bluuebunny/crossref_metadata_2025 huggingface dataset:
12604 Use Of A Novel Program "WordMiner" To Identify Cellular Proliferation Related Genes Induced In FSTL3 KO Mouse Testis
Authors: Mukherjee Neelkantha , Ballesteros Randy , Mukherjee Abir
Published: October 2024

Disclosure: N. Mukherjee: None. R. Ballesteros: None. A. Mukherjee: None.

TGFβ family ligands play crucial roles in promoting cellular proliferation. Moreover, activin and TGFβ are linked with cancer. Deletion of FSTL3, an inhibitor of a subset of TGFβ ligands, in mice leads to increased proliferation in all tissues investigated including the testis. We also find increased SMAD2/3 activation in FSTL3 knockout (KO) compared to wildtype (WT) in these tissues. Therefore, the FSTL3 KO mouse is a model of increased activity of endogenous TGFβ ligands that are inhibited by FSTL3, such as activin. It is likely that increased signalling by these ligands leads to the observed increased cellular proliferation in FSTL3 KO mice. To discover genes that might be involved in activin-dependent mitosis, we studied gene expression datasets linked to cellular proliferation. We hypothesised that genes important in cellular proliferation will be downregulated in senescent cells and upregulated in models of increased cellular proliferation and activin action such as the FSTL3 KO mice. We queried GEO datasets to identify studies related to senescence and selected Hutchinson-Gilford progeria syndrome (HGPS): fibroblast (HG-U133A), GSE3860. We found 4048 transcripts showing significantly (p<0.05) altered expression in HGPS fibroblasts compared to WT. We developed a Python-based program, “WordMiner”, that inputs a keyword and a list of terms (e.g. genes) and then searches a specified database sequentially for publications including the keyword and each term. The output is a table of search result frequencies and hyperlinks to the search result pages, compiled in an auxiliary file, produced with greater speed and efficiency than manual search methods. The greater the search result frequency, the stronger the known link between the keyword and the term. We used WordMiner to query the association of the search term “mitosis” with the 4048 genes above using PubMed as the database and identified 1235 transcripts. We refined this list further using the keyword “activin” to identify 420 transcripts linked to activin and mitosis. Importantly, by comparing against our RNAseq data, we find 20 of these genes upregulated in the FSTL3 KO postnatal day 3 transcriptome. This finding supports our hypothesis, and also demonstrates WordMiner as an efficient and versatile cross-referencing query tool. Among the 20 genes identified are transcripts known to be important in proliferation, such as Akap9 and Wnt2b. These and the remainder in the list of genes highlighted are therefore likely to be involved in pathways induced by activin, promoting cellular proliferation in FSTL3 KO testis. Currently, siRNA transfection experiments are underway to address whether knockdown of these genes in a Sertoli cell line (TM4) limits proliferation. This will help in the elucidation of the molecular pathways involved in postnatal Sertoli cell proliferation.

Presentation: 6/3/2024
7963 Analysis of the inhibition of adrenal synthesis and peripheral metabolism of corticosteroids by oteseconazole and two preclinical tetrazole antifungals
Authors: Jäger Marie-Christin , González-Ruiz Víctor , Joos Friedrich L , Winter Denise V , Boccard Julien , Degenhardt Thorsten , Brand Steve , Rudaz Serge , Thompson George R , Odermatt Alex
Published: October 2024

Disclosure: M. Jäger: None. V. González-Ruiz: None. F.L. Joos: None. D.V. Winter: None. J. Boccard: None. T. Degenhardt: Employee; Self; Mycovia Inc. S. Brand: Employee; Self; Mycovia Inc.. S. Rudaz: None. G.R. Thompson: None. A. Odermatt: None.

The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia by blocking adrenal cortisol synthesis and its peripheral inactivation [1]. Mechanisms of pseudohyperaldosteronism include inhibition of adrenal cytochrome P450 enzymes CYP11B1 and CYP17A1, as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazole compounds have been developed [2]. Here, we used adrenal H295R cells and enzyme activity assays to assess the inhibition of steroidogenesis by the tetrazoles oteseconazole, VT-1129 and VT-1598. In addition, the three tetrazoles were tested for inhibition of 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted LC-HRMS with steroid annotation indicated common features of the oteseconazole and VT-1129 patterns with that of the triazole itraconazole, and similarities between VT-1598 and the triazole isavuconazole. Targeted quantification of nine adrenal steroids by UHPLC-MS/MS in supernatants of treated H295R cells showed an overall inhibition of steroidogenesis by the tetrazoles and the triazoles itraconazole and isavuconazole. Experiments using recombinant human enzymes suggested that this effect is not caused by direct inhibition of steroidogenic enzymes because no or very weak inhibition could be observed. Furthermore, oteseconazole, VT-1129 and VT-1598 did not inhibit 11β-HSD2, suggesting that they unlikely cause pseudohyperaldosteronism. Further research needs to uncover the exact mechanism for the observed overall inhibition of steroidogenesis by the tetrazoles as well as itraconazole and isavuconazole, and whether concentrations reached in patients are high enough to cause adrenal insufficiency and hyperplasia. References: [1] Beck K. R. and Odermatt A. 2021, Mol. Cell. Endocrinol., 524, 111168. [2] Gintjee T. J., Donnelley M. A. and Thompson G. R. III 2020, J. Fungi, 6.

Presentation: 6/2/2024
7404 Evaluation Of Cortisol Reserve And Adrenal Imaging In Patients With Graves’ Disease Before And Six Months After Treatment
Authors: Sharma Pooran , Ahmad Mir Shahnaz , Mohd Patto Shoiab , Hussain Bhat Abid , Dar Basharat , Hayat Bhat mohammad , Ahmad Bhat Khurshid , Singh Madhumita , Agrawal Ruchi
Published: October 2024

Disclosure: P. Sharma: None. S. Mir: None. S. Mohd Patto: None. A.H. Bhat: None. B. Dar: None. M. Bhat: None.

Introduction: There is scarcity of data regarding the effect of thyrotoxicosis on cortisol metabolism and adrenal gland size. An increase in cortisol metabolism can deplete the functional reserve of adrenal cortex and lead to adrenocortical insufficiency even when there is no pre-existing Addison's disease. In developing countries patients with Graves’ disease present in advanced states of thyrotoxicosis. Besides they are also exposed to a variety of environmental stresses such as recurrent febrile illnesses, salt, and water loss due to manual labour in hot and humid climates etc., which can precipitate an adrenal crisis in the presence of compromised adrenal reserve. So present study was undertaken to assess cortisol reserve and adrenal gland size in patients with treatment naive Graves' disease. Objectives- The present study, was undertaken to assess cortisol reserve and adrenal imaging in patients with treatment naive Graves' disease. Specific information in this regard would help alert physicians dealing with clinical thyrotoxicosis in developing countries of tropics to the possibility of co-existing adrenal decompensation and adopt appropriate life saving measures promptly. Material & Methods: We examined 38 treatment-naive Graves' Disease patients at GMC, SSH, Srinagar, Kashmir, INDIA. Basal cortisol and cortisol response to ACTH were measured before and after six months of treatment, alongside adrenal CT imaging. Results: In hyperthyroid state, Graves' patients exhibited significantly lower basal cortisol compared to euthyroid and healthy controls (306 vs. 410 vs. 421 nmol/l, p < 0.05). 23.6% patients had subnormal cortisol response to ACTH(250ug). Those with T3 ≥ 400 ng/dl had lower cortisol response (560±133 nmol/l) and delta cortisol response than T3 < 400 ng/dl (724 ± 294 nmol/l, 213+/-73 vs. 428+/-265 nmol/l). After achieving euthyroid state, cortisol levels improved significantly (410±213 nmol/l vs. 306 ± 103 nmol/l, p < 0.05). Adrenal CT scans in 34 patients was done out of which 19 showed statistically significant increases in gland thickness, width, and AP diameter compared to controls (p < 0.01, p < 0.05. Repeat CT in 26 patients demonstrated resolution of hyperplasia (p < 0.05). Conclusion: Treatment-naive Graves' disease patients have compromised adrenocortical reserve and adrenal gland enlargement. Adrenal changes are reversible after achieving euthyroid state. These findings support steroid supplementation in impending thyrotoxic crisis and highlight a unique feature of reversible adrenal gland enlargement in this context. Keywords: Graves’ Disease, Adrenal hyperplasia, Cortisol reserve.

Presentation: 6/3/2024
12220 Impaired Esrra-mediated Regulation Of Lysosomal Protein Translation And Autophagy In MASH: Restoration And MASH Reversal By Alternate Day Fasting
Authors: Tripathi Madhulika , Gauthier Karine , Sandireddy Reddemma , Park Sung-Hee , Giguere Vincent , Chow Pierce K H , Ghosh Sujoy , McDonnell Donald Patrick , Yen Paul Michael , Singh Brijesh Kumar
Published: October 2024

Disclosure: M. Tripathi: None. K. Gauthier: None. R. Sandireddy: None. S. Park: None. V. Giguere: None. P.K. Chow: None. S. Ghosh: None. D.P. McDonnell: None. P.M. Yen: None. B. Singh: None.

The regulation of global and specific protein synthesis during the progression of metabolic dysfunction-associated steatohepatitis (MASH) is poorly understood. Accordingly, we performed a comprehensive analyses of protein translation by employing label-free quantitative proteomics, puromycin-labeling, and polysome profiling, and found a reduction in protein synthesis during lipotoxic stress in vitro and in liver tissues from MASH mouse models. We also found that expression of estrogen receptor-related receptor-α(ERRa/Esrra) and ribosomal Rplp1 were significantly downregulated at protein levels. Additionally, Esrra recruitment was decreased on the Rplp1 promoter, and led to diminished Rplp1 mRNA and protein expression. Taken together, these events reduced overall translation activity and the specific translation of lysosomal (e.g.,Lamp2, Ctsd) and autophagy (e.g., Sqstm1, Map1lc3b) proteins during MASH. Moreover, Esrra-Rplp1-mediated translation of these lysosomal and autophagy proteins and autophagy was compromised in MASH patients and liver-specific Esrra-deficient mice. Remarkably, alternate day fasting induced hepatic Esrra expression and reactivated Esrra-Rplp1 signaling in mice with MASH, leading to the re-expression of autophagy and lysosomal proteins to restore autophagy and reduce lipotoxicity, inflammation, and fibrosis. Thus, the Esrra-Rplp1-mediated translation of lysosomal and autophagy proteins critical for preventing lipotoxicity, inflammation, and fibrosis was suppressed during MASH. Reactivation of this pathway by intermittent fasting was able to reverse MASH. Our findings showed that Esrra not only regulated the transcription of genes involved in lipid metabolism, but also the specific translation of autophagy and lysosomal proteins via induction of Rplp1; thus, providing a molecular explanation for the beneficial hepatic effects of alternate day fasting in MASH.

Presentation: 6/2/2024
8018 Improving Anti-Breast Cancer Activities by Optimizing Torsion Angle Energies
Authors: Zak D R , Fink E C , Hancock G R , Young K S , Fanning S W
Published: October 2024

Disclosure: D.R. Zak: None. E.C. Fink: None. G.R. Hancock: None. K.S. Young: None. S.W. Fanning: None.

Overexpression of estrogen receptor alpha (ER-alpha) is found in 70% of breast cancer tumors. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. The majority of breast cancers are treated successfully with ER-targeted endocrine therapies, but hotspot ER-alpha LBD mutants are selected for, namely Y537S and D538G causing therapeutic resistance, relapse, and aggressive metastatic disease. The selective estrogen receptor modulator (SERM) lasofoxifene (laso) and selective estrogen receptor degrader (SERD) elacestrant (RAD1901) are chemically distinctive and show great promise in the ER-alpha mutant setting with potent anti-tumor effects and improved side effect profiles compared to the standard-of-care SERD fulvestrant (ICI). To elucidate the structural-transcriptional relationships of these ligands, we created a laso/RAD1901 chemical hybrid T6I-29 that demonstrated both canonical and unexpected therapeutic mechanisms of action. However, it possesses reduced anti-proliferative potency compared to ICI. We hypothesized that minor chemical changes to T6I-29 could improve potency while maintaining its favorable pharmaceutical profiles. To address this hypothesis, we performed quantum mechanical calculations of a series of T6I-derivatives. The addition of a methyl linker within the scaffold core significantly improved the torsion angle energies of the ligand binding pose. Multiple derivatives were synthesized based on these computations. The new compound T6I-B2 exerted profound anti-proliferative effects on breast cancer cells and adopted a unique ligand binding pose within the LBD. This approach shows that T6I-SERM potency can be improved by optimizing ligand torsion angle energies.

Presentation: 6/3/2024
5119 Structural basis for glucocorticoid receptor multimerization
Authors: Estébanez-Perpiñá E
Published: October 2024

Disclosure: E. Estébanez-Perpiñá: None.

Abstract ENDO-2024 - BostonStructural basis for glucocorticoid receptor multimerization Andrea Alegre-Martí[1]*, Alba Jimenez-Panizo2*, Agustina Lafuente3, Montserrat Abella[1], Thomas A Johnson2, Paloma Pérez4, Juan Fernández-Recio5, Diego M. Presman3, Gordon L. Hager2, Pablo Fuentes-Prior[1], Eva Estébanez-Perpiñá[1] [1]Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain.2National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.3IFIBYNE, UBA-CONICET, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, C1428EGA, Argentina.4Instituto de Biomedicina de Valencia (IBV)-CSIC, 46010, Valencia, Spain.5Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC - Universidad de La Rioja - Gobierno de La Rioja, 26007 Logroño, Spain. Abstract: The glucocorticoid receptor (GR) is a ubiquitously e2xpressed ligand-regulated transcription factor essential for life and one of the most targeted proteins in drug discovery due to its powerful anti-inflammatory actions. The functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity in cells, remains disputed. Here we present a new crystal structure of agonist-bound ancient GR-LBD in a large cell, along with a thorough analysis of previous structural work. The building block of the current structure is a homodimer we previously identified in GR-LBD crystals and its biological relevance has been verified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in live cells. Several mutually exclusive multimeric assemblies of this dimer in the crystal highlight the versatility of GR-LBD for self-association and reveal implications for the conformation of the active full-length receptor. Our results underscore the relevance of non-canonical dimerization modes for GR-LBD, especially of contacts made by key residues such as Tyr545, Pro637 and Asp641. Of note, a non-conservative mutation of the latter, p.Asp641Val, causes Chrousos syndrome in humans. Understanding relevant quaternary assemblies of the GR is pivotal not only to understand and predict the therapeutic outcome of major blockbuster drugs but also to lessen their deleterious side effects and open new avenues for drug design.

Presentation: 6/3/2024
7881 Using Selective Estrogen Receptor Modulators to Reveal Therapeutic Vulnerabilities in ESR1 Mutant Breast Cancer
Authors: Fanning S W
Published: October 2024

Disclosure: S.W. Fanning: Grant Recipient; Self; Olema Oncology.

Hotspot activating somatic mutations to ESR1, the gene for estrogen receptor alpha (ER), enable hormone therapy resistance and drive breast cancer metastasis. The Y537S missense mutation within the ER ligand binding domain is the most activating, therapy resistant, and increases metastatic potential. Next generation antiestrogens including lasofoxifene (laso) and elacestrant (RAD1901) show improved progression-free survival over fulvestrant (fulv), but further progress is needed to achieve durable response. To fully address Y537S ESR1, it is critically important to understand how the mutation boosts metastasis. We have developed a small molecule antiestrogen, T6I-29, that uniquely impacts transcriptional pathways related to cell-cell adhesions and morphology. Two allele-specific phenotypes identified by the Oesterreich Laboratory enhance the metastasis of Y537S ESR1 breast cancer cells. T6I-29-specific pathway effects were driven by a significant downregulation of dickkopf-1 (DKK1), which was also observed but to a lesser extent with fulv, laso, and RAD1901. DKK1 is an immunosuppressive, tumor-secreted glycoprotein and its overexpression correlates with poor outcomes in multiple cancers. However, DKK1 acts as a tumor-suppressor in colorectal cancer, which does not rely on ER. Our preliminary studies suggest that DKK1 plays a role in ER+ breast cancer progression. We measured significantly elevated DKK1 protein levels in the blood plasma of 108 diverse ER+ breast cancer patients compared to 100 matched healthy female donors and levels increase coincident with tumor stage. Unfortunately, we lack ESR1 mutation status and other critical details to make further insights on these patients. DKK1 gene expression and protein secretion is stimulated in WT cells by the pathogenic hormone 17β-estradiol (E2), while it is constitutively expressed in Y537S ESR1 cells. DKK1 is characterized as a WNT antagonist but can also induce PI3K/Akt signaling. Interestingly, DKK1 is elevated and ERα responsive in WT not mutant PI3KCA cell lines. DKK1 knockdown also reduced proliferation of Y537S ESR1 breast cancer cells where elevated DKK1 was observed.

Presentation: 6/3/2024
6850 A Case of Anaplastic Thyroid Carcinoma With a Complete Metabolic Response to Pembrolizumab
Authors: Tirthani Ekta , Kung Jacqueline Tam
Published: October 2024

Disclosure: E. Tirthani: None. J.T. Kung: None.

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive disease with limited therapeutic options and generally poor prognosis. Post-surgery, most patients are treated with a combination of chemotherapy, radiation, and tyrosine kinase inhibitors +/- immune checkpoint inhibitors. We describe a unique case of ATC with a complete metabolic response to pembrolizumab, a selective PD-1 inhibitor, as evidenced by imaging. Clinical Case: A 69-year-old female presented to the clinic for evaluation of a rapidly enlarging neck mass. The initial ultrasound showed a large mixed cystic-solid right thyroid nodule with irregular margins with micro- and macrocalcifications, which was biopsied. Cytology showed discohesive high-grade malignant tumor cells with enlarged nuclei, nuclear hyperchromasia in the background of necrosis, and dense neutrophilic infiltration concerning for ATC. A CT scan of the neck and chest showed a complex cystic thyroid mass with central necrosis and calcification with paratracheal, supraclavicular, and mediastinal lymphadenopathy. MRI of the brain was negative for metastatic disease. The patient underwent a total thyroidectomy with right and left level 6 and 7 neck dissection. Intra-operatively, gross extrathyroidal extension of the tumor was noted to the right carotid, larynx, right recurrent laryngeal nerve, and esophagus, with residual tumor left behind near the larynx. Pathology confirmed stage IVC ATC, positive for PIK3CA, NF1, p53 mutations, and BRAF negative. 90% of tumor cells showed PD-L1 expression on immunohistochemical staining. The post-surgical PET scan showed two discrete, well-defined foci of very intense FDG uptake, corresponding to the right lower cervical and para-esophageal lymph nodes with no evidence of distant metastasis. Systemic chemotherapy with carboplatin and paclitaxel (5 cycles) was initiated with concurrent intensity modulated radiation therapy (total 60 Gy/40 fractions to thyroid bed and bilateral neck). Repeat imaging showed minimal change in the size of the PET-positive lymph nodes. Immunotherapy was initiated and with just 2 cycles of 400 mg IV pembrolizumab, a repeat PET scan was obtained, which showed a complete metabolic response to therapy. Minimal residual FDG activity in the right supraclavicular region was thought to be secondary to posttreatment changes. The patient was able to resume her activities of daily living and had an improvement in appetite. The plan is to continue 400 mg IV pembrolizumab every 6 weeks while cautiously assessing for adverse effects from immunotherapy. Conclusion: It is rare to see a complete metabolic response to therapy with pembrolizumab without concurrent use of tyrosine kinase inhibitors in patients with ATC. A high tumoral PD-L1 expression may be the key to having this kind of dramatic response.

Presentation: 6/3/2024
8791 A Case of Hyperfunctioning Thyroid Nodules Evaluated for Thyroid Metastasis in the Setting of Oropharyngeal Squamous Cell Carcinoma
Authors: Alashoor Maram , Gogineni Jyothi , Bakar Ayla
Published: October 2024

Disclosure: M. Alashoor: None. J. Gogineni: None. A. Bakar: None.

Introduction: Identifying and evaluating hyperfunctioning thyroid nodules in the setting of metastatic head and neck cancers represents a diagnostic challenge that may result in inaccurate identification of perithyroidal lymph node metastasis as malignant or metastatic thyroid nodules with standard workup. Case presentation: A 72-year-old male with a history of stage IV metastatic oropharyngeal squamous cell carcinoma, metastasized to the lymph nodes, lungs, mediastinum, and bilateral iliac bones. He was diagnosed two years ago and received chemotherapy, maintenance immunotherapy with pembrolizumab, and targeted palliative radiation therapy, with good clinical response. Restaging PET-CT two years later revealed local progression. During his workup, he was noted to have persistently abnormal thyroid function test with low TSH (0.03​​µIU/mL, n 0.3-5.33), normal free T4 (0.97ng/dL, n 0.60 - 1.40), mildly elevated free T3 (3.91pg/mL, n 2.5-3.9), negative thyrotropin receptor antibodies levels, negative TSI, negative TPO antibody, noted evidence of subclinical hyperthyroidism consistent over the past year. Radioactive iodine uptake demonstrated multinodular gland, mildly elevated 24-hour uptake of 28% consistent with hyperthyroidism, with decreased activity in the left lobe. Thyroid ultrasound revealed multiple probable malignant thyroid nodules, a 1.8 cm TI-RADS 5 lesion of the deep margin of the lower pole of the right lobe, and a 1.6 cm TI-RADS 5 lesion of the upper pole on the right lobe. He was treated with methimazole 5 mg. Further workup with fine needle aspiration demonstrated the right upper lobe nodule sample was positive for squamous cell carcinoma, findings suspicious for metastasis. He subsequently proceeded with radical tonsillectomy, right neck dissection, and right hemithyroidectomy. Surgical pathology results noted, right neck metastatic HPV-associated squamous cell carcinoma involving the lymph nodes with extranodal extension, right oropharyngeal HPV-mediated squamous cell carcinoma. The thyroid gland biopsy was significant for incidental papillary microcarcinoma 2mm, thyroid follicular nodular disease, without evidence of squamous cell carcinoma or metastatic infiltration. Post-hemithyroidectomy, his thyroid function normalized, and methimazole was discontinued. Conclusion: Thyroid metastasis from head and neck cancers represent a rare entity. In patients with a history of malignancy, evaluation of new thyroid masses remains crucial. While FNA is a sensitive method for detecting thyroid metastases, inaccuracies may occur, impacting the identification of thyroid nodules in the presence of local metastatic lymphadenopathy. Identifying squamous cell carcinoma in the thyroid can significantly influence the treatment plan of patients with metastatic carcinomas, therefore careful consideration must be undertaken on evaluation.

Presentation: 6/1/2024
12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation
Authors: Rodriguez Isabella Marranzini , Lemelman Michelle , Canham Lorraine
Published: October 2024

Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients >= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range <= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T>C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00

Presentation: 6/2/2024
7067 A Pilot Study on Levothyroxine Administration- Understanding the Effects on Thyroid Hormone Levels and Patient Compliance Without Restrictions on Food or Time
Authors: Patel Riya , Pandya Krutarth Kandarp , Olson Dan
Published: October 2024

Disclosure: R. Patel: None. K. Pandya: None. D. Olson: None.

Background- Hypothyroidism is one of the most common treatable endocrinological disorders that can be managed by replacement therapy. In most cases, compliance is a major hindrance for maintenance medications to express the intended effect. Thus, prescribing medications in a more convenient way would make it easier for the patients to remember and hence amplify compliance. Traditional practice dictates thyroid replacement medication to be administered early in the morning on an empty stomach for optimum absorption. This mandates some patients to set an alarm clock for early morning to take their thyroid medication, which can not just be cumbersome but also increase the chances of having a fall and can alter sleep hygiene as well. We aimed to identify if allowing patients with a more lenient approach in medication timing can help increase compliance while still maintaining thyroid hormone levels with fewer side effects. Methods- As an initial single-arm pilot study, we retrospectively looked at thirteen patients from a single center, for whom patient preference was respected in allowing them to take thyroid replacement in conjunction with any other medication, food, coffee, or any combination of those, as long as it was consistently taken the same way and at the same time each day. In this study, the patient population ranged in age from 44 to 95, with a mean age of 77.38. Most of these patients had follow-ups for over a decade while their TSH levels were observed with minimum follow-up duration being 4 years. Results- On the serial measurement of TSH on this patient cohort, it was discovered that patients were still euthyroid, ranging from 0.36 to 5.28 with a mean of 2.654. This euthyroid state was achieved without requiring any frequent monitoring or extraordinarily high doses of thyroid supplement hormones compared to patients following traditional measures for the same. The highest dose required to achieve Euthyroid status was no more than 125 mcg once/day without any major hormonal fluctuations or adverse events during their treatment course. Thus, indicating that the proposed amendment to thyroid replacement instructions did not negatively impact thyroid function Conclusion- Hence, we propose a more lenient approach to taking Thyroids supplements allowing the patients to take them more conveniently and hence improving the compliance, improving overall outcomes. This can primarily be applied to the elderly population, minimising potential harm, i.e., falls, and other limitations in an attempt to take it consistently. However, this will be further investigated through a clinical trial to gather more comprehensive data on outcomes as well as identify any potential limitations of this concept.

Presentation: 6/2/2024
6781 A Rare Case of Diffuse Large B Cell Lymphoma of the Thyroid
Authors: Deyar Dylan , Herrera Melanie , Ahmad Mobeen , Ucciferro Peter
Published: October 2024

Disclosure: D. Deyar: None. M. Herrera: None. M. Ahmad: None. P. Ucciferro: None.

Introduction: Primary thyroid lymphoma (PTL) is rare, comprising less than 5% of thyroid cancers. It is frequently seen in middle-aged women and 1.5% of patients with Hashimoto’s thyroiditis. PTL may present with rapidly growing mass, dysphagia, stridor, or hoarseness. We describe a case of a female patient presenting with a neck mass and new onset hypothyroidism who was found to have DLBCL of the thyroid. We aim to raise clinical awareness regarding PTL and elucidate its association with Hashimoto’s disease and discuss treatment strategies. Case presentation: The patient was a 62-year-old female with a past medical history of type 2 diabetes, hypertension, and hyperlipidemia, presenting for worsening neck swelling for the past four weeks. She reported tenderness around the mass along with voice hoarseness and difficulty swallowing. She also reported increased shortness of breath associated with the mass while lying flat and denied any heat intolerance, cold intolerance, weight changes or bowel habit changes. The patient’s vitals were as follows: blood pressure: 146/104 mmHg, heart rate: 58 beats per minute, temperature: 36.3 C, respiratory rate: 20 breaths per minute. Initial blood work demonstrated the following: sodium: 137 mmol/L, potassium: 4.2 mmol/L, 9.4 mg/dL, white blood cell count: 12.1 × 109/L, hemoglobin: 14.5 g/dL, platelets: 330 × 109/L, thyroid stimulating hormone: 17.1 uIU/mL, free T4: 0.4 ng/dL, and TPO antibodies: 300 IU/mL. A CT scan of her neck demonstrated a left sided mass measuring 6.6 cm, by 5.6 cm, by 11 cm. The patient was started on 50 mcg of levothyroxine and was assessed by otorhinolaryngology and underwent fine needle aspiration biopsy. The patient’s biopsy demonstrated diffuse large B cell lymphoma of the thyroid gland. The patient was started on R-CHOP chemotherapy for her lymphoma as an outpatient and had a significant decrease in the size of her neck mass and improvement in her compressive symptoms. She is scheduled for six cycles of R-CHOP therapy and continues to follow with oncology. Discussion: Diffuse Large B Cell Lymphoma (DLBCL) of the thyroid is rare and necessitates distinct therapeutic considerations. Patients with Hashimoto's thyroiditis have been found to be 60-fold times more likely to develop primary thyroid lymphoma as compared to those without thyroiditis. The pathophysiology regarding this association remains unclear, however some suggest it may be due to chronic lymphocytic inflammation of the thyroid gland leading to monoclonal lymphocyte growth. Treatment of DLBCL of the thyroid requires immunotherapy, most commonly with the R-CHOP therapy which distinguishes it from the conventional management of thyroid carcinomas. Physicians should be vigilant in considering these treatment differences and to consider PTL as an etiology of growing thyroid mass in patients with Hashimoto’s thyroiditis.

Presentation: 6/2/2024
7817 A Rare Case of Intrathyroidal Thyroglossal Duct Cyst Presenting as a Rapidly Expanding Left Thyroid Goiter
Authors: Godar Cassandra M , Spiro Andrew J , Brown Kevin F , Shakir Mohamed K M , Hoang Thanh D
Published: October 2024

Disclosure: C.M. Godar: None. A.J. Spiro: None. K.F. Brown: None. M.K. Shakir: None. T.D. Hoang: None.

Introduction: Thyroglossal duct cysts are the most common congenital cyst in the head and neck, found during childhood as a midline neck mass. We present a rare case of a large intrathyroidal thyroglossal duct cyst with left lateral extension in an adult patient. Case Report: A 50-year-old man with family history of familial adenomatous polyposis presented for thyroid nodule evaluation. Thyroid ultrasound for screening of thyroid cancer showed a 4.8 x 4.5 x 2.5cm mixed cystic/solid hyperechoic thyroid nodule with smooth margins in the left lower thyroid lobe. He reported no compressive symptoms. FNA with standard 27G needle was insufficient for evaluation with Bethesda I result. Attempted syringe aspiration did not produce cystic fluid for analysis. The patient returned to clinic 8 weeks later due to visible enlargement of his anterior neck and new neck pressure with swallowing. Physical exam was significant for a new, firm palpable mass over the left thyroid isthmus. Bedside ultrasound noted expansion of the previously visualized mass now extending into the thyroid isthmus. FNA was reattempted with a 25G needle, and cytologic material was again inadequate. He elected to undergo left hemithyroidectomy. Histologic sections demonstrated a 3.4cm simple squamous, non-keratinizing cyst lining overlying a thickened fibrotic wall with mixed acute and chronic inflammation surrounded by benign thyroid tissue, consistent with an intrathyroidal thyroglossal duct cyst. Discussion: The thyroglossal duct derives from epithelial tissue during embryogenesis and atrophies during weeks 8-10 of gestation. A persistent duct may lead to cyst formation in the presence of remnant epithelial tissue secretions and local neck inflammation. A thyroglossal duct cyst is usually located midline in the anterior neck. This stands in comparison to a branchial cleft cyst, which arises due to failure of atrophy of the second branchial groove during embryogenesis and forms a cyst that is usually located in the upper lateral neck compartment. Other common neck masses include lipomas, dermoid cysts, or ectopic thyroid tissue. This case highlights the rarity of intrathyroidal thyroglossal duct cyst in an adult patient and the importance of definitive diagnosis and appropriate management.

Presentation: 6/2/2024
7081 A Spotlight on Marine Lenhart Syndrome
Authors: Alshantti Raeda , Hernandez Aleyda Maria San , Wu Jane , Barsano Charles P , Siddiqui Mahwash Fatima
Published: October 2024

Disclosure: R. Alshantti: None. A.M. San Hernandez: None. J. Wu: None. C.P. Barsano: None. M.F. Siddiqui: None.

Introduction: Marine-Lenhart Syndrome is a rare condition with a prevalence of 0.8-4.1% of cases with Graves’ disease. It is defined by the coexistence of Graves’ disease and autonomously functioning thyroid nodule(s). It is an under-recognized cause of hyperthyroidism. A limited number of cases have been reported in the literature. We report an interesting case of Marine-Lenhart Syndrome characterized by the presence of elevated thyroid stimulating immunoglobulins (TSI) and an autonomous right thyroid nodule. Case Description: A 37-year-old man with a history of hyperthyroidism from Graves’ disease and a right thyroid nodule was referred to endocrinology clinic. He was diagnosed with hyperthyroidism in 2015 at an outside facility. He had elevated thyroid stimulating immunoglobulins (TSI) and a 2.9 cm right thyroid nodule which was biopsied and had benign cytopathology. Hyperthyroidism was treated with methimazole (MMI) but without subsequent remission of Graves’ disease. He ran out of MMI and re-presented with symptomatic hyperthyroidism with fatigue, tremors, and hyperdefecation. There was no ocular involvement or thyroid compressive symptoms. Biochemical work up was consistent with uncontrolled hyperthyroidism (suppressed TSH 0.01 uIU/mL [Ref range: 0.45-5.33], and elevated FT4 2.58 ng/dl [Ref range: 0.70-2.20], elevated free T3 8.7 pg/ml [Ref range: 2.5-3.9], and mildly elevated TSI 0.72 IU/L [Ref range: 0.54 or less]. MMI was therefore reinitiated. Thyroid Uptake scan demonstrated an increased focal 24-hour Iodine-131 uptake of 57% in the right lobe with suppression of the left lobe. Thyroid ultrasound support the finding of large right thyroid nodule (2.3 x 2.4 x 3.9 cm) with diffuse heterogeneous thyroid. The presence of TSI, lack of control of hyperthyroidism for more than 2 years of treatment, and presence of a functioning thyroid nodule raise the suspicion of Marine-Lenhart Syndrome. Indeed, the findings of an autonomously functioning right thyroid nodule with concomitant Graves’ disease establish the diagnosis of Marine-Lenhart Syndrome. The option of RAI ablation vs total thyroidectomy was discussed with the patient. The patient opted for thyroidectomy. Conclusion: Based on studies, approximately 35% of patients with Graves’ disease have thyroid nodule(s) and only 2.7% are functioning adenomas. The combination of positive TSI or TrAb and functioning thyroid nodules has been termed Marine-Lenhart syndrome. The syndrome was named after David Marine and Carl Lenhart who initially described it in 1911. Unlike Graves’ disease, patients with Marine-Lenhart Syndrome have a lower remission rate with thioamides, require definitive treatment with RAI ablation at a high dose or total thyroidectomy, and may easily be misdiagnosed by many endocrinologists.

Presentation: 6/2/2024
7589 A Survey On the Current Status of Universal Screening Thyroid Indicators During Pregnancy in Real World Study
Authors: Zhou Ning , Sun Weijie , Meng Haiyan , Huang Youyuan , Zhao Junqing , Gao Ying , Yang Huixia , Zhang Yang
Published: October 2024

Disclosure: N. Zhou: None. W. Sun: None. H. Meng: None. Y. Huang: None. J. Zhao: None. Y. Gao: None. H. Yang: None. Y. Zhang: None.

A Survey on the current status of universal screening thyroid indicators during pregnancy in real world study Background: Thyroid dysfunction and thyroid auto-immunity (TAI) are common in women of childbearing age, which have been proven to increase the risk of maternal and fetal adverse pregnancy outcomes. China has adhered to the strategy of universal screening for early pregnancy thyroid indicators since 2012, and is currently the only country that recommends universal screening. This study aimed to investigate the implementation situation of universal screening for thyroid indicators during pregnancy in real world study. Methods: We retrospectively collected medical record information from 18,932 women who underwent regular prenatal examinations at Peking University First Hospital from January 2014 to December 2016 until the end of pregnancy, grouping based on whether thyroid indicators were screened during pregnancy, and comparing the general characteristics and pregnancy outcomes. Furthermore, the treatment compliance status of women who took levothyroxine and antithyroid drugs (ATD) before pregnancy was also analyzed. Results: The screening rate for thyroid indicators in pregnancy was 88.7% in our hospital, 93.3% of pregnant women underwent screening in early pregnancy, with a median gestational age of 7.0 (6.6, 10.1) weeks. Non-screening ones were more inclined to be aged>40 years or <25 years, with a BMI ≥24 kg/m2, pluriparity (≥2), and without thyroid disease history prior to conception (P < 0.05). After correcting covariates, the risks of early miscarriage (8-12 weeks) (OR=21.96, 95% CI: 19.2, 25.1) and late miscarriage (12-28 weeks) (OR=3.0, 95% CI: 2.5, 3.6) were significantly higher in non-screening group than in the screening group, but there was no significant difference in the risk of preterm labor between the two groups (P=0.985). The achievement rate (0.23≤TSH<2.5uIU/mL, FT4 within normal range, 53.7%-64.2%) of early pregnancy thyroid function among levothyroxine intervention participants increased from 2014 to 2016. Compared with those in the thyroid function controlled group, the patients in the uncontrolled group had earlier screening gestational weeks (6.7 vs. 8.0 weeks), higher TPOAb positivity (58.6% vs. 44%), and a greater incidence of other autoimmune disorders (14.2% vs. 9.8%) (P<0.05). The achievement rate of early pregnancy thyroid function among ATD intervention participants ranged from 63.6 to 71.2%. Conclusions: The screening rate for thyroid indicators in pregnancy is nearly 90% in comprehensive hospitals. The lack of screening may be related to miscarriage to some extent. The current treatment compliance status pre-pregnancy neither for levothyroxine nor ATDs was not satisfactory.

Presentation: 6/2/2024
8107 A Unique Convergence of Graves' Disease and Concurrent Lung Adenocarcinoma
Authors: Desai Prarthana , Yeasmin Shamima , Volquez Lorena Escano , Shah Deesha
Published: October 2024

Disclosure: P. Desai: None. S. yeasmin: None. D. Shah: None.

Introduction: Graves' disease (GD) is a primary cause of hyperthyroidism in developed countries, predominantly affecting those aged 30-60 years. It is notably more prevalent in women, and its association with various solid tissue cancers is under study. However, the specific link between GD and lung adenocarcinoma remains inadequately explored. This vignette aims to shed light on a potential association between GD-induced hyperthyroidism and lung adenocarcinoma. Case Presentation: A 57-year-old woman presented with palpitations, chest pain, and near syncope. Notably, she had a remote history of breast carcinoma treated with lumpectomy and radiation. Initial evaluations indicated sinus tachycardia, elevated D-dimer, and transaminitis. Imaging excluded pulmonary embolism but highlighted irregularities in the lung and an anterior mediastinal mass suggesting thymic hyperplasia. Subsequent elevated free T4 (FT4) and suppressed thyroid-stimulating hormone (TSH) levels pointed towards GD, which was later confirmed by positive thyroid-stimulating immunoglobulin (TSI) and thyrotropin receptor antibody (TRAB) results. Despite methimazole therapy, persistent GD necessitated a total thyroidectomy. Further evaluations unveiled a newly diagnosed invasive adenocarcinoma of the lung, prompting a multidisciplinary approach involving surgical interventions and ongoing monitoring. Discussion: Research suggests that thyroid hormones influence oncogenic pathways, notably the phosphatidylinositol-3-kinase (PI3K) and ERK1/2 pathways. Elevated FT4 levels correlate with heightened susceptibility to solid cancers, including lung adenocarcinoma. Discrepancies in TSH and FT4 concentrations have been observed in lung cancer patients compared to healthy individuals. Understanding the nuanced relationship between hyperthyroidism, particularly GD, and malignancies like lung adenocarcinoma is vital. Delving deeper can pave the way for utilizing thyroid hormone levels as potential prognostic biomarkers.

Presentation: 6/3/2024
6548 A Young Female with Stroke
Authors: Bulut A , Pearce E N
Published: October 2024

Disclosure: A. Bulut: None. E.N. Pearce: None.

Introduction: Moyamoya disease (MMD), known as spontaneous occlusion of the circle of Willis, is a rare cause of stroke. MMD can be associated with hyperthyroidism. Case: A 22 year-old female presented to the emergency department with intermittent right-sided weakness and numbness for three weeks. Vitals were notable for sinus tachycardia with heart rates in the 140s. Due to abnormal neurologic evaluation a head/neck CT was obtained, which showed a large left middle cerebral artery ischemic stroke. Brain CTA demonstrated a beaded appearance of the anterior and posterior intracranial arterial vasculature, raising the possibility of vasculitis. TFTS were checked due to ongoing tachycardia and showed suppressed TSH (<0.01 mIU/L, reference range (RR): 0.35 - 4.9), high fT4 (>5.00 ng/dl, RR: 0.6 - 1.8), high total T3 (427 ng/dl, RR: 83 - 160) and high total T4 (23.7 ug/ml, RR: 5.1 - 11.4). Bedside thyroid ultrasound showed normal vascularity without nodules. She was started on methimazole and propranolol. Her thyroid stimulating immunoglobulin was subsequently found to be elevated (328%, RR: <140%), confirming Graves’ disease. Secondary workup for vasculitis detected no other disease pathology. Cerebral angiogram showed findings consistent with “Moyamoya disease” (bilateral hypoplastic internal carotid arteries (ICAs) along with bilateral occlusion of the ophthalmic arteries with collateral vessels reconstituting the left and right anterior cerebral arteries). Thyrotoxic symptoms were well controlled during hospitalization. The patient was discharged with a plan to perform an Encephaloduroarteriosynangiosis (EDAS) procedure in three months. Discussion: MMD was first described by Takeuchi and Shimizu in 1957. It is characterized by progressive stenosis and occlusion of the terminal portion of the ICAs and their branches, accompanied by the formation of net-like collateral vessels known as “puff of smoke” (moyamoya in Japanese). The most common presentation is ischemic stroke, however hemorrhagic stroke can also be seen due to of rupture of moyamoya vessels. In most cases the etiology is unknown. However, Moyamoya syndrome (MMS) refers to MMD that occurs in the setting of a known associated disease such as sickle cell disease, neurofibromatosis type 1, cranial irradiation, Trisomy 21 or hyperthyroidism. Fewer than 100 cases of MMS have been reported in association with hyperthyroidism, with most cases due to Graves’ disease. Although the exact pathophysiology is unknown, thyrotoxicosis is believed to increase cerebral metabolism and oxygen consumption, resulting in impairment of cerebral perfusion. In most cases, thyrotoxicosis is present on initial presentation with ischemic stroke, as seen in our patient. It is believed that controlling symptoms of hyperthyroidism may prevent progression of MMS.

Presentation: 6/1/2024