bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histological Study on the Thyroid Tissue Adjoining the Noninvasive Thyroid Follicular Neoplasm With Papillary-Like Nuclear Features, Seeking a Possible Association With Hashimoto’s Thyroiditis
Authors: Pereira Paola N 
Published: May 2021

Abstract
Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer (TC), and advances in ultrasound methods resulted in better and higher detection of this tumor. Thus, the increase in the incidence of PTC is due to the detection of microcarcinomas by ultrasound, as well as partially, due to the increased diagnosis of the encapsulated and/or well-defined non-invasive follicular variant of thyroid papillary carcinoma (NIEFVPTC). Recently, there was a change in the histological classification of NIEFVPTC, currently known as non-invasive follicular thyroid neoplasm with papillary-like features (NIFTP), thus the clinical evidence leads to an excellent prognosis once its a indolent neoplasia, dismissing additional treatments as lymphadenectomy and radioiodotherapy, therefore reducing psychological impact. This study was approved by the ethics and research committee and addressed the analysis and review of histological slides of thyroid neoplasia that currently meet the criteria for NIFTP. Furthermore, the study sought to evaluate the concomitant existence of NIFTP with histological findings consistent with Hashimoto’s Thyroiditis (HT). Underlying studies evoke a possible increase in the imperil of developing PTC when associated with HT. It should be noted that this morphological correlation is poorly described in the literature. Accordingly, a retrospective study was carried out by histological review of 232 cases diagnosed as PTC from total thyroidectomies with cervical lymphadenectomy from 1993 to 2014, previously diagnosed as NIEFVPTC. The histological slides of these cases came from the Surgical Pathology files of the Pathology Department of UNICAMP, Brazil. After histological review, 14 cases reclassified as NIFTP were selected, all referring to female patients, of which 6 presented histological criteria of NIFTP associated with HT. Additionally, a histological and laboratory correlation of the 14 selected cases was performed through the dosages of relevant serum titers of antithyroid antibodies (anti-TPO and TgAb). Out of the 6 patients detected with association of NIFTP and TH, 5 had significant titers above 65IU/ml for anti-TPO and 120IU/ml for TgAb. Additional data from thyroid ultrasonography were collected and showed that cases of NIFTP without association with HT, presented nodules ranging from 1.5 cm to 5.1 cm, predominantly hypoechoic, solid, with regular contours, peripheral vascularization and located predominantly in the right lobe. In conclusion, 14 cases of NIFTP were detected, among 232 cases of PTC, with 6 cases being histologically associated with HT. Of these, 5 cases had laboratory tests with positive antithyroid antibody titers, proving this association, from a clinical point of view. All cases of NIFTP with and without HT association were female, with nodules ranging from 0.3cm to 5.0cm to ultrasound, predominantly in the right lobe.
Indeterminate Thyroid Nodules With RAS Mutations Have Higher Rates of Malignancy When Multiple Non-Cystic Nodules or Irregular Borders Are Present
Authors: Bernuy Mario Carlos C Rivera , Tessnow Alex , Hussain Iram 
Published: May 2021

Abstract
Background: There is heterogeneity in positive predictive value for cancer in RAS-mutated cytologically indeterminate nodules and paucity of data with regards to specific ultrasound features that are associated with malignancy in these nodules. The goal of this study is to assess the ultrasonographic characteristics, in relation to clinical and histopathologic outcomes of thyroid nodules known to have a RAS mutation. Design and Methods: Cases were identified using our institutional Afirma® Genetic Sequence Classifier (GSC) database, and a retrospective review of electronic medical records for thyroid nodules biopsied between January 2018 and August 2020. Nodules categorized as Bethesda III or IV and harboring a RAS mutation by Xpression Atlas® were included. Thyroid ultrasound images were reviewed by the authors and were risk stratified according to the 2015 American Thyroid Association Thyroid Nodule and Differentiated Thyroid Cancer Guidelines (ATA Guidelines) and the 2017 ACR TIRADS system (ACR Guidelines). The nodules were divided into benign or malignant categories based on surgical pathology. Noninvasive follicular thyroid neoplasms with papillary like nuclear features (NIFTP) were categorized as benign. Results: A total of 22 nodules were identified to have a RAS mutation. NRAS mutated nodules, all with the same point mutation (pQ61R c.182A&gt;G), were most common 14/22 (63.6%). There was no significant difference in clinical features, ultrasonographic appearance or histopathologic outcomes between NRAS- and HRAS-mutated nodules. 12/22 (54.4%) were low risk by ATA Guidelines and 11/22 (50%) were TIRADS 4 (moderately suspicious) by ACR Guidelines. There was no significant difference in predictive value of ATA Guidelines vs ACR Guidelines. The prevalence of malignancy was 45.4% (only slightly lower than the general risk for a suspicious GSC). Invasive follicular variant papillary thyroid cancer (FVPTC), was the most common malignancy, 4/10 (40%). 6/10 (60%) were classified as low risk of recurrence post-operatively. All malignant RAS-mutated nodules (10/10) had at least one other non-cystic nodule present on ultrasonography whereas only 4/9 (44%) of RAS-mutated benign nodules did [P=.006]. RAS-mutated malignant nodules had significantly more nodules with irregular borders compared to RAS-mutated benign nodules (4/10 and 0/10, 40% and 0% respectively) [P=.03]. Conclusions: This is the first study to observe higher rates of malignancy in RAS-mutated indeterminate nodules when other non-cystic nodules are present. A lobectomy is the preferred surgical approach for RAS-mutated nodules, however a total thyroidectomy may be considered in patients with other non-cystic nodules or irregular nodules borders. Overall, RAS-mutated nodules have a low risk of recurrence post-operatively.
Macrophage-Tumor Crosstalk in the Pathogenesis of Follicular Thyroid Cancer
Authors: Caperton Caitlin , Franco Aime T 
Published: May 2021

Abstract
Thyroid cancer is the most common endocrine malignancy and one of the fastest growing cancers in the United States. Follicular thyroid carcinoma (FTC) represents the second most common form of thyroid cancer diagnosed in the US and is most often tied to mutations in the RAS protein family of the MAP kinase pathway. In addition to driver mutations, FTC is characterized by a unique tumor microenvironment (TME) composed of cellular and non-cellular components that impact tumorigenesis and disease progression. Preliminary data from our lab has shown that CD45+ immune cells account for approximately 68% of all cells found in whole tumors collected from mouse models of RAS-driven disease. Macrophages account for the largest portion of known immune cell populations. Further experiments have demonstrated that tumor cell lines isolated from our RAS-driven models secrete cytokines known to impact the recruitment and activation state of cells of the myeloid lineage, particularly macrophages. However, it’s unclear what type of functional characteristics are induced by these secreted factors and how the resulting macrophage phenotype affects disease progression. Here, we sought to determine how bidirectional communication between macrophages and thyroid cancer cell lines could contribute to the development of a protumorigenic microenvironment. First, we began by defining how RAS-driven thyroid cancer cell lines affected the functional phenotype of previously unstimulated macrophages. Through gene expression analysis encompassing several markers of macrophage activation states, we determined that tumor cell-secreted factors induced the expression of multiple genes associated with tumor associated macrophages (TAM). In particular, we observed consistent upregulation of IL-10 and TNF-alpha, factors that have been associated with worsening disease. These results were further validated through quantification of protein secretion. In addition, we determined the role of activated macrophages in the progression of thyroid cancer, and specifically the effect of macrophage-secreted factors on tumor cell proliferation. Through direct and indirect assays of proliferation, we determined that factors secreted by classically-activated M1 macrophages inhibited cell proliferation. Surprisingly, secretions from alternatively-activated M2 macrophages reduced in vitro cell growth in some cell lines. Further analysis demonstrated that reduced cell proliferation was not associated with cell death, but rather was a result of delayed progression through the cell cycle. These results help to further define the macrophage phenotype within our model of FTC and will identify potential therapeutic targets to reduce the activity of protumorigenic cell populations.
Management of Papillary Thyroid Cancer Metastatic to the Central Nervous System: A Narrative Review of the Literature
Authors: Zambrano Jose Leonel , Ramos Andrés Felipe García , Pico Víctor Manuel Blanco , García Franco Alejandro Vallejo , Arboleda Marcela Patiño , Valencia Carlos Mario Balcázar , Chaparro Jose Mauricio Ocampo 
Published: May 2021

Abstract
Introduction: Brain metastases (BM) associated with papillary thyroid cancer (PTC) occur with an approximate frequency of 0.15% to 1.3% of PTC cases. There is little evidence regarding the treatment of this association (PTC and BM). A narrative review of the literature is presented. We assessed multiple treatment options and its effectiveness in this vulnerable population. Methods: The data were collected using the PubMed search engine and Google Scholar. There were selected all studies that included: &lt;&lt; thyroid carcinoma &gt;&gt; &lt;&lt; brain metastases &gt;&gt; &lt;&lt; radiotherapy &gt;&gt; &lt;&lt; surgery &gt;&gt; &lt;&lt; iodine-131 &gt;&gt; &lt;&lt; papillary carcinoma &gt;&gt; &lt;&lt; differentiated carcinoma &gt;&gt;. Once the relevant works had been listed and compared, the main findings of each one were related and analyzed. Results: We found 15 studies between the years 1990 and 2019 that describe 187 patients with thyroid cancer and brain metastases; of which 138 presented PTC, and 62% (58/93) were women. The average age was 59 years. Patients who received multimodal treatment (association of 2 or more therapies; one of them, brain metastasis resection) had a longer survival, with an average of 54 months, compared to monotherapy. Discussion: Patients with PTC who also present BM require a multimodal therapy approach: when it is associated with brain metastasis resection, better results are evident; in contrast, when monotherapy is used, a limited performance is observed, with poor results. Conclusion: Patients with PTC who also present BM have better outcomes and higher survival rate with a multimodal therapy approach, including brain metastasis resection.
Machine Learning-Based Models for Prediction of Subtype Diagnosis of Primary Aldosteronism Using Blood Test
Authors: Kaneko Hiroki , Umakoshi Hironobu , Ogata Masatoshi , Wada Norio , Iwahashi Norifusa , Fukumoto Tazuru , Yokomoto-Umakoshi Maki , Nakano Yui , Matsuda Yayoi , Miyazawa Takashi , Sakamoto Ryuichi , Ogawa Yoshihiro 
Published: May 2021

Abstract
Context: Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who can be cured by unilateral adrenalectomy and should be referred to specialized centers. The use of machine learning has been introduced in some fields of clinical prediction. Combining machine learning with clinical data could lead to the development of new models for predicting unilateral subtype of PA. Objective: The aim of this study was to develop a predictive model of subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Design and setting: This was a retrospective cross-sectional study in referral centers. Patients: We retrospectively analyzed 91 patients with unilateral and 138 patients with bilateral subtype of PA diagnosed according to adrenal venous sampling findings, and stratified randomly split to the training (80%) and test cohorts (20%). Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop prediction models from 21 clinical variables. Classifiers were trained using stratified 10 fold cross-validation of the training cohort and hyperparameters of each classifier were adjusted using grid search to optimize the accuracy in the training cohort. Main Outcome Measures: The accuracy and the area under the receiver operating characteristic curve (AUC) for subtype prediction in the test cohort were compared among the optimized classifiers. Results: Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium levels, plasma aldosterone concentrations, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF. Conclusions: Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.
Navigating the Debate on Large (4+cm) Thyroid Nodules: Local Insight on a Persisting Problem
Authors: Steinmetz-Wood Samantha , Kennedy Amanda , Tompkins Bradley , Gilbert Matthew Philip 
Published: May 2021

Abstract
Background: Thyroid nodules are a common clinical finding, however discordant practice guidelines for managing large nodules may result in unnecessary surgeries and excess costs. Recent data suggest similar false negative rates in fine needle aspiration (FNA) biopsies between small (&lt;4cm) and large (4+ cm) nodules, indicating that monitoring rather than surgery may be appropriate for large nodules. Evaluating current management strategies may reveal insights regarding excess surgeries, costs and opportunities for improvement.
Objectives: The goal of this project was to describe the patients at our institution with large thyroid nodules and determine the proportion of potentially unnecessary surgeries and the associated predictors.
Methods: This was a retrospective cohort study that included patients who received a FNA of nodule (s) ≥4cm between 11/1/2014 and 10/31/2019 at our tertiary care institution. Patient demographics, sonographic nodule size, fine needle aspiration cytology, molecular testing results, final surgical pathology, history of neck irradiation, family history of thyroid cancer, presence of compressive symptoms or presence of a toxic nodule or toxic multinodular goiter, were compared between patients who had surgery and those who did not. A surgery was considered inappropriate if the FNA result was benign in the absence of any of the following: a suspicious result on molecular testing, compressive symptoms, family history of thyroid cancer in a first degree relative, history of neck irradiation, toxic nodule or toxic multinodular goiter or substernal extension. Continuous variables were evaluated using Wilcoxon rank-sum test while categorical variables were tested using chi-square or Fisher’s exact test.
Results: A total of 177 patients had a 4+ cm nodule during the timeframe. Half of patients (54.2%)with 4+ cm nodules had surgery. Patients who underwent surgery were significantly younger (51.5 years vs 62 years; P&lt;0.001), more likely to report obstructive symptoms (34.4% vs 12.1%; P=0.001) and have a larger nodule size (5.0 cm vs 4.7 cm; P=0.26) than patients who did not have surgery. Forty-one patients with benign (Bethesda II) FNA results went on to have surgery. All 41 patients were found to be negative at surgery, yielding a false negative rate of 0.0% in our cohort. Twenty-three surgeries (24.0%) were considered inappropriate and overall 13% (23/177) of patients with 4+cm nodules had unnecessary surgery. The median charge for these surgeries was $13,183.
Conclusion: Approximately half of our patients with 4+ cm nodules had surgery, especially patients who are younger, report obstructive symptoms, and have larger nodule sizes. Overall 13% of our patients with 4+cm nodules had unnecessary surgery revealing opportunities for improving care and costs.
Prevalence and Spectrum of DICER1Mutations in Adult-Onset Thyroid Nodules
Authors: Chong Anne-Sophie , Nikiforov Yuri E , Condello Vincenzo , Wald Abigail , Nikiforova Marina , Foulkes William , Rivera Barbara 
Published: May 2021

Abstract
Context: DICER1 mutations are found in multinodular goiter and differentiated thyroid carcinoma in children, and can be a manifestation of DICER1 syndrome, but the prevalence of DICER1 mutations and their significance in adult-onset thyroid nodules is unknown.
Objective: Determine 1) the prevalence of DICER1 hotspot mutations in thyroid nodules; 2) the frequency of a second DICER1 pathogenic variant in thyroid nodules with DICER1 hotspot mutations; 3) the prevalence of other thyroid cancer driver mutations in thyroid nodules with and without DICER1 hotspot mutations.
Design: Population-based study of 14,993 consecutive fine needle aspiration biopsies of thyroid nodules evaluated by ThyroSeq v3. From 214 DICER1 hotspot-positive cases, we selected 61, matched to DICER1 hotspot-negative nodules. We performed full sequencing of all exons and exon-intron boundaries of DICER1.
Setting: Commercial and university-based laboratories in the United States and Canada
Results: Among 14,993 thyroid nodules, 214 (1.4%) revealed a DICER1 hotspot mutation. A second pathogenic/likely pathogenic variant in DICER1 was found in 45/59 (76%) DICER1 hotspot-positive nodules studied while no other DICER1 variant was identified in the DICER1 hotspot-negative group by full DICER1 sequencing. Other alterations in thyroid-related genes were significantly more frequent in DICER1 hotspot-negative nodules (32/61) than in DICER1 hotspot-positive nodules (4/59) (p&lt;0.0001).
Conclusions: DICER1 alterations occur in a proportion of adult thyroid nodules and appear mutually exclusive with alterations in other thyroid cancer-related genes. DICER1 hotspot mutations occur with a second hit in most cases and could suggest occult DICER1 syndrome in adults with thyroid nodules.
MiR-122-5p: A Novel Biomarker of Glucocorticoid Action
Authors: Chantzichristos Dimitrios , Svensson Per-Arne , Garner Terence , Glad Camilla A M , Walker Brian Robert , Bergthorsdottir Ragnhildur , Ragnarsson Oskar , Trimpou Penelope , Stimson Roland H , Borresen Stina Willemoes , Feldt-Rasmussen Ulla , Jansson Per-Anders , Skrtic Stanko , Stevens Adam , Johannsson Gudmundur 
Published: May 2021

Abstract
Background: Glucocorticoids are among the most prescribed medications for various indications, and treatment with glucocorticoids is associated with increased morbidity and mortality. A biomarker allowing quantification of glucocorticoid action could improve treatment safety and efficacy. Objective: To identify and validate circulating biomarkers of glucocorticoid action using a clinical experimental study and multi-omic network analysis. Methods: In a randomized, controlled, crossover, single-blind trial, 10 subjects without endogenous glucocorticoid production (Addison’s disease) received intravenous hydrocortisone infusion in a circadian pattern (physiological glucocorticoid exposure) or isotonic saline (glucocorticoid withdrawal) over 22 hours. Food intake and sample collections were standardized during both treatment periods. The transcriptomes of peripheral blood mononuclear cells and adipose tissue, plasma miRNAome and serum metabolome were collected at 7 AM (end of infusion). These multi-omic data were compared between the two interventions, within and between subjects, using network analysis of higher order interactions along with statistical and machine learning approaches. Samples from 120 subjects with varying glucocorticoid exposure from independent studies were used for the replication of the miRNA findings. The study was pre-registered at ClinicalTrials.gov with identifier NCT02152553. Results: We identified a transcriptomic profile derived from both peripheral blood mononuclear cells and adipose tissue, and a multi-omic signature including genes, miRNAs and metabolites that were associated with glucocorticoid exposure. Within the multi-omic signature we identified a single microRNA (miR-122-5p, p=0.009) regulated by glucocorticoid exposure, which we then replicated as a novel biomarker of glucocorticoid action in 120 subjects from independent studies (0.01 ≤ p ≤ 0.05). Conclusions: The discovery of miR-122-5p as a novel circulating biomarker of glucocorticoid action may have a significant impact on clinical practice. Our data also improves the understanding of glucocorticoid action and may have impact on future studies on the mechanistic understanding for the role of glucocorticoids in the etiology of common diseases, such as cardiovascular disease and obesity.
Ultrasensitive Detection of BRAF Mutations in Circulating Tumor DNA of Patients With Metastatic Thyroid Cancer
Authors: Gouda Mohamed A , Ong Emily , Huang Helen J , McPhaul Laron , Yoon Steve , Janku Filip , Gianoukakis Andrew G 
Published: May 2021

Abstract
Background: Liquid biopsy is a promising technology that can offer various advantages for molecular testing over tissue-based approaches. Most studies trying to address the utility of liquid biopsy in thyroid cancer have failed so far to achieve satisfactory rates of detection of relevant mutations. In this study, we examined a newly developed approach for ultrasensitive detection of oncogenic mutations in thyroid cancer using BRAF mutation as a proof-of-concept. In an exploratory analysis, we also correlated our findings with clinical outcomes and with levels of standard of care biomarkers. Methods: We included a group of patients with metastatic thyroid carcinoma. Cell free DNA (cfDNA) was isolated from an average of 2 ml of plasma and from matched formaldehyde fixed paraffin tissue blocks (FFPB) that were obtained from prior surgery. Extracted DNA was subject to preamplification of mutant copies using Q5 High-Fidelity PCR kit. Digital droplet PCR was performed on pre-amplified purified DNA where BRAF mutated allele frequencies (AF) were measured using BioRad ddPCR Qx200. Results: Thirty-three patients were included in our study with a median age at diagnosis of 62. Our method achieved a sensitivity of detection of 47.6% and a specificity of 80%. Mutant BRAF V600E was detected in cfDNA of 54.5% of patients (n=18) compared to 80.8% in isolated DNA from matched FFPB. Median overall survival (OS) was shorter in patients with wild type (WT) BRAF in both ctDNA and tissue (127m vs 218m, p=0.015; 116m vs 223m, p=0.004). Thyroglobulin (Tg) levels did not correlate with BRAF mutations either quantitatively or qualitatively. In the papillary thyroid carcinoma-classic variant cohort (n=20), however, patients with cfDNA mutant BRAF were more likely to have elevated Tg (90.9% versus 44.4% respectively, p=0.05). Conclusions: Our study provided a proof of concept for a newly developed technique to provide high sensitivity of mutation detection in thyroid cancer. The achieved sensitivity of detection is the highest to date using liquid biopsy in this tumor type. While we addressed only BRAF mutations in our study, the same approach can potentially be used for other mutations as well, likely changing the paradigm for use of liquid biopsy in thyroid cancer.