bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cepharanthine Blocks the Presentation of Thyroid & Islet Peptides in a Novel Humanized Autoimmune Polyglandular Syndrome Type 3 Variant (APS3v) Mouse Model
Authors: Li Cheuk Wun , Osman Roman , Menconi Francesca , Concepcion Erlinda , Tomer Yaron 
Published: May 2021

Abstract
Introduction: There is a strong genetic association between autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D), and the co-occurrence of AITD and T1D in the same individual is referred to as Autoimmune Polyglandular Syndrome type 3 variant (APS3v). We previously discovered a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v, and we found that both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides can bind to this flexible APS3v HLA-DR pocket. The goal of the present study is to identify small molecules that can block the presentation of these thyroid and islet peptides by the APS3v HLA-DR pocket as a potential therapeutic approach for APS3v. Methods: We screened a panel of small molecules using an in vitro screening assay we developed using Baculovirus-generated recombinant APS3v-DR. To validate “hit” compounds discovered by the in vitro assay in a mouse model we established a novel mouse model of APS3v. The APS3v mouse model was established by immunizing humanized NOD-DR3 mice with Tg.1571, TPO.758 and GAD.492 combined, together with adjuvant. We then validated hit small molecules for their effectiveness in blocking stimulation of T-cell responses in the APS3v mouse model. Results: Our screen identified 4 small molecules (S5, S9, S15, S53) that showed more than 50% inhibition in our in vitro assay. We were also able to establish a novel APS3v mouse model. Immunized mice showed an increase in cytokine production in response to all 3 thyroidal and islet peptides. The immunized mice also developed antibody responses against each peptide. When we tested the 4 “hit” compounds, only Cepharanthine (S53) which we previously identified as a small molecule blocking AITD immune responses, could block all 3 thyroidal/islet peptides in the APS3v mouse model. Treating with Cepharanthine prior to inducing APS3v in the mice also reduced T-cell proliferation in the immunized mice. Conclusions: We established a novel humanized APS3v mouse model by co-immunizing 3 thyroidal and islet peptides. We also identified Cepharanthine as a small molecule that can block thyroid and islet specific T-cell responses in this model. Cepharanthine can be further tested in APS3v patients carrying the specific APS3v-DR pocket as a potential therapeutic treatment.
A Case of Paraneoplastic Erythropoietin Secretion Secondary to Medullary Thyroid Cancer
Authors: Pare Aurelie , Tamilia Michael 
Published: May 2021

Abstract
Background: Paraneoplastic erythropoietin (EPO) secretion is a well-described phenomenon that is classically seen in renal cell carcinoma. It has also been described in parathyroid adenoma and in pheochromocytoma. Additionally, follicular thyroid cancer cells, papillary thyroid cancer cells, and anaplastic thyroid cancer cells have all been found to express EPO in vitro. To our knowledge, EPO expression by medullary thyroid cancer has not previously been studied. Here, we describe a case of suspected paraneoplastic EPO secretion in the setting of advanced medullary thyroid cancer.
Clinical Case: A 46 year-old woman presented to our clinic with hoarseness and was proven to have a medullary thyroid cancer with enlarged lymph nodes on the right at levels IV, V and VI. Genetic testing was negative for a germline RET mutation. She underwent total thyroidectomy with bilateral lymph node dissection and was subsequently treated with external beam radiation therapy. Pathology confirmed the diagnosis of medullary thyroid cancer, with extension beyond the thyroid capsule and bilateral lymph node involvement. Rising calcitonin and CEA were noted over the following years. A MRI of the abdomen showed indeterminate subcentimetric liver lesions. A Gallium-68 Dotatate PET scan confirmed the suspicion of liver metastases. Five years after the initial surgery, the patient developed rising hemoglobin levels, despite a long-standing history of iron deficiency anemia. JAK2 testing was negative. EPO levels were elevated (43.45 mU/mL, reference range 2.59 - 18.5 mU/mL) suggesting secondary polycythemia. The patient had a negative smoking history and a pulse oximetry of 98%; there was no evidence of hypoxia that could cause an elevation in EPO. Other differential diagnoses including pheochromocytoma, Cushing’s syndrome from ectopic ACTH production, and renal and brain tumors were excluded. Biopsy of the liver lesions is not technically feasible at this time. Since discovery of the erythrocytosis, the patient has undergone repeated therapeutic phlebotomies, to maintain acceptable hematocrit levels.
Conclusion: We believe that our patient’s case may be the first reported case of ectopic EPO production from medullary thyroid cancer causing polycythemia. We encourage other clinicians to report similar clinical cases in order to better understand this rare clinical entity.
A Rare Case of Aggressive Ectopic Thyroid Cancer in a Patient With Graves Disease
Authors: Mahmood Ejaz , Anastasopoulou Catherine , Blocher Nissa 
Published: May 2021

Abstract
Background: Ectopic thyroid tissue is a rare entity with a prevalence of 1 per 300,000 persons. Malignancy in ectopic thyroid tissue is reported in &lt;1% of these cases.[1] We report a case of aggressive papillary carcinoma in ectopic thyroid gland in a patient with Graves’ disease.
Case: A 65-year old woman was incidentally found to have a 3.1 cm mass with coarse calcifications in the superior mediastinum on CT scan of chest. Ultrasound confirmed the presence of hypoechoic mass which was separate from thyroid. Additionally, a 0.5cm TI-Rad 4 left thyroid lobe nodule was found. FNA of the mediastinal mass was suspicious for follicular thyroid neoplasm. Thyramir testing was positive for BRAF V600E and TERT c-124C&gt;T mutations. Thyroid function tests showed frank hyperthyroidism and elevated thyroid stimulating immunoglobulins. Thyroid uptake and scan showed diffuse uptake of 67% at 24 hours.
The patient underwent simultaneous excision of mediastinal mass and total thyroidectomy. The pathology of mediastinal mass showed papillary thyroid cancer with tall and sclerosis features with one involved lymph node. The pathology of thyroid gland did not show any malignancy. She was treated with 100 mCi I-131. Post treatment Whole Body Nuclear Scan after treatment revealed metastatic disease in left lower lung area.
Discussion: Ectopic thyroid gland is usually found anywhere between forman caecum and mediastinum. It is rare to find ectopic thyroid tissue in the presence of eutopic thyroid gland which can create a diagnostic dilemma. Only a very few case reports of thyroid cancer arising from ectopic thyroid tissue have been reported. Our case is unique as the eutopic thyroid gland had Graves’ disease with no malignancy but the ectopic thyroid tissue developed aggressive papillary thyroid cancer. There are no specific guidelines for the management of carcinoma in ectopic thyroid glands, possibly due to the rarity of the condition. Our case has a clear metastasis to the lungs. However, it is important to differentiate ectopic thyroid tissue with carcinoma from thyroid cancer metastasis which can be difficult at times. Without specific guidelines for the management of cancer in ectopic thyroids, an individualised approach can be taken using the same therapeutic principals used in the management of eutopic thyroid cancer. Additionally, a finding of a normal thyroid gland or a benign condition in the thyroid gland should not exclude the diagnosis of malignancy in ectopic thyroid tissues.
1) Vázquez, Oscar R., et al. “Ectopic papillary thyroid cancer with distant metastasis.” Case reports in endocrinology 2018 (2018).
A Rare Case of Classical Hodgkin Lymphoma of the Thyroid Gland
Authors: Chandran Chandriya , Prater Janna , Mayrin Jane Valerie , Young Nancy A , Lytle Andrew , Bhattacharyya Siddharth 
Published: May 2021

Abstract
Background: Hodgkin lymphoma (HL) classically occurs in the lymph nodes and only in about 5% of cases occurs in extra-nodal sites. Primary thyroid lymphomas, most of which are non-Hodgkin lymphomas, comprise less than 5% of all thyroid malignancies. Only a few cases of HL of the thyroid have been reported in the literature, and in most of these cases, fine-needle aspiration biopsy (FNAB) was unreliable for diagnosis. We present a case of classical Hodgkin lymphoma of the thyroid that was falsely negative from both FNAB and core needle biopsy specimens and was diagnosed after surgery.
Clinical Case: A 51-year-old female was seen for a rapidly enlarging neck mass associated with progressive dyspnea and dysphagia. Despite being a telemedicine visit due to the COVID-19 pandemic, significant enlargement and deformity of the neck were startling. The patient was clinically and biochemically euthyroid with a TSH of 2.49 mIU/L (0.5-5.0 mIU/L) and normal FT4. She denied a personal or family history of thyroid disease and neck irradiation. Thyroid ultrasound revealed a 5.3 cm hypoechoic, wider than tall nodule with smooth margins in the left lobe, and a 1.9 cm hypoechoic and taller than wide nodule in the right lobe of the thyroid. A CT scan of the neck also revealed a 1.2 cm lymph node in the left lateral aspect of the thyroid. FNAB of the nodules showed Hurthle cells in a background of crushed lymphocytes with occasional large atypical lymphoid cells. Flow cytometry performed on a repeat FNAB specimen revealed no evidence of lymphoma. A repeat CT scan of the neck performed 2 weeks later due to worsening symptoms demonstrated middle mediastinal lymphadenopathy and a large 8x4.7x4.7 cm mass contiguous with the thyroid with a 3.8 cm cystic collection within. The patient was scheduled for an oncology consultation due to the high likelihood of lymphoma but was admitted to another institution with symptoms. She underwent a thyroid core biopsy and flow cytometry, which again failed to reveal her diagnosis. She then underwent left partial thyroidectomy, and pathology demonstrated infiltrates of small lymphocytes with histiocytes, interspersed with clusters of large, irregular, multilobate cells consistent with Reed-Sternberg cells. She was diagnosed with nodular sclerosing variant of classical HL. Chemotherapy was instituted with rapid improvement in symptoms.
Clinical Lesson: Primary HL of the thyroid is extremely rare and most often presents as a rapidly enlarging neck mass with or without compressive symptoms. Diagnosis with FNAB is challenging and can be misinterpreted as lymphocytic thyroiditis. In our patient, flow cytometry was performed twice and was falsely negative. The treatment of HL differs entirely from that of other primary thyroid cancers and thyroiditis. Hence, in patients presenting with classic symptoms, a high index of suspicion is needed to make an accurate and prompt diagnosis of HL.
Brain Metastases in a Patient With Papillary Thyroid Carcinoma. Clinical Case Report
Authors: Ramos Andrés Felipe García , Zambrano Urbano Jose Leonel , Pico Víctor Manuel Blanco , García Franco Alejandro Vallejo , Arboleda Marcela Patiño , Valencia Carlos Mario Balcázar , Chaparro Jose Mauricio Ocampo 
Published: May 2021

Abstract
Introduction: Papillary thyroid carcinoma (PTC) is the most common neoplasm of the endocrine system and the least aggressive, representing between 70% and 80% of thyroid neoplasms. This is characterized by slow growth and a low risk of progression to metastasis. Brain Metastases (BM) associated with PTC occur with a incidence rate of 0.15%. Tyrosine kinase inhibitors (TKI) are a very promising alternative for managing these patients. Here is described the case of a patient with PTC with brain and lung metastases, her respective management and evolution. Clinical Case Report: A 64-year-old patient with a history of controlled hypothyroidism, who was recently diagnosed with high cell variant PTC, positive for BRAF V600E mutation. Neck CT revealed a thyroid mass extending to the superior mediastinum, with associated lung metastases. We started by suppressing TSH with levothyroxine. Brain MRI was done due to persistent and as safety precaution before starting thyrotropin alfa This showed multiple intra-parenchymal lesions compatible with BM. Patient received management with gamma Knife radiosurgery for BM and with lenvatinib 24mg day. The patient presented a decrease in tumor size by more than 50% in the neck, with disappearance of the majority of BM at 90 days. After 18 months of treatment, she was still alive. Discussion and Conclusion: PTC associated with BM has a very poor life expectancy, and there are not guidelines for its management and the treatment is based on case reports and expert opinions. Radiosurgery plus ITK combined therapy could provide better outcomes to these patients
Cardiac Metastasis From Anaplastic Thyroid Carcinoma
Authors: Gonzalez Michelle N Garcia , Palomo Antonio Segovia , Torres Juanita H Lastra 
Published: May 2021

Abstract
Background: Anaplastic thyroid carcinoma represents 2% of all thyroid carcinomas. The most common metastatic sites are lung and neck lymph nodes. Cardiac metastasis is extremely rare. Autopsy studies of patients with thyroid cancer have documented a frequency of metastatic cardiac involvement of 0%–2%. Clinical Case: A 57- year- old woman was admitted to the emergency room with a rapidly expanding neck mass of 3 months duration. She complained of pain in the anterior neck, dysphagia, dyspnea, palpitations and hemoptoic sputum. She further reported history of weight loss. She denied medical history of cancer in the family. Prior medical history was described as non- significant. On clinical examination, vital signs were normal. General swelling around the thyroid region was noted. A hard, tender, immobile mass was palpated. A superficial lymph node of about 5 cm in diameter was palpated in level II A and IIB. The patient was admitted to the hospital for further workup. Laboratory work up revealed, hemoglobin 7.6 g/dL, hematocrit 22.5%, white blood cells 15,000/mm3, fasting plasma glucose 135 mg/dL and urea 59 mg/dL. Thyroid function tests revealed TSH 2.46 mUI/ml (normal range: 0.38-5.33 mUI/ ml), fT3 1.69 pg/ml (normal range: 2.39-6.79 pg/ml), fT4 0.57 ng/dl (normal range: 0.58-1.64 ng/dl). A fine needle aspiration cytology from the thyroid lesion described a poorly differentiated thyroid carcinoma. CT scan of the neck and chest revealed a large heterogeneous mass with hypointense areas involving the thyroid gland of 9 x 8 x 7 cm that surrounded the vertebral bodies and displaced and infiltrated the neck vessels, trachea and esophagus. In the right atrium and right ventricle three well- circumscribed ovoid masses were observed, the largest one measured approximately 21 x 17 mm, suggestive of cardiac metastases. Bilateral adrenal masses were also observed the largest one measuring 69 x 51 mm. Diagnosis of anaplastic thyroid cancer stage IVC was established with a large thyroid mass, widespread metastasis and poorly differentiated metastatic carcinoma on fine needle aspiration biopsy. During her hospitalization she presented both atrial tachycardia and atrial fibrillation and was started on amiodarone. A week later, the patient′s condition deteriorated and she died of respiratory arrest without having any further treatment for the tumor. Conclusion: In patients with established thyroid malignancy who develop cardiac arrhythmias, cardiac metastasis should be considered.
Coexistence of Pituitary Adenoma Causing Acromegaly and Medullary Thyroid Cancer
Authors: Pare Aurelie , Tamilia Michael 
Published: May 2021

Abstract
Background: We present a case of coexisting acromegaly and medullary thyroid cancer. As both conditions are rare, the association raises the possibility of causality (non-genomic) as opposed to pure coincidence.
Clinical Lesson: A 73 year-old man presented to our clinic with an incidental finding of a left thyroid nodule. The patient underwent an ultrasound-guided fine needle aspiration biopsy which revealed medullary thyroid carcinoma. Shortly afterward, the patient underwent a total thyroidectomy with bilateral cervical lymph node dissection. The patient tested negative for mutations involving RET exons 8, 10, 11, 13, 14, 15, and 16.
On initial presentation, the patient was also noticed to have an appearance typical of acromegaly, with spade-like hands and characteristic acromegalic facial features, including prognathism and macroglossia. These findings were long-standing. He was found to have elevated IGF-1 (121.4 nmol/L, reference range 6.1 - 26.9 nmol/L) and hyperprolactinemia (78.2 mcg/L, reference range 2.7 - 16.9 mcg/L). His growth hormone (GH) levels did not suppress following a 75 g oral glucose tolerance test. Magnetic resonance imaging of the sella turcica revealed a prominent pituitary gland and stalk with a rightward deviated infundibulum, with a suspected 1.1 cm left-sided pituitary macroadenoma. The patient declined surgical management, and he was instead managed medically with octreotide.
Conclusion: Coexistance of GH-producing pituitary adenoma and medullary thyroid cancer is a rare occurrence. We identified ten cases previously described in the literature. Specifically, this is the second reported case of a patient presenting with both medullary thyroid cancer and pituitary adenoma causing acromegaly.
The advanced acromegalic phenotype suggested long standing disease and therefore prolonged tissue exposure to elevated levels of IGF-I. Although acromegaly is more commonly associated with nodular goiter of follicular-cell origin, the possibility of a thyroidal C-cell neoplasm must be entertained especially if GLP-1 agonist therapy is being considered for the treatment of hyperglycemia.
Paragangliomas the Forgotten Neuroendocrine Neoplasms: A Retrospective Review of 237 Cases From 2 Centers in 2 Years
Authors: Ramirez-Renteria Claudia , Albarran-Sanchez Alejandra , Hernandez-Calderon David Enrique , Cardenas Pattsy Etual Espinosa , Sosa Ernesto , Lopez-Juarez Nitzia , Irisson Irene Mora , Noyola-Garcia Maura E , Portocarrero-Ortiz Lesly A , Moreno-Jimenez Sergio , Melgar-Manzanilla Virgilio , Almeida-Gutierrez Eduardo , Mercado Moises 
Published: May 2021

Abstract
Background: paragangliomas (PGN) (including adrenal PGN or pheochromocytomas) are uncommon neuroendocrine neoplasias. Their ubiquity and lack of uniform nomenclature has resulted in systematic sub-registry and limited resources for patients and clinicians. However, 40% of them are hereditary, 10–20% are hormonally active and 50% result in treatment-related complications.
Objectives: to describe the clinical and biochemical characteristics of PGN in two referral centers in a 2-year period.
Materials and Methods: a retrospective review of the files of patients evaluated in the Centro Medico Nacional Siglo XXI or the Instituto Nacional de Neurología y Neurocirugia between June 2018 and May 2020, even if diagnosis was prior to those dates. The search was performed using ICD-10 terms in the outpatient registries. Data is described using non-parametric statistics, including medians (interquartilic ranges, IQR). According to the reported incidences we expected to find 35 new cases per year in each hospital.
Results: 237 patients, 86.4% female with a median age at diagnosis of 54 years (IQR 45–64) were found. The tumors were located in the head 23.9%, neck 63.3%, thorax 0.4%, adrenal in 11.1%, other sites in the abdomen 1.3%. The most common symptoms in head PGN were hypoacusia (85.2%) and cranial nerve palsies (39.3%), in the neck, a visible mass and pain (30.6%) while the “classic” catecholaminergic symptoms were more common in thoracic and abdominal tumors (&gt;50%). Tumors were large or invasive in 50.1% of the cases and at least one hormone was above the upper limit of normal (ULN) in 40.6% of the 64 evaluated cases, mostly urinary dopamine (70% of cases tested, 1.1–2.1 ULN) and plasma and urine metanephrines (60% of cases tested, 1.1- 33.7 ULN and 50% cases, 1.1–22 ULN, respectively). Severe systolic hypertension was more frequent in male patients &lt;30 years of age and 41.6% were candidates to genetic testing due to the tumor characteristics or patient history. Surgery was performed in 55.6%, radiotherapy in 25.2% and 12.1% are under surveillance or pending surgery, 7.1% were lost to follow up. Only 5 cases with metastasis were documented in 1215 patient-years of follow-up. Treatment-related complications were reported in 14.7% and persistence in 32.2%.
Conclusions: despite the retrospective nature of the study and sub registry, we found more tumors than expected. The frequency of hormonal production was high, but it is likely related to patient selection bias (mostly symptomatic cases studied). Dopamine and metanephrines are useful in the evaluation of PGN. Endocrinologists should be aware of these common tumors and be part of the multidisciplinary team.
Identification of a Novel DICER1 Germline Mutation in Thyroid Follicular Adenoma Using Whole Exome Sequencing
Authors: Cheon Chong Kun 
Published: May 2021

Abstract
Backgrounds: DICER1 protein is a member of the ribonuclease III family of proteins that cleaves non-coding small RNA precursors to generate mature miRNAs, which in turn regulate gene expression post-transcriptionally. Thyroid abnormalities are frequently observed in DICER1 syndrome with multinodular goiter present in families in which a germline DICER1 mutation is segregating. Recently, we identified a germline DICER1 mutation in a family with multiple tumors using whole exome sequencing (WES). Methods and Materials: Following informed consent, WES of peripheral blood DNA was carried out on affected individual. Sanger sequencing was performed to confirm the DICER1 variant detected by WES and to assess her family for mutation in the same DICER1 exon (exon 20). Results: An 8 year-old girl presented with abdominal mass. Laparoscopic radical nephrectomy was done due to Wilms tumor. At age 12, palpable mass on the right thyroid lobe was found, and right hemithyroidectomy was performed. She was diagnosed with follicular adenoma, and she started to take levothyroxine. At age 13, palpable thyroid mass on the left thyroid lobe was identified, and total thyroidectomy was performed due to progressively enlarged remnant thyroid gland with multiple nodules. The pathological result was adenomatous goiter with a cystic change. During the evaluation, a 1.5cm follicular cyst in the left ovary, 0.7cm cystic lesion in the right middle lobe of the lung, and air-trappings in both lungs were observed. We performed WES which revealed a novel heterozygous missense mutation, c.3506C&gt;G(p.S1169*) in exon 20 of the DICER1 gene. During the follow-up, she showed a severely enlarged right kidney with multiple septated cysts. Right total nephrectomy was done due to hemorrhage progression in cysts and biopsy revealed cystic nephroma. Continuous renal replacement therapy was applied after right nephrectomy, and maintenance hemodialysis was applied. Conclusions: We identified a novel DICER1 germline mutation in a family with thyroid follicular adenoma, Wilms tumor, and contralateral progressive cystic nephroma which is the first report in Korea.