bluuebunny/crossref_metadata_2025 huggingface dataset:
LBODP107 Real World Performance Of The Afirma Xpression Atlas In Bethesda III And IV Thyroid Nodules. A Private Practice Experience
Authors: Ortega Dayron , Mhaskar Rahul , Pinero-Pilona Antonio
Published: November 2022

Fine Needle Aspiration (FNA) has modified all methods for diagnosing thyroid cancer; and in conjunction with the Bethesda System and the genomic sequencing classifiers (GSC), clinicians can objectively identify the risk of malignancy of thyroid nodules prior to surgical interventions. To further characterize these thyroid nodules, the Afirma Xpression Atlas (XA), a form of The Cancer Genome Atlas, was created and launched in May 2018. In November 2019 and March 2020, the Afirma XA panel was expanded to include 905 genomic variants and 235 fusions from 593 genes. Post-validations studies for the Afirma XA have been developed in well recognized large academic centers with unclear applicability or extrapolation to small endocrinology centers, which may have a different patient's population and thyroid cancer prevalence. This study was designed to analyze and objectively measure the performance of the Afirma XA in Bethesda III and IV thyroid nodules classified as GSC suspicious in our private endocrinology practice. We conducted a retrospective cohort analysis comparing all indeterminate and GCS suspicious nodules with their respective final surgical pathology results between June 2018 to October 2021. Forty-two thyroid nodules were studied, and the Bethesda III category was the predominant cytopathology discovered, representing 69% of all indeterminate nodules. Afirma XA was able to identify genomic alterations in only 40% of all included nodules. We found a 35% (CI: 15%-59%) sensitivity, 54% (CI: 32%-75%) specificity, 47% (CI: 35%-59%) of negative predictive value, and 41% (CI: 25%-60%) of positive predictive value when a 47% of cancer prevalence is applied. Based on this data, we conclude that Afirma XA cannot be used exclusively as a rule-out or a ruled-in test in GSC suspicious, Bethesda category III and IV thyroid nodules in small private endocrinology practices.

Presentation: No date and time listed
LBSUN255 Recurrent Hypoglycemia In A Patient With Beckwith-Wiedemann Syndrome Secondary To Insulinoma
Authors: Akcan Tugce , Shariff Julia Rose R
Published: November 2022

Background

Beckwith-Wiedemann Syndrome (BWS) is a genetic condition characterized by macrosomia, childhood tumors, and neonatal hypoglycemia and hyperinsulinemia. The cause of this hyperinsulinemic hypoglycemia is unknown, but it is believed to be caused by chromosomal mutations at 11p15.5 and genes encoding beta-cell ATP-sensitive potassium channels. In our case, we have an adult patient with a history of BWS who is experiencing hypoglycemia due to a different cause: an insulinoma. This is the first report of insulinoma in an adult with this syndrome.

Case Presentation

The patient is a 53-year-old male with a history of BWS. Due to shortness of breath, the patient was admitted and discovered to have new and severe systolic heart failure. Patient was started on beta blockers by cardiology. During his hospital stay, he developed hypoglycemia, with glucose levels in the 20s. As the hypoglycemia became more frequent, he was placed on dextrose. Dextrose was turned off to obtain hypoglycemia labs such as insulin, proinsulin, C-peptide, and hydroxybutyrate, but his blood sugar never fell below 80mg/dL. His hypoglycemia was attributed to a beta-blocker side effect or rebound from a dextrose infusion. He was discharged from hospital and sent home. After a loss of consciousness episode at home two weeks later, the patient was readmitted. When he arrived at the emergency department, his blood glucose level was 18mg/dL, and he was given dextrose. After being admitted to the hospital, dextrose was again discontinued, and blood glucose levels dropped to 45mg/dL on serum testing. At the time, C-peptide levels were elevated at 25.7ng/mL, B-hydroxybutyrate levels were 0. 06mmol/L, and insulin levels were above 700uIU/mL. At the time, the choice was between insulin autoantibody syndrome and insulinoma. The patient then had an abdominal computed tomography scan, which revealed a 3.7×2.9cm neuroendocrine tumor in the distal pancreas. Changes in the liver were found to be alarming for metastases, thus an MRI was conducted to confirm this. There was no sign of liver metastases on the MRI. In the interim, the patient was started on subcutaneous octreotide 50 mcg twice daily. Given the patient's underlying heart problems, diazoxide was not pursued. Octreotide was increased to 100mcg subcutaneously three times daily throughout his hospital stay, and he was discharged home with a continuous glucose monitor and intentions to operate later that month.

Conclusions

Although BWS has been linked to a higher risk of childhood malignancies, it's uncertain whether BWS could be a predisposing factor for the development of insulinoma. Because this is such a rare disorder, there is a paucity of information on predisposition or risk factors. However, the link between macrosomia and tumor growth in BWS suggests that there may be a predisposition to insulinoma that has yet to be investigated.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
ODP548 Fatty acid metabolism-related factors in breast and endometrial cancers
Authors: Miki Yasuhiro , Naraoka Hiyori , Iwabuchi Erina , Sato Ai , Takagi Kiyoshi , Sasano Hironobu , Ishida Takanori , Suzuki Takashi , Ito Kiyoshi
Published: November 2022

Obesity is a well-known risk factor for gynecological malignant tumors such as breast and endometrial cancers. In the cancer microenvironment, the interaction between cancer cells and adipocytes reportedly contributes to the malignant behavior of cancer. In breast cancer, the fatty acid transporter CD36, also known as fatty acid translocase, has been shown to mediate fatty acid uptake into cancer cells and activate signaling pathways that promote tumor progression. Fatty acids are speculated to play important roles in breast and endometrial cancer; however, detailed mechanisms remain unclear. In the present study, we first examined the expression of CD36 and acyl-CoA dehydrogenase long chain (ACADL) in breast (30 cases) and endometrial (35 cases) cancer tissues using immunohistochemistry. CD36 is a membrane protein that transports long-chain fatty acids, and ACADL catalyzes the initial β-oxidation reaction. We detected no correlation between the CD36 status and clinicopathological factors, including the estrogen receptor status in breast cancer tissues. CD36 status revealed a significant positive correlation with lymph node metastasis in endometrial cancer. There was no immunoreactivity for CD36 in morphologically normal mammary glands. Otherwise, CD36 immunoreactivity was detected in the endometrial glandular cells. In both cancers, ACADL expression did not correlate with any clinicopathological factor. Both CD36 and ACADL showed higher positivity rates in endometrial cancer than in breast cancer. In addition, the effect of lipid addition on cell proliferation was examined using breast (T-47D) and endometrial (AN3CA) cancer cell lines exhibiting equivalent CD36 levels. Lipid (Refeed JNS) was obtained from Remembrane, Italy. Lipid addition promoted cell proliferation in both T-47D and AN3CA cells. Intracellular fatty acid β-oxidation (FAO) was visualized using FAOBlue (Funakoshi, Tokyo, Japan), a nonanoic acid (C9) derivative of coumarin, a blue fluorescence dye. Following FAOBlue decomposition in the fourth FAO cycle, coumarin is released from propionic acid, and released coumarin shows strong blue fluorescence excited at 405 nm. T-47D cells showed blue fluorescence in the lipid-supplemented medium, indicating β-oxidative activity. Conversely, AN3CA cells exhibited weak fluorescence under the same conditions. It can be postulated that intracellular lipid uptake and subsequent β-oxidation are mediated via a specific pathway in breast and endometrial cancers. Lipid-mediated effects differ between breast and endometrial cancers, and further investigations are needed to elucidate intracellular signals mediating these effects.

Presentation: No date and time listed
ODP549 From Positive to Negative, a Histidine to Aspartic Acid Change in SDHB is Breaking Bad in Cardiac Paraganglioma
Authors: Harbuz-Miller Inga , Carafone Lindsay , Archibald William , Victor Adrienne
Published: November 2022

Introduction

Cardiac paraganglioma (PGL) are extremely rare tumors. They are derived from chromaffin cells of the neural crest. Up to 40% of PGL foster germline mutations, while some bear somatic mutations. Here, we describe a sympathetic paraganglioma presenting as a cardiac mass, found to have a novel mutation of SDHB.

Clinical Case

A 64-year-old man with uncontrolled type 2 diabetes mellitus presented with chest pain, progressive fatigue and unintentional weight loss. An echocardiogram demonstrated a right atrial mass. Cardiac magnetic resonance imaging showed a 6.9×5.8×4.9 cm mass in the lateral right atrial wall and right atrioventricular groove, encasing the right coronary artery. Surgical removal was attempted and aborted due to involvement of the tricuspid valve. Incisional biopsy was consistent with paraganglioma. Plasma free normetanephrine was elevated at 1.87 nmol/L (ULN 0.89 nmol/L) and plasma free metanephrine was normal at 0.14 nmol/L (ULN 0.49 nmol/L). Chromogranin A was elevated at 1,038 ng/mL (normal <93 ng/mL). Iodine-123 meta-iodobenzylguanidine scan demonstrated increased and persistent MIBG activity of the cardiac mass. Ga-68 DOTATATE PET/CT scan revealed DOTATATE avidity of the mass without evidence of distant metastatic disease. Next-generation sequencing of the specimen revealed a variant of unknown significance of SDHB H244D at a variant allele frequency of 62.2%. This missense mutation replaces the histidine to aspartic acid, resulting in changes in charge of the side chain from positive to negative. Systemic treatment with tyrosine kinase inhibitor (TKI) cabozantinib was initiated due to unresectable tumor. Three month surveillance with Ga-68 PET/CT DOTATATE scan revealed partial response to treatment. Chromogranin A and normetanephrine are trending down, suggesting biochemical response.

Conclusion

Cardiac PGL are rare and SDHB mutations are associated with worse prognosis. This is the first case of a missense mutation of SDHB at H244D, which may be clinically relevant in characterizing cardiac paraganglioma and potential response to TKI therapy.

Presentation: No date and time listed
ODP555 In-vitro Combo Treatments of Human Melanoma (1205Lu, WM238) Cell Lines with Curcumin, Vitamins and Steroids
Authors: Ramaraj Pandurangan , Chiu Albert
Published: November 2022

Previous combo treatment experiments on BLM human melanoma cell line identified two combos vit-A + RU-486 and Cur+P+RU as the best combinations to decrease melanoma cell growth as well as IL-8 secretion in -vitro. In order to confirm this finding, experiments were repeated on two other human melanoma cell lines 1205Lu and WM238. Initial single or solo compound treatment on 1205Lu cells resulted in cell growth in the range of 37–59% compared to untreated control 1205Lu cell growth at 100%. A double combo treatment with combinations such as D+P, D+RU, A+P, A+RU, A+D resulted in cell growth in the range of 17 to 37% on the 1205Lu cell line. Whereas on WM238 cell line resulted in cell growth in between 18–22%. A triple combo such as combinations of three compounds (Cur+P+RU, Cur+A+P, Cur+D+RU) resulted in cell growth in the range of 19-30% on 1205Lu cells, whereas on WM238 cells resulted in between 19–20% cell growth. Elisarray of the supernatants from the combos which showed a significant decrease in cell growth revealed the regulation only in IL-8 secretion. IL-8 secretion in the supernatants of combos treated with A+RU and Cur+P+RU was17.5 and 8. 0 pg/ml respectively on the 1205Lu cell line. Whereas, IL-8 secretion was 0.515 and 0.926 pg/ml respectively in the supernatants of A+RU and Cur+P+RU combo treatments on the WM238 cell line.

Conclusion

Based on cell growth, Elisarray and IL-8 quantitation, two combos A+RU and Cur+P+RU also fared well on the two other cell lines 1205Lu and WM238.

Presentation: No date and time listed
ODP556 Krüppel-like factor 9 (KLF9) Links Hormone Dysregulation and Circadian Disruption to Breast Cancer Pathogenesis
Authors: Ybañez Weand , Bagamasbad Pia
Published: November 2022

Circadian disruption is an emerging driver of breast cancer (BCa), with epidemiological studies linking shift work, chronic jet lag, and undue exposure to light at night to increased cancer risk. Indeed, several clock genes participate in the gating of mitotic entry, regulation of DNA damage response, metabolite sensing, and epithelial-to-mesenchymal transition, thus impacting BCa etiology. Dysregulated estrogen (E2) and glucocorticoid (GC; hydrocortisone, CORT) signaling prevalent in BCa may further contribute to clock desynchrony by directly impacting the expression and cycling dynamics of genes comprising the local breast oscillator. In this study, we identified the tumor suppressor gene, KLF9, as an important point of crosstalk between hormone signaling and the circadian molecular network and further established its functional role in BCa. We determined that KLF9is a direct GC receptor (GR) target gene in mammary epithelial cells, and that induction is likely mediated through coordinate transcriptional activation from multiple CORT-responsive enhancers in the KLF9 locus. Interestingly, the clock-controlled rhythmic expression of KLF9observed in normal MCF10A cells was abolished in the highly aggressive TNBC MDA-MB-231 line. As a transcription factor, in turn, KLF9 modulated the baseline mRNA levels of several clock genes and influenced the GC/E-induced alterations in clock gene expression indicating that KLF9 may function as a feedback regulator of the core clock machinery. We then characterized the functional role of KLF9 in context of the hormone-circadian axis in BCa using cellular assays on survival, proliferation, apoptosis, and migration. We determined that KLF9 plays a tumor-suppressive role in BCa regardless of molecular subtype. In addition, KLF9 overexpression potentiated the anti-tumorigenic effects of CORT in ER+ luminal MCF7 cells, while it played a converse effect in triple-negative MCF10A and MDA-MB-231 cells by restraining CORT-enhanced proliferation and survival. Taken together, our findings suggest that dysregulation of KLF9expression and oscillation in BCa may impinge on circadian network dynamics, thus ultimately aggravating BCa oncogenic landscape.

Presentation: No date and time listed
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

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 >0.3 and p<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

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

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

Introduction

Parathyroid cancer (PC) is a rare malignant tumor which represents <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 >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

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>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

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

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

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 <1.8 mcg/dL). High dose DST was repeatedly abnormal, with cortisol levels at 4.0 and 4.4 mcg/dL (normal <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 <45 pg/dL). 24 h urinary free cortisol (UFC) was repeatedly elevated at 123.2 and 83.8 mcg/d (normal <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.
RF07 | PSUN359 Alpelisib-induced Diabetic Ketoacidosis
Authors: Majumdar Sachin , Parekh Jay , Ostas Anca , Tan Jia Wei , Mathialagan Karthik , Polisetty Lakshmi
Published: November 2022

Background

Alpelisib is an oral α-specific phosphatidylinositol 3-kinase (PI3K) inhibitor use in combination with fulvestrant to treat postmenopausal women with HR+/HER2−, PIK3CA-mutated, advanced or metastatic breast cancer that has acquired resistance to endocrine-based therapy. (1)Alpelisib interferes with the PI3K/Akt signalling pathway resulting in impaired peripheral glucose uptake, increased liver glycogenolysis, loss of beta-cell mass and insulin secretion dysfunction(2). Hyperglycemia is a frequent adverse effect of alpelisib but diabetic ketoacidosis (DKA) is considered a rare occurrence. We describe a patient without a previous history of diabetes who developed DKA after 2 months on alpelisib.Clinical caseA 81 year-old woman with metastatic ER+ PR – Her2 - breast cancer, presented with a 1 week history of nausea, vomiting, and polyuria. Her hemoglobin A1C was 5.5% on two separate occasions last year. She had started alpelisib at 300 mg/day 7 weeks prior to presentation. She presented with a blood glucose (BG) of 659 mg/dL, anion gap of 21, serum bicarbonate 17 mmol/L, beta-hydroxybutyrate 3.82 mmol/L (normal < 0.27 mmol/L), serum osmolarity 319 mOsm/kg, serum creatinine 2.83 mg/dL (baseline 1.38 mg/dL), C-peptide 4.3 ng/mL (normal 1.1–4.4 ng/mL), negative GAD-65 antibodies and Islet Antigen 2 antibodies, septic workup were non-revealing, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with intravenous insulin and hydration. DKA resolved in 12 hours, however, she had persistent hyperglycemia. She was started with insulin regimen of 0.2 units/kg and discharged with Humalog 75/25 5 units twice daily.

Conclusion

Patients with no pre-existing history of diabetes mellitus can also be at risk for DKA which may develop within weeks to months of initiation of alpelisib. Risk factors for development of DKA are yet to be identified, but would be useful to help tailor frequency of BG monitoring. This warrants further research. The hyperglycemic effects of alpelisib appear to be reversible upon drug discontinuation, however when DKA is the presenting syndrome, insulin therapy is indicated.

Reference

André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20): 1929-1940. doi: 10.1056/NEJMoa1813904. PMID: 31091374.

Nguyen P, Musa A, Samantray J. Alpelisib-Induced Diabetic Ketoacidosis. Cureus. 2021 May 1;13(5): e14796. doi: 10.7759/cureus.14796. PMID: 34084688; PMCID: PMC8166359.

Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSAT025 Functional Adrenocortical Oncocytic Neoplasm: A Rare Cause of ACTH Independent Cushing's Syndrome
Authors: Chang Alan , Shah Kajal , Hand Jane
Published: November 2022

Background

Adrenal oncocytomas (AOCs) or adrenocortical oncocytic neoplasms (ACONs) are extremely rare tumors of adrenal glands characterized by the presence of oncocytes, which are epithelial cells with eosinophilic cytoplasm. Only about 140 cases have been reported in literature so far. AOCs are more common in females (2.5: 1), more prevalent on the left adrenal gland (3.5: 1), and tumor size ranges from 3 to 17 cm. About two thirds of AOCs are reported to be nonfunctioning, and only less than 6% of functioning are cortisol secreting. The malignant potential of these tumors has been described quite variably in current literature. Based on the most recent systematic literature review, about 35% were found to be benign, 24% malignant, and 41% borderline, based on the Lin Weiss Bisceglia system. The mainstay of treatment is surgical resection. Here we describe a case where biochemical workup and pathology revealed a functional AOC with uncertain malignant potential.

Clinical Case

A 68 year old female with hypertension was found to have an incidental left 3 cm adrenal nodule on CT abdomen and pelvis during a workup for hematuria. The nodule was biopsied and initially found to be benign. Afterwards, she was referred to endocrinology where biochemical testing was consistent with ACTH-independent Cushing's syndrome. She had three elevated late night salivary cortisol - 0.10 mcg/dL, 0.14 mcg/dL, and 0.19 mcg/dL (≤0. 09 mcg/dL), three abnormal 1 mg dexamethasone suppression tests - 16.4 mcg/dL, 15.1 mcg/dL, and 17.1 mcg/dL (<1.8 mcg/dL), two normal 24 hour urinary cortisol - 22.5 and 31.5 mcg/24h (4-50 mcg/24h), and ACTH <5 pg/mL (6-50 pg/mL). She was then referred to surgery and was treated by laparoscopic adrenalectomy. Surgical pathology showed a 3.5 cm adrenal cortical tumor with oncocytes infiltrating into the periadrenal adipose tissue, with positive staining for synaptophysin and negative for P53. On Ki67 staining, some hot spots were greater than 5%. Therefore, the tumor was characterized as AOC with undetermined malignant potential or a low grade, oncocytic adrenocortical carcinoma. She was evaluated by oncology and radiation oncology, and it was decided to monitor the patient without systemic therapy or adjuvant radiation therapy. A surveillance approach was favored given that the risks of adjacent bowel and kidney toxicity outweighed the benefits of radiation.

Conclusion

We hereby report a case of AOC with undetermined malignant potential. This case highlights many challenges in the diagnosis, management and long-term surveillance of patients with AOCs, and need for further research.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSUN48 Serum leptin levels among chronic kidney diseased subjects with hypertensive heart disease: An observational cross-sectional study
Authors: Ofori Emmanuel Kwaku
Published: November 2022

Background

Chronic kidney disease (CKD) is one of the main health concerns in Sub-Saharan Africa. Leptin, a peptide hormone produced by the adipocytes have been observed to trigger complications such as cardiovascular diseases with significant mortality. The precise role of leptin in hypertension-mediated development of CKD is unknown. Research findings in this area have been inconsistent. The aim of the study was to evaluate serum leptin levels among CKD patients attending a tertiary referral hospital.

Methodology

An observational cross-sectional study. One hundred and eight (108) participants took part in the study. A structured questionnaire was used to gather their anthropometric and demographic characteristics. Blood samples were obtained and analyzed for leptin and other biochemical parameters.

Results

There were significant differences in the plasma levels of leptin, glucose (FBG), creatinine and triglyceride among CKD subjects compared with controls (p <0.05 respectively). An inverse correlation was found for leptin vs estimated GFR (r = -0.505, p= 0.0001) among CKD subjects. In the CKD group, being at stage 5 made the largest unique contribution (beta = 0.47, p < 0.0001) to the variance in serum leptin levels, followed by HDL, FBG, HHD diagnosis of more than 6 years, female gender and BMI respectively (p< 0.05). In the control group, female gender made the largest unique contribution to circulating leptin levels (beta = 0.709, p < 0.0001) followed by BMI (beta = 0.341, p < 0.0001), and eGFR (beta = -0.222, p = 0.011).

Conclusion

Serum leptin levels were significantly higher among CKD subjects co-burdened with hypertension heart disease in Accra. Stage 5 CKD was the most significant predictor of serum leptin levels. These findings underscore the role of leptin in the biochemical complexities observed in CKD subjects. Therapeutic strategies targeting leptin reduction are welcomed in the management of CKD.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.