bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP560 Thyroid Hormones membrane receptor, Integrin αvβ3, as a potential prognostic marker of chemotherapy response in breast cancer
Authors: Haedo Mateo Campos , Florencia Cayrol M , Cremaschi Graciela , Mercedes Debernardi M , Albuja Johanna Diaz , Albuja M Celeste Díaz , Alejandra Paulazo M , Rosemblit Cinthia , Sterle Helena 
Published: November 2022

Abstract
Despite the development of novel therapies, breast cancer (BC) tumors are treated with conventional therapy eventually. Due to tumor heterogeneity, it is necessary to define new biomarkers to identify groups with different molecular characteristic and on this basis improve the treatment decision. The impact of thyroid status in BC growth has previously been studied. In particular, alterations of thyroid function during chemotherapy for BC treatment have been found and it has been demonstrated that T3 induces chemosensitization of BC cells. However, the relationship between thyroid hormones (THs) membrane receptor, integrin αvβ3, and BC response to chemotherapy remains unclear. The aim of this study is to evaluate the relationship between THs and integrin αvβ3 expression as prognostic value in BC patients. The mRNA expression of ITGB3 in the TCGA-PanCancer Atlas BC dataset (1084 patients) was associated with worse overall survival. Moreover, ITGB3 mRNA expression was significantly correlated with genes encoding multidrug resistance transporter proteins MDR1 and BCRP, (Pearson, R score &gt;0.3 and p&lt;0,05). The diagnostic role of ITGB3 in BC was assessed by receptor operating characteristic (ROC) curve analysis. ITGB3 mRNA levels were higher in non-responder patients treated with anthracycline (AUC=0,673, p=1.8e-10) and taxanes (AUC=0.675, p=1.9e-07). To confirm the association between the integrinαvβ3-mediated effects and multidrug resistance protein transporters, we conducted in vitro assays ofMDA-MB-231 cells treated with physiological concentrations of THs and evaluated their action on MDR1 protein levels and Rhodamine efflux as an indicator of the transporter activity. We found that THs induce MDR1 protein expression and transporter activation and this effect is blocked by the presence of the integrin selective inhibitor cilengitide. Furthermore, in MDA-MB-231 doxorubicin-resistant cells THs induce MDR1 and BCRP greater protein expression than in MDA-MB-231 parental cells and this effect is abrogated by cilengitide. Therefore, we found that integrin β3 is correlated with worse overall survival and response to anthracyclines and taxanes pointing out its role as acancer biomarker with potential clinical utility. In patients with high integrin β3 mRNA expression, we found a significant correlation with proteins involved in drug transport such as MDR1 and BCRP. We also demonstrated that THs through integrin αvβ3 modulate the expression and activity of drug transporters. These results pointout the role of THs, and their membrane receptor, in BC response to treatments and introduce a new biomarker with potential clinical significance.
Presentation: No date and time listed
ODP563 Breast Cancer With Liver Metastasis Responds Poorly to Fulvestrant-Based Combination Therapy and Chemotherapy
Authors: Chien Christine , Raghavendra Akshara S , Tripathy Debasish , Madak-Erdogan Zeynep 
Published: November 2022

Abstract

Background
Estrogen receptor-positive (ER+) metastatic breast cancer (MBC) contributes to nearly 70% of breast cancer-related deaths. Liver metastasis is the third most common site and has been found to carry a poor prognosis. One contributing factor is resistance to available treatments. Meanwhile, estrogen receptor alpha gene (ESR1) activating mutations, which can be enriched in metastatic tumors of the viscera such as the liver, have also been linked to resistance against hormone-blocking agents. We seek to characterize the efficacy of available treatment modalities, including hormone therapy, immunomodulators, and chemotherapy, for MBC with liver disease, and the role of ESR1 mutations in poor treatment response.

Methods
We conducted a retrospective review of 3388 adults with ER+/HER2- MBC who were treated at a single U. S. cancer center between 1997-2021. All patients received fulvestrant monotherapy or fulvestrant-based combination therapy with CDK4/6 inhibitors, mTOR kinase inhibitors (everolimus), or PI3K inhibitors (alpelisib). We compared the overall and metastatic survival of patients with liver versus non-liver metastasis between different treatment regimens. We also evaluated the impact of chemotherapy administered before or after metastasis. To account for confounders, we included age at first cancer diagnosis, BMI, and stage IV at diagnosis as covariates in our multivariate analyses.

Results
We identified 1556 (46%) patients in our cohort with liver metastasis. Patients with liver metastasis experienced shorter overall and metastatic survival across all treatment regimens (HR 1.5; CI 1.3-1.6). While fulvestrant-based combination therapies offered a survival benefit over fulvestrant alone in patients with non-liver metastasis, this benefit did not extend to the liver metastasis group. Chemotherapy administered before liver metastasis improved survival, but chemotherapy administered after liver metastasis did not. Patients with first metastasis to the liver did not significantly differ in survival when compared to those who developed liver metastasis later. ESR1 mutations were identified in only a minority of our cohort (4%), but a higher prevalence of liver metastasis was found in patients with ESR1mutations (49% vs. 45% in wild type group). Independent of ESR1 status, patients with liver metastasis were found to have worse survival.

Conclusion
We find liver metastasis to be a negative prognostic factor in patients with metastatic breast cancer, independent of ESR1 status. While novel fulvestrant-based combination therapies have been promising for MBC, similar survival benefits are not seen in those with liver metastasis. Liver metastasis proves to be aggressive and difficult to treat, and current therapies are insufficient.
Presentation: No date and time listed
OR30-1 Cloning, Sequencing, and Characterization of Aromatase Interacting Partner in Breast (AIPB). A New Protein Regulating Estradiol Synthesis.
Authors: Bose Himangshu , Burak William , Hall Neal M , Whittal Randy , Hall Neal M 
Published: November 2022

Abstract
Breast cancer is the most common invasive cancer in females worldwide and accounts for 16% of all female cancers, 22.9% of invasive cancers in women, and 18.2% of all cancer-related deaths worldwide. About 80% of these cancers, once established, depend on available estrogens (i.e., estradiol) to grow. The production of estrogens occurs via a catalytic process governed by the enzyme Aromatase. This process occurs primarily in the ovaries in pre-menopause, while in post-menopause, this occurs in peripheral tissues, including the breast. In patients whose cancers have specific hormone receptors, such as Estrogen Receptor positive (ER+), Progesterone Receptor positive (PR+), and Human Epidermal Growth Factor 2 Receptor positive (HER2+), these tumors can continue receiving nutrients and signals to grow, which provides targets for therapy. Although many of the currently available drugs for breast cancer seek to suppress this process and thus reduce available estrogens, they have numerous harmful side effects and have high rates of therapy failure due to the development of resistance. Therefore, new therapies and targets for this devastating disease are needed. We observed that breast tumors had increased estrogen production in postmenopausal women, leading us to question the cause of this increase. Further, the complete mechanism of aromatase action and the possibility of targetable cofactors remained previously unknown. Thus, we set out to identify the mechanism of Aromatase action to provide prognostic and therapeutic insight into this distressing disease. As Aromatase is an endoplasmic reticulum (ER) resident protein, we purified ER fractions from breast tissues, separated through 1D, and then each ten kDa fractions were further separated and analyzed through Mass-spectrometry to determine the cofactors associated with aromatase activity. We observed an 11 mer peptide LEVVVDQPMER, which on cloning resulted in a 207 amino acid protein not present in the database. This previously undiscovered protein is colocalized with Aromatase in the ER. We saw that knocking down its expression by siRNA in wild-type breast cells (MCF-12A) or tumorigenic MCF-7 or T47-D cells increased estradiol synthesis significantly without affecting aromatase expression. Further biochemical experiments showed that Aromatase and the 207 amino acid protein interacted directly without affecting the expression of other ER-resident proteins. Additionally, our experiments showed that the new protein is not hormonally stimulated or transcriptionally inhibited and thus, regulates the aromatase catalytic activity of estradiol synthesis. Therefore, we have termed this new protein "Aromatase Interacting Partner in Breast" (AIPB).
Presentation: Tuesday, June 14, 2022 9:45 a.m. - 10:00 a.m.
PSUN377 Use of Novel Therapy in Management of Metastatic Parathyroid Cancer
Authors: Fernandes Jyotika , Kaczmar John , Welsh Cynthia , Gibbs Otto , Gannamani Gowtham 
Published: November 2022

Abstract

Introduction
Parathyroid cancer (PC) is a rare malignant tumor which represents &lt;1% of patients with primary hyperparathyroidism (PHPT). With less than 1000 reported cases, PC is the rarest endocrine cancer. Complicating its rarity, is the known resistance to radiation and chemotherapy, and complete surgical resection is the only curative treatment available. Genomic sequencing targeted therapy has shown encouraging results. We hereby present a case where Pembrolizumab was used in treatment of metastatic PC.

Case
A 50 year old lady with a history of nephrolithiasis, hypercalcemia(HC) presented for evaluation of neck mass. She had a recent admission to outside hospital for HC, dehydration, bone pain, polyuria, constipation and workup was suggestive of PHPT with Calcium(Ca) 13.2mg/dL and PTH 1,500pg/ml. Neck ultrasound demonstrated a 3 cm nodule in the left thyroid and fine needle aspiration was suspicious for malignancy. She underwent left hemithyroidectomy, and left parathyroidectomy. PTH levels pre-, intra- and postoperatively were 680, 220, 20 pg/ml respectively with normalization of Serum Ca. Histopathology revealed high grade PC with lymphovascular and perineural invasion. Postoperatively she received adjuvant radiotherapy. Ten months later CT Neck surveillance revealed a 4cm Left prevertebral(PV) mass with recurrence of bone pain, PTH 110pg/ml, and Ca-11.2mg/dL. Parathyroid scan showed Left PV mass and Left level 2 lymph node. PET/CT later revealed fluorodeoxyglucose avidity of the recurrent mass, as well as bilateral lung, right ventricle, and pelvic lesions. Incisional biopsy confirmed carcinoma consistent with PC. Her neck lesions were deemed unresectable. Germline mutation testing confirmed Next Generation Sequencing: PDL1 5% by CPS, TMB 10 mut/Mb, IDH2, JAK1, KMT2C, NF1, PIK3RI. On the basis of TMB &gt;10 mut/Mb Pembrolizumab was then initiated with good response, noting improvement in symptoms, and normalization of Ca 8.7mg/dL and PTH 35pg/ml. Within 4 months of therapy Surveillance CT showed an approximate 40% reduction in tumor burden noting decrease in size of neck mass and lesions in lungs, right ventricle, and pelvis.

Discussion
Approximately 10%-30% of PCs have metastasis at presentation, most commonly to the lung, bone, or liver. However they can often develop local recurrence and or distant metastases despite early intervention. Surgical resection remains the mainstay of treatment, and is often used to decrease tumor burden which has been shown to improve morbidity. However when surgical resection is not an option, newer approaches using gene sequence targeted therapy may be an attractive option in the future as was demonstrated in this patient.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN382 Hold Still – A Large Neck Paraganglioma Limiting Head Movement
Authors: Puzio Helene , Nachawi Noura , Borgan Saif , Makin Vinni 
Published: November 2022

Abstract

Background
A head and neck paraganglioma is a rare diagnosis with most cases found incidentally or diagnosed due to mass effect symptoms. Only 3.5% of them are found to secrete catecholamines leading to episodic symptoms. Herein, we present a rare case of a functioning neck paraganglioma with head movement induced hyperadrenergic paroxysms.

Clinical Case
A 79-year-old Caucasian man, with previous left neck mass found incidentally on imaging after a motor vehicle accident, presented to the ER with syncope. While the mass had been growing for 10 years, he sought medical attention when he could no longer turn his head to the left due to worsening symptoms. He reported recurrent brief syncopal attacks along with intermittent episodes characterized by profuse sweating, headaches, palpitations, and flushed skin. Upon evaluation, he was afebrile, tachycardic and had labile blood pressure readings (high of 340/150 mmHg and a low of 70/40 mmHg). He was oriented to time and place but appeared lethargic and underweight. A solid non-tender neck mass, with an audible bruit, was apparent at the Level II of the left neck. A CT scan of the neck showed a 7.7cm left glomus vagale tumor with partial encasement of the left internal and external carotid artery. He was admitted to the intensive care unit for close blood pressure monitoring via an intra-arterial line. Due to high suspicion for a catecholamine driven process, he was started on Doxazosin 1 mg every 12 hours which stabilized his blood pressure and improved his symptoms. CT scan of the abdomen and pelvis showed a 1.1 cm left adrenal nodule with an intensity of 4 Hounsfield units. A trial of Hyoscyamine was done to help with hypotension and symptoms of dizziness and bradycardia. Labs showed plasma catecholamines that were significantly elevated to ten times the upper limit of normal. An MIBG scan showed uptake in the left carotid mass. He was a poor surgical candidate because of the proximity of the mass to the neuro-vascular bundle and was treated with radiation during hospitalization. The patient was discharged home on Doxazosin with improvement in his blood pressure. Genetic testing was negative for a pathogenic variant but detected a variant of uncertain significance (VUS) in CDKN2A, c.373G&gt;C (p.Asp125His). Unfortunately, three months later the patient was admitted with an intracranial hemorrhage secondary to a fall and was transitioned to hospice care. There was no change in the tumor size noticed during that admission.

Conclusion
To our knowledge, this is the first case to describe hypertension paroxysms triggered by movements of the neck in the setting of a functional neck paraganglioma.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN357 Scaffold Protein IQGAP1 Bridges Proliferative Signaling Between Bile Acids and the Cellular Microenvironment to Mediate Hepatic Cell Proliferation
Authors: Anakk Sayeepriyadarshini , Underhill Gregory , Hobbs Steven , Conover-Kimmel Hannah 
Published: November 2022

Abstract
The cell-cell and cell-extracellular matrix (ECM) communication is central to maintain cellular functions, including proliferation. Scaffold proteins can mediate these communications by binding specific protein effectors of signaling pathways and tethering them into a stable complex. IQ-domain containing GTPase Activating Protein 1 (IQGAP1) is a multi-domain scaffold protein that is involved in cytokinesis, proliferation and apoptosis. Each of the five domains of IQGAP1 bind distinct effector proteins to transduce cellular signals. In the liver, supraphysiological levels of bile acids, a cholesterol metabolite, is linked to the increase in IQGAP1 levels and is positively associated with transcriptional co-activator YAP. However, how bile acids induce expression of IQGAP1 remains unknown. We hypothesize that supraphysiological levels of bile acids act on the cell microenvironment to activate IQGAP1. As bile acids are induced during liver regeneration, we examined and found that Iqgap1 levels are increased. Remarkably this increase in Iqgap1 transcript coincides with that of bile acids after 2/3 partial hepatectomy in mice. In addition, IQGAP1 demonstrated increased localization into puncta at the cell surface in HepG2 cells, seeded on ECM microarrays with higher stiffness indicating mechano-sensing signals can alter IQGAP1 protein levels. We will examine IQGAP1 localization during liver regeneration and investigate if there is a cross talk between ECM stiffness, bile acid and IQGAP1 expression. Using domain deletion constructs, we will also identify the IQGAP1 domain responsible for coordinating the bile acid and cell-ECM communication in the liver. Collectively, these results will help elucidate the IQGAP1-specific cell signaling pathways used in facilitating liver cell proliferation, and test if IQGAP1 scaffold can integrate metabolite cues (bile acids) to communication between liver cells and the cellular microenvironment.
Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN358 ANPEP: A potential regulator of tumor cell - macrophage metabolic interactions in prostate cancer of African American men
Authors: Yamoah Kosj , El-Kenawi Asmaa , Awasthi Shivanshu , Serna Amparo , Dhillon Jasreman 
Published: November 2022

Abstract
African American men (AA) are more than twice as likely to die of prostate cancer (PCa) compared to European American men (EA). Among many contributing factors, unraveling the metabolic derangements in PCa of AA holds a promise in reducing health disparity. We recently discovered that aminopeptidase N (ANPEP, CD13) represents one of the differentially expressed genes in PCa of AA compared with EA. While ANPEP plays regulatory and/or modulatory functions in many immune and metabolic pathological conditions, its role in PCa remains unknown. We sought to investigate the metabolic functions of ANPEP in PCa development and exploit its role as a therapeutic vulnerability, particularly in AA men. Accordingly, we prospectively examined the differential gene expression of PCa from clinically matched AA and EA in the VANDAAM clinical trial. The VANDAAM study is a validation study of DecipherTM genomic testing in 240 men with localized PCa. Our findings indicate that ANPEP is the top differentially expressed gene between AA and EA men. To explore the molecular mechanisms of ANPEP in PCa in unbiased fashion, we combined computational and experimental approaches. Our preliminary computational analyses revealed that ANPEP correlates with signatures of cholesterol transport, estrogen and androgen receptor (AR) signaling. Based on our recent study demonstrating dominance of these signatures in macrophage-rich PCa, we reasoned that ANPEP expression may be driven in part by high macrophage infiltration in AA. Thus, we compared immune cell repertoire in patients with high ANPEP and low ANPEP by deconvoluting immune cell content using the in silico approach, CIBERSORT. These analyses illustrated that only AA patients with high ANPEP expression significantly accumulated high content of M1 inflammatory macrophages. Immune phenotyping of prostate tumors demonstrated that ANPEP indeed represents a marker of M1 inflammatory macrophages and tumor-associated macrophages. In conclusion, these findings suggest that ANPEP is a macrophage related protein in PCa with a potential role in cholesterol transport and / or androgen signaling. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry (LC-HRMS) and explants derived from AA and EA prostate cancer patients.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSAT009 Cushing's Syndrome Developing 42 Years After Successful Treatment for Metastatic Adrenocortical Carcinoma
Authors: Kaur Jasleen , Luiza Caramori M 
Published: November 2022

Abstract

Introduction
ACC is a rare malignancy with poor prognosis. ACC is associated with CS in about 10% of the cases. Herein we report a case of a patient with metastatic ACC who developed contralateral functional adrenal adenoma causing Cushing's syndrome 42 years later.

Clinical Case
A 72-year-old female presented for evaluation of right adrenal incidentaloma, measuring 4.4×3 cm, on CT abdomen and pelvis (CTAP), done as part of the evaluation for hip pain. In addition to the adrenal incidentaloma, a large left adnexal mass (8×7 cm) was also observed. Her past medical history was significant for left adrenal ACC diagnosed at the age of 30, The patient's initial presentation included virilization and menstrual abnormalities. Laboratory evaluation revealed hyperandrogenism and hypercortisolism. There was no evidence of metastatic disease, and the patient was managed surgically (total left adrenalectomy) with normalization of laboratory abnormalities and resolution of symptoms. Four years later, patient pulmonary metastasis were observed in a surveillance scan and the patient underwent wedge resection and chemotherapy. The patient did not have any evidence of recurrent disease thereafter.
At the current presentation, there were no symptoms or signs of adrenal hormone excess. Hormonal workup revealed borderline elevation of plasma metanephrines, with normal 24 h urinary metanephrines and catecholamines. DHEA-S and testosterone levels, as well as other androgens, were normal. 1 mg dexamethasone suppression (DST) was abnormal, with cortisol of 5.5 mcg/dL 8 h after dexamethasone administration (normal &lt;1.8 mcg/dL). High dose DST was repeatedly abnormal, with cortisol levels at 4.0 and 4.4 mcg/dL (normal &lt;1.8 mcg/dL). AM cortisol was elevated, at 23.4 mcg/dL (normal 4-22 mcg/dL) with ACTH at 12 pg/mL (normal &lt;45 pg/dL). 24 h urinary free cortisol (UFC) was repeatedly elevated at 123.2 and 83.8 mcg/d (normal &lt;45.0 mcg/d). CA 125 was normal. As there are case reports of ectopic Cushing's syndrome related to ovarian malignancies, and the patient had a large adnexal mass, adrenal and ovarian vein sampling was performed. Cortisol levels were higher in the right adrenal vein compared to the periphery, and the gradient was normal for the left ovarian vein. The right ovary was not visualized, and it was not possible to catheterize the right ovarian vein. Whole body FDG scan revealed intermediate uptake by right adrenal mass and normal uptake by left adnexal mass. Based on these results, it was determined that the right adrenal was the source of excess cortisol, and the patient underwent laparoscopic right adrenalectomy. Pathology evaluation showed adrenal adenoma, without evidence of ACC. The patient was started on physiologic replacement doses of hydrocortisone and fludrocortisone. The patient has been doing very well clinically.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.