bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Hypothalamic TRH Neurons in Regulating Thyroid Hormone Levels
Authors: Costa e Sousa Ricardo H , Rorato Rodrigo , Hollenberg Anthony Neil , Vella Kristen R 
Published: May 2021

Abstract
Thyroid hormone (TH) is a major regulator of development and metabolism. An important mechanism controlling TH production is the negative feedback at the hypothalamic and pituitary level and it has been suggested that thyroid hormone receptor β (TRβ) is the main mediator of TH actions in the hypothalamic paraventricular nucleus (PVN). Nevertheless, the direct actions of TH and TRβ in the negative regulation of TRH have yet to be demonstrated in vivo. Here we used two approaches to investigate the TRH neuron. First, we used a chemogenetic tool to directly investigate the role of TRH neurons on the regulation of thyroid hormone levels. Mice expressing Cre-recombinase in TRH neurons received bilateral injections of the activating designer receptors exclusively activated by designer drugs (DREADD) directly into the PVN. Activation of TRH neurons produced a rapid and sustained increase in circulating TSH levels in both males and females. TSH levels increased approximately 10-fold from baseline within 15 minutes of injection of CNO, returning to baseline within 2.5 hours. TH levels were increased approximately 2-fold in males and females. Therefore, using a chemogenetic approach, we were able to directly evaluated the role of PVN TRH neurons on the control of thyroid activity, for the first time. Next, we generated mice deficient in TRβ specifically in neurons expressing melanocortin 4 receptor (MC4R), which overlaps with TRH expression in the PVN. Knockout mice (KO) developed normally and showed no change in TH and TSH levels. TRH mRNA levels in the PVN of KO mice were similar to control mice. To investigate if the deletion of TRβ in the PVN changes the sensitivity of the HPT axis to T3, mice were rendered hypothyroid and given increasing doses of T3 for 2 weeks. Results show no difference in TRH mRNA or serum TSH between controls and KO. Surprisingly, despite the presence of detectable genomic recombination on the TRβ gene in the PVN, there was no difference in TRβ mRNA expression between control and KO mice, suggesting that either MC4R-positive neurons do not express TRβ or they represent a very small population of TRβ-positive cells in the PVN. Present data show that TRH neuron activation rapidly stimulates TSH release and increases TH levels, demonstrating a major role of these neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Nevertheless, deletion of TRβ from MC4R neurons had no major effect on either TRH or TH levels in in mice. Additionally, TRβ in MC4R-positive TRH neurons in the PVN is not necessary for TH-induced suppression of TRH mRNA. Although further studies are necessary, these data suggest that there are distinct populations of hypophysiotropic TRH neurons in the PVN, some of which are not regulated by thyroid hormone and TRβ.
Assessment of the Thyroid Function During the Three Trimesters of Pregnancy Among the Egyptian Population
Authors: Amara Mohamed Fahmy 
Published: May 2021

Abstract
Background: Pregnancy is associated with significant but reversible changes in the thyroid function that might cause maternal and fetal complications. Undetected and untreated thyroid disorders are associated with adverse maternal and fetal outcomes, thus screening is important. There are limited data on the prevalence of newly diagnosed thyroid disease during pregnancy from Egypt. Therefore, this study was designed to evaluate the prevalence of thyroid dysfunction during the three trimesters of pregnancy. Subjects and Methods: This was a cross-sectional study conducted at the antenatal clinic of El-Shatby Maternity Hospital at Alexandria University. The total sample population comprised of 90 pregnant women divided into 30 women for each trimester compared with 30 non- pregnant healthy women regarding thyroid function parameters and thyroid peroxidase antibody (anti - TPO) by using COBAS analyzer measured by the electrochemiluminescence immunoassay “WCLIA” employs monoclonal antibodies specifically directed against human thyroid-stimulating hormone (TSH), free thyroxine (FT4), FT3 and anti TPO. Results: 120 ladies were enrolled for this study aged between 20-45 years excluding subjects with previously diagnosed endocrinal anomalies. There were significant differences between pregnant and non-pregnant females regarding TSH and FT4, but no significant difference regarding FT3 and anti TPO in all trimesters. Conclusion: There is a discrepancy between FT4 & TSH in pregnancy due to the presence of other stimulatory and inhibitory factors in pregnancy, thyroid anomalies increased with the advance in pregnancy, thus screening of TSH and anti TPO is important. Considering the immense impact that maternal thyroid dysfunction has on maternal and fetal outcomes, prompt identification of thyroid dysfunction and its timely treatment is essential.
Maternal Hypothyroidism Delayed Retinal Opsin-Development in the Neonatal Period: Analysis of TRH-Deficient Mice
Authors: Saito Kazuma , Horiguchi Kazuhiko , Buyandalai Battsetseg , Nishikido Ayaka , Okamura Takashi , Toki Akiko , Ishida Emi , Matsumoto Shunichi , Yoshino Satoshi , Nakajima Yasuyo , Yamada Eijiro , Saito Tsugumichi , Ozawa Atsushi , Akiyama Hideo , Yamada Masanobu 
Published: May 2021

Abstract
Introduction: Retinal cone photoreceptor cells contain short (S) and medium (M) wavelength opsins, which are light-sensitive substances involved in color vision and visual acuity by sensing lights of different wavelengths. Thyroid hormones promote M-opsin expression and suppress S-opsin expression during the differentiation of cone photoreceptors. It was previously reported that M-opsin expression was delayed and S-opsin expression increased in TSH receptor-deficient mice and methimazole-induced hypothyroid mice. In addition, no M-opsin expression and increased S-opsin expression were observed in thyroid hormone receptor (TR) β2-deficient mice (Ng L et al, Nature Genetics. 2001; 27(1): 94-98.). This suggested that impaired thyroid function affects opsin development. We therefore examined retinal development in TRH-deficient mice, which are a model of central hypothyroidism established in our laboratory. Methods: We performed HE staining of the retina at postnatal 30 days and electroretinography at postnatal 10 weeks using TRH-/- and wild-type (WT) mice. We also examined expression levels of S/M opsin mRNA in WT, TRH-/- and TRH-/- pups born from TRH-/- dams at postnatal 12,17 and 30 days, and TRβΔ337T knock-in mice (TRβmut/mut) at postnatal 30 days. Furthermore, we performed immunohistochemistry to examine S/M opsin protein expression in these mice. Results: The retinal structures by HE staining and retinal functions by electroretinography in TRH-/- mice were unchanged compared with those in WT mice. Although M-opsin expression was not detected and S-opsin expression was higher in TRβmut/mut mice than in WT mice, the mRNA and protein expression levels of S/M-opsin did not significantly differ between TRH-/- pups born from TRH+/- dams and WT pups at all postnatal days. TRH-/- pups born from TRH-/- dams exposed to maternal hypothyroidism had similar serum total T4 levels to TRH-/- pups born from TRH+/- with normal maternal thyroid function. In contrast, the mRNA expression level of M-opsin was significantly lower (1.00±0.06 vs 0.64±0.05: mean ± SE, p&lt;0.01) and the protein expression level was lower in TRH-/- pups born from TRH-/- dams than in WT pups at postnatal 12 days. However, these differences disappeared after postnatal 17 days, and there was no difference in M-opsin expression in TRH-/- pups born from TRH-/- dams compared with WT pups. Conclusions: Although no delay in opsin development was observed in TRH-/- pups born from TRH+/- dams, TRH-/- pups born from central hypothyroid dams exhibited delayed opsin development, suggesting that maternal hypothyroidism affects the development of retinal opsin in the neonatal period.
Efficacy of Differential Diagnosis of Thyroid Nodules by Shear Wave Elastography, the Stiffness Map
Authors: Yoo Myung Hi , Kim Hye Jeong , Choi In Ho , Park Suyeon , Yun Sumi , Park Hyeong Kyu , Byun Dong Won , Suh Kyoil 
Published: May 2021

Abstract
Background: Fine-needle aspiration (FNA) is the first step in the differential diagnosis of thyroid nodules. However, malignancy rate of the indeterminate FNA is reported as 20-50 %. We aimed to evaluate the efficacy of shear wave elastography (SWE), the map of stiffness in the differential diagnosis of the histopathology of thyroid nodules. Methods: We retrospectively reviewed the medical records of 258 consecutive patients who visited the thyroid clinic for thyroid nodules and who underwent SWE before ultrasound-guided FNA and/or core-needle biopsy. We analyzed the EI using the total nodular region of interest method by the Q-Box Trace program. Thyroid nodules were divided in to 4 categoies according to maximum elasticity (EMax) and nodule depth/width (D/W) ratio; Category 1 (EMax ≥42.6 kPa & D/W&lt;0.9), Category 2 (EMax &lt;42.6 kPa & D/W&lt;0.9), Category 3 (EMax ≥42.6 kPa & D/W≥ 0.9) and Category 4 (EMax&lt;46.2 kPa & D/W≥ 0.9). The cutoff value of EMax was set using ROC curve analysis to predict follicular neoplasm (FN) from nodular hyperplasia (NH). Cutoff value ​​for nodule D/W ratio was set using ROC curve analysis to differentiate malignant nodule. Results: FN showed the lowest EMax among all pathologies and lower EMax than NH (p&lt;0.05). FN was distributed mostly in the category 2 (70%) and NH was distributed mainly in the category 1 (73.9%). CLT belonged mostly to the category 1 (57.1%). PTC belonged in majority to the category 3 (58.9%) and the rest.to the category 1 (25%). So NH was the most frequent pathology group in category 1.FN was the most frequent pathology group in the category 2 and PTC was the most frequent pathology group in the category 3. Conclusion: SWE showed characteristic patterns of various pathology groups reflecting the degree of fibrosis and the information of EMax and nodule depth/width (D/W) ratio determining the category was useful to predict the pathology of thyroid nodules along with the advantage of noninvasiveness.
PD-L1 Expression in Papillary Thyroid Cancer
Authors: Joshi Tripti , Gupta Ruta , Olaya A Luisa Fernanda , Yu Bing , Gargya Ash , McLennan Susan , Chua Elizabeth Lian 
Published: May 2021

Abstract
There is limited data on prevalence of PD-L1 expression in papillary thyroid cancer (PTC). Anti- PD-L1 therapy is now being trialled for head and neck cancers including thyroid cancer. Whether presence of PD-L1 staining in PTC might result in a better response to anti-PD-L1 therapy is uncertain.
We evaluated the frequency of tumoral PD-L1 expression using standard antibody (SP263) and clinicopathologic factors including mutation status - BRAF, NRAS, KRAS using OncoFocus Mass Array System in an Australian PTC cohort with low or high risk of recurrence /treatment response as per 2015 ATA guidelines.
The cohort had 128 patients; 66% were females; 40% had both multifocal and bilateral PTC; 47% had low recurrence risk, of whom 92% had excellent treatment response; 34% had high recurrence risk, of whom 37% had structural incomplete treatment response. There was nil (0%) PD-L1 staining in 59%, 1% staining in 20%, 5-10% staining in 11%, &gt;10% staining in rest of the cohort; 30%, 40% and 70% staining was seen in 2% each. PD-L1 in immune cells was positive in 62%. There was no significant association between PD-L1 tumour status and age, gender, size of tumour, multifocality, bilaterality, both multifocality and bilaterality, lymphovascular invasion, perineural invasion, extrathyroidal extension (ETE), histological variants, risk stratification, treatment response, metastases or mutation status. Among PD-L1 negative vs positive patients, BRAFV600E was present in 64.9% vs 67.5%, NRAS in 8.8% vs 0% and nil mutation in 26 % vs 33 % p=0.15. The staining thresholds were chosen according to existing literature. When analysed according to the percentage of PD-L1 staining (0%, 1-10% and &gt;=10% thresholds), there was no significant association between PD-L1 staining category and other features, except for ETE (35% vs 65% vs 27%; p=0.007), a relationship that remained significant in a multivariable-adjusted model (OR 9.9, p=0.04). PD-L1 staining thresholds of &lt;5% and &gt;=5% were significantly associated with the size of tumour (24.7±15.4 vs 33.3±21.8; p=0.02) and histological variants (57 % vs 61% for classic variants and 27% vs 11% for follicular variants, p=0.03).
This is the first study to our knowledge that analysed PD-L1 staining based on the risk stratification categories. The majority of PTC showed negative or low staining intensity for PD-L1 expression. There was no significant association between PD-L1 staining, clinicopathologic characteristics and mutation status of the PTC. Relatively less ETE was seen in the group that showed &gt;=10% and also &gt;=5% PD-L1 staining as compared to the group that showed 1% &lt;10% and 1% to &lt;5% staining which is an interesting observation and needs further investigation. The significant variation in reported PD-L1 staining in current literature reiterates that the method is yet to be optimised. Moreover the relationship between PD-L1 staining and PTC remains to be further investigated.
Recurrence Factors and Characteristic Trends of Papillary Thyroid Cancer Over Three Decades
Authors: Chatchomchuan Waralee , Thewjitcharoen Yotsapon , Karndumri Krittadhee , Porramatikul Sriurai , Krittiyawong Sirinate , Wanothayaroj Ekgaluck , Vongterapak Somboon , Butadej Siriwan , Veerasomboonsin Veekij , Kanchanapituk Auchai , Rajatanavin Rajata , Himathongkam Thep 
Published: May 2021

Abstract
Background: The prevalence of thyroid cancer is rising worldwide. Although thyroid cancer has a favorable prognosis, up to 20% of patients experienced recurrent disease at some point during follow-up. The present study aimed to examine the recurrent factors that determined the outcomes of papillary thyroid cancer (PTC) and the characteristic trends in Thai patients over the last 30 years in a single institute. Methods: We reviewed the clinical data of all patients with PTC who were treated between 1987 and 2019. Clinical characteristics, epidemic trends, factors associated with the persistent or recurrent disease, disease-specific survival rate and disease-free survival rate were analysed. Results: A total of 235 patients with PTC who were registered between 1987 and 2019 were reviewed. The mean age was 41.0 ± 14.3 years, with a mean follow-up of 113 months. Papillary thyroid microcarcinoma (PTMC) was consistently increased and accounted for 21.4% (50/235) of total cases. According to American Thyroid Association (ATA) risk stratification, high ATA risk was found 24% of all PTMCs in the last decade, and 16.7% of these patients experienced local recurrence during the follow-up period. Coexistence with Hashimoto’s thyroiditis (HT) was found in one-fifth of the patients with PTC and was correlated with a low recurrent rate (HR 0.21, p = 0.009). Factors associated with the persistent or recurrent of disease included age &gt; 55 years and high ATA risk. The overall disease-free survival rate and disease-specific survival rate were 77.4% and 98.3%, respectively. Conclusions: The prognosis of PTC is generally considered favorable. However, more than one-third of patients with PTMC demonstrated more aggressive clinical behavior, particularly in the last decade of the study. Coexistence with HT might contribute to a better prognosis in cases of PTC.
Research on Clinical, Subclinical Characteristic of Incidental Thyroid Nodules
Authors: Nguyen Bay Quang 
Published: May 2021

Abstract
Background: Incidental thyroid nodules has become more prevalent in recent years due to applying diagnostic imaging tests. Many studies show that the rate of thyroid cancer in this group of patients is relatively high. Objective: To assess patients with incidentally detected thyroid nodules, including those who were diagnosed with thyroid cancer. Materials and Methods: A cross-sectional study, which involved 208 patients with 389 thyroid nodules detected by thyroid ultrasound. All patients have thyroid function tests. 272 nodules were performed fine-needle aspiration. Patients with thyroid cancer were assessed histopathology after removal. Results: The participants’ mean age was 47.22 ± 12.02. The female / male ratio is 6.7/1. No patients had history of head and neck irradiation or living in epidemiological areas with high prevalence of goiter. TSH level: 96.2% normal, 2.4% low, 1.4% high. In thyroid cancer group: 100% of patients had normal thyroid function. Nodule characteristics on ultrasound: Majority of thyroid nodules had diameters less than 1.5 cm (85.6%), multi-nodularity(52.9%). The largest carcinoma nodule was 2.35 cm, 22.2% of patients with thyroid cancer had ≥ 3 nodules. The malignancy rate of TIRADS 5 was 70.6%. FNA results of 272 thyroid nodules: the majority were Bethesda II (74,2%); the incidence of carcinoma (Bethesda V, VI) is 17.4%. 36 patients account for 17,3%, with 42 nodules were performed surgery, the results of histopathology were 100% of papillary thyroid carcinoma, which was consistent with cytological results. Conclusion: Thyroid nodules are common in women patients at the age of 31-60 with normal thyroid function. Most of them are &lt;1.5 cm in size. There are 17.3% of patients were thyroid carcinoma.
A Rare Case of T-Cell Histiocyte Rich Large B-Cell Lymphoma of the Thyroid in a Patient With Hashimotos
Authors: Zainal Abir , Maradana Jhansi , Torres Mira 
Published: May 2021

Abstract
Introduction: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare form of large B-cell lymphoma, which usually involves the lymph nodes exclusively. We describe a patient with Hashimoto’s thyroiditis who was discovered to have THRLBCL arising from the thyroid. Clinical Case: A 78-year-old female with a history of Hashimoto’s thyroiditis noted increase in the size of her left thyroid lobe for two months despite normal TSH on Levothyroxine, prompting an ultrasound which revealed several enlarged left sided cervical lymph nodes and an enlarged left thyroid gland. Cytology from an FNA of a left level 3 lymph node showed atypical lymphoid infiltrate featuring scattered large atypical cells in a background of small lymphocytes. Immunohistochemical testing was PAX5+, CD30- and CD15-. Cytology from an FNA of left thyroid revealed identical changes and immunohistochemistry demonstrated PAX5+ and CD20+. Concurrent flow cytometric studies demonstrated increased CD4 to CD8 ratio among T cells. Excisional biopsy of a left cervical lymph node confirmed a diagnosis of THRLBCL. PET/CT exhibited lymphadenopathy above her diaphragm and splenic involvement. Her bone marrow biopsy was negative for involvement. She was deemed Stage III with international prognostic index (IPI) of 2 corresponding with low-intermediate risk. She was commenced on chemotherapy R-CHOP with plan to complete 6 cycles. Discussion: THRLBCL is characterized by scattered atypical B lymphocytes on a background of T lymphocytes and histiocytes. Usually, T-cells are predominantly CD8+, in contrast to our patient. Some studies identified cases of predominant CD4+ and PD1+ T cells. Cytology revealed scattered small B-cells and large B-cells, a feature that is not typically seen in THRLBCL. A diagnosis of diffuse transformation of nodular lymphocyte predominant Hodgkin lymphoma was considered but the diffuse proliferation outside of CD21+ and involvement of the thyroid is not compatible with such diagnosis. Similarly, a diagnosis of follicular helper T-cell lymphoma with admixed large B-cells was considered but while PD1+ CD4+ T cells are present, there was no aberrant antigen expression by flow cytometry or T cell clonality. THRLBCL mainly involves lymph nodes and presents at advanced Ann Arbor stages with high IPI. Malignant lymphomas of the thyroid gland are exceedingly rare, accounting for 2% of thyroid cancers, out of which the literature reveals a single case report of THRLBCL arising from the thyroid. THRLBCL represents an aggressive form of lymphoma and is treated according to stage-matched DLBCL, although the effects of Rituximab in this population is variable. Conclusion: Hashimoto’s is considered a risk for thyroid lymphoma usually diffuse large B-cell lymphoma and MALT lymphoma. We present a rare case of THRLBCL occurring in the setting of Hashimoto’s with acute thyroid gland enlargement.
Breaking the 2015 ATA Recommendation for Medullary Thyroid Cancer (MTC) Guidelines. Case Report
Authors: Mardones Adelqui Sanhueza 
Published: May 2021

Abstract
Male patient, 49 years old. Thyroid US with a suspicious nodule. Fine Needle Aspiration Biopsy (FNAB) suggest MTC, with a pre-operative serum calcitonin (CTN) of 591 pg/mL. Total thyroidectomy with central and bilateral dissection was performed. Biopsy. Results: MTC in left thyroid nodule of 2,6 cm without metastasis in 29 lymph nodes. In the follow up, undetectable serum CTN for 6 years. In 2015 serum CTN of 4.7 pg/mL and Carcinoembryonic antigen (CEA) 1.2 ng/mL. Evolution of serum markers in table 1.
Along with the rise of markers, the neck US showed bilateral subcentimetric LN in the group IV. In the follow-up, the size is stable; FNAB of the LN in different centers don′t show any sign of malignancy, along with undetectable CTN levels in the sample. The doubling time of CTN and CEA (March 2020): 16 and 51.3 months respectively. Given the lack of cervical compromise and going against MTC ATA 2015 recommendations, a neck and thorax CT, hepatic MRI and bone scintigraphy were ordered, despite not presenting CTN levels &gt;150 pg/mL. The hepatic MRI shows 3 hypervascular hepatic lesions, which are recommended to be contrasted with a liver-specific agent (gadoxetic acid) to improve characterization of the lesions. Thanks to this procedure, 4 focal lesions are discovered, one larger than 10 mm, without contrast agent retention, suggests metastasis. PET 68Ga-DOTATATE: 2 focal lesions with overexposure of somatostatin receptors in the hepatic parenchyma, which correlate to known lesions, with SUVmáx of 6,8 y 7,3. After an evaluation by a surgeon, surgery is done in July 2020 removing 5 lesions; the biopsy confirmed MTC metastasis. Conclusions: the clinical guidelines may give general direction and allow to manage cases based on evidence; however, they must always be used considering the context of each particular case. In this one, if the guidelines had been strictly followed, it would not have been possible to detect the hepatic metastases within the window of opportunity to achieve a surgical resection with curative intent.
Table1. Mar15 CTN 7,3 Pro- CTN 0,12 CEA 1,2. Oct15 CTN 16,1 Pro- CTN 0,15 CEA 0,7. Jan16 CTN 17 Pro- CTN 0,18 CEA 0,5. Jul16 CTN 17,9 Pro- CTN 0,18 CEA 1,6. Nov16 CTN 20,7 Pro- CTN 0,33 CEA 1,8. Aug17 CTN 35,2 Pro- CTN 0,4 CEA 1,8. Jun18 CTN 42,5 Pro- CTN 0,34 CEA 1,8. Nov18 CTN 50,7 Pro- CTN 0,57 CEA 1,8. Mar19 CTN 59,5 Pro- CTN 0,52 CEA 2,4. Nov19 CTN 80,7 Pro- CTN 0,66 CEA 2,4. Mar20 CTN 111 Pro- CTN 0,8 CEA 2,9. Normal Values: CTN &lt; 2 pg/mL, Pro- CTN &lt; 0,12 ng/mL, CEA &lt; 0,1 ng/mL