bluuebunny/crossref_metadata_2025 huggingface dataset:
6422 Identifying Predictive Symptoms Of Adrenal Insufficiency
Authors: Han Ashley J , Achenbach Sara J , Atkinson Beth J , Bancos Irina
Published: October 2024

Disclosure: A.J. Han: None. S.J. Achenbach: None. B.J. Atkinson: None. I. Bancos: None.

Background: Diagnosis of adrenal insufficiency (AI) is often delayed due to its vague and non-specific symptomatology. As classic symptoms of AI such as fatigue and nausea are prevalent in the general population, identifying clinical features that are more specific to AI may help clinicians determine which patients require additional testing. Methods: A single-center retrospective study was performed of patients who underwent outpatient Cosyntropin stimulation testing (CST) between 2005-2018. Patients with oral glucocorticoid or estrogen use within 2 months of CST, and patients without available Current Visit Information (CVI) form at the time of CST were excluded. Presence of symptoms was obtained from CVI, and laboratory findings were electronically extracted. Adrenal insufficiency was defined as post-CST peak cortisol <18 mcg/dL. Morbidity was assessed using the Elixhauser index. Variables for multivariable analysis were defined a priori and included fatigue, dizziness, muscle pain, joint pain, weight loss >10 pounds, abdominal pain, nausea/vomiting, and hyponatremia. Results: Among 5347 patients who underwent CST, 376 (7.0%) of patients were found to have AI. There were no sex differences between patients with and without AI, however patients with AI were slightly older (median age 48.9 vs 47.1 years, p=0.026), and had a higher median BMI (26.5 vs 25.6 kg/m2, p=0.002). Prevalence of comorbidities was similar between the two groups, with a median Elixhauser index of 1 (IQR 1-3), however, patients with AI were more likely to report difficulties with activities of daily living (69% vs 57%, p<0.001). Hyponatremia was diagnosed in 4% of patients with AI and 3% of those without AI, p=0.208. Although patients in our cohort reported a high prevalence of fatigue (79%), dizziness (50%), joint pain (50%), muscle pain (48%), nausea (40%), abdominal pain (39%), and weight loss in the past 6 months (29%), there were no statistically significant differences in reported symptoms between patients with and without AI with the exception of joint pain (59% vs 49%, p<0.001) and muscle pain (54% vs 47%, p=0.009). Based on multivariable analysis, only joint pain (OR 1.51, 95% CI 1.14-1.99) and weight loss >10 pounds in the past 6 months (OR 1.31, 95% CI 1.02-1.68) were associated with higher odds of AI diagnosis. Interestingly, patients who reported fatigue had lower odds of AI diagnosis on CST (OR 0.66, 95% CI 0.49-0.88). Conclusions: Commonly associated symptoms of AI such as fatigue, dizziness, nausea, and abdominal pain were poor predictors of AI diagnosis based on CST. Consequently, the presence of these symptoms alone may not warrant additional testing. Notably, clinical features such as myalgia, arthralgia, and weight loss >10 pounds in the past 6 months were found to be more predictive of AI.

Presentation: 6/1/2024
7679 The Role of Thyrotoxicosis in Determining Clinical Outcomes for Hospitalized Patients with Dilated Cardiomyopathy: A Propensity Match National Cohort
Authors: Mukhtar R , Younas H , Taha A , Virlan D , Ceban A , Racovita A , Patel J
Published: October 2024

Disclosure: R. Mukhtar: None. H. Younas: None. A. Taha: None. D. Virlan: None. A. Ceban: None. A. Racovita: None. J. Patel: None.

Background: Thyrotoxicosis, a condition associated with high morbidity and mortality, has been notably linked to adverse clinical outcomes in patients with cardiovascular diseases. This study aims to comprehensively analyze the clinical impact of thyrotoxicosis on in-hospital outcomes in patients hospitalized with DCM. Methods: Based on 2020 National In-patient Sample Database, DCM patients were categorized into two groups depending on whether thyrotoxicosis was present or absent at the time of admission. To evaluate the impact of thyrotoxicosis on clinical outcomes, comparative analyses were conducted using propensity score matching and multivariable regression analysis. All statistical analyses were performed using STAT v 17. Results: Among 545,390 hospitalizations for DCM, 2,900 (0.5%) patients were presented with thyrotoxicosis. Propensity score matching revealed that DCM patients with thyrotoxicosis had higher heart failure rates (7.87% vs. 5.62%, aOR: 1.39, 95% CI: 1.04-1.86, p-value: 0.03). There was no statistically significant difference in in-patient mortality (2.60% vs. 3.65%, aOR: 0.81, 95% CI 0.58-1.13, p-value: 0.21), conduction disorders (3.26% vs. 2.70%, aOR: 1.38, 95% CI: 0.89-2.13, p-value: 0.15), acute coronary artery syndrome (0.62% vs. 0.86%, aOR: 0.94, 95% CI: 0.54-1.64, p-value: 0.82), acute kidney injury (18.57% vs. 18.59%, aOR 0.99, 95% CI: 0.77-1.17, p-value: 0.62), and acute stroke (0.29% vs. 0.30%, aOR: 0.60, 95% CI: 0.15-2.44, p-value: 0.48) between DCM patients with and without thyrotoxicosis. Thyrotoxicosis was associated with increased length of stay [5 days (IQR: 6) vs. 4 days (IQR: 7)] and total charge [$54,256 (IQR: 82,126) vs. $47,942 (IQR: 75,003)] in patients admitted with DCM. Conclusion: This research indicates that DCM patients co-presenting with thyrotoxicosis have an increased risk of heart failure and resource utilization during hospitalization. There were no significant effects observed in conduction disorders, in-patient mortality, acute coronary, kidney, or stroke outcomes among DCM patients hospitalized with or without thyrotoxicosis. Future prospective studies are warranted to enhance our understanding of clinical outcomes associated with thyrotoxicosis in patients hospitalized with DCM.

Presentation: 6/3/2024
7865 Thyroid Acropachy: A Clinical Response to Teprotumumab
Authors: Lira J , Zaidi M , Kim S M
Published: October 2024

Disclosure: J. Lira: None. M. Zaidi: None. S. Kim: None.

Background: Thyroid acropachy is a rare extrathyroidal manifestation of Graves disease (1). Due to its rarity, generally benign clinical course and the limited understanding of its pathophysiology, there is currently no specific treatment for thyroid acropathy. Clinical Case: A 25-year-old Asian male with a history of Graves disease, for which he had undergone total thyroidectomy 2 years prior, presented with worsening double vision. The patient also complained of swelling in the legs, and pain and stiffness in his hands and feet. On exam, he displayed bilateral asymmetric proptosis, conjunctival injection, and lid lags. Nodular and plaque-like lesions with non-pitting edema were observed on both pretibial skin. The fusiform swelling of fingers and prominent clubbing of finger- and toe-nails was noted. Upon further questioning, he admitted to smoking at least a pack of cigarettes a day. His laboratory findings were as follows: TSH 0.40 uIU/ml (0.4 - 4.2) with levothyroxine supplement, thyrotropin receptor Ab (TRAB) 81.1 IU/L (0.0 - 1.75), which was significantly elevated compared with 34.6 IU/L right after thyroidectomy. A skin biopsy was performed, revealing well-differentiated myxomatous lesion involving dermis and subcutaneous fat, with a splaying of the collagen by abundant mucin representing hyaluronic acid, confirming thyroid dermopathy. Bilateral hand X-rays showed soft tissue swelling and extensive bilateral periostitis and subperiosteal bone formation in metacarpals and phalanges, consistent with thyroid acropachy. After showing non-response to a trial of Prednisone, Teprotumumab was initiated for Graves ophthalmopathy. The patient was advised to quit smoking. Following five infusions, significant improvement was observed in proptosis and orbital inflammation. The pretibial myxedematous lesion also improved. Furthermore, there was a marked decrease in swelling in bilateral metacarpals and phalanges with regaining full range of motion. All extrathyroidal manifestations further improved after the completion of a total of eight infusions of Teprotumumab, with TRAB levels down to 14.3 IU/L. Conclusion: Our case is the first example demonstrating clinical improvement in patients with thyroid acropathy following Teprotumumab treatment. This observation implies that the pathophysiology of thyroid acropathy encompasses the interplay between TSH receptor and IGF-1 receptor signaling, akin to Grave ophthalmopathy, and suggests that the direct skeletal effect of TSH may be caused by the interaction with IGF-1 pathway, as shown in pre-clinical study (2). Reference: (1) Fatourechi V et al, J Clin Endocrinol Metab. 2002 (2) Boutin A et al, Front Endocrinol (Lausanne). 2020

Presentation: 6/1/2024
7553 Thyroid Paraganglioma: A Complex Tale of the Familiar Thyroid Nodule
Authors: Moorthy Vivek , Kondapally Apoorva , Kimball-Ravari Laura Elizabeth
Published: October 2024

Disclosure: V. Moorthy: None. A. Kondapally: None. L.E. Kimball-Ravari: None.

Background: Thyroid paragangliomas are rare and often misdiagnosed on fine-needle aspiration (FNA). Clinical Case & Discussion: A 58-year-old female presented with an asymptomatic “cold” thyroid nodule. Ultrasound demonstrated a 2 cm hypoechoic nodule in the isthmus. FNA yielded a follicular lesion of undetermined significance, and genomic sequencing estimated a 50% risk of malignancy prompting the patient to opt for total thyroidectomy. Histopathology and immunohistochemistry (IHC) confirmed the diagnosis of benign paraganglioma (PGL). SDH-B (succinate dehydrogenase subunit B) was notably absent on IHC. Past medical history is significant for hysterectomy for uterine fibroids and obesity, along with a confirmed family history of Hereditary Leiomyomatosis with Renal Cell Cancer (HLRCC). The patient and several family members tested positive for a pathogenic variant of fumarate hydratase (FH) gene implicated in HLRCC and undergo annual MRIs for cancer surveillance. The loss of SDH-B suggests underlying mutation. Germline SDH mutations occur in 20% of patients with pheochromocytoma and PGLs, predisposing to hereditary syndromes. PGLs are catecholamine-secreting neuroendocrine tumors with carotid body and jugular PGLs accounting for 80% of head and neck PGLs (HNPGLs). Thyroid PGLs originate from the inferior laryngeal paraganglia. They are very rare, often non-secretory, and commonly present as asymptomatic solitary nodules. For these reasons, FNA, while contraindicated, is frequently performed. If FNA is considered, pre-procedural alpha-adrenergic blockade is recommended, although catecholamine secretion triggered by FNA is uncommon. Thyroid PGLs are misdiagnosed on FNA as other thyroid neoplasms. Awareness of the more unique cytopathology of thyroid PGLs and a comprehensive IHC can aid in accurate diagnosis. Interestingly, SDH (complex 2) and FH are closely linked enzymes in the Krebs cycle. Emerging evidence correlates germline FH mutations and hereditary pheochromocytoma-paraganglioma. PGLs are less commonly associated with MEN 2A and 2B, NF type 1, VHL, and Carney-Stratakis syndrome and Carney triad. Therefore, additional testing for SDH, RET, VHL and MAX genes was recommended in this case. Total thyroidectomy or lobectomy with or without elective lymph node dissection remains the treatment of choice. Annual 24-hour urine and plasma metanephrine testing will help screen for potential recurrence. Use of GLP1 agonists for weight loss in this patient warrants further genetic and safety evaluation. Clinical Lesson/Conclusion: Often misdiagnosed on FNA, thyroid paragangliomas are rare, with multiple genetic predispositions. FNA is contraindicated and if considered, must be performed after alpha-blockade. Germline SDH mutations are implicated in PGLs and increasing evidence links FH mutations to hereditary PGLs.

Presentation: 6/3/2024
8113 Thyroid Storm in a Patient with Thyroid Nodule on Anticoagulation
Authors: Kulkarni Rohit , Krishnasamy Sathya S , Mon Nandar , Downs Richard
Published: October 2024

Disclosure: R. Kulkarni: None. S.S. Krishnasamy: None. N. Mon: None. R. Downs: None.

Background: There are very few case reports related to hyperthyroidism due to anticoagulation use. We describe a case, of a less common cause of hyperthyroidism due to hemorrhagic thyroiditis in a patient on anticoagulation and history of metastatic colon cancer. Clinical case: A 67-year-old white male with PMH significant for colon cancer with liver metastasis s/p exploratory laparotomy with sigmoid colectomy, end-colostomy with Hartman's pouch creation, pre-diabetes, recent left IJ & axillary vein thrombus on Eliquis, and thyroid nodule; presented with complaints of shortness of breath, difficulty swallowing and dizziness. Other symptoms included weight loss, complaints of heart racing and generalized body aches. The patient had a recent admission for similar complaints and was newly diagnosed with left IJ/axillary vein thrombus and expanding hemorrhagic thyroid nodule on imaging. He was discharged on anticoagulation for the DVT with 2 week follow up for elective thyroidectomy for goiter. The patient was admitted to the ICU for worsened respiratory status needing ventilatory support and pressor support. Physical findings on admission included jaundice, sinus tachycardia, lethargy with agitation. Initial labs showed TSH 0.02 uIU/mL, FT4 4.85 ng/dL and FT3 6.8 pg/mL, LFTs >500 U/L. Burch-Wartofsky Point Scale score was >60 suggestive of thyroid storm. Imaging with PET CT was concerning for thyroid enlargement with multiple nodules with increased uptake. Thyroid US was consistent with heterogenous gland with hemorrhagic nodules. Based on clinical history, physical findings, diagnostic labs, and imaging the patient was diagnosed with severe hyperthyroidism with thyroid storm secondary to hemorrhagic thyroid nodules in the setting of anticoagulation. The patient underwent thyroid artery angiogram with particle embolization of left inferior and right superior thyroid arteries. Endocrinology started the patient on methylprednisolone, cholestyramine and propranolol. Thionamide was held since the patient had abnormal liver function tests in the setting of shock liver. The patient’s thyroid function slowly improved on current regimen to TSH 0.05 uIU/mL, FT4 1.7 ng/Dl and FT3 4.1 pg/mL on day 3. At the family interdisciplinary meeting, due to guarded prognosis, family opted for comfort care, and the patient finally succumbed to multiple co-morbidities. Conclusion: The case presented discusses diagnosis and management of less common causes of hyperthyroidism and management of thyroid storm in liver dysfunction. The patient would have needed a thyroid biopsy at a later date to rule out colonic metastasis as a cause of hemorrhage if he had survived the thyroid storm and comorbid illnesses.

Presentation: 6/3/2024
9355 Thyroid Storm: In the Aftermath of Thyrotropin Stimulated Scan
Authors: Bhandari S , Jamshed I , Bag A , Rastogi N , Ramsetty A
Published: October 2024

Disclosure: S. Bhandari: None. I. Jamshed: None. A. Bag: None. N. Rastogi: None. A. Ramsetty: None.

Introduction: Cases of thyroid storm have been reported in metastatic follicular thyroid cancer following surgery and radioactive iodine treatment [1]. Our patient developed thyroid storm after receiving thyrotropin followed by radioactive iodine scan (RAIU), a phenomenon not described in any formal reports to date. Clinical Case:74-year-old woman with history of metastatic follicular thyroid cancer, presented with altered mental status. CT head was negative. CT C/A/P showed heterogeneous thyroid gland with substernal extension, lucent 2 cm lesion involving T10 vertebrae. She had received 0.9 mg of recombinant human thyrotropin (rhTSH) 2 days before presentation and had thyrotropin-stimulated whole-body scan, and RAIU scan showing enlarged multinodular goiter. RhTSH is used to augment the thyroid radioiodine uptake (RAIU) in the surveillance of thyroid cancer without rendering the patient hypothyroid. TSH was 0.008 ng/ml (n 0.270-4.200 UIU/ml) a month back. Labs now revealed TSH 6.58 UIU/ml (reflecting residual rhTSH activity), total T4 19.8 ng/dl (n 4.9-11.7 ng/dl), free T4 3.0 ng/dl (n 0.7-1.5 ng/dl), total T3 2.52 ng/ml (n 0.35-1.93 ng/ml) and thyroglobulin 2525 ng/ml (n 2.8-40.9 ng/ml) concerning for thyroid storm. Treatment with IV hydrocortisone, methimazole, and beta blockers was initiated which led to normalization of thyroid levels (TSH 3.75 UIU/ml, Total T4 10.6 ng/dl, Free T4 1.4 ng/dl, Total T3 0.47 ng/ml), and clinical improvement.Our patient had a co-occurrence of follicular thyroid cancer with multinodular goiter. Administration of thyrogen could have activated the multinodular goiter leading to precipitation of thyroid storm. Thyroid storm in patients with thyroid cancer following treatment is usually due to destruction of thyroid tissues and activation of metastatic thyroid glands from the primary tumor[2]. Thyroidectomy or radioactive ablation of thyroid is the definitive treatment. Patients should however be bridged to euthyroid state prior to this. Our case highlights a unique presentation in terms of pathophysiology for patients with thyroid cancer in the setting of thyrogen use. Conclusion: Although rare, if patients with known thyroid cancer receive thyrotropin subsequently develop symptoms concerning for thyroid storm, clinicians should evaluate with a thyroid panel for prompt diagnosis and treatment. References: 1.Raef H, Dahhan T, Ahmed M, et alRecurrent thyroid storm induced by heretofore unrecognised causes in a patient with thyroid cancer Case Reports 2009;2009:bcr0720080442. 2.Folkestad L, Brandt F, Brix T, Vogsen M, Bastholt L, Grupe P, Krogh Petersen J, Hegedüs L. Total Thyroidectomy for Thyroid Cancer Followed by Thyroid Storm due to Thyrotropin Receptor Antibody Stimulation of Metastatic Thyroid Tissue. Eur Thyroid J. 2017 Sep;6(5):276-280. doi: 10.1159/000479061. Epub 2017 Aug 3. PMID: 29071241; PMCID: PMC5649237.

Presentation: 6/1/2024
7342 Thyrotoxic Periodic Paralysis
Authors: Arora Gunjan
Published: October 2024

Disclosure: G. Arora: None.

Case presentation: A 40 year old male with no significant past medical history presented to the emergency department with diffuse body weakness for one day. On the night prior to admission, his thighs started getting sore which in a matter of a few hours, progressed to weakness involving his entire body. He was unable to flex his hips, shoulders, and neck. He was unable to get up or move without assistance. He was found to have an irregular heartbeat two weeks prior to admission and had undergone a thyroid ultrasound which showed inflammation of the thyroid gland. He was not started on any new medications. He endorsed fatigue, palpitations, neck swelling, and 45 lbs unintentional weight loss over 6 months. No fever, chills, vision changes, congestion, chest pain, shortness of breath, cough, tingling, numbness or weakness. He denied alcohol or drug use. Physical examination was notable for blood pressure 151/80 mm Hg, heart rate 120 bpm, enlarged thyroid gland tender to palpation, and muscle weakness (motor strength 3/5 in flexors and extensors of hips and knees). Labs were notable for K 2.3 (3.5 - 5.1 mmol/L), ALP 218 (32 - 91 U/L), TSH <0.010 (0.400 - 4.300 mcIU/mL), Free T4 3.5 (0.6 - 1.6 ng/dL), CK 608 (49 - 397 U/L). Urine toxicology was negative. MRI spine did not show any acute abnormality except for thyromegaly. He received potassium supplementation which led to symptomatic improvement and was admitted to medical floor. Further tests revealed: TSI 39.50 (<=0.54 IU/L), TSH receptor antibody 26 (<=1.75 IU/L), thyroid microsomal antibody 773.3 (0.0 - 9.0 IU/mL), anti-thyroglobulin antibody 4 (<4 IU/mL). Thyroid ultrasound showed an enlarged, heterogenous, hypervascular thyroid without any nodules. He was started on Propranolol and Propylthiouracil, which led to symptom resolution and he was discharged. Discussion: Thyrotoxic periodic paralysis (TPP) is a rare muscle disorder, belonging to the family of diseases called channelopathies. Thyroid hormone increases tissue responsiveness to beta-adrenergic stimulation, which increases Na-K ATPase activity on the skeletal muscle membrane driving potassium into cells. This leads to hyperpolarization of the muscle membrane and relative inexcitability of the muscle fibers, especially in the presence of a trigger such as provocation with exercise, fasting state or a high carbohydrate meal (insulin stimulates Na-K ATPase pump). Furthermore, more than 95% of TPP cases occur in males. This predominance is due to androgen-induced Na-K ATPase sensitization, more pronounced hyperinsulinemia, comparatively higher sympathetic and catecholamine-induced Na-K ATPase activity and higher muscle mass in males. Given the life-threatening association of severe hypokalemia, TPP should be considered in all patients presenting with acute painless muscle weakness.

Presentation: 6/3/2024
7683 Tipping the Balance: Development of Graves’ Disease in a Patient with Longstanding Hashimoto’s Thyroiditis
Authors: Hazen K S , Gigliotti B J
Published: October 2024

Disclosure: K.S. Hazen: None. B.J. Gigliotti: None.

Background: Development of persistent Graves’ hyperthyroidism in patients with hypothyroidism from Hashimoto’s thyroiditis is a rare phenomenon that is presumed to be due to a shift in the shift in the balance of inhibitory, neutral, and stimulatory thyroid stimulating hormone (TSH) receptor autoantibodies. Clinical Case: A 70-year-old female with a history of obstructive sleep apnea, hypertension, hyperlipidemia, osteopenia, positive antinuclear antibody, positive antinuclear ribonucleoprotein antibody, and hypothyroidism on relatively stable dose of levothyroxine 75 mcg 6 days weekly for about 20 years was slowly weaned off levothyroxine over 3 years by her primary care physician due to persistently low TSH levels. Symptoms included increased thirst, cold intolerance, dry skin, increased appetite, and fatigue. Exam showed no thyromegaly. Despite levothyroxine discontinuation, her TSH remained suppressed at 0.21 uIU/mL (0.27-4.20 uIU/mL) with normal free T4 1.0 ng/dL (0.9-1.7 ng/dL) and total T3 122 ng/dL (80-200 ng/dL). The patient had been taking biotin, but thyroid function testing remained unchanged after discontinuation. Additional testing revealed a thyroid stimulating immunoglobulin (TSI) 29.30 IU/L (<= 0.54 IU/L), TSH receptor antibody 33.40 IU/L (<= 1.75 IU/L), thyroglobulin Ab >2,500.0 IU/ml (0.0-3.9 IU/mL), and thyroid peroxidase Ab 2,792.8 IU/mL (0.0-8.9 IU/mL). After remaining off the levothyroxine for several months, her TSH rose to 11.20 uIU/ml (0.27-4.20 uIU/mL) and she was restarted on low dose levothyroxine with a subsequent decrease in TSH to 0.11 uIU/ml (0.27-4.20 uIU/mL) after 5 weeks. Conclusion: This case demonstrated a rare situation in which a patient with hypothyroidism from Hashimoto’s thyroiditis subsequently developed hyperthyroidism from Graves’ disease. Given she was not on a weight-based levothyroxine replacement dose, it is suspected she still had underlying active thyroid tissue that was able to respond to stimulatory antibodies. Elevation of the TSH receptor antibody and TSI suggest that the patient also had underlying Graves’ disease with either new onset, or a possible shift of antibodies from inhibitory or neutral to stimulatory, resulting in decreased levothyroxine requirement and subsequent endogenous hyperthyroidism. This demonstrates the importance of considering non-iatrogenic causes of dramatic changes in levothyroxine dose requirements and close monitoring required for such patients.

Presentation: 6/2/2024
8208 Unexpected And Significant Rise In TSH In The Setting Of Relugolix Use
Authors: Groysman A Y , Poloju A , Majety P , Abraham T
Published: October 2024

Disclosure: A.Y. Groysman: None. A. Poloju: None. P. Majety: None. T. Abraham: None.

Background: Relugolix is a gonadotropin-releasing hormone antagonist used as androgen deprivation therapy for metastatic and nonmetastatic castration-resistant prostate cancer that was FDA-approved in December 2020. Common side effects include hot flashes, increased glucose and triglycerides, and decreased hemoglobin. We report a case of Relugolix interference with the absorption of levothyroxine, which has not been reported in the literature. Case: A 79-year-old white man with high-risk, Gleason 9 prostate cancer and Hashimoto’s hypothyroidism presented for evaluation of elevated thyroid stimulating hormone (TSH) level- 52.87 mIU/L (0.28-4.10 mIU/L). He did not have cold intolerance, constipation, fatigue, or weight gain. He was diagnosed with hypothyroidism in 1998 and was on a stable dose of levothyroxine 88mcg daily from 2016 until the time of this presentation. He is adherent and reports following a routine of having breakfast with coffee soon after taking levothyroxine for many years. In June 2022, his TSH was 4.48 mIU/L. In July 2022, he started taking Relugolix along with levothyroxine. Following this, his TSH levels increased to 30.08 mIU/L (FT4: 0.67 ng/dL), 35.43 mIU/L (FT4: 0.57 ng/dL), 52.87 mIU/L (FT4: 0.48 ng/dL) on 2/24/23, 3/3/23, and 3/14/23, respectively. No new medications were reported. His other medications were atorvastatin, tamsulosin, and vitamin D, which he took at night. He did not take calcium or biotin supplements. He had gradual weight gain (8 lbs) over the last 9 months. Levothyroxine dose was increased from 88 to 125 mcg daily and he was instructed to separate Relugolix from levothyroxine so he started taking Relugolix at bedtime. Repeat TSH was low at 0.12 mIU/L. The levothyroxine dose was eventually titrated back to 88 mcg daily and TSH was 5.2 (appropriate for age). Conclusion: Several medications are known to interfere with the absorption of levothyroxine. Our case suggests that Relugolix may be one of them. The significant rise in TSH and levothyroxine requirements months after starting Relugolix and the ability to return to the previous dose of levothyroxine only by separating Relugolix from levothyroxine strongly suggests that there is an interference between these medications that has not been reported.

Presentation: 6/2/2024
8581 Unusual Case Of Multifactorial Hyperthyroidism
Authors: Daw Bagar Darin , Meyers Erin , Correia Marcelo
Published: October 2024

Disclosure: D.D. Bagar: None. E. Meyers: None. M. Correia: None.

Background: Nivolumab is an immune checkpoint inhibitor that is used to treat specific types of cancer, including melanoma, by increasing the ability of the immune system to detect cancer through activating cytotoxic T-cells. The side effects of immune checkpoint inhibitors are mainly through the overactivation of the immune system that can affect many organs with autoimmune diseases, including endocrine glands, which could be severe and irreversible, like hypothyroidism or immune thyroiditis. The uniqueness of this case is the presence of multifactorial causes of hyperthyroidism; in addition, it is one of the few cases of immune checkpoint inhibitor induced positive TSI thyroiditis.Clinical Case: An 82-year-old male with a known history of atrial fibrillation on amiodarone presented to his dermatologist with a left forearm lesion. A shave biopsy showed melanoma, and he underwent wide local excision with negative sentinel lymph node biopsy. However, he had significant melanoma in situ present within 5 mm of the margin and was deemed not a candidate for further excision. Tumor board recommended close surveillance. He then received two cycles of pembrolizumab for one year, followed by nivolumab. During his treatment course, he had CT scans with iodinated contrast every 8-12 weeks for the clinical trial. At his clinic visit, routine thyroid function tests were significant for hyperthyroidism with a TSH <0.01 and free T4 of 6.07 (0.8-1.8). He was asymptomatic except for unintentional weight loss. He denied using any biotin supplements. His labs also showed positive thyroid stimulating immunoglobulin (TSI) of 1.10 (<=0.54 IU/L). A thyroid US with doppler showed two nodules less than 1.1 cm and no increased vascularity. Amiodarone was discontinued, and prednisone and methimazole were started. His free T4 has since normalized and both prednisone and methimazole are being tapered down. Conclusion: This case is a multifactorial cause of hyperthyroidism. He had been using amiodarone for atrial fibrillation, had multiple imaging studies with iodinated contrast, and was on immune checkpoint inhibitor therapy with a positive TSI. The uniqueness of this case is not only that combined factors can affect thyroid function but also that he developed a positive TSI, which indicates either Graves’ disease or immune-induced thyroiditis by nivolumab, which has been reported only in a few cases.

Presentation: 6/3/2024
7510 Use Of Tumor Markers And Surgery In The Management Of Medullary Thyroid Cancer During Pregnancy
Authors: Garver Megan , Lisa Vaz Cherie
Published: October 2024

Disclosure: M. Garver: None. C. Vaz: None.

Introduction: Thyroid cancer is the second most diagnosed cancer during pregnancy, predominantly differentiated thyroid malignancies. [1] MTC during pregnancy is rare and challenging to manage due to its aggressive nature. We describe the successful diagnosis and management of MTC during pregnancy. Clinical Case: A 28 yo woman presented with a rapidly growing neck lump for 2 months with an associated unintentional 10lb weight loss and without compressive symptoms. She had no history of childhood radiation exposure or family history of thyroid cancer. Physical exam revealed a hard L lobe thyroid nodule without palpable lymphadenopathy. The patient was 5 weeks pregnant at the time. A neck US revealed a 4.2x2.7x2.0 cm L solid isoechoic thyroid nodule with punctate echogenic foci and microcalcifications. The nodule was classified as TIRADS 4 and ATA high suspicion. FNA noted Bethesda IV with positive IHC stains for chromogranin and calcitonin. Afirma MTC classifier was positive, confirming diagnosis of MTC. At 7 weeks gestation, calcitonin was markedly elevated at 3508 pg/mL (n <5 pg/mL), CEA 29.5 ng/mL (n <2.5 ng/mL) and calcium 10.3mg/dL (8.6-10.2mg/dL). Plasma normetanephrines were elevated to176 pg/mL (n <148 pg/mL) with normal metanephrines 28 pg/mL (n <57 pg/mL) and normal 24-hour urine metanephrines. CT neck revealed 3.2x2.8cm L thyroid nodule without cervical lymphadenopathy. Due to pregnancy status, additional imaging to assess for metastatic disease was deferred until after delivery. Genetic testing did not identify mutations within the thyroid cancer panel including APC, CHEK2, DICER1, MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, and TP53. The patient underwent total thyroidectomy with neck dissection at 19 weeks gestation without complication. Two weeks postoperative Calcitonin was 2 pg/mL(n <5 pg/mL) and CEA was undetectable. Conclusions: The effect of pregnancy on MTC is not well studied because of low incidence. Guidelines on the timing of surgery for MTC diagnosed during pregnancy are lacking. While evidence confirms that surgery can be safely postponed until after delivery for low risk differentiated thyroid malignancies, there is no consensus on timing of surgery for MTC. Given the aggressive nature of MTC, along with marked elevation of calcitonin and CEA in this case, surgery was performed in the 2nd trimester with excellent outcome. Data is conflicting on accuracy of calcitonin and CEA during pregnancy, with some reports suggesting falsely high levels due to pregnancy. The sharp decline in calcitonin and CEA 2 weeks postoperatively suggested these were truly elevated due to MTC and unaffected by pregnant status. We suggest that calcitonin and CEA be followed similar to non-pregnant cases with MTC. Resources: 1.Khaled, H. M., Lahloubi, N. A., & Rashad, N. (2016). A review on thyroid cancer during pregnancy: Multitasking is required. Journal of Advanced Research, 7(4), 565–570.

Presentation: 6/2/2024
6564 A Case Of Severe Hypercalcemia In Carney's Complex
Authors: Chippior Jessica , Rayan Melanie , Wright Laura , Steven Kirschner Lawrence , Wai Ing Steven
Published: October 2024

Disclosure: J. Chippior: None. M. Rayan: None. L. Wright: None. L.S. Kirschner: Grant Recipient; Self; Medpace, Sparrow, Corcept Therapeutics, Corcept, Spruce, CinCor, Crinetics, Adrenas. S.W. Ing: Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Bridge Bio.

Carney complex is a rare syndrome with fewer than 750 reported cases, characterized by lentigniosis, myxomas, and the occurrence of both endocrine and non-endocrine tumors. An inactivating mutation PRKAR1A, which encodes for the type 1A regulatory subunit of Protein kinase A, is responsible for over 70% of familial cases and 37% of sporadic cases. A 31-year-old female with a history of Carney complex, Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD), facial lentigines, spinal Schwannomas, and recent ischemic stroke secondary to embolization of a cardiac atrial myxoma, was transferred to our medical center for hyperemesis and severe hypercalcemia. Albumin-corrected serum calcium measured 15.4 mg/dL (8.6-10.5 mg/dL), ionized calcium 7.8 mg/dL (4.6-5.3 mg/dL) associated with suppressed PTH, normal PTH-related protein, and elevated bone turnover markers, C-telopeptide 4,273 pg/ml (150-635) and Procollagen Type 1 N-terminal Propeptide 222 mcg/L (19-83). Evaluation for etiology of hypercalcemia revealed elevated 1,25 dihydroxy vitamin D at 107.0 pg/ml (20-79) and elevated interleukin-6 at 11 pg/ml (<6.4). IL-6 is expressed by cardiac myxomas. Serum angiotensin-converting enzyme level was 50 U/L (16-85) and infectious workup was negative for potential granulomatous causes of elevated calcitriol (including testing for tuberculosis, histoplasma, blastomyces, bartonella, and coccidioides). CT angiogram of the abdomen and pelvis (completed in preparation of atrial myxoma resection) revealed ground-glass opacities in bilateral posterior lung fields and multiple pulmonary nodules, with the largest measuring 8 mm. After treatment with aggressive intravenous fluid resuscitation, intramuscular calcitonin, and intravenous zoledronic acid, corrected calcium normalized to 9.4 mg/dL at discharge. Urinary cortisol was 6.2 mcg per 24-hr (3.5-45), for which she started hydrocortisone 20 mg daily to treat suspected adrenal insufficiency as excess cortisol secretion in PPNAD may be episodic. Thus remission of hypercortisolism may have unmasked an underlying hypercalcemia, and adrenal insufficiency itself may have contributed to this finding. She had excision of left atrial myxoma and has continued to exhibit normal calcium levels on steroid replacement therapy. Repeat chest CT to further characterize these pulmonary findings is planned. This case illustrates a unique constellation of endocrine features associated with severe hypercalcemia in Carney complex.

Presentation: 6/1/2024
8213 A Splicing Modulator Inhibits Proliferation And Steroid Production Of H295R Adrenocortical Cancer Cells
Authors: Tanaka T , Ohe K , Yanase T , Kodama S
Published: October 2024

Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None.

Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer.

Presentation: 6/1/2024
8636 Characterization Of The Role Of Neutrophils In Promoting Progression Of Lymphangioleiomyomatosis
Authors: Henson Thomas R , Minor Briaunna , Hammes Stephen R
Published: October 2024

Disclosure: T.R. Henson: None. B. Minor: None. S.R. Hammes: None.

Lymphangioleiomyomatosis (LAM) is a rare, multisystemic disease that is associated with cystic lung destruction. LAM is caused by small smooth muscle cell-like tumors throughout the lung that contain deleterious mutations in the tuberous sclerosis complex genes TSC1 or TSC2. This attenuates the activity of the mammalian target of rapamycin complex 1 (mTORC1) causing increased proliferation of the smooth muscle cells. LAM is a sexually dimorphic disease that primarily affects genetic females. Clinical observations implicate the role of estrogen in disease progression, as it is exacerbated during pregnancy and by use of exogenous estrogens in birth control. LAM tumor-derived cells lines have shown that direct estrogen stimulation of cell proliferation is modest compared to the dramatic in vivo effects of estradiol (E2) stimulation in a uterine-specific TSC2-null mouse model. Creation of a monoclonal cell line from these mice resulted in the generation of the LTM3 cell line, which also demonstrates low response to direct estrogen stimulation in vitro. This indicates that direct E2 stimulation may act upon other cell types in the tumor microenvironment. Immunophenotyping of uterine-specific TSC2-null mice has shown that the tumor microenvironment is enriched with myeloid cells specifically neutrophils. Functional analysis of neutrophil suppression in vivo has shown a reduction in myometrial growth in the uterine-specific TSC2-null mice, indicating a key role for neutrophil-mediated LAM tumor growth. Altered transcriptional regulation of neutrophils further highlights the importance of neutrophils in LAM progression. Bulk messenger RNA sequencing revealed E2 dependent increase in the neutrophil derived serine protease neutrophil elastase (NE). NE in vitro has been shown to increase migration, invasion, and proliferation of LAM cell lines, while inhibition in vivo has shown a reduction to the myometrial growth. Previously published data by the lab has shown that E2 increases tumor induced expansion of neutrophils in the bone marrow. Isolation and purification of Neutrophils from mouse bone marrow stimulated with tumor conditioned media from the LTM3 cells has shown signs of activation via upregulated gene expression. The focus of the current research has been the characterization of bone marrow derived neutrophils. Currently working with an in vitro system to study the proliferation of LTM3 and the rat leiomyoma (ELT3) cell lines when they are co-cultured with neutrophils. Understanding the mechanism by which neutrophils are activated and interact with LAM cells can give understanding to disease progression may provide insight into future treatment options.

Presentation: 6/3/2024
12347 Cholesterol Biosynthesis Inhibitor Ro 48-8071 Suppresses Growth Of Triple-negative Breast Cancer Cells By Inducing Apoptosis And Suppressing Angiogenesis
Authors: Liang Y , Hyder S M
Published: October 2024

Disclosure: Y. Liang: None. S.M. Hyder: None.

Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu, proteins that are commonly targeted in breast cancer therapies. Women who suffer from TNBC have limited treatment options and are administered toxic chemotherapeutic agents. They have poor prognosis due to the emergence of drug-resistant cells that lead to tumor metastasis. New non-toxic therapeutic strategies to control TNBC progression, and prevent metastasis are urgently needed. Cholesterol is an essential structural and functional component of cell membranes necessary for tumor growth and progression. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy since tumor cells grow rapidly, and need a greater supply of cholesterol. We targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor growth. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors but its effect on TNBC is not known. Pharmacological doses of RO potently reduced the viability of both MDA-MB-231 and BT20 TNBC cells in a dose dependent manner (1-50 μM). IC50 values for loss of cell viability was approximately 10 μM for both cell lines following 48 h exposure to RO. Doses close to the IC50 for OSC (1-10 nM) also reduced cell viability following exposure of TNBC cells to RO for a week. Importantly, RO had no effect on the viability of normal human mammary cells. FACS analysis revealed that RO dose-dependently induced apoptosis of TNBC cell lines in vitro. In vivo, administration of 5-10 mg/kg RO to mice with BT-20 TNBC cell-derived xenografts (100 mm3) inhibited tumor growth with no apparent toxicity. Immunohistochemical analysis of tumor tissues at the end of treatment showed that RO increased TUNEL expression, suggesting that the in vivo effects of RO were also exerted through mechanisms affecting apoptosis. Furthermore, IHC of tumor sections showed that RO also reduced levels of the angiogenic markers VEGF and CD-31 (blood vessels) in vivo, indicating that suppression of angiogenesis is also part of the mechanism through which RO exerts its anti-tumor effects. We conclude that RO is a potent inhibitor of TNBC and that its anti-tumor effects involve mechanisms that induce apoptosis and suppress angiogenesis.

Presentation: 6/2/2024
9354 Combination Of Novel Ruthenium-Based Small Molecule Bold-100 And Capecitabine Is Effective In Inhibiting Growth Of Estrogen Receptor Positive Metastatic Breast Cancer
Authors: Scheidemann Erin R , Demas Diane M , Ashai Nadia , Shajahan-Haq Ayesha N
Published: October 2024

Disclosure: E.R. Scheidemann: None. D.M. Demas: None. N. Ashai: None. A.N. Shajahan-Haq: None.

The most common breast cancer subtype in both women and men is estrogen receptor alpha positive (ER+). In the adjuvant setting, ER+ tumors are initially treated with endocrine therapy that includes antiestrogens. Mechanistically, estrogen triggers a mitogenic signaling cascade through the ER, which activates the cyclin D1-cyclin-dependent kinase 4 and 6 (CDK4/6) complex to promote cell growth. ER+ tumors that progress on antiestrogens are subsequently treated with a combination of antiestrogens and CDK4/6 inhibitors (palbociclib, ribociclib or abemaciclib). However, 20% of ER+ tumors never respond to CDK4/6i due to intrinsic resistance and the tumors that initially respond will develop acquired resistance. In the absence of driver mutations, resistant tumors are treated with standard chemotherapies, including capecitabine, which interferes with DNA synthesis. However, treatment with capecitabine show meager success and accompany adverse side effects. BOLD-100 is a ruthenium-based novel small molecule drug that demonstrated antitumor activity as a monotherapy in a phase I clinical trial with a manageable safety profile at the maximum tolerated dose. BOLD-100 has recently been investigated in a multicenter global Phase 1B/2A trial (NCT04421820) of gastrointestinal cancer patients in combination with chemotherapy FOLFOX, which includes fluorouracil, the active form of capecitabine. Previously, we have shown that in breast cancer cells, treatment with BOLD-100 disrupted proteins involved in DNA repair pathway, stimulated reactive oxygen species (ROS) and induced cell death via interrupting autophagy and inducing apoptosis. In this study, we show that combination of BOLD-100 and capecitabine synergistically inhibits growth of breast cancer cells and tumors that are resistant to CDK4/6 inhibitors. Cells treated with combination of capecitabine and BOLD-100 shows increase in apoptosis and DNA damage compared with cells treated with monotherapies or control. Therefore, capecitabine and BOLD-100 is a potential novel combination therapy for breast cancer that has progressed on standard of care treatment.

Presentation: 6/2/2024
5110 Development Of Exosome-Mediated Suicide Gene Therapy For Enhanced Cancer Treatment
Authors: Ku J , Flojo R , Zhang P , Lu B
Published: October 2024

Disclosure: J. Ku: None. R. Flojo: None. P. Zhang: None. B. Lu: None.

Development of Exosome-mediated Suicide Gene Therapy for Enhanced Cancer Treatment Joy Ku#, Renceh Flojo#, Pengyan Zhang, and Biao Lu* Department of Bioengineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA#Authors contributed equally to this work. *Correspondence: blu2@scu.edu Existing suicide gene therapy strategies are designed to express prodrug-converting enzymes in the cytosol of cancer cells, limiting their therapeutic reach to gene-transfected cells and their immediate neighbors through bystander effects ([1]). This study proposes a novel approach to enhance cancer treatment by redirecting prodrug-converting enzymes into extracellular vesicles, also known as exosomes, potentially enabling metastatic cancer cells to receive therapeutic drugs through cancer-homing mechanisms (2, 3). To achieve this, we aimed to develop an exosome-based suicide gene therapy strategy employing human herpes simplex virus-thymidine kinase (HSV-TK) and cytosine deaminase-uracil phosphoribosyl transferase (CD-UPRT) enzymes. We designed and constructed two lentiviral vectors expressing chimeric fusion proteins, incorporating exosome-targeting motifs, green fluorescent protein, Gaussia luciferase, and HSV-TK/CD-UPRT. We demonstrated that both chimeric fusion proteins were properly shunted into the exosome pathways by transfection of cultured 293T and HepG2 cells, followed by real-time monitoring and confocal imaging. This was further corroborated by colocalizing these fusion proteins with well-established exosome markers, such as CD9, CD63, CD8[1], and XPACK. Furthermore, the isolation and characterization of secreted exosomes confirmed the successful loading of engineered enzymes onto exosomes, which were subsequently released into the conditioned media of both cell models. Importantly, initial experiments involving transfection and prodrug treatment showed that HepG2 cells were significantly inhibited (up to 84%) in a dose- and time-dependent manner when treated with the prodrug Ganciclovir in the HSV-TK model. Our study demonstrates the potential adaptation of prodrug therapy to an exosome-based platform, opening the door to a novel nano-treatment approach for cancer. Reference: ([1]) Thoidingjam et al., Translational Medicine communications. 2023. 8:[1][1]. (2) Lu et al., Advanced Drug Delivery Reviews. 2022. [1][1]4465. (3) Zhang et al., Signal Trnsductio and Targeted Therapy. 2023. 8:[1]24.

Presentation: 6/2/2024