bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU518 Ectopic Cushing Syndrome In A Case Of Ewing Sarcoma
Authors: Fasen Madeline , Mayson Sarah Emily 
Published: October 2023

Abstract
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 &lt; 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 (&lt;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

Abstract
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: &lt; 60 ug/d), ACTH 807 pg/mL (n:7.2-63.3 pg/mL) and gastrin level &gt;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

Abstract
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
THU544 Prostatic Acid Phosphatase Is Negatively Regulated By Androgens And Persists In Castrate-resistant Metastatic Prostate Cancer
Authors: Rajagopalan Vinodh , Kirschenbaum Alex , Yao Shen , Levine Alice 
Published: October 2023

Abstract
Disclosure: V. Rajagopalan: None. A. Kirschenbaum: None. S. Yao: None. A. Levine: None.
Abstract: Prostate cancer (PCa) is the most common cancer and second leading cause of cancer death in American men. Most patients with metastatic PCa respond initially to androgen deprivation therapy (ADT) but the majority will progress to lethal, metastatic, castrate-resistant PCa (mCRPC). The identification of markers of mCRPC that are not regulated or negatively regulated by androgens can serve as markers and therapeutic targets in mCRPC. We hypothesized that prostatic acid phosphatase (PAP), a protein phosphatase and 5’ectonucleotidase that is expressed in both the cytoplasm and transmembrane (TM-PAP) of PCa cells, is negatively regulated by androgen signaling and can serve as a therapeutic target. Methods: Protein expression of PAP was assessed with western blotting in PCa cell lines. TM-PAP is identified by sub-cellular fractionation analysis, confocal microscopy, and flow cytometry. Effects of androgens and anti-androgens on PAP expression were assessed in VCaP cells with dihydrotestosterone (DHT) and Enzalutamide treatment followed by PAP, AR and PSA protein expression determined with Western Blotting. Loss of function analysis of PAP was performed with siRNA-mediated silencing and functional analysis was evaluated with migration and colony formation assays. Transcriptional regulation of PAP was determined by real time qPCR analysis. ChiPseq was done to confirm the binding of AR to PAP promoter. Results: All forms of PAP including TM-PAP are expressed in VCaP cell line. However, we did not detect PAP protein expression in-vitro in the LNCaP, C42B or 22Rv1 cell lines. In VCaP cell lines, we demonstrated that androgens decreased while anti-androgens increased PAP expression in a time and dose dependent fashion. Androgenic regulation of PAP occurred, at least in part, at the transcriptional level. We successfully knocked down TM and secretory PAP expression in VCaP cells using siRNA technology and showed that loss of PAP decreased migration and colony formation. Conclusions: The identification of markers of mCRPC that not regulated or negatively regulated by androgen could help identify recalcitrant tumor cells and mount targeted delivery of therapeutic agents. In the VCaP cell line, derived from a patient with mCRPC, TM and cytosolic PAP is one such protein that is negatively regulated by androgen signaling and may therefore serve as a viable therapeutic target in mCRPC.
Presentation: Thursday, June 15, 2023
THU548 The Role Of Sirtuin 3 In Endocrine Therapy Resistant Breast Cancer Cells Response To Fulvestrant
Authors: de Oliveira Karla Andrade , de Oliveira Andrade Fabia , Ozgul-Onal Melike , Yadav Anil , Onal Tuna , Jin Lu , Sengupta Surojeet , Clarke Robert 
Published: October 2023

Abstract
Disclosure: K.A. de Oliveira: None. F.D. Andrade: None. M. Ozgul-Onal: None. A. Yadav: None. T. Onal: None. L. Jin: None. S. Sengupta: None. R. Clarke: None.
Endocrine therapy can lead to cellular nutrient deprivation by reducing glucose and glutamine uptake and total cellular ATP production in breast cancer cells. The ability to bypass this metabolic stress is fundamental to how breast cancer cells regulate growth and acquire endocrine resistance. SIRT3, which can be activated by calorie restriction, modulates mitochondrial adaptation to low energy input. It has a key role in mitochondrial integrity and function, regulating cell survival, death, and metabolism, regulating the shift to amino-acid and fatty-acid catabolism. SIRT3 can maintain ROS levels at the appropriate levels for sustaining a proliferative phenotype, preventing apoptosis and promoting carcinogenesis. A role of SIRT3 in epigenetic regulation has also been reported. The ability of SIRTs to sense and respond to changes in energy, coupled with their intrinsic deacetylase/deacylase functions, could provide a mechanism for the cell to rewire signaling and maintain a newly acquired drug-resistant phenotype. Using antiestrogen sensitive (LCC1) and cross-resistant (LCC9) breast cancer cells, we confirmed higher expression of SIRT3 in LCC9, compared with LCC1 cells. Upregulation of SIRT3 expression within 24 hrs of Fulvestrant (ICI 1 µM) treatment (p=0.0176) in LCC1 was shown, whereas no effect was observed in LCC9 cells. Inhibition of SIRT3 activity, using the inhibitor LC0296 (15 µM), reduced growth rate in both LCC1 and SIRT3-silenced LCC9 cells under treatment with ICI (p&lt;0.0001, p&lt;0.001 respectively). Treatment with SIRTUIN 3 inhibitor and ICI induced caspase-independent cell death in LCC1 and SIRT3-silenced LCC9 cells compared to the untreated control and ICI only treated cells (p&lt;0.001). The combination of SIRT3 inhibition (LC0296, 15 µM) and ICI treatment (0.5 µM) increased ROS production in LCC9-SIRT3 silenced cells in 24 hrs compared with the untreated control and ICI only treated cells (p&lt;0.001). The combination of LC0296 and ICI induced a decrease in mitochondrial membrane potential and ATP production, and a decrease in glycolytic capacity and glycolytic reserve in both LCC1 and SIRT3-silenced LCC9 cells, compared with the untreated control (p&lt;0.001). Moreover, ICI significantly reduced ATP production in the mitochondria of the SIRT3-silenced LCC9 cells (p&lt;0.001) but not in the non-silenced (control) LCC9 cells. Taken together, these results show that SIRT3 may have a key role in determining the response to fulvestrant response in ER+ breast cancer cells; a more detailed understanding of this role for SIRT3 is under investigation in our laboratory.
Presentation: Thursday, June 15, 2023
THU550 The Splicing Factor SRSF6 Regulates Androgen Receptor Activity And Represents A Potential Therapeutic Target In Prostate Cancer
Authors: Luque Raul M , Montero-Hidalgo Antonio J , Gomez-Gomez Enrique , Olmos David , Gahete Manuel D , Jimenez-Vacas Juan M 
Published: October 2023

Abstract
Disclosure: R.M. Luque: None. A.J. Montero-Hidalgo: None. E. Gomez-Gomez: None. D. Olmos: None. M.D. Gahete: None. J.M. Jimenez-Vacas: None.
Background: Prostate cancer (PCa) is the fifth leading cause of cancer-related death worldwide. Finding novel therapeutic strategies to tackle PCa, especially its most advanced phenotype [i.e., castration-resistant prostate cancer (CRPC)], is urgently needed. In this sense, although the dysregulation of the splicing process has emerged as a distinctive feature of advanced PCa, the potential role that splicing regulators may play in this disease remain poorly understood. In this study, we aimed to analyse the levels, pathophysiological role and associated molecular landscape of the splicing factor SRSF6 in PCa. Methods: SRSF6 levels (mRNA, protein and CNA) were interrogated in seven well-characterized cohorts of PCa patients and in the Hi-MYC transgenic model. The effect of SRSF6 overexpression and silencing was tested in vitro (proliferation, migration, colony- and tumorspheres-formation) and in vivo (tumor growth of xenograft tumours). RNAseq was performed in 22Rv1 cells to analyse splicing and gene expression changes in response to SRSF6 silencing. Findings: Our results showed that SRSF6 levels (mRNA/protein) are upregulated in PCa vs non-tumour prostate samples, linked to clinical parameters of tumour-aggressiveness (e.g., Gleason score, T-stage, perineural infiltration, metastasis at diagnosis), and associated with poor prognosis (i.e., shorter disease-free survival time) in PCa patients. Moreover, SRSF6-overexpression increased, while its silencing decreased, functional parameters of aggressiveness in vitro and tumour growth in vivo. Mechanistically, SRSF6 modulation resulted in dysregulation of Androgen-Receptor (AR) activity through transcriptional control of APPBP2 and TOP2B. Discussion: SRSF6 could represent a new therapeutic target to inhibit persistent AR-signalling in advanced PCa. Funding: Spanish Ministry of Science, Innovation, and Universities (PID2019-105564RB-I00, FPU18/02485), Health Institute Carlos III (DTS20-00050), and CIBERobn.
Presentation: Thursday, June 15, 2023
THU558 Combination Therapy Of Acetyl-CoA Synthetase Inhibitor And Fulvestrant Reverse Epigenetic Alterations Of Metastatic Breast Cancer Cells And Reduce Cancer Cell Proliferation
Authors: Mogol Ayca N , Erdogan Zeynep Madak 
Published: October 2023

Abstract
Disclosure: A.N. Mogol: None. Z. Madak Erdogan: None.
Endocrine therapies exploit the hormone dependencies of the cancer cells in various ways, including by targeting estrogen receptor alpha (ERα) that is expressed by approximately 70% of human breast cancers. After treatment, recurrence and metastasis are still observed in 30-40% of ER+ patients and the 5-year relative overall survival rate for these patients is just 24%. Acetyl-CoA production significantly regulates histone acetylation and gene regulation, which support tumor progression. In our previous study, we showed the synergistic effect of the ERα agonist Fulvestrant (Fulv) and Acetyl-CoA Synthase Inhibitor (ACSI) in reducing cell viability in ER+ metastatic breast cancer (MBC) cells in vitro. To study the synergistic contribution of ACSS2 to endocrine resistance, we used ChIP analysis, which showed that ACSS2 was recruited to ERα binding sites with Fulv treatment in cell line xenograft tumors and PDX samples. We used the CUT&RUN method to investigate specific protein (H3k27ac, ERα and ACSS2) and DNA interactions in ER+ MBC cells globally. Enriched chromatin samples were then used for qPCR and sequencing. Combination therapy of the ACSI and Fulv significantly altered the epigenetic landscape of the breast cancer cells in a manner to decrease cell viability. High histone acetylation at lysine 27 residue was observed in Veh treatment group and combination therapy of ACSI+Fulv further decreased the enrichment of this histone modification in classical ER binding sites. Interestingly, ACSS2 binding was increased with Fulv treatment. Targeting epigenetic alterations caused by cancer cell adaptations is a novel approach that could potentially lead to new therapies to reduce metastasis mortality.
Presentation: Thursday, June 15, 2023
THU560 Serum miRNA-483 As A Diagnostic And Therapeutic Marker Of IGF-II-producing Non-islet Cell Tumor Hypoglycemia (NICTH)
Authors: Okazaki-Hada Mikiko , Nagao Mototsugu , Asai Akira , Fukuda Izumi , Eliasson Lena , Iwabu Masato 
Published: October 2023

Abstract
Disclosure: M. Okazaki-Hada: None. M. Nagao: Grant Recipient; Self; The Foundation for Growth Science. A. Asai: None. I. Fukuda: None. L. Eliasson: None. M. Iwabu: None.
Objective: Non-islet cell tumor hypoglycemia (NICTH) is known as the second major cause of spontaneous hypoglycemia next to insulinoma. Abnormal higher molecular weight forms of insulin-like growth factor II (IGF-II), so-called “big IGF-II”, are frequently detected in the sera of patients with NICTH. Thus, the disease is referred to as IGF-II-producing NICTH. We have previously reported a significant elevation of serum microRNA (miRNA)-483-5p and -3p levels in patients with IGF-II-producing NICTH. The miRNA-483 family are encoded in an intron of IGF2 gene and thus suggested to be co-expressed with IGF-II. The aim of this study was to validate the usefulness of miRNA-483 family as a diagnostic and therapeutic marker of IGF-II producing NICTH, then to examine if the IGF-II-producing tumor tissues could be the source of these circulating miRNAs Design: Serum samples from patients who had been suspected to have IGF-II-producing NICTH (n = 134) were tested. The presence of big IGF-II was confirmed by Western blotting, and miRNA-483-5p and -3p levels were evaluated by quantitative PCR. IGF-II level was also analyzed by ELISA. In addition, IGF-II, miRNA-483-5p and -3p levels were compared before and after tumor removal in serum samples from surgically treated patients with IGF-II-producing NICTH (n=21). Expression levels of miRNA-483-5p and -3p were also analyzed in the big IGF-II-expressing tumor tissues and the surrounding surgical margins (n=9). Results: Big IGF-II was detected in the sera of 91 out of 134 patients. IGF-II, miRNA-483-5p and -3p levels were significantly higher in sera with big IGF-II than in those without. The area under the receiver operating characteristic curve of miRNA-483-5p (0.85) for IGF-II-producing NICTH were higher than those of miRNA-483-3p (0.75) and IGF-II (0.75). After tumor removal, serum miRNA-483-5p level decreased (P=0.0025), but serum miRNA-483-3p and IGF-II levels did not change significantly. The expression levels of miRNA-483-5p and -3p in the tumor tissues were significantly higher than those in the surgical margins (18 and 51 times for miRNA-483-5p and -3p, respectively). Conclusion: The present study confirms that miRNA-483-5p and -3p are elevated in sera of patients with IGF-II-producing NICTH and shows that miRNA-483-5p is significantly reduced after the surgical removal of big IGF-II-producing tumors. These results highlight the usefulness of the miRNA-483 family as a diagnostic and therapeutic marker for IGF-II-producing NICTH, and strongly suggest that the tumors produce miR-483-5p and -3p in parallel with the production of big IGF-II.
Presentation: Thursday, June 15, 2023