalectomy. CABG was performed with pericardiectomy. After initial recovery, patient was discharged to in-patient rehabilitation, indefinitely delaying definitive pheochromocytoma therapy.

Reference

Jacques W. M. Lenders, Quan-Yang Duh, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Stefan K. G. Grebe, Mohammad Hassan Murad, Mitsuhide Naruse, Karel Pacak, William F. Young, Jr, Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 6, 1 June 2014, Pages 1915–1942, https://doi.org/10.1210/jc.2014-1498

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT019 A Rare Case of Massive Bilateral Adrenal Myelolipomas in a Patient with Congenital Adrenal Hyperplasia
Authors: Arasu Aarthi , Patel Reema
Published: November 2022

Background

Myelolipomas are rare, benign tumors of the adrenal gland that consist of adipose and hematopoietic tissue. Most present unilaterally and rarely exceed 4 cm, but bilateral and large myelolipomas have been reported. The development of these neoplasms has been associated with congenital adrenal hyperplasia (CAH) (1).

Clinical Case

A 44-year-old woman with a history of simple virilizing CAH follows in endocrine clinic. She was diagnosed with CAH at birth and underwent vaginoplasty procedures at age 8 and 16. She has been on glucocorticoid therapy with hydrocortisone or prednisone throughout her life, but has had long gaps in treatment (sometimes up to a year) and reports often skipping doses due to concerns regarding facial swelling. She has not had a menstrual cycle for many years and reports shaving her facial hair daily. Her ACTH has been as elevated as 830 pg/mL, 17-alpha-OH-P has been as elevated as 17740 ng/dL, and testosterone as elevated as 401 ng/dL. She now presents for evaluation of an umbilical hernia. She did not have any abdominal or flank discomfort. CT abdomen and pelvis with contrast was obtained and showed bilateral, massive (approximately 25 cm and 18 cm in the largest dimensions on each side) suprarenal masses thought to most likely represent adrenal myelolipomas. She was referred to endocrine surgery and is undergoing discussions regarding possible adrenalectomy. Since the discovery of these adrenal masses, she has been consistently taking prednisone 5 mg daily.

Conclusion

This case illustrates the potential role of poorly-controlled CAH in the development of massive adrenal myelolipomas. Many hypothesize chronic ACTH stimulation can cause metaplasia of adrenocortical cells and lead to the development of myelolipomas. Review of the medical literature reveals no clear consensus on the management of these rare neoplasms (2).

References

(1) Al-Bahri S, Tariq A, Lowentritt B, Nasrallah DV. Giant bilateral adrenal myelolipoma with congenital adrenal hyperplasia. Case Rep Surg. 2014;2014: 728198. doi: 10.1155/2014/728198. Epub 2014 Jul 16. PMID: 25140269; PMCID: PMC4124659. (2) German-Mena E, Zibari GB, Levine SN. Adrenal myelolipomas in patients with congenital adrenal hyperplasia: review of the literature and a case report. Endocr Pract. 2011 May-Jun;17(3): 441-7. doi: 10.4158/EP10340.RA. PMID: 21324823.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT022 A Rare Case of Androgen Secreting Adrenal Cortical Carcinoma in a Young Woman
Authors: Javvaji Abhiram , Anastasopoulou Catherine
Published: November 2022

Introduction/Background

Adrenal cortical carcinoma (ACC) is a rare disease occurring in 1 to 2 per million per year. (1) The pure androgen secreting carcinomas are even more rare and occur in only 6% of the cases of ACC. (2) These tumors have an occurrence of age which is usually bimodal either in the first or fifth decade of life. (3) Herein, we report an unusual case of malignant pure androgen secreting adrenal tumor in a woman in her second decade.

Clinical Case

A 19 year old female presented to the ED with abdominal pain and was found to have incidental adrenal tumor and therefore referred to endocrinology. She complained of hirsutism in the upper lip, chest and abdomen, weight gain and amenorrhea for 18 months?. Hormonal work-up revealed elevated DHEAS 755 mcg/dL (normal 27-240), serum testosterone level 306 ng/dL (normal 10-75), whereas cortisol and metanephrines levels were within normal limits. A diagnostic MRI showed a large left 10.5cm adrenal tumor and patient subsequently underwent laparoscopic left total adrenalectomy. Final pathological report revealed low grade adrenocortical carcinoma confined to the adrenal cortex. Oncology was consulted and the patient was started on adjuvant cytotoxic chemotherapy with cisplatin and etoposide followed by radiation, and mitotane therapy. Postoperatively at two months testosterone and DHEAS levels were normalized.

Conclusion

This case illustrates how ACC may present with atypical symptoms of hirsutism, amenorrhea, and hyperandrogenic state. Hypersecretion of both androgen and cortisol is more common occurring approximately 46% of patients with ACC but the presence of hypersecretion of isolated androgens in adrenal tumors has been associated with an increased likelihood of malignancy. (3) Physicians of different specialties should have a high degree of suspicion for adrenal involvement in the evaluation of patients with hirsutism and hyperandrogenism. Work-up should include laboratory testing along with radiographical images to help establish the diagnosis.

References

Angelousi A, Kassi E, Kaltsas GA. Adrenocortical Carcinoma. [Updated 2018 Oct 2]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278924/

Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 2006 Jul;91(7): 2650-5. doi: 10.1210/jc.2005-2730. Epub 2006 May 2. PMID: 16670169.

Cavlan D, Bharwani N, Grossman A. Androgen- and estrogen-secreting adrenal cancers. Semin Oncol. 2010 Dec;37(6): 638-48. doi: 10.1053/j.seminoncol.2010.10.016. PMID: 21167382.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
OR20-2 Bilateral Primary Aldosteronism Is Not Excluded by High Adrenal Vein Sampling Lateralization Indices
Authors: Giordano Thomas , Konzen Sonja , Rainey William , Salman Zara , Tezuka Yuta , Udager Aaron , Turcu Adina F
Published: November 2022

Background

Primary aldosteronism (PA) is broadly divided into unilateral and bilateral forms, and the most reliable subtyping tool available is adrenal vein sampling (AVS). Unilateral PA is generally diagnosed based on AVS lateralization indices (LI=[aldosterone/cortisol] ratio between the dominant and contralateral adrenal vein) ≥4, or even ≥2 when AVS is performed without cosyntopin stimulation. Long-term follow-up data from patients with PA treated with unilateral adrenalectomy have been minimal.

Objective

To assess the rates of residual and recurrent PA after AVS-guided unilateral adrenalectomy.

Methods

We enrolled patients with PA who underwent unilateral adrenalectomy between 09/2017 and 08/2021 in a single tertiary referral center and followed them longitudinally. Demographics, laboratory, imaging, and pathology data were collected. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue blocks.

Results

During the study period, 80 patients (52 men) with median age 53 (range, 19-76) years underwent unilateral adenectomy, and were followed for a median 80 days (range, 6-653 days). In total 14 (17.5%) patients had evidence of residual PA following surgery, including 3 who had complete biochemical failure, and 1 who had apparent cure of PA immediately post-operatively. All 14 patients had severe PA, with baseline plasma aldosterone concentrations between 23.4 and 496 ng/dL and suppressed renin. Baseline and post-cosyntropin stimulation LIs ranged from 2.7- 187.5 and 1.3-53.7. The LI was >4 only at baseline in 3 cases, and only after cosyntropin stimulation in 2 cases. Histology showed single adenomas, ranging from 0.7-5.3 cm in 7 (50%) patients, and multiple adenomas and/or nodular hyperplasia in 7 (50%) patients. Of the 7 cases analyzed for aldosterone-driver mutations so far, 4 harbored CACNA1D mutations, 2 ATP1A1 mutations, and 1 a KCNJ5 mutation.

Conclusions

Patients with severe PA and frank AVS aldosterone lateralization might have multifocal, bilateral disease. Long-term follow up and targeted medical therapy should be pursued after unilateral adrenalectomy for presumed unilateral PA.

Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.