bluuebunny/crossref_metadata_2025 huggingface dataset:
7873 Integration of Glucocorticoid and Mineralocorticoid Receptor Signaling in Triple-negative Breast Cancer Models
Authors: Posani S , Lange C A
Published: October 2024

Disclosure: S. Posani: None. C.A. Lange: None.

Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes.

Presentation: 6/2/2024
9316 Modulation Of Intracellular Lipid Access By ATGL Determines Ferroptosis Sensitivity In Castration-resistant Prostate Cancer
Authors: Cao P , Awad D , Han J , Frigo D E
Published: October 2024

Disclosure: P. Cao: None. D. Awad: None. J. Han: None. D.E. Frigo: Grant Recipient; Self; GTx, Inc.. Other; Self; Familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics.

Ferroptosis induction has recently been recognized as a novel therapeutic approach to alter the outcomes of drug-resistant cancer. Ferroptosis is cell death that is caused by the intracellular accumulation of toxic lipid hydroperoxides. Due to their elevated metabolism, castration-resistant prostate cancer (CRPCs) are highly prone to ferroptosis; yet, many of them manage to avert this cellular fate. We have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders CRPCs with the ability to resist ferroptosis. Our data has shown that ATGL deletion by CRISPR-Cas9 knockout method sensitized human CRPC cell lines such as C4-2, C4-2BLT, and PC3 cells to the ferroptosis inducer RSL3. In all cases, RSL3-mediated cell death could be blocked by the antioxidant Ferrostatin-1, confirming ferroptosis as the mechanism of cell death. Knocking out ATGL also augmented the ferroptosis inducer-mediated increase in lipid peroxides as indicated by the increased ratio of oxidized to non-oxidized C11-BODIPY 581/591. With regards to the mechanism for the sensitivity of ATGL KO to ferroptosis induction, previous research has established that the enzyme long-chain acyl-CoA synthetase 4 (ACSL4) is universally essential to facilitate ferroptosis. More specifically, ATGL(PNPLA2) was found to inversely correlate with ACSL4 in the Taylor et al., the TCGA PanCancer Atlas, and Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team) datasets in both primary and metastatic tumors. qPCR and western blot analysis of ACSL4 levels further showed that ACSL4 expression is closely tied to the lipase activity of ATGL. Addition of arachidonic acid significantly induced ferroptosis when combined with RSL3 in a dose-dependent manner only in ATGL KO cells. This indicates that PUFAs can render ATGL KO cells even more sensitive to RSL3-induced ferroptosis while cells with functional ATGL remain highly resistant, further reinforcing that ATGL is an essential safeguard of CRPC against ferroptosis. ATGL KO cells also demonstrated sensitivity to the antiandrogen Enzalutamide. The combination of Enzalutamide and RSL3 substantially decreased cell viability in ATGL KO cells as compared to control cells, indicating a strong synergy effect particularly seen in ATGL KO cells. In summary, this work demonstrates that ATGL is an important and novel regulator of ferroptosis in CRPC and supports the use of ferroptosis inducer as a new therapeutic approach in CRPC.

Presentation: 6/2/2024
7906 Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy
Authors: Yakubu Jibira
Published: October 2024

Disclosure: J. Yakubu: None.

Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy. Jibira Yakubu a,b,c, Oya Taritd, Evangelos Natsaridisd, Amit V. Pandey a,ba Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, b Paediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, c Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. d Biointerfaces, Institute of Chemistry and Bioanalytics, University of Life Sciences FHNW, Muttenz, Switzerland. Abstract: Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate are a recognized challenge. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. We performed steroid profiling with LC-MS, as well as gene and protein expression studies. Initial results demonstrated that curcumin nanoparticles exhibited superior efficacy in reducing CYP17A1 activity compared to known drug Abiraterone acetate. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, ongoing studies include western blot investigation of the drug's interaction with the CYP17A1 protein and cell cycle effects. We confirmed the efficacy of our nano formulation by testing its impact on the growth of androgen-sensitive prostate cancer cell lines. Notably, nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while having no effect on CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as a game-changing method for targeting CYP17A1 for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. Funding: Cancer Research Switzerland grant number: KFS 5557-02-2022

Presentation: 6/3/2024
8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency
Authors: Aranda Guillen Maribel , Botusan Ileana , Fernando Venuja , Christine Røyrvik Ellen , Bøe Wolff Anette Susanne , Johansson Stefan , Sverre Husebye Eystein , Bensing Sophie , Kampe Olle , Eriksson Daniel
Published: October 2024

Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None.

Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling.

Presentation: 6/2/2024
6477 Surprise Finding for a Thyroid Nodule: Metastatic Renal Cell Carcinoma
Authors: Xu Adele , Hsu Emory
Published: October 2024

Disclosure: A. Xu: None. E. Hsu: None.

Introduction: A patient with an incidental and asymptomatic thyroid nodule underwent fine needle aspiration biopsy (FNA) after the nodule increased in size. Without a definite pathology after three FNA attempts, thyroidectomy was performed, where pathology found metastatic renal cell carcinoma (RCC). Clinical Case: A 64 year old woman had a past medical history of obesity, type 2 diabetes, RCC (stage I: pT1bN0M0) treated with right radical nephrectomy five years prior and thought to be in remission, remote smoking history smoking, and coronary artery disease with coronary artery bypass graft (CABG) two months prior, on anticoagulation. The patient reported a distant history of right thyroid lobectomy over a decade prior for unclear reasons, but she was adamant that the pathology was benign. Two years prior to presentation, CT chest done for RCC surveillance had detected a left thyroid nodule. Ultrasound at the time revealed a 3.6 x 1.9 x 2.3 cm solid, isoechoic nodule in the upper left lobe, which was not taller than wide, and had smooth margins and no echogenic foci. A repeat ultrasound at the time of presentation showed interval growth of the nodule, now measuring 4.3 x 2.1 x 2.9 cm. FNA was unsatisfactory, yielding predominantly blood. Patient felt well and had no compressive neck symptoms. We opted to wait two months and repeat FNA, which resulted as atypia of undetermined significance - Bethesda category III (AUS). We recommended completion thyroidectomy, but patient preferred to avoid surgery. We decided to wait two months and repeat FNA with molecular testing. This third FNA resulted AUS again; however, due to non-medical reasons, molecular testing was not performed. Another ultrasound showed slight growth of the nodule, 5.1 x 2.9 x 2.0 cm, which appeared hypoechoic now, but was still not taller than wide, with smooth margins and no echogenic foci. Completion thyroidectomy was performed, with pathology showing metastatic clear cell renal cell carcinoma. Immunostains were positive for carbonic anhydrase and renal cell carcinoma marker and negative for TTF-1. Whole-body PET-CT showed no hypermetabolic foci, and a repeat PET-CT one year later still showed no evidence of metastatic disease. Other than a hospitalization for COVID-19, patient is doing well and asymptomatic now over a year after her thyroidectomy. Oncology will continue routine surveillance imaging for her metastatic renal cell carcinoma thought to be in remission. Clinical Lessons: This case of metastatic renal cell carcinoma to the thyroid adds to the small body of literature showing the thyroid as a possible site of RCC metastasis. The long time interval between initial RCC presentation and metastasis to the thyroid makes this diagnosis more difficult; however, clinicians should be aware of the possibility, making thyroidectomy a stronger option in cases where FNA cytology is indeterminate.

Presentation: 6/2/2024
8414 Utilization of Cell Free DNA Integrity Index to Differentiate Benign from Malignant Thyroid Nodules
Authors: Tarafdar S , Dutta S , Mukhopadhyay P , Bhattacharya N P , Ghosh S
Published: October 2024

Disclosure: S. Tarafdar: None. S. Dutta: None. P. Mukhopadhyay: None. N.P. Bhattacharya: None. S. Ghosh: None.

Introduction: Recent advances in molecular genetics have evaluated a potential role for plasma cell-free DNA (cfDNA) integrity index as a non-invasive cancer marker. Data on cfDNA integrity in differentiated thyroid cancer is sparse and needs to be investigated further. Aim of the study: The purpose of this study is to investigate the hypothesis that longer DNA strands in plasma may serve as a marker for thyroid cancer. Methods: Patients presenting with thyroid nodules underwent ultrasonography with Thyroid Image Reporting and Data Systems (TIRADS) scoring and FNAC (Bethesda classification).Patients with Bethesda 3, 4, 5, and 6 had surgery and confirmation by histopathology. Patients with Bethesda 2 presenting with compressive symptoms and cosmetic concerns underwent surgery; the remaining patients were considered benign based on clinical follow-up, USG, and FNAC characteristics. Blood sample collected prior to FNAC was used to extract and quantify cfDNA. To assess the integrity index 180/67, 306/67, and 476/67 for the APP gene, we used a quantitative real-time PCR (qPCR) method based on the quantification of four amplicons of varying lengths (67, 180, 306, and 476 bp, respectively). Because culture cells had extremely intact genomic DNA, the genomic DNA obtained from the MDA-T32 papillary thyroid cancer cell line was utilised as a reference to estimate the relative DNA strand integrity in plasma DNA. To determine the (ΔCt) value for 67,180, 306, and 476 bp, the Ct value of the sample was subtracted from that of the MDA-T32 control. Results: A total of 161 subjects were recruited, of these 92 were benign and 69 had differentiated thyroid cancer(confirmed by histopathology). Using the 180/67 bp integrity index benign thyroid nodule patients had significant lower value (median 0.39, 95% CI: 0.33-0.46) compared to patients with differentiated thyroid cancer (median 0.62, 95% CI: 0.56-0.68). A cfDNA integrity index of 180/67 bp could significantly differentiate between benign and malignant thyroid nodules (P<0.001). However, there was no significant difference between malignant and benign thyroid nodules based on the cell free DNA integrity indexes of 306/67 and 476/67. Conclusions: The cfDNA integrity score of 180/67 exhibits potential as a circulating marker for the detection of thyroid nodules and as a means of monitoring cfDNA fragmentation in patients with thyroid cancer. However, further confirmation through prospective trials is necessary.

Presentation: 6/3/2024
6702 Management And Complications Of Metastatic Adrenocortical Carcinoma Presenting With Severe Cushing Syndrome
Authors: Rodrigues Sonia , Singh Sumal Amit Kartar
Published: October 2024

Disclosure: S. Rodrigues: None. A.K. Sumal: None.

Background: Metastatic adrenocortical carcinoma (ACC) presenting with Cushing syndrome (CS) is a complicated, aggressive disease that commonly requires multiple adrenal steroidogenesis inhibitors and chemotherapy to achieve hormonal and tumor control. Clinical Case: A 66-year-old man with a history of prostate cancer and hypertension presented with right flank and back pain, worsening type 2 diabetes, profound proximal muscle weakness, and 3+ lower extremity edema to his thighs. CT and PET-CT revealed a 10.9 cm right adrenal mass with pericaval lymphadenopathy and metastatic disease at the L2 vertebral body. Laboratory testing demonstrated evidence of hypercortisolism with elevated 24-hour urinary cortisol excretion (449 mcg/24h; n<45 mcg/24h), and abnormal 1 mg dexamethasone suppression test (cortisol 15 mcg/dL; n< 1.8 mcg/dL) with suppressed ACTH (<6 pg/mL; n=7-63 pg/mL). Surgical resection of the primary tumor was aborted intraoperatively given the discovery of new peritoneal metastases, which were confirmed by biopsy to be metastatic ACC. He was started on mitotane and osilodrostat to manage his severe CS. He was also started on dexamethasone, both to prevent adrenal insufficiency and to avoid influencing serum cortisol measurements used to assess disease control. However, given his significant peripheral edema and weakness, he was functionally unable to receive chemotherapy. Despite rapid uptitration of mitotane and osilodrostat over three weeks, his CS remained uncontrolled, and he was ultimately hospitalized for lower extremity paralysis and septic shock due to pyelonephritis. Repeat imaging revealed severe spinal canal stenosis from an L2 pathologic fracture, as well as worsening hepatic, osseous, peritoneal, and retroperitoneal metastases. After recovery from his septic shock, he was started on chemotherapy with carboplatin and etoposide while hospitalized, but his mitotane was intermittently held due to elevated transaminases. His hospital course was complicated by hypotension requiring pressor support, atrial fibrillation, hemoperitoneum, worsening anasarca, and acute kidney injury requiring continuous renal replacement therapy. Given his worsening condition that precluded him from further chemotherapy or palliative radiation, he elected to pursue comfort care measures and expired shortly thereafter. Conclusion: This case highlights the therapeutic challenges of metastatic ACC presenting with life-threatening CS. Simultaneous use of multiple adrenal steroidogenesis inhibitors is often required for control of hypercortisolism, and chemotherapy is equally necessary to manage tumor burden. However, as in this case, disease-related complications can limit treatment management and result in rapid deterioration. Thus, early diagnosis and prompt treatment of metastatic ACC presenting with CS is critical to prevent morbidity and mortality.

Presentation: 6/3/2024
7662 Mass Spectrometry Imaging Reveals Region-, Age-, And Sex-Specific Effects Of Lipopolysaccharide Administration On Glucocorticoids In Mouse Lymphoid Organs
Authors: Salehzadeh Melody , Khan Shazia , Andrew Ruth , Soma Kiran K
Published: October 2024

Disclosure: M. Salehzadeh: None. S. Khan: None. R. Andrew: None. K.K. Soma: None.

Glucocorticoids (GCs) are steroids that are critical for immune function. Immune organs, such as the thymus and spleen, locally produce GCs (i.e., immunosteroids). However, GC concentrations in the thymus and spleen at the cellular level, and how these levels are affected by stress, remain largely unknown. We used state-of-the-art mass spectrometry imaging (MSI) to elucidate the spatial distribution of GCs in the neonatal and adult mouse thymus and spleen 1) at baseline and 2) after an acute stressor. We used MSI to measure 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) in different regions of the thymus (medulla/cortex) and spleen (white/red pulp) after an immunological challenge. We administered lipopolysaccharide (LPS; i.p.) at low (50μg/kg) and high (400μg/kg) doses or saline (vehicle) to male and female C57BL/6J mice at post-natal day (PND) 5 (neonatal) and 90 (adult) (n=6/sex/group/age). 4hr after treatment, we collected thymus and spleen on liquid nitrogen. Cryosections (10μm) were subject to MSI following Girard-T reagent derivatization and α-cyano-4-hydroxycinnamic acid matrix application. Matrix assisted laser desorption/ionisation (MALDI) was used for sampling, coupled to Fourier-transform ion cyclotron mass spectrometry (100μm resolution; positive mode; Bruker 12T SolariX). Adjacent sections were taken to determine histological zones by H&E staining. Preliminary results indicate that LPS increased DOC, corticosterone, and DHC levels by 2- to 9-fold in lymphoid organs at both ages. There was a dose-dependent increase in thymus and spleen GC levels at PND5, but not PND90. At PND5, GC levels were similarly distributed across each tissue in both sexes. In contrast, at PND90, thymic corticosterone levels were greater in males than females in the medulla and cortex. Interestingly, in PND90 thymus, the medulla had greater DHC levels than the cortex only after LPS treatments. In PND90 spleen, GC levels significantly increased after LPS, yet there was no significant difference in GC distribution between sexes or red and white pulp. These results suggest that GC production is uniform across neonatal lymphoid organs. However, in adulthood, the thymus exhibits region-specific GC metabolism. Our results expand knowledge of steroid intracrinology in thymus and spleen and potential effects of environmental stressors (e.g., infectious diseases, toxins) on immune GC responses. Further, our novel MSI method for GC detection in murine lymphoid organs can help inform future techniques in pharmacokinetics for localized thymic and splenic targeting of steroids and steroid modulators.

Presentation: 6/3/2024
5141 Metastatic Adrenocortical Carcinoma
Authors: Anwaar Nida
Published: October 2024

Disclosure: N. Anwaar: None.

Adrenocortical carcinomas are rare and frequently aggressive tumors that may be functional (hormone secreting) and cause Cushing's syndrome and/or virilization or nonfunctional and present as an abdominal mass or as an incidental finding. We report a case of a 72-year-old lady who was presented to the ER with chest pain and elevated blood pressure. CTA was performed to evaluate for aortic dissection, which incidentally found a 5.0 x 3.7 cm right-sided adrenal mass. 1 mg overnight dexamethasone suppression study showed non-suppression of cortisol. The ACTH was suppressed, consistent with the autonomous production of cortisol from the adrenal gland. CT abdomen with adrenal protocol showed an indeterminate suspicious 5.1 x 3.9 cm right-sided adrenal mass. She underwent an adrenalectomy and the final pathology showed adrenocortical carcinoma. Postoperatively she was treated with adjuvant radiotherapy and chemotherapy. A few years later, she developed metastatic lesions and overt Cushing syndrome. She was started on pembrolizumab, which was later discontinued due to poor response and then placed on mitotane. The metastatic disease progressed, and the patient was transitioned to hospice care. Due to tumor’s rarity, the understanding and experience of management modalities are limited. New treatment options may be available in the coming years.

Presentation: 6/1/2024
7533 Mifepristone For Primary Hypercortisolism Contributing To Profound Hypokalemia
Authors: Watkins Jacqueline , Melendez-Rivera Juan Gabriel , Florin Evan , Balagot Rivera Krystal
Published: October 2024

Disclosure: J. Watkins: None. J.G. Melendez-Rivera: None. E. Florin: None. K.B. Rivera: None.

Background: Primary hypercortisolism is typically treated surgically, but when adrenalectomy is not pursued, medical therapy can be effective. Adrenal enzyme inhibitors or glucocorticoid antagonists can be used. Mifepristone is the only available glucocorticoid antagonist at this time. Mifepristone is approved specifically for glucose control in Cushing’s syndrome. Because mifepristone blocks cortisol action rather than production, hormone levels may increase and are unhelpful in titrating the mifepristone dose. Rather, titration is based on clinical manifestations of Cushing’s syndrome. Further, the increased hormone levels can lead to increased activation of mineralocorticoid receptor, in addition to the increased activation caused by hypercortisolism, which can cause hypokalemia. Clinical Case: An 82-year-old woman had been following with endocrinology for hypercortisolism found to be secondary to bilateral adrenal adenomas. She preferred medical therapy rather than surgery given her age, and she was started on mifepristone 300 mg/day. Within a few weeks, she developed leg swelling and was started on a low dose of chlorthalidone by her primary care doctor. She then presented to the emergency department after five days of nausea, abdominal pain, palpitations, and reduced oral intake. She was found to have severe hypokalemia (potassium 1.8 mEq/L, normal 3.5 - 5.0 mEq/L), and her creatinine was 0.97 µmol/L (baseline 0.6-0.75 µmol/L). Physical exam was unremarkable. CT abdomen/pelvis revealed three adrenal lesions, similar to a study from one year prior. Her mifepristone was stopped, and she was given potassium supplementation and started on spironolactone with eventual stabilization of her potassium level. She was also started on ketoconazole for management of her hypercortisolism. It was discussed that she might now consider adrenal vein sampling to pursue adrenalectomy. Severe hypokalemia and borderline metabolic alkalosis were most likely multifactorial in etiology. Hypercortisolism predisposed the patient to hypokalemia. She was then started on mifepristone, which inhibits the glucocorticoid receptor thereby increasing activation of the mineralocorticoid receptor, which likely further contributed to hypokalemia. The leg swelling that she developed and saw her primary doctor for may have been a sign of over-activation of the mineralocorticoid receptor due to the mifepristone, and prescription of chlorthalidone at that time would have worsened the hypokalemia that was likely present at that time. Conclusion: It is important to be aware of the possible severity of side effects of medical therapy for hypercortisolism, such as severe hypokalemia. There is a role for increased awareness of routine monitoring of potassium levels, as well as considering spironolactone in many patients even prior to onset of hypokalemia.

Presentation: 6/3/2024
8191 Navigating The Maze Of Adrenal Insufficiency, A Complex Case Of Late Presentation
Authors: Pereira K N , Sundaram V , Mehta V , Desai K , Agrawal B
Published: October 2024

Disclosure: K.N. Pereira: None. V. Sundaram: None. V. Mehta: None. K. Desai: None. B. Agrawal: None.

Adrenal insufficiency, a rare but potentially life-threatening endocrine disorder, arises from the inadequate production or ineffective response to adrenal hormones, particularly cortisol and aldosterone. It poses diagnostic challenges, especially in individuals with intricate medical histories and manifests as either primary (Addison's disease) or secondary. The subtlety of initial symptoms often leads to a delayed diagnosis, emphasizing the importance of a high index of suspicion among healthcare providers. Timely recognition and intervention are crucial to prevent adrenal crises, which includes severe hypotension, electrolyte imbalances and life-threatening complications. This case report delves into the presentation, diagnosis, and management of primary adrenal insufficiency in a 51-year-old female with a myriad of co-morbidities who presented with persistent low blood pressure, syncope episodes and dizziness both at rest and with exertion, despite being on midodrine with systolic blood pressure readings ranging from 60s to 80s mmHg. She was also noted to be bradycardic and laboratory results showed hyponatremia, hyperkalemia, hypoglycemia and anemia. She was given prompt fluid resuscitation, stress dose steroids and fludrocortisone, leading to a remarkable improvement in blood pressure and overall clinical status. Subsequent testing showed low serum cortisol level and elevated ACTH level, confirming the diagnosis of primary adrenal insufficiency. Continued steroids resulted in significant symptomatic improvement and with no further episodes of hypotension or syncope on ensuing follow ups. This case serves as a poignant illustration for the need for a heightened clinical suspicion, as the symptoms of adrenal insufficiency can often masquerade within the intricate tapestry of comorbidities. When the utilization of midodrine, aimed at managing orthostatic hypotension, did not abate symptoms, it prompted a thorough investigation into the possibility of underlying adrenal dysfunction. This case also highlights the collaborative, multidisciplinary approach in the management of adrenal insufficiency, with endocrinology playing a pivotal role.

Presentation: 6/1/2024
8543 Non-Specific Uptake Of Magnetic Iron Oxide Nanoparticles Into Adrenocortical Carcinoma Cells, Endothelium And Primary Monocytes
Authors: Surya Challapalli Ritihaas , Sorushanova Anna , Hong Cong , John Mullen Nathan , Feely Sarah , Covarrubias-Zambrano Obdulia , Covarrubias Jose , Varghese Sunitha , Hantel Constanza , Owens Peter , O’Halloran Martin , Prakash Punit , Bossmann Stefan H , Conall Dennedy Michael
Published: October 2024

Disclosure: R. Challapalli: None. A. Sorushanova: None. C. Hong: None. N.J. Mullen: None. S. Feely: None. O. Covarrubias-Zambrano: None. J. Covarrubias: None. S. Varghese: None. C. Hantel: None. P. Owens: None. M. O’Halloran: None. P. Prakash: None. S.H. Bossmann: None. M.C. Dennedy: None.

Adrenocortical carcinoma (ACC), a rare malignancy with a poor prognosis and a survival rate of up to 24 months, requires varied treatments such as surgery, chemotherapy, or radiation. The high recurrence rate emphasizes the need for innovative therapies. Magnetic iron oxide nanoparticles have emerged as promising candidates for cancer treatment due to their versatility in size and shape and the ability to modify their surface for targeted cellular uptake. In our initial investigation, we assessed the uptake of magnetic iron oxide nanoparticles (IONP) by ACC (H295R, HAC15, and MUC1) cells, HUVECs and primary monocytes, incubated with 0, 5, 10, 20, and 50 µg/ml of IONP for 24 hours. The results demonstrated concentration and time-dependent nanoparticle uptake and its impact on cellular viability. The optimal concentration of IONP was identified as 10 µg/ml, subsequently used to evaluate the rate of uptake and intracellular location. The efficiency of IONP uptake by ACC cells decreased when exposed to primary monocytes and an HUVEC layer, as demonstrated through a Transwell migration system. This study revealed insights into the non-specific uptake of IONP by ACC, primarily attributed to the mechanism of macropinocytosis. These preliminary findings lay the groundwork for exploring potential modifications to enhance specific uptake by ACC cells, particularly for applications like magnet-induced thermal ablation or nanobiocontrast.

Presentation: 6/2/2024
6919 Overstimulation Overload- Evidence Of Overuse Of The Cosyntropin Stimulation Test In The Hospital Setting
Authors: Goldberg R , Thelmo F , Ahmed I
Published: October 2024

Disclosure: R. Goldberg: None. F. Thelmo: None. I. Ahmed: None.

Introduction The cosyntropin stimulation test (CST), which utilizes a synthetic adrenocorticotropic hormone (ACTH) analog to stimulate the adrenal glands to release cortisol, is a test used to help define the presence or absence of adrenal insufficiency (AI). In primary and secondary AI, cortisol is inappropriately low (<18 mcg/dL) when measured 30 minutes and 60 minutes after administration of cosyntropin. The aim of this study was to assess utilization of CST in Jefferson hospital enterprise and initiation of steroid therapy based on results. Methods A retrospective analysis, using the Slicer Dicer feature of Epic electronic records (Verona, USA) was performed on all adult hospitalized patients from 5/5/2023 and 9/5/2023. Results 149 CST were performed in the above-mentioned period, 61 patients (41%) were male, and 88 patients (59%) were female. Two were excluded from the study as one test was performed incorrectly, and one study had insufficient sample to produce a result. Of the 147 patients, 47 patients (32.0%) were positive for AI. Five of 20 patients (25%) in the ICU were positive for AI. 42 of the 127 patients (33.1%) on the floor were positive for AI. Of the 47 patients diagnosed with AI, 37 were placed on steroid treatment and ten patients were not started on steroids; despite inadequate stimulation, the patient’s clinical picture was not thought to represent AI. Discussion Our analysis points to a relative overutilization of CST in Jefferson hospitals. This may be due to the relative ease of CST in the hospital setting, and clinicians should be overly cautious about ruling out AI despite the presence of more likely explanations for the clinical scenario. Notably, although several patients in the study met criteria for AI, endocrinology chose not to treat them with steroids, which raises the topic of defining AI in the critically ill patient. The validity of CST and normal cortisol cut-offs in the critically ill remain a topic of intense debate. The results of this study should prompt clinicians to think critically before ordering a CST. Despite strict cutoffs for diagnosis of AI, careful consideration of the clinical scenario should be taken into account before initiating patients on steroid therapy. If the diagnosis of AI is confirmed, patients should be followed closely as an outpatient to ensure proper adjustments to medication regimens are made.

Presentation: 6/2/2024
7705 Paliperidone Induced Central Adrenal Insufficiency: A Case Report
Authors: Shevtsova Inga , Gerstner Steven J
Published: October 2024

Disclosure: I. Shevtsova: None.

Introduction: Atypical antipsychotics reduce ACTH and control secretion in healthy subjects. However, the clinical significance of it is still unclear with only a few case reports tying antipsychotics to clinically relevant adrenal insufficiency. Case: A 32-year-old male with schizoaffective and polysubstance abuse disorders was admitted to a hospital with a complex right hand infection complicated by MRSA bacteremia, and native mitral and tricuspid valves infective endocarditis. To control the source of infection, the patient underwent multiple surgical interventions and the bacterial endocarditis required a prolonged course of IV antibiotics. The patient’s mental health negatively affected his hospital course. He was diagnosed with a schizoaffective disorder several years ago, and his mental disease has been difficult to control. There were multiple ED visits and hospitalizations for mental health issues due to significant positive and negative symptoms, substance abuse and medication noncompliance. For the last several months, the patient had not taken his medication (paliperidone). Initially, the patient displayed impulsive, aggressive, and irrational behavior caused by substance withdrawal and uncontrolled mental health illness. Paliperidone was restarted with great clinical response within 5-6 days. On week 2, the patient developed prominent symptomatic hypotension, extreme fatigue, and sleepiness. The repeat blood count was within normal limits, and chemistry showed normal electrolyte levels. Transesophageal echocardiography showed resolution of vegetation, normal ventricles and valves functions. Morning cortisol level was low, 1.58 ug/dl (3.2-22.4 ug/dl) with significant increase to 23.07 ug/dl after cosyntropin stimulation. ACTT level was inappropriately borderline low, 7.8pg/ml (7.2-63 pg/ml) and 21 hydroxylase antibodies were negative. Considering all the findings, a confident clinical diagnosis of central adrenal insufficiency was made. MRI of pituitary gland did not reveal any pathology. Drug induced central adrenal inefficiency became a primary working diagnosis. Paliperidone was discontinued. After 2 days, there was improvement in vital signs and other symptoms of adrenal insufficiency. This established a potential association between adrenal insufficiency and paliperidone. Unfortunately, the patient became restless and agitated again after withholding paliperidone for 5 days, so it was resumed. Adrenal insufficiency was treated with hormonal replacement therapy. Conclusion: This is the first case demonstrating possible paliperidone induced central adrenal insufficiency. It is important to note that even relative adrenal insufficiency caused by atypical antipsychotic might be life-threatening in a high stress state, such as sepsis. This needs to be recognized in a timely manner and managed appropriately.

Presentation: 6/2/2024
6574 Pheochromocytoma In A Patient With ESRD; Clinical Challenges And Lessons From A Successful Evaluation
Authors: Anthony Younes Sam , Sayed Alaa , Selk Karen , Willard Lauren A
Published: October 2024

Disclosure: S. Younes: None. A. Sayed: None. K. Selk: None. L.A. Willard: None.

Introduction: Pheochromocytomas are rare tumors that arise from the chromaffin cells in the adrenal medulla, that secrete norepinephrine, epinephrine and dopamine. Common presentations include resistant hypertension (HTN) and adrenergic spells with headaches, sweating and tachycardia. The literature has few cases of pheochromocytoma in the setting of end stage renal disease (ESRD). Case: A 46-year-old male with a history of resistant HTN on amlodipine, lisinopril, and labetalol, complicated by ESRD on hemodialysis (HD) and secondary hyperparathyroidism initially presented with gross hematuria. The patient reported sporadic, intermittent headaches associated with palpitations and sweating. A renal ultrasound revealed a left-sided complex renal cystic mass. CT abdomen/pelvis demonstrated an enhancing left adrenal lesion and MRI abdomen/pelvis confirmed an enhancing 4.6 x 2.8 cm adrenal mass. Laboratory studies revealed elevated normetanephrine of 1186 pg/mL (ref <149 pg/mL), elevated metanephrine at 139 pg/mL (ref <57 pg/mL) and elevated epinephrine at 128 pg/mL (ref <95 pg/mL). Given the laboratory and imaging findings in conjunction with clinical presentation, an excision of the adrenal mass was set. Two weeks prior to the surgery, alpha blockade was started with doxazosin 1mg daily with a goal blood pressure <130/80. He was admitted to the hospital with a goal to keep him 1-1.5kg above his dry weight. His dry weight was 81.5kg close to admission weight, so he was started on gentle IV hydration. He had a left robotic assisted adrenalectomy and was given stress dose steroids and a steroid taper given no preoperative Cushing’s screen was completed. No postoperative complications reported, and doxazosin was discontinued. 2 weeks later, he reported his adrenergic spells had resolved. Surgical pathology confirmed pheochromocytoma and he was referred for genetic consultation. Conclusion: Although there is little in the literature regarding management of a pheochromocytoma in patients with ESRD, similar principles of management in patients with normal renal function apply, including blood pressure control, alpha blockade, and establishment of euvolemia with recommendation of a high-sodium diet and 1-2 liters of saline the day prior to the procedure. This case highlights successful perioperative management with traditional use of alpha blockade but also incorporated maintaining the patient 1-1.5 kg above their dry weight for surgery to limit postoperative hypotension.

Presentation: 6/3/2024
7305 Pheochromocytoma Presenting With Resistant Hyperglycemia
Authors: Economou Magdalene , Devine Alma
Published: October 2024

Disclosure: M. Economou: None. A. Devine: None.

Background: Pheochromocytoma is a rare catecholamine producing tumor arising from the adrenal gland. Impaired glucose tolerance is a well-recognized hormonal and metabolic manifestation of pheochromocytoma caused by catecholamine excess [1]. Insulin resistance requiring very high doses of insulin in association with pheochromocytoma is, however, rare. Here we report a case of pheochromocytoma in a woman with diabetes mellitus that proved difficult to control despite high-dose insulin therapy. Case presentation: A 72-year-old woman with a longstanding history of type 2 diabetes mellitus, uncontrolled hypertension, hyperlipidemia and CVA presented to the hospital after she was found to have a hemoglobin of 7.0 ng/mL on routine labs. Notably, over the past 4 years, her insulin requirement gradually increased from 20 units/day to 50 units/day despite an A1c level of 6.1%. On presentation, our patient was hypertensive to 170/90 with limited response to multiple antihypertensive medications. Additionally, her glucose was severely uncontrolled, fluctuating between 200-500 mg/dL. Within days, the patient’s total daily insulin requirement increased tremendously to as much as 300 units/day. As part of her anemia workup, she underwent a contrast-enhanced CT abdomen & pelvis which identified a left adrenal mass measuring 2.2 x 2.8 x 2.9 cm. Further evaluation with MRI confirmed an adrenal mass suspicious for pheochromocytoma. Evaluation of plasma hormone levels revealed an elevated normetanephrine level of 7.10 nmol/L (normal: less than 0.89 nmol/L). Furthermore, the 24-h urinary normetanephrine level and chromogranin A levels were elevated to 145 mcg/day and 1203 ng/mL, respectively. Initial treatment with alpha and beta blockade improved blood pressure but glucose levels remained persistently elevated. The patient underwent left laparoscopic adrenalectomy and pathology revealed pheochromocytoma, measuring, 3.2 cm in diameter, with stains positive for CD56, synaptophysin and chromogranin. Surgical resection margins were negative for tumor. Postoperatively, insulin requirements returned to roughly that of her baseline, 40 units/day. Conclusion: Impaired glucose tolerance is a known phenomenon associated with pheochromocytoma. Despite this, it is unusual to see an insulin requirement rise as abruptly and drastically as seen in this case. Our patient, with relatively controlled diabetes had an enormous increase in her insulin requirement during her hospital course as evidenced by her insulin regimen which increased sixfold. This case highlights the importance of maintaining a high degree of suspicion for pheochromocytoma in patients with a sudden rise in insulin requirement and uncontrolled hypertension. Reference: (1) Ronen JA, Gavin M, Ruppert MD, Peiris AN. Glycemic Disturbances in Pheochromocytoma and Paraganglioma. Cureus. 2019 Apr 27;11(4): e4551.

Presentation: 6/3/2024
6426 Pregnancy-induced ACTH-independent Cushing Syndrome: A Rare Phenomenon Secondary To Aberrant Receptors On Adrenal Glands
Authors: Manglani Kajol , Sharma Susmeeta T
Published: October 2024

Disclosure: K. Manglani: None. S.T. Sharma: None.

Pregnancy-induced hypercortisolism is a rare phenomenon with very few cases reported in the literature. The pathogenesis is thought to be secondary to the expression of aberrant LH/hCG receptors on the adrenal gland that stimulate cortisol production in pregnancy. We present a case of a 31-year-old female with no past comorbidities until her first pregnancy in 2017 when she gained around 50lbs, developed violaceous striae, acne, hirsutism, depression with suicidal ideation for which she was hospitalized twice, and underwent emergent C-section at 34 weeks’ gestation due to pre-eclampsia. She was referred to the Endocrinology clinic post-delivery, and screening for Cushing syndrome was negative at that time: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC) and 1-mg dexamethasone (dex) suppression test (DST) were normal. She presented again in 2020 during her second pregnancy at 14 weeks gestation, with 20lb weight gain in the first trimester, acne, hirsutism, and easy bruising. Labs showed cortisol of 22.4 mcg/dL (6.2-19.4), ACTH <1.5 pg/mL, total testosterone 168 ng/dL (8-48), androstenedione 751 ng/dL (41-262), DHEAS 91.2 mcg/dL (84.8-378), 24-hour UFC 277 mcg/day (6-42), LNSC 0.671 mcg/dL, 1mg DST with post-dex cortisol 24 mcg/dL (dex level 58 ng/dL), and 8-mg DST with post-dex cortisol level of 28.2 mcg/dL (dex level 457 ng/dL). Testing was consistent with ACTH-independent Cushing syndrome. Ultrasound and MRI of the abdomen/pelvis showed normal adrenal glands with no hyperplasia or mass. Given worsening hypercortisolism and her course during a prior pregnancy, medical treatment with metyrapone was initiated. We started at a dose of 500 mg daily and gradually increased to 1500 mg with close monitoring of her blood pressure and cortisol levels. She underwent vaginal delivery at 38 weeks’ gestation, and the baby required a brief stay in the NICU for respiratory distress but was otherwise doing well. The patient developed secondary adrenal insufficiency post-delivery requiring hydrocortisone, with recovery of her HPA axis in around 10 weeks. Since then, she has been off hydrocortisone with normal UFC, ACTH, and cortisol levels. This case enables discussion regarding the underlying etiology, diagnostic difficulties, and management of this rare condition. Although the exact etiology is unknown, the postulated mechanism is aberrant LH/hCG receptor expression given the patient’s presentation during each pregnancy, normal cortisol levels between both pregnancies, and a brief period of adrenal insufficiency post-delivery. Management of hypercortisolism during pregnancy remains challenging. Metyrapone, a steroidogenesis inhibitor, can be considered for control of hypercortisolemia during pregnancy (off-label) in select cases to prevent maternal and fetal complications.

Presentation: 6/1/2024
9313 Prevalence And Incidence Of Fragility Fractures In Patients With Nonfunctioning Adrenal Incidentalomas
Authors: Favero Vittoria , Cairoli Elisa , Eller-Vainicher Cristina , Morelli Valentina , Stefano Salcuni Antonio , Della Casa Silvia , Muscogiuri Giovanna , Columbu Carla , Pugliese Flavia , Corbetta Sabrina , Persani Luca , Scillitani Alfredo , Chiodini Iacopo
Published: October 2024

Disclosure: V. Favero: None. E. Cairoli: None. C. Eller-Vainicher: None. V. Morelli: None. A.S. Salcuni: None. S. Della Casa: None. G. Muscogiuri: None. C. Columbu: None. F. Pugliese: None. S. Corbetta: None. L. Persani: None. A. Scillitani: None. I. Chiodini: None.

Context: The risk of vertebral fractures (VFx) in patients with non-functioning adrenal incidentalomas (NFAI) is unknown. Objective: To evaluate the VFx prevalence and incidence in NFAI patients. Design. Cross-sectional and longitudinal study on retrospective data. Setting. Four Italian endocrinology units. Patients. 306 NFAI patients (cross-sectional arm) and 213 matched control subjects to evaluate VFx prevalence; 85 NFAI patients (longitudinal arm, follow-up 30.3±17.5 months) to evaluate VFx incidence. Main outcome measures: serum cortisol after 1 mg-dexamethasone test (F-1mgDST), bone mineral density (BMD) at spine (LS) and femur (FN), and VFx presence by x-ray. Results:. Cross-sectional arm: prevalent VFx was associated with F-1mgDST with the cut-off set at 1.2 µg/dL (33 nmol/L, area under the curve 0.620±0.39, p=0.002). As compared with controls and with NFAI patients with F-1mgDST <1.2 µg/dL (33 nmol/L, Group NFAI-A), NFAI patients with F-1mgDST ≥1.2 µg/dL (33 nmol/L, Group NFAI-B) showed higher VFx prevalence (10.8%, 12.6% and 29.5%, respectively, p<0.001 for all comparisons), which was independently associated with F-1mgDST ≥1.2 µg/dL (33 nmol/L, odds ratio 3.02, 95% confidence interval 1.63-5.58, p<0.001) regardless for influencing factors including BMD. Longitudinal arm: the VFx incidence was higher in Group NFAI-B than in Group NFAI-A (19.3% vs 3.6%, p=0.05). In NFAI-B group, all incident VFx occurred in patients without low BMD. The F-1mgDST cut-off for predicting an incident VFx was 1.2 µg/dL (33 nmol/L), but the incident VFx was not independently predicted by F-1mgDST ≥1.2 µg/dL (33 nmol/L) after adjusting for possible influencing factors, including BMD and presence of prevalent VFx. Conclusions: In NFAI patients, F-1mgDST levels ≥1.2 µg/L (33 nmol/L) are associated with prevalent VFx and may identify NFAI patients at higher risk of incident VFx

Presentation: 6/3/2024