bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI223 Ectopic ACTH Syndrome
Authors: Sudhakar Shwetha Mallesara , Story Ellen Shannon 
Published: October 2023

Abstract
Disclosure: S. Mallesara Sudhakar: None. E.S. Story: None.
Introduction: Ectopic ACTH Syndrome (EAS) is caused by hypercortisolism from extra-hypophysial tumors. EAS accounts for 10-15 % of Cushing’s Syndrome. Case 1: A 36 year old male with recently diagnosed stage IV well differentiated grade 2 neuroendocrine tumor (NET) of the pancreas with liver metastases developed new hypertension, hyperglycemia, hypokalemia, metabolic alkalosis, fatigue and muscle weakness. There were no obvious signs of Cushing’s Syndrome. ACTH was 679 pg/ml, cortisol 120 ug/ml. MRI pituitary was normal. He required 4 antihypertensives, insulin, and metyrapone was initiated for hypercortisolism. Due to difficulty obtaining medications during the COVID pandemic, intolerance to therapies and lack of improvement in clinical symptoms, decision was made to perform laparoscopic bilateral adrenalectomy. He was started on hydrocortisone and fludrocortisone. Pathology revealed diffuse adrenal hyperplasia. Post-surgery he improved dramatically and was able to discontinue antihypertensives and insulin. Chemotherapy for the underlying tumor was discontinued due to cytopenias. His cancer progressed and he succumbed to disease 10 months from initial diagnosis. Case 2: A 60 year old female presented with severe hypokalemia, metabolic alkalosis, hypercalcemia, cytopenias, HTN, weight loss, muscle weakness, nausea and mental status changes. CT abdomen showed bilateral adrenal hyperplasia. ACTH was 489 pg/ml, cortisol 81 ug/ml. MRI pituitary was unremarkable. PET-CT additionally showed hypermetabolic mediastinal lymph nodes and right upper lobe nodular opacity, and widespread osseous lesions. She was started on ketoconazole and antihypertensives. Bilateral adrenalectomy was considered but could not be performed due to rapid clinical deterioration. Etomidate was initiated. Fine needle aspiration of a mediastinal lymph node showed small cell carcinoma. Patient became too frail to receive systemic chemotherapy and succumbed within 2 weeks of hospitalization. Discussion: Most Ectopic ACTH Syndrome cases are caused by NET of the lung, pancreas and thymus. In children, Ewing’s sarcoma has been reported. Small cell carcinoma of lung, malignant pancreatic NETs, and medullary carcinoma of thyroid often present with metastasis and carry an ominous prognosis. Not all patients have clinical features of classic Cushing's syndrome. The outcome of EAS correlates with tumor type. Optimum treatment is surgical resection of the tumor, often not possible with metastatic disease. Hypercortisolism may be controlled with adrenal enzyme inhibitors and receptor blockers. Bilateral surgical adrenalectomy may be needed when symptoms are not controlled by medical management. Early and rapid control of Cushing’s Syndrome is important to facilitate antineoplastic treatment of the underlying tumor.
Presentation: Friday, June 16, 2023
THU555 Stress Induced AIPB Expression In Triple Negative (ER-/PR-/Her2-) Breast Tumors Reduces Estradiol
Authors: Patrawala Mahjabin , Bose Himangshu S 
Published: October 2023

Abstract
Disclosure: M. Patrawala: None. H.S. Bose: None.
In the United States, 1 in 8 women will develop invasive breast cancer in their lifetimes, and currently, more than 3.8 million individuals are survivors. Breast cancers are hormonally regulated and are categorized ER+/PR+/HER2-, ER-/PR-/HER2+, ER+/PR-/HER2-, and ER-/PR-/HER2-. In patients with Estrogen Receptor positive (Er+) and Progesterone Receptor positive (PR+), these receptors are used for targeted therapy. However, about fifteen percent of patients are diagnosed with triple-negative breast cancer. Currently, there are no molecular therapies for this cancer and only 20% of the cases respond to chemotherapy, so new prognostic markers and therapies are necessary. Aromatase, the rate limiting enzyme catalyzes testosterone to estradiol, is expressed in the ovaries of pre-menopausal women and increases 20-fold in peripheral tissues and fat bodies, like breast, in post-menopausal women contributing to tumor growth. We observed “Aromatase Interacting Partner in Breast (AIPB)” overexpression inhibits aromatase activity resulting by decreasing in estradiol. In triple-negative breast cancer, patients have a more than ten-fold decline in the expression of AIPB compared to ER+/PR+/Her2- breast tumors. Patients diagnosed with triple-negative breast cancer are profoundly stressed considering the low survival rate, which induces higher cortisol synthesis. We hypothesize the stressor will change the expression of AIPB in the tumor cells which will possibly reduce estradiol synthesis. The stress was emulated using a laboratory model in which a heat shock of 42° was delivered for varying periods (0,15,30,45 minutes). The model was used on engineered triple-negative tumor cells which conditionally overexpress AIPB with the addition of tetracycline. We observed MDA-MD-231 cells had a 50% reduction of estradiol from 160 ng/ml to 100 ng/ml following stress for 45 minutes. Interestingly MDA-MD-231-AIPB cells synthesized only 62 ng/ml, which is an 18.75% reduction. On addition of doxycycline, the estradiol level was further decreased to 47 ng/ml, which is about 29.4%. Western blot with a CT antibody of the MDA-MB-231-AIPB cells showed an increase in AIPB expression at the maximum level when stress was performed in combination with doxycycline. Aromatase is absent in triple-negative breast cancer, so we conclude aromatase independent action AIPB in these triple-negative tumorigenic cells plays a crucial role in estradiol synthesis. With our current data, we can suggest a model in which stimulating higher expression of AIPB in patients can provide them with better and longer lives.
Presentation: Thursday, June 15, 2023
THU556 Targeting Breast Cancer Stem Cells With Oncolytic Virus
Authors: Roman Ortiz Natasha Ivelisse , Danthi Pranav , Ostrander Julie Hanson 
Published: October 2023

Abstract
Disclosure: N.I. Roman Ortiz: None. P. Danthi: None. J.H. Ostrander: None.
Breast cancer is the second leading cause of cancer deaths among women in the United States. Estrogen receptor positive [ER+] breast cancer has a more favorable prognosis; however, patients can experience recurrence for many years after initial diagnosis. Breast cancer stem cells (BCSC), which are dormant and exist as a minority sub-population (0-5%), drive recurrence, metastasis and resistance to therapies that primarily target rapidly proliferating tumor cells. Current treatments are insufficient to cure metastatic ER+ breast cancer and there are no FDA approved therapeutics that target BCSC. Mammalian orthoreovirus (MRV) is an oncolytic virotherapy tested in clinical trials for many cancer types including metastatic breast cancer. MRV was found to be safe, but efficacy limited as a monotherapy. In our studies we compared several laboratory MRV strains (T1L, R2) to the strain most similar to Reolysin, which is being tested in clinical trials (i.e. T3D). Our studies suggest that T3D is less effective in killing ER+ breast cancer cells and BCSCs. We propose to generate a novel MRV strain with enhanced BCSC-targeting capacity using forward genetic approaches by serially passaging MRV strains in BCSC enriched 3D tumorsphere cultures of MCF-7 Paclitaxel resistant (TaxR) cells to generate a selective oncolytic virus. Preliminary data has shown that serially passaged (SP) MRV strains (T1L SP, R2 SP) are more effective in decreasing cell viability and inhibiting tumorsphere formation compared to the parental (P) strains (T1L P, R2 P). We anticipate these studies will lead to an improved MRV oncolytic virotherapy that will be combined with clinically relevant inhibitors, such as CDK4/6 inhibitors and anti-estrogens, to prevent and treat therapy-resistant ER+ breast cancer.
Presentation: Thursday, June 15, 2023
OR05-02 Silencing Of Adenylosuccinate Lyase Impairs Growth And Perturbs Mitochondrial Function Of Endocrine Therapy Resistant Breast Cancer Cells
Authors: Yadav Anil K , Jin Lu , Clarke Robert , Sengupta Surojeet 
Published: October 2023

Abstract
Disclosure: A.K. Yadav: None. L. Jin: None. R. Clarke: None. S. Sengupta: None.
The estrogen receptor positive (ER+) subtype comprises of ∼80% of all breast cancers and is the major contributor to cancer related deaths in women. While ER+ breast cancers respond to treatment with endocrine therapies (ET) such as tamoxifen, Fulvestrant and aromatase inhibitors, a major limitation is emergence of resistance to ET resulting from adaptive pathways that promote relapse and disease progression. Hence, there is an urgent need for identification and validation of new molecular targets for potential therapeutic treatment of ET resistant-ER+ breast cancer. Here, we have determined the role of adenylosuccinate lyase (ADSL), a crucial enzyme involved in the de novo purine synthesis pathway, as a potential molecular target for ER+ breast cancer cells. ADSL enzyme catalyzes two non-sequential steps in de-novo purine synthesis pathway that produces aminoimidazole carboxamide ribonucleotide (AICAR) and adenosine monophosphate (AMP); fumarate is generated as a byproduct. We observed higher protein expression of ADSL in LCC9 (endocrine therapy crossresistant cells) when compared with LCC1 or MCF-7 (antiestrogen sensitive) cells. Additionally, T47D-4HT cells (also endocrine therapy resistant) also expressed modestly higher ADSL protein level in comparison to its parental endocrine therapy sensitive T47D-A18 cells. Notably, siRNA-mediated knockdown of ADSL in both LCC9 and T47D-4HT cells leads to strong inhibition of cell proliferation, long-term colony, and spheroid formation. Furthermore, ADSL depletion in LCC9 increased the accumulation of cells in G0/G1 phase along with elevated protein expression of cyclin D1. In T47D-4HT cells, ADSL knockdown caused cells to accumulate in S-phase, with a reduction of total cyclin D1 protein levels. Further investigation revealed that ADSL knockdown decreased ATP levels and mitochondrial membrane potential in both LCC9 and T47D-4HT cells and significantly reduced the basal oxygen consumption rate (OCR) and maximal respiration capacity. Notably, addition of AICAR (100 µM) to ADSL deficient LCC9 cells partially rescued cell proliferation, colony formation, and restored the mitochondrial membrane potential. In clinical datasets higher expression of ADSL transcripts correlates with poor relapse free survival in ER+ breast cancer patients treated with endocrine therapies. Overall, our results indicate that ADSL-mediated de novo purine synthesis plays an important role in growth and proliferation of endocrine therapy resistant ER+ breast cancer cells through mitochondrial function. Therefore, targeting ADSL is a novel potential therapeutic approach for ER+ endocrine resistance breast cancer.
Presentation: Thursday, June 15, 2023
FRI224 A Rare Case Of Recurrent Paraganglioma Presented With Liver Metastasis
Authors: Gupta Eisha , Al Mushref Mazen 
Published: October 2023

Abstract
Disclosure: E. Gupta: None. M. Al Mushref: None.
Malignant Paragangliomas (PGLs) and Pheochromocytomas (PCC) are extremely rare. Approximately 10% of PCCs and 25% of PGLs are metastatic. Metastatic PGLs typically occur in patients with predisposing genetic mutations. We present a case of recurrent metastatic PGL in a young female with no known genetic predisposition to metastatic disease occurring after surgical resection. Our patient is a 28-year-old female with a history of PGL status post left adrenalectomy and nephrectomy two and a half years prior who presented to the ED for abdominal pain. She was first diagnosed after being admitted for hypertensive emergency. During time of diagnosis, plasma and urinary metanephrines were significantly elevated at 1.13 nmol/L and 907 ug/gCr respectively and plasma and urinary normetanephrines were elevated at 80.2 nmol/L and 52043 ug/gCr respectively. MRI showed a 16 cm left retroperitoneal mass and MIBG scan showed increased uptake in the mass however no evidence of metastatic disease was noted then. The patient had immigrated from Haiti. Her mother had passed away at age 20 of unknown cause and her father has no known history. Genetic testing was negative for hereditary gene mutations including multiple SDHDs, VHL, NF1, MEN1 and MAX. Surgical exploration showed a giant left retroperitoneal neoplasm involving the left kidney and left adrenal and both organs were resected. Pathology revealed PGL, focally extending to peripheral specimen margin and benign retroperitoneal lymph nodes and soft tissues. Post-resection meta- and normetanephrines levels were normal. Unfortunately, the patient was lost to follow up after surgery. On this admission, she endorsed right lower quadrant abdominal pain. Plasma normetanephrine was 1.72 nmol/L, metanephrine was normal, and chromogranin A level was elevated at 545 ng/mL. CT scan revealed multiple hepatic lesions and MIBG scan further showed new increased uptake suggesting metastasis. The patient was asymptomatic and blood pressure remained normal during her hospitalization. Due to concerns of recurrent PGL with metastasis, she established care with Oncology for initiation of treatment. PGL is an extremely rare neuroendocrine tumor and is closely related to PCC. Sympathetic PGLs cause catecholamine surge symptoms but low volume disease may remain asymptomatic. Genetic predisposition is common in malignant PGL particularly succinate dehydrogenase mutation subunit B. Patients should be closely followed up to screen for recurrence and genetic testing should also be done. In our patient’s case, despite surgical resection and negative genetic testing, she developed recurrence of the PGL with new metastasis emphasizing the importance of close surveillance in the case of PGL to monitor for recurrence.
Presentation: Friday, June 16, 2023
OR05-04 Growth Hormone Receptor Antagonism Markedly Improves Therapeutic Response In Mouse Models Of Melanoma, Liver Cancer, Pancreatic Cancer And Cholangiocarcinoma
Authors: Basu Reetobrata , Kulkarni Prateek , Ortiz Silvana Duran , Davis Emily , Kopchick John Joseph 
Published: October 2023

Abstract
Disclosure: R. Basu: None. P. Kulkarni: None. S. Duran Ortiz: None. E. Davis: None. J.J. Kopchick: None.
A major hurdle in tackling cancer, the second biggest cause of human mortality, is resistance to therapy. Human growth hormone (GH) mediated activation of the growth hormone receptor (GHR) promotes the initiation and invasive progression of several types of human cancers, known since 1950. Recently, through a series of mechanistic studies using in vitro models and in silico analyses of human cancer patient databases, we have identified a covert role of GH in promoting cancer drug resistance via direct upregulation of: (i) the expression of ATP-binding cassette containing multi-drug transporters (ABC transporters) leading to increased drug efflux, (ii) the epithelial-to-mesenchymal transition (EMT) associated gene expression program, and (iii) the mediators of fibrosis and extracellular matrix remodeling. Additionally, based on the known effects of GH and robust expression of GHR in multiple cell types that constitute the tumor microenvironment, autocrine / paracrine GH putatively exerts potent tumor supportive actions. Therefore, we hypothesized that combining GHR antagonist to chemotherapy can markedly improve therapeutic outcome in human cancers. Melanoma and liver cancer jointly and annually constitute &gt;150,000 patients and &gt;60,000 deaths in the US, much due to resistance to therapy. We used a syngeneic murine model of both cancers using C57BL6 mice transgenic for a GHR antagonist (GHA mice) compared against wild-type (WT) counterparts implanted with either B16F10 melanoma or Hepa-1-6 hepatoma cells. GHA expression drastically sensitized melanoma tumors to cisplatin treatment and hepatoma tumors to sorafenib treatment. Additionally, the five-year survival rates of pancreatic cancer and cholangiocarcinoma are a dismal 10% in 2022, indicating an urgent need for new therapeutic approaches for both of these devastating diseases. For this, we used Nude mice for human pancreatic cancer xenografts treated +/- GHA (Pegvisomant and another in development at our laboratory) combined with gemcitabine. Combination of GHA markedly sensitized pancreatic cancer xenografts to gemcitabine in Nude mice, leading to ∼40% of mice being tumor-free at the end of study. GHA similarly also sensitized human cholangiocarcinoma xenografts in Nude mice to gemcitabine-cisplatin therapy. In all cases, GHA led to a marked reduction in gene expression of multidrug efflux transporters, EMT markers, and fibrosis mediators. Collectively, our data provides strong pre-clinical validation for treatment regimens combining GHR antagonist and chemotherapy leading to highly efficacious tumor clearance.
Presentation: Thursday, June 15, 2023
FRI232 Importance Of Rapid Treatment Initiation In Ectopic Cushing Syndrome: Abstract
Authors: Mendez Dianelys , Fernandez Maria Gabriela , Selen Daryl J 
Published: October 2023

Abstract
Disclosure: D. Mendez: None. M.G. Fernandez: None. D.J. Selen: None.
Background: Endogenous Cushing syndrome may result from an ectopic non-pituitary tumor. Severe hypercortisolism has high mortality, so prompt medical management to acutely decrease cortisol levels is necessary when no surgical options are available. Clinical Case: A 67-year-old male presented to the hospital with four weeks of fatigue and was found to have a right hilar mass with unsuppressed cortisol levels for which an ectopic tumor was suspected. On initial evaluation, the patient presented with hypokalemia, acute kidney injury, and metabolic alkalosis. In addition, a CT of the chest and abdomen with contrast revealed a right hilar mass with multiple liver lesions concerning for metastasis. These findings prompted workup for hypercortisolism, including 1mg and 8 mg dexamethasone suppression tests. Both tests demonstrated unsuppressed cortisol levels above 150 (reference range [RR] 5.5-20 ug/dl and assay maximum&gt;150) and elevated 24-hour urinary cortisol of 8125 (RR &lt;60 ug/dl), suspicious for an ACTH-secreting tumor. Subsequently, he underwent a liver biopsy to characterize the tumor further and was started on Bactrim for Pneumocystis pneumonia prophylaxis. Metyrapone and osilodrostat were considered for treatment but not available at our facility such that treatment was initiated with ketoconazole 200 mg orally twice daily with subsequent dose titration. He had a mild elevation of AST 52 (RR 7-42 IU/L) and ALT 52 (RR 10-45); therefore, his liver profile was monitored daily due to his elevated risk for hepatotoxicity. With the initiation of ketoconazole, cortisol serum levels decreased to 145 ug/dl after two days of treatment. The pathology report revealed small lung cell carcinoma as the etiology for ectopic Cushing’s syndrome, for which the oncology team-initiated etoposide and carboplatin. Unfortunately, on day 6 of the initiation of treatment, the patient rapidly deteriorated and passed away from pneumonia and septic shock. Conclusion: Severe hypercortisolism leads to an immunosuppressed state resulting in high mortality. Therapeutic options depend significantly on the accessibility of first-line treatment options and prompt initiation of medical treatment. When no other agents are available, ketoconazole should be started at high doses despite the mild elevation of liver enzymes with close monitoring of LFTs. While it is unclear if the patient’s deterioration was due to his cancer burden, chemotherapy, severe hypercortisolism, or a combination, given that osilodrostat and metyrapone are first-line treatment options, standardized systems should be reviewed in hospitals for faster acquisition of these medications to avoid delays in treatment initiation. In addition, the decision to transfer patients to the intensive care unit for etomidate infusion while awaiting the acquisition of the above medications should be considered promptly.
Presentation: Friday, June 16, 2023
FRI242 Primary And Secondary Adrenal Insufficiency Post Transsphenoidal Surgery In Patient On Abiraterone Therapy
Authors: Akande Rukayat Olabisi , Abramowitz Jessica , Mirfakhraee Sasan 
Published: October 2023

Abstract
Disclosure: R.O. Akande: None. J. Abramowitz: None. S. Mirfakhraee: None.
Introduction: This case report describes the co-existence of primary and secondary adrenal insufficiency in a patient who received abiraterone therapy for metastatic prostate cancer and had transsphenoidal surgery for symptomatic pituitary adenoma. It sheds light on the presentation of the patient and explains the subsequent management. Clinical Case: A 67-year-old man with a history of metastatic prostate cancer (status post prostatectomy and radiation) and recent transsphenoidal surgery for pituitary adenoma presented with 3+ pedal edema. The patient had been discharged on hydrocortisone as per neurosurgery protocol and continued abiraterone after his transsphenoidal surgery. His pedal edema started two months after discharge. He denied fatigue, nausea, and dizziness. His vital signs and electrolytes, including serum potassium, were within normal limits. The patient was diagnosed with mineralocorticoid excess in the context of combined primary and secondary adrenal insufficiency. His hydrocortisone was changed to prednisone 5mg daily and his pedal edema subsequently resolved. Conclusion: Abiraterone, a hormonal therapy for the treatment of metastatic prostate cancer, is an irreversible inhibitor of CYP17, a microsomal enzyme with 17 alpha-hydroxylase and 17,20-lyase activities. This inhibition reduces cortisol and androgen concentrations while stimulating ACTH production. Thus, abiraterone use led to primary adrenal insufficiency in this patient. As a result of the 17 alpha-hydroxylase and 17,20-lyase pathway inhibition, there is increased production of deoxycorticosterone, which can lead to fluid retention. This patient was post pituitary surgery with partial secondary adrenal insufficiency and received hydrocortisone postoperatively as an appropriate glucocorticoid replacement in this setting. He developed pedal edema due to mineralocorticoid excess from abiraterone use while on hydrocortisone therapy. He was placed on prednisone, a more potent synthetic glucocorticoid than hydrocortisone, with subsequent rapid resolution of his edema.
Presentation: Friday, June 16, 2023