bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT545 Erythropoietic Thyroid Nodule in the Setting of Myelofibrosis
Authors: Vasquez Libia M , Bruder Jan M , Koops Maureen , Trejo Jonathan
Published: October 2023

Disclosure: L.M. Vasquez: None. J.M. Bruder: None. M. Koops: None. J. Trejo: None.

Background: Extramedullary hematopoiesis is frequently seen in non-osseous locations but not endocrine organs, this is a case of hematopoesis in a thyroid nodule. Clinical Case: A 79-year-old man with myelofibrosis diagnosed at age 66, CAD post CABG, atrial fibrillation on anticoagulation and HFrEF was referred to the endocrinology clinic due to enlarging left lobe thyroid nodule. He was diagnosed with a goiter at age 72 but denied compressive symptoms. He had no history of radiation to his neck or family history of thyroid cancer. On physical exam, the left thyroid lobe was visibly enlarged with slight right tracheal deviation without lymphadenopathy. TSH level was normal. Thyroid ultrasound demonstrated a 6.4 x 4.0 x 4.8 cm, complex cystic-solid, taller than wide nodule in the left lobe and a sub-centimeter cystic nodule in the right lobe. FNA showed hematopoietic elements, including maturing cells in three lineages of hematopoiesis. On repeat ultrasound 5 years later. The left nodule increased in size to 7.3 x 5.4 x 4.4 cm and highly suspicious (TR4 and TR3) by Ti-RADS criteria. Repeat FNA of the nodule showed many red blood cells with few hematopoietic cells, flow cytometry did not show any abnormal populations. No thyroid follicular cells were reported. Myelofibrosis was diagnosed by bone marrow biopsy many years prior. He had maintained a stable CBC without palpable spleen or hepatomegaly. Given this history without thyroid dysfunction or reported symptoms, surgery was not pursued. External beam radiation was a treatment option should the nodule cause symptoms. He continued to have mild anemia not requiring blood transfusions. He passed away 2 years later in hospice care after hospitalization for severe heart failure decompensation. Conclusion: Extramedullary hematopoiesis involving the thyroid is rare but has been reported(1). This type of extramedullary hematopoiesis. can be treated with surgery or low-dose radiation because of the radiosensitivity of hematopoietic tissue (2). This was a potential treatment modality if compressive symptoms arose, but they did not. This case illustrates a situation in which surgical intervention on highly suspicious nodules would not have been the optimal treatment choice.

Reference: 1. Jan I., Weng M., Wang C., et al. Extramedullary hematopoiesis involving the thyroid: A rare cytologic finding in otherwise healthy patients and review of literature. Journal of the Formosan Medical Association. (2018) 117, 1108-1114.

2. Taher A, Vichinsky E, Musallam K et al., authors; Weatherall D, editor. Guidelines for the Management of Non-Transfusion Dependent Thalassaemia (NTDT) [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2013. Chapter 11, EXTRAMEDULLARY HEMATOPOIESIS. Available from: https://www.ncbi.nlm.nih.gov/books/NBK190455/

Presentation Date: Saturday, June 17, 2023
OR26-06 Cardiovascular Morbidity And Mortality In Patients With Resistance to THYROID Hormone (RTH): A Linked Record Study
Authors: Okosieme Onyebuchi , Usman Danyal , Taylor Peter , Dayan Colin , Lyons Greta , Moran Carla M , Chatterjee V Krishna K , Rees Aled
Published: October 2023

Disclosure: O. Okosieme: None. D. Usman: None. P. Taylor: None. C. Dayan: None. G. Lyons: None. C.M. Moran: None. V.K. Chatterjee: None. A. Rees: None.

Introduction: Individuals with Resistance to Thyroid Hormone β (RTH-β) may develop cardiac disease, including cardiomyopathy or arrhythmia. Long-term survival outcomes in this group of patients have not been systematically evaluated. Objectives: We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTH-β in endocrine clinics in Wales. Methods: In a retrospective cohort study using linked datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank, Welsh patients with genetically-proven RTH-β were identified from laboratory records (n=55), matched to population controls by age and sex (n=2750), and linked to outcomes in SAIL. We used Kaplan-Meier and Cox regression models to analyse the association of RTH-β with all-cause mortality, acute myocardial infarction, atrial fibrillation, heart failure, strokes and major adverse cardiovascular events (MACE; a composite of cardiovascular death, acute myocardial infarction, heart failure, and strokes). We also investigated any association between baseline thyroid hormone concentrations and outcomes using restricted cubic splines. Results: Compared to controls, patients had an increased risk of all-cause mortality (Hazard ratio [HR] 2.84, 95% Confidence Interval [95%CI] 1.59-5.08), MACE (HR 3.49, 95%CI 2.04-5.99), atrial fibrillation (HR 10.56, 95%CI 4.72-23.63), and heart failure (HR 6.35, 95%CI 2.26-17.86). Positive associations between FT4 concentration at diagnosis and subsequent cardiovascular morbidity or death were observed, with a 7% increased risk of death per pmol/L increase in FT4. The relationship between FT4 and outcomes was non-linear, with increased risk associated with FT4 concentration exceeding 30 pmol/L. When compared to no intervention, treatment with antithyroid drugs, radioiodine/surgical ablation or levothyroxine, alone or in combination, did not effectively control thyroid hormone excess in the long-term. Conclusion: Patients with RTH-β have increased mortality and cardiovascular outcomes that correlates with high, circulating thyroid hormone levels. Ideal future therapies would target both thyroid hormone excess and tissue resistance and could potentially reduce cardiovascular risk in this disorder.

Presentation: Saturday, June 17, 2023
SAT393 Resilience And Resistance In The Face Of Stigma And Trauma: A Qualitative Study Of Transgender People’s Reactions To Interactions With The Healthcare System
Authors: Stroumsa Daphna , Maksutova Mariam , Indig Gnendy , Ballard Jesse Y , Trammell Racquelle , Popoff Elliot E , Wu Justine P , Gamarel Kristi
Published: October 2023

Disclosure: D. Stroumsa: None. M. Maksutova: None. G. Indig: None. J.Y. Ballard: None. R. Trammell: None. E.E. Popoff: None. J.P. Wu: None. K. Gamarel: None.

IntroductionFor many transgender people, interactions with healthcare, including for initiating gender affirming hormones, can be stigmatizing and traumatic. This study sought to explore how trans people navigate interactions with the healthcare system when accessing gender-affirming hormones.

MethodsWe conducted semi-structured interviews with trans adults ages 21 to 54 (mean=31.7) who had initiated gender-affirming hormone therapy (n=21) using purposive and snowball sampling methods. Interviews were transcribed verbatim and de-identified. Interviews were analyzed using a reflective thematic analysis approach in which codes were deductive and inductive in nature. The study was designed in collaboration with a community advisory board. ResultsParticipants included 9 (42.9%) who identified as men or trans men, 9 (42.9)% who identified as women trans women, and 3 (14.3%) who identified as nonbinary; 8 (38%) identified as a person of color, and 8 (38.1%) participants resided in an urban area. Four overarching themes were identified: (1) multi-level minority stress barriers to care; (2) resilience and resistance in response to minority stress; (3) the cost of stigma and discrimination; and (4) recommendations for change. Multilevel minority stressors included internalized, anticipated, and enacted/interpersonal stigma, as well as vicarious trauma in healthcare systems when initiating gender-affirming hormones. In response to stigmatizing and traumatic experiences, participants engaged in a number of resilience and resistance strategies including selective-disclosure, self-advocacy, relying on community support, as well as innovative “workarounds” to overcome the bureaucratic and traumatic hurdles to accessing gender-affirming hormones. These strategies were however not unassailable, and the stigma and discrimination did have negative consequences. Participants described areas for change, which included provider training and addressing the political environment.

ConclusionTransgender people encounter stigma when accessing gender-affirming hormones; however, they also engage in a range of resilience strategies. Ensuring access to gender-affirming care necessitates addressing stigma in healthcare systems. Structural interventions addressing root causes of stigma and trauma transgender people experience are needed to complement provider-level interventions.

Presentation: Saturday, June 17, 2023
SAT419 Characteristics Of Trans Male Children And Adolescents Care Followed Up In A Children Hospital
Authors: Esposito Mariela , Gonzalez Veronica G , Pasqualotto Julio , Morin Analia
Published: October 2023

Disclosure: M. Esposito: None. V.G. Gonzalez: None. J. Pasqualotto: None. A. Morin: None.

Introduction Transgender and gender diverse (TGD) people are those whose gender identity do not correspond with their sex assigned at birth. Gender identity law was approved in 2012, guarantees access to health care including hormones and surgical procedures reassignment without any requirement except "informed consent by the individual concerned". Last years the number of youth with TGD seeking gender affirming care has increased, resulting in the formation of multidisciplinary care teams to respond to the growing demand. Objective To characterize the population of transgender male(TM) attended in a Pediatric Endocrinology Service. Method Medical records of the Pediatric Endocrine Service were reviewed for youth with TGD seen from December 2017 to November 2022. Results We received 92 TGD individuals in our care team, of which 64 (69.6%) consulted in Endocrinology Service, 52 trans-male (TM) (81.3%) and 12 trans-female (TF) (18.7%). We describe TM group. Median age was calculated for first medical advice: 14 (9-16) years; self-perception TGD: 9 (3-14) years; and gender affirmation: 13 (6-16) years. Obesity and overweight was present in 22 (42.3%), normoweight in 25 (48%) and underweight in 5 (9.7%). Vitamin D levels (N: 35) were insufficient in 30 children (85.7%). At first visit 45 (86%) were in Tanner stage 5. Gonadotropin releasing hormone agonists (Gnrh) were used in 27 TM (51.9 %) to prevent the progression of biological puberty, median age at start of treatment was 14 (11-15) years. Testosterone (T) was used in 18 (34.6%) to develop sex characteristics of the self-identified gender, median age of beginning was 16 (14-17) years of which 12 have previously used GnRH. In 4 adolescents (7.7%) thoracic masculinization surgery was performed at a median age of 16 years. Conclusion Most of the TGD children and adolescents were TM with a median age at first visit of 14 years and tanner stage 5. Overweight and obesity rates were higher than international norms and are a common problem among TGD youth. They should be considered a high-risk group and targeted in obesity prevention and treatment efforts. The majority of transgender youth had vitamin D insufficiency, so we recommend sun exposure and physical activity. Although they consulted in the Pediatric Endocrinology Service, only 63.5% started some hormonal therapy. Gender affirmation require multidisciplinary approach in which endocrinologists play an important role.

Presentation: Saturday, June 17, 2023
SAT644 Gender Affirming Hormone Therapy (GHAT) In Adult Male-to-female Mice Increases Cortical And Trabecular Bone, Resulting In An Increase In Bone Strength
Authors: Zajac Jeffrey D , Nie Tian , Venkatesh Varun , Golub Suzanne , Stok Kathryn , Desai Reena , Handelsman David J , Grossmann Mathis , Davey Rachel A
Published: October 2023

Disclosure: J.D. Zajac: None. T. Nie: None. V. Venkatesh: None. S. Golub: None. K. Stok: None. R. Desai: None. D.J. Handelsman: None. R.A. Davey: None.

There are conflicting reports of the effects of GAHT on bone health and fracture risk in adult transgender women, and the underlying changes are poorly understood. We aimed to determine the effects of GAHT administered during adulthood on bone microarchitecture and strength in a mouse model of male-to-female transition. To model male-to-female transition in adults, C57BL/6 male mice aged 16 weeks that had reached peak bone mass were administered an estradiol-filled silastic implant (∼1.3mg) intraperitoneally for 12 weeks. Controls included vehicle treated intact males and females, n=9-10/group. At study end, serum sex steroids were determined by LCMS/MS, femoral bone microarchitecture by μ-CT, and strength by 3-point bending. Mean serum estradiol was 4.7-fold higher in males treated with estradiol (91.8±10.4 pg/mL) than the peak estradiol levels observed during the proestrus stage of the estrus cycle in adult female mice (19.4±13.5 pg/mL, Handelsman, 2020). Estradiol treatment in males increased the endocortical deposition of bone evidenced by an increase in cortical thickness (mm)(P<0.05) and a decrease in medullary volume (mm3)(P<0.05) compared to male and female controls. Periosteal circumference was not effected by estradiol treatment in males compared to controls. Trabecular bone volume/tissue volume (%) was 4-fold higher in estradiol treated males compared to male controls and 12-fold higher than female controls due to an increase in trabecular number (μm)(P<0.0001). The increase in both cortical and trabecular bone contributed to increased bone strength, as the maximum force (N) the bone could withstand prior to fracture was 2-fold higher in males treated with estradiol compared to both male and female controls (P<0.0001). Measurement of the material properties of the femur showed an increase in ultimate stress (MPa)(P<0.001) and elastic modulus (MPa)(P<0.01) in males following estradiol treatment compared to male controls, indicative of increased rigidity. In this model of adult male-to-female transition, supraphysiological levels of estradiol in male mice increases cortical and trabecular bone mass leading to increased bone strength. The increased rigidity of the femur following estradiol treatment suggests increased bone mineral content. It may be possible therefore, to preserve bone health and prevent fractures in trans women treated with GAHT, however a dose of estradiol that protects the bone without adverse side effects needs to be identified.

Presentation: Saturday, June 17, 2023
FRI215 Rifampin Induced Adrenal Insufficiency
Authors: Campbell Spencer Ramon , Tierney Ryan M , Lim Jonea
Published: October 2023

Disclosure: S.R. Campbell: None. R.M. Tierney: None. J. Lim: None.

Introduction: Rifampin is a main component of antimycobacterial therapy in active tuberculosis disease. Although adrenal insufficiency can be caused by infiltration of the pituitary or adrenal glands by Mycobacterium tuberculosis, rifampin has also been suggested as a potential causative agent. This case shows a rare example of rifampin-induced adrenal insufficiency in the setting of active tuberculosis disease. Case Presentation: A 42-year-old man with a history of gout and anemia presented with fevers, chills, unintentional weight loss, and productive cough for two weeks. He immigrated from Guatemala 20 years prior and was treated for tuberculosis disease as a child. Upon presentation, he was borderline hypertensive with chest CT showing bilateral nodular opacities in a pattern suggestive of atypical pneumonia. Acid fast bacilli stains were positive and cultures grew Mycobacterium tuberculosis. The patient was started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) therapy. Serum cortisol levels on day 4 of RIPE therapy were appropriate in the setting of acute illness (>20 mcg/dl). On day 6 of RIPE therapy, the patient became hypotensive requiring vasopressor support. Labs at that time showed hyponatremia, hypokalemia, and inappropriately low cortisol levels (<20 mcg/dl). ACTH stimulation testing was performed and was blunted with values of 14.50 mcg/dL at 30 minutes and 16.32 mcg/dl at 60 minutes. CT abdomen was also performed and showed no evidence of infiltration. He was started on IV hydrocortisone 50 mg every 6 hours with plans to taper after shock resolved. Following steroid taper, the patient again became hypotensive requiring vasopressors. IV hydrocortisone was resumed, and RIPE therapy was held. He was restarted on PO hydrocortisone 40 mg every 12 hours. Isoniazid, ethambutol, pyrazinamide, and rifampin were sequentially resumed. Pyrazinamide was replaced with moxifloxacin due to recurrent gout flares. The reintroduction of rifampin and rifabutin both resulted in fevers leading to the stoppage of rifamycin therapy. The patient was discharged with stable vital signs on isoniazid 300 mg daily, ethambutol 800 mg daily, moxifloxacin 400 mg daily, and hydrocortisone 30 mg every 12 hours with plans to follow-up with the State Department of Health, internal medicine, and endocrinology. Conclusion: Many drugs are known to cause adrenal insufficiency. There are a few examples in which rifampin has been suggested as a potential cause of adrenal insufficiency. Classically, adrenal insufficiency has been associated with infiltration of the adrenal glands or pituitary gland with Mycobacterium tuberculosis. This case, however, shows further clinical evidence of adrenal insufficiency caused by rifampin therapy and highlights the need for further research to be done to study this adverse effect.

Presentation: Friday, June 16, 2023
THU486 Identification Of Metabolic And Molecular Mechanisms Driving Estrogen Receptor Positive Breast Cancer Disparities Using A Machine-Learning Pipeline
Authors: Casiano Ashlie Santaliz , Mehta Dhruv , Patel Hariyali , Rauscher Garth , Kim Julie , Frasor Jonna M , Hoskins Kent , Erdogan Zeynep Madak
Published: October 2023

Disclosure: A. Santaliz Casiano: None. D. Mehta: None. H. Patel: None. G. Rauscher: None. J. Kim: None. J.M. Frasor: None. K. Hoskins: None.

Background: African American (AA) women in the United States have a 40% higher breast cancer mortality rate compared with Non-Hispanic White (NHW) women. The survival disparity is particularly striking among ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ positive breast cancer. Methods: We collected pretreatment plasma from AA and NHW ER+ breast cancer cases and cancer-free controls to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Statistical methods combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from TCGA. Results: We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed changes in metabolites associated with amino acid metabolism, while fatty acid metabolism was significantly enriched in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant association with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene NELFE with histone methyltransferase activity was associated with poor survival exclusively for AA individuals. Conclusion: We employed a comprehensive and novel approach that integrates multiple machine learning methods and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women, and may ultimately lead to identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer, and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

Presentation: Thursday, June 15, 2023
FRI217 False Negative Plasma Metanephrines In A Patient With A Bladder Paraganglioma
Authors: King Thomas F J , Sng Gerald , Puar Troy
Published: October 2023

Disclosure: T.F. King: None. G. Sng: None. T. Puar: None.

Introduction: Both plasma free metanephrines and urinary metanephrines have high (>90%) sensitivity to detect phaeochromocytoma and paragangliomas (PPGL). False positive urine metanephrines are seen in many conditions including obstructive sleep apnoea (OSA), and plasma metanephrines have been proposed to be a useful diagnostic tool in this patient population. Clinical Case: A 53 year old female was recruited into a study evaluating the utility of plasma and urine metanephrines in the diagnosis of PPGL in patients with OSA. She had a 6 year history of hypertension that was well controlled with amlodipine 5mg daily. She had no headache, palpitations or paroxysmal symptoms. She had 3 previous uneventful pregnancies and there was no significant family history of note. She was overweight (BMI 28.3 Kg/m2) and blood pressure was 130/80 mmHg. Sleep studies revealed severe OSA. Screening plasma and 24 hour urine metanephrines were performed at baseline and again after 6 months (Table 1).

24 hr Urinary normetanephrine, mcg/day (Upper Reference interval 423): Baseline 437, Visit 2 (Six Months later) 535, Post-operative 235. Table 1. Serial measurements of urine and plasma metanephrines. In view of the persistently elevated urinary normetaneprine, a CT abdomen and pelvis was performed. This revealed normal adrenal glands, but an avidly enhancing 2cm focal nodular lesion was seen at the left lateral posterior wall of the urinary bladder. Transurethral biopsy revealed a tumour with immunohistochemistry positive for synaptophysin and GATA3, consistent with a paraganglioma. A CT/PET Ga68 dotatpeptide scan showed intense uptake in the same area with no evidence of lymphadenopathy or distant disease. Amlodipine was changed to terazosin pre-operatively and the patient went on to have an uneventful robot assisted excision and partial cystectomy. Histology was consistent with a bladder paraganglioma with clear tumour margins. Genetic analysis for hereditary PPGL was negative for mutations in SDHx, VHL, RET, NF1, but there was a variant of uncertain significance in the MUTYH gene, namely c.767C>T (p.Thr245Ile). At two months post-operative review, the patient remained well and home blood pressure readings were all >120/80mmHg on 5mg amlodipine. Repeat urine and plasma metanephrines were normal. Conclusions: Plasma metanephrines may not be sensitive enough to detect small asymptomatic bladder paragangliomas. Further studies are warranted to elucidate the optimal diagnostic tests in patients with sleep apnoea and suspected PPGL. Interval measurements of metanephrines may be useful in the diagnosis of small PPGL that may manifest with time.

Presentation: Friday, June 16, 2023
THU494 VHL Protein Deficiency Alters The Immune Microenvironment Of Pancreatic Neuroendocrine Neoplasms
Authors: Chmelnik Adiel , Telerman Alona , Tirosh Amit
Published: October 2023

Disclosure: A. Chmelnik: None. A. Telerman: None. A. Tirosh: None.

Introduction - Pancreatic neuroendocrine tumors (PanNENs) may develop sporadically or as part of an inherited disease, such as von Hippel-Lindau (VHL). VHL disease is caused by a germline pathogenic variant in the VHL gene encoding VHL protein (pVHL). Hypoxia inducible factor (HIF) is responsible for cellular oxygen supply. Its degradation is mediated by pVHL via ubiquitination in normoxic states. In pVHL-deficient state leads to HIF overexpression and pseudohypoxia. Several studies suggested immunomodulatory role for HIF in kidney cancer. Aims- To assess the impact of pseudohypoxia on PanNEN immune tumor microenvironment (iTME). Methods- A total of 16 vPanNEN and 23 sPanNEN were processed. Whole genome DNA methylation was performed by Illumine Infinium EPIC Array and analyzed using ChAMP on RStudio. Immune cells composition was compared using methylation-based deconvolution algorithms (MethylResolver, Robust Partial Correlations, Constrained Projection and Cibersort), and gene set enrichment analysis identified pathways affected in each group based on promoter methylation analysis. Results- Unsupervised hierarchical analysis of immune-related gene promoter methylation demonstrated separation of vPanNEN vs. sPanNEN. In GSEA analysis methylation was altered in immune memory-related genes in vPanNEN, and in T cells receptors-related genes in sPanNEN. Deconvolution algorithms revealed a lower fraction of CD4 and NK cells (p<0.05) and a lower PD-L1 expression in vPanNENs (p=0.037). Conclusion- Pseudohypoxic vPanNEN have distinct iTME than sPanNEN, in immune cells composition and PD-L1 expression.

Presentation: Thursday, June 15, 2023
THU497 Elucidating The Role Of The IQGAP1-YAP Axis In ECM Stiffness-Mediated Hepatocellular Carcinoma Progression
Authors: Hobbs Steven E , Kimmel Hannah , Underhill Gregory , Anakk Sayeepriyadarshini
Published: October 2023

Disclosure: S.E. Hobbs: None. H. Kimmel: None. G. Underhill: None. S. Anakk: None.

Hepatocellular Carcinoma (HCC), the primary form of liver cancer, is the second leading cause of cancer associated-associated deaths worldwide. Complex signaling mechanisms and several cellular processes are coordinated using scaffolding proteins. IQ motif-containing GTPase Activating Protein 1 (IQGAP1) is a scaffolding protein that is overexpressed in multiple epithelial cancers, including ovarian, breast, and liver. Previous work has shown that overexpression of IQGAP1 activates Yes-associated Protein (YAP) to promote HCC in mice. Extracellular matrix (ECM) stiffness, due to liver fibrosis in HCC, can activate YAP to promote tumor progression. Remarkably, our preliminary data show that IQGAP1 has increased localization at the plasma membrane when HepG2 cells (an HCC cell line) are seeded onto a stiff ECM (25 kPa). YAP is modulated by actin dynamics, which can be altered by changes in the plasma membrane. Therefore, IQGAP1’s movement to the plasma membrane can potentially activate YAP by modulating actin dynamics. We also found that the anti-HCC drug sorafenib, can induce the expression IQGAP1 and activate YAP in HepG2 cells grown on plastic. These sorafenib-mediated changes are counterproductive and can contribute to drug resistance of HCC. Finally, we found that inhibition of YAP in HepG2 cells significantly decreases IQGAP1 expression, indicating that there is bidirectional crosstalk between the two proteins. Future directions will elucidate if loss of IQGAP1 decreases ECM stiffness-induced YAP activation, proliferation, and migration in HCC cells. In addition, we will determine if ECM stiffness alters sorafenib-mediated IQGAP1 upregulation, as ECM stiffness has been linked to drug resistance in HCC. Overall, this work will shed light on the potential role of the IQGAP1-YAP axis in ECM stiffness-mediated HCC progression.

Presentation: Thursday, June 15, 2023
THU499 The Mesenchymal Stem Cells Induce Immunosuppressive Microenvironment In Pituitary Tumors
Authors: Marrero-Rodríguez Daniel , Cortes-Morales Victor A , Taniguchi-Ponciano Keiko , Valenzuela-Perez Alejandra , Vela-Patiño Sandra , Cano-Zaragoza Amayrani , Martinez-Mendoza Florencia , Kerbel Jacobo , Andonegui-Elguera Sergio , Montesinos Juan Jose , Mercado Moises
Published: October 2023

Disclosure: D. Marrero-Rodríguez: None. V. Cortes-Morales: None. K. Taniguchi-Ponciano: None. A. Valenzuela-Perez: None. S. Vela-Patiño: None. A. Cano-Zaragoza: None. F. Martinez-Mendoza: None. J. Kerbel: None. S. Andonegui-Elguera: None. J. Montesinos: None. M. Mercado: None.

The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells. MSC are a subset of heterogeneous cell populations characterized by the expression of CD105, CD73, and CD90 that can differentiate into chondrocytes, osteoblasts, and adipocytes in vitro. They are known to have immunomodulatory capabilities. Our aim was to isolate and characterize the immunomodulatory capabilities of MSC from pituitary tumors (PT) and non-tumoral gland as well as to describe the immune TME. We isolated and cultivated MSC from LH/FSH-PT and ACTH-PT, as well as non-tumoral pituitary glands. The MSC obtained from PT and non-tumoral gland were co-cultured in the presence of monocytes from healthy donors and their ability to transform into M0, M1 or M2 macrophages was assessed by flow cytometry. The results showed that pituitary tumors derived MSC induce an immunosuppressive M2 macrophage state, by increasing the expression of CD14 and CD206 markers, and decreasing HLA-DR. Upon co-culturing them with naïve T cells, PT MSC were capable inducing a Treg phenotype. To identify PT TME, we performed tumor whole transcriptome characterization and cellular deconvolution using CIBERSORT. Our analysis was indicative of a strong presence of M2 macrophages, TCD4+ and TCD8+ cells, which was confirmed by immunofluorescence, suggesting an immunosuppressive TME. Thus, the MSC immunosuppressive induction correlates directly with immune TME. ACTH-PT derived MSC showed a stronger anti-inflammatory activity than LH/FSH-PT. We also characterized the transcriptomic differences between non-tumoral and PT derived MSC by means of RNAseq. We found differences between the non-tumoral MSC and pituitary tumor derived MSC, but mainly between ACTH- and LH/FSH-PT derived MSC. In conclusion our data suggest that the presence of MSC influence an immunosuppressive tumor microenvironment alongside with tumor cells.

Presentation: Thursday, June 15, 2023
THU500 Geospatial Analysis To Quantify Spatial Heterogeneity Of Tumor Microenvironment
Authors: Yoo Jin Young , Mitra Chancharik , Yue Yang , Soliman Aiman , Erdogan Zeynep Madak
Published: October 2023

Disclosure: J. Yoo: None. C. Mitra: None. Y. Yue: None. A. Soliman: None. Z. Madak Erdogan: None.

Metabolic heterogeneity, a concept describing distinct differences in nutrient metabolism within the cells of a healthy or diseased tissue, is a common challenge in development and cancer research. Current methods, such as histology and Magnetic Resonance Imaging (MRI), cannot visualize nutrient uptake into single cells, making it difficult to understand the heterogeneity that affects cellular growth and metabolism. Visium Spatial Transcriptomics, a method that shows regional gene expression, is emerging as a powerful spatial analysis tool, and we aim to integrate this transcriptomic method with other biologically relevant datasets to highlight the importance of cell-microenvironment interactions. We propose to leverage geostatistical tools to model the multivariate covariance structure of genes expression profiles to allow: 1) understanding of their spatial characteristics and covariance changes under certain conditions (e.g. drug treatment or damage), 2) using these covariance structures to simulate synthetic samples at a scale sufficient to train the state of art neural network architectures, and 3) incorporating spatial awareness directly in the machine learning/deep learning models by enriching the spatial transcriptomics data using distance proximity functions. We will quantify the tumor microenvironment spatial heterogeneity using different approaches. First, we will analyze the degree of spatial auto-correlation to estimate the ranges of spatial heterogeneity within a tumor. We also plan to quantify the degree of anisotropy to identify if the tumor heterogeneity is happening along specific axis. Different local clustering indicators will be also calculated, such as the Getis-Ord (Gi*) statistic and Local Moran's I to identify the prevalence of hot and cold spots in the tumor. These hot and cold spots will be used to segment the tumor area into sub-regions and further quantify the local heterogeneity with a single tumor. We hypothesize that transcriptional heterogeneity reflects phenotypic differences in different regions of healthy or diseased tissue, rendering cells in certain regions to display a differential response to external stimuli (e.g. diet or drugs). Integration of multiple information (e.g. retrospective patient data) with different spatial heterogeneity indicators identified from the geospatial analyses could aid in identification of patients who are resistant to cancer therapies and further advance personalized therapy.

Presentation: Thursday, June 15, 2023
THU501 Examining The Link Between Exposure To Neighborhood Violence And PRMT6 And Glucocorticoid Receptor Binding To Chromatin In Lung Tumors
Authors: Heath Hannah , Kim Sage , Erdogan Zeynep Madak
Published: October 2023

Disclosure: H. Heath: None. S. Kim: None. Z. Madak Erdogan: None.

Despite smoking less, Black men experience a higher incidence of lung cancer than white men. This health disparity is even more prevalent in Black men from Chicago, suggesting local neighborhood factors impacting tumorigenesis. Preliminary data found that Black men compared to white men exhibit overexpression of the epigenetic regulator known as PRMT6, have elevated levels of hair cortisol, and live in neighborhoods with disproportionately high levels of violence. This research aims to investigate the receptor for cortisol called glucocorticoid receptor (GR), and PRMT6 recruitment to chromatin and to correlate this recruitment with tumor cortisol levels and exposure to neighborhood violence. Using a version of ChIP-sequencing known as CUT & RUN, the gene binding sites of PRMT6 and GR will be identified using 16 lung tumor samples from patients living in Chicago. Cortisol levels present in lung tumors will be detected using LC-MS. These cortisol levels will be correlated with GR and PRMT6 recruitment to chromatin and neighborhood homicide data obtained using patients’ zip codes. We hypothesize that PRMT6 and GR will be recruited to regulatory regions of genes related to increased lung tumor aggressiveness. We also anticipate that cortisol levels will correlate with neighborhood violence levels and elevated PRMT6 and GR colocalization, indicating chronic exposure to stress as a regulator of lung tumor formation.

Presentation: Thursday, June 15, 2023
THU510 The Frequency Of Mutations In Advanced Thyroid Cancer In Japan: A Real Clinical Setting
Authors: Toda Soji , Takahashi Akari , Masudo Katsuhiko , Iwasaki Hiroyuki
Published: October 2023

Disclosure: S. Toda: None. A. Takahashi: None. K. Masudo: None. H. Iwasaki: None.

Background: Thyroid cancer has a high incidence of actionable genetic alterations, but the frequency of mutations in advanced thyroid cancer that requires drug therapy is unknown. Therefore, we examined the outcomes of genetic testing performed in a real clinical setting for the purpose of pharmacotherapy. Methods: In Japan, Oncomine Dx is approved for thyroid cancer that requires drug therapy, and comprehensive genomic profiling is approved for anaplastic thyroid carcinoma and other thyroid carcinomas after the induction of tyrosine kinase inhibitors. We retrospectively reviewed the cases of those who had their tests performed between 2020 and 2022. Results: The study included 65 patients, and the testing methods used were Oncomine Dx in 36 cases, FoundationOne in 25 cases, and FoundationOne Liquid in 4 cases. With a median age of 74 years (range 17–86), 42 were female and 23 were male. Moreover, 13 cases had anaplastic thyroid carcinoma (ATC), 4 follicular thyroid carcinoma (FTC), 42 papillary thyroid carcinoma (PTC), and 6 poorly differentiated thyroid carcinoma (PDTC). Of the PTC examined by Oncomine Dx, 96.8% (30/31) were RAI-refractory; all comprehensive genomic profiling testing cases except ATC had previously been treated with tyrosine kinase inhibitors. In the following cases, actionable mutations were observed. Among 13 ATC cases, 46.2% (6) had BRAF mutation and 7.7% (1) had RET fusion. Of 42 PTC cases, 85.7% (36) had BRAF mutation and 7.1% (3) had RET fusion. Of 6 PDTC cases, 33.3% (2) had BRAF mutation and 16.7% (1) had RET fusion. No actionable mutations were observed in FTC (0/4). We found one case each of ATC and PTC with tumor mutation burden of 10 or higher, both with BRAF mutation. NTRK fusion was not observed in any of the 65 patients studied. There were four PTC cases (9.5%) with iodine accumulation in metastases, two with BRAF mutations, one with RET fusion, and one without detectable mutations. Comparing mutations in ATC and non-ATC, TERT promoter mutations were found in 84.6% of ATC (11/13) vs. 56.2% of non-ATC (9/16), whereas TP53 mutations were found in 76.9% of ATC (10/13) vs. 12.5% of non-ATC (2/16). ATC has a significantly higher prevalence of TP53 mutations. Conclusion: Advanced thyroid cancer is more likely to have actionable mutations. BRAF mutations in advanced PTC may be more common than those previously reported in standard PTC. Moreover, ATC has a higher rate of TP53 mutation than other thyroid carcinomas.

Presentation: Thursday, June 15, 2023
THU518 Ectopic Cushing Syndrome In A Case Of Ewing Sarcoma
Authors: Fasen Madeline , Mayson Sarah Emily
Published: October 2023

Disclosure: M. Fasen: None. S.E. Mayson: None.

Background: Ewing sarcoma (ES) is a rare and aggressive neoplasm occurring in bone and soft tissue in children to young adults. It is part of a spectrum of neoplastic diseases known as the ES family of tumors that display varying degrees of neuroendocrine features. Ectopic Cushing’s syndrome (ECS) is also a rare but severe condition associated with unregulated ACTH or CRH secretion by neuroendocrine tumors (NETs) that can cause severe hypercortisolism. The most common tumors associated with ECS include small cell lung carcinoma, bronchial carcinoid and medullary carcinoma of the thyroid gland. Sarcomas causing ECS are extremely rare with only a handful of cases reported in the literature, mostly in children. Herein we detail what we believe to be the first reported case of ECS occurring in an adult male patient with ES. Clinical Case: A 23-year-old man with ES metastatic to pancreas, liver and bone was admitted to the hospital with acute on chronic back pain and lower extremity weakness, and subsequently diagnosed with cord compression and neutropenia from chemotherapy. New onset hypertension and refractory hypokalemia were observed prompting endocrinology consultation. Physical examination revealed facial fullness, central obesity and wide violaceous striae on his abdomen and axillae. Biochemical evaluation demonstrated blood glucose consistently over 300 mg/dL, serum potassium 2.5 mmol/L, renin 0.9 ng/ml/hr (0.2-1.6 ng/ml/hr), aldosterone renin ratio < 3.3, morning cortisol 73 ug/dL (4-22 ug/dL), and ACTH 1020 pg/mL (72-63 pg/mL). A 1 mg overnight dexamethasone suppression test yielded a serum cortisol of 90 ug/dL and 24-hour urine free cortisol was 6388 ug/d (<60 ug/d). MRI brain demonstrated a normal pituitary gland, and FDG PET-CT showed new areas of uptake in bone concerning for metastatic progression and new bilateral adrenal enlargement without nodularity. High dose dexamethasone suppression testing was deferred in the context of rapid neuropsychiatric deterioration characterized by somnolence and psychosis. The decision was made to treat immediately with spironolactone and ketoconazole, as well as insulin for hyperglycemia management. His mental status, blood pressure, serum potassium, glucose and cortisol improved following the initiation and titration of medical therapy. He was discharged home with addition of metyrapone and hospice support. Two months later the patient succumbed to his illness. Conclusion: The severity of hypercortisolism is a negative predictor of survival and prompt control should be the main therapeutic goal along with prevention of cortisol-induced complications in patients with ECS. ACTH and CRH immunostaining of the patient’s ES histopathology slides is pending.

Presentation: Thursday, June 15, 2023
THU520 Successful Treatment Of Ectopic ACTH From Metastatic Gastrinoma With Temozolomide Monotherapy
Authors: Syeda Asma , Khan Aysha , Larosa Dena , Kunz Pamela , Esayag-Tendler Beatriz
Published: October 2023

Disclosure: A. Syeda: None. A. Khan: None. D. Larosa: None. P. Kunz: None. B. Esayag-Tendler: None.

Background: Temozolomide is a promising therapeutic agent for the treatment of refractory ACTH-secreting pituitary tumors. However, its role in the management of ectopic ACTH secretion due to neuro endocrine tumors (NETs) has not been well elucidated. Case: A 46-year-old man with a refractory functional pancreatic NET/ high grade metastatic gastrinoma, post distal pancreatectomy and splenectomy, briefly on everolimus therapy, presented with altered mentation and worsening edema. Clinically he had proximal muscle weakness, anasarca and hypokalemia with a potassium of 2.8mmol/L (n:3.6-5.1 mmol/L). Further work up revealed AM cortisol 79.6 ug/dL (n:7-23 ug/dL), 24-hour urine cortisol was 1820 ug/d (n: < 60 ug/d), ACTH 807 pg/mL (n:7.2-63.3 pg/mL) and gastrin level >10,000 pg/mL (n:0-100 pg/mL). Imaging studies of the brain, chest, abdomen, and pelvis were unremarkable. Octreotide infusion at 100 mg/hour was started with a goal to decrease gastrin and ectopic ACTH production. There was no response to Octreotide even after 5 days of continuous infusion, hence it was switched to subcutaneous injection form to control diarrhea. Lutathera/Peptide receptor radionuclide therapy was considered but held off due to the patient's delirium. As hypercortisolism is associated with multiple risks including thromboembolic events, rapid reduction of cortisol biosynthesis was achieved with Ketoconazole. Other options to inhibit steroidogenesis were available; the goal was to decrease both ACTH and Gastrin levels and for this reason Temozolomide was started. It crosses the blood-brain-barrier and hence was a preferred agent in this patient as he was noted to have atypical cells in the CSF. He received Temozolomide 150 mg/m² for 5 days of a 28-day cycle. Subsequently, AM cortisol decreased to 3.4 ug/dL, ACTH and gastrin started to trend down to 144 pg/mL and 3505 pg/mL respectively. Thereafter, the patient was given steroids and ketoconazole as part of a block and replace strategy to avoid adrenal insufficiency and hypercortisolism respectively. Temozolomide was very well tolerated; there were different reasons to hold Capecitabine including severe thrombocytopenia. Bilateral adrenalectomy was discussed but deferred as the ACTH levels decreased. Clinically, the patient reported improved muscle strength, edema and weight decreased significantly. The hospital stay was complicated by several other comorbidities which were managed appropriately by a multidisciplinary approach. Conclusion: Temozolomide should be considered in ACTH producing NETs refractory to conventional treatment strategies.

Presentation: Thursday, June 15, 2023
THU527 Metastatic Adenocarcinoma Of The Colon Concealing An ACTH Secreting Neuroendocrine Differentiated Cluster: A Lethal Zebra Within A Trojan Horse
Authors: Velasquez Mariana , Shekhar Skand , Manju Rachna , Nieman Lynnette K
Published: October 2023

Disclosure: M. Velasquez: None. S. Shekhar: None. R.M. Goyal: None.

Background: Ectopic ACTH secreting tumors are responsible for almost 10% of all cases of Cushing Syndrome. Tumors associated with this entity are most commonly small cell lung, thymic, and pancreatic neuroendocrine tumors. Few cases of colon adenocarcinoma with paraneoplastic ACTH secretion have been reported. They are associated with poor outcomes. Clinical case: A 57-year-old previously healthy male presented with shortness of breath and hypertension. CTA of the chest revealed metastatic liver lesions. CT abdomen and pelvis confirmed metastatic liver lesions with an apple core colonic mass consistent with a primary malignancy. Liver biopsy showed well-differentiated neuroendocrine tumor; tumor cells were negative for CK20, chromogranin, and CD56 but positive for CK7 and synaptophysin. The Ki-67 index was 30%. He was not evaluated for paraneoplastic hormonal secretion and the colonic mass wasn’t biopsied at that time. Ga-DOTATATE scan was negative for somatostatin uptake. He was started on carboplatin-etoposide + dexamethasone (three doses of 4mg each). Two months later presented with large bowel obstruction. Colonoscopy was performed and histopathology demonstrated colonic adenocarcinoma with focal neuroendocrine differentiation with positive CDX2 and negative CK7 and CK20. Synaptophysin was diffusely positive with sparse chromogranin positivity. ACTH stain of the colonic biopsy was negative. Chemotherapy was switched to FOLFORINOX and dexamethasone (one dose of 12mg). After two weeks of being on this regimen, he developed refractory hypokalemia and metabolic alkalosis and was sent to the emergency department. Vitals signs were within normal limits except for mildly elevated blood pressure. Physical examination remarkable for redness of his truncal skin. He did have changes in his handwriting, 0/3 three-word recall, and reduced short term memory. Primary team performed a morning cortisol that was elevated, and endocrinology was consulted. Two repeated 8AM cortisol level and a serum ACTH were found to be elevated. An 8mg overnight dexamethasone suppression test revealed an increase in cortisol. MRI brain showed no evidence of intracranial abnormalities. Refractory hypokalemia due to ectopic ACTH-dependent Cushing syndrome was diagnosed warranting treatment with ketoconazole. Unfortunately, he developed septic shock which led to his demise. Conclusion: This case illustrates a paradoxical rise in serum cortisol levels after dexamethasone suppression test suggesting the presence of positive feedback effects of exogenous corticosteroids on tumor’s ACTH release/production. Recognition of this syndrome is critical to avoid unnecessary use of exogenous glucocorticoids since they could trigger paraneoplastic Cushing syndrome in these patients.

Presentation: Thursday, June 15, 2023