Thyroid最新文献

{"title":"International Women's Day: An Occasion for a Tribute to Women Leaders in the American Thyroid Association.","authors":"Jacqueline Jonklaas","doi":"10.1089/thy.2025.0073","DOIUrl":"10.1089/thy.2025.0073","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"227-229"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroid Nodule Sphericity Metrics Discriminate Benign and Malignant Follicular and Oncocytic Neoplasms.","authors":"Caitlin Bell, Samantha L White, Tracy Tylee, Manjiri Dighe, Amanda La Greca, Whitney Goldner, Sarah Mayson, Bryan R Haugen, Nikita Pozdeyev","doi":"10.1089/thy.2024.0670","DOIUrl":"10.1089/thy.2024.0670","url":null,"abstract":"<p><p><b><i>Background:</i></b> We investigated if thyroid nodule taller-than-wide (TTW) feature and sphericity metrics are helpful in separating benign neoplastic thyroid nodules (follicular and oncocytic adenomas) from follicular thyroid carcinomas (FTC) and oncocytic thyroid carcinomas (OCA). <b><i>Methods:</i></b> This is a retrospective study of TTW sonographic feature as reported by radiologists and nodule sphericity metrics at two academic health systems. Surgical pathology reports for benign and malignant follicular and oncocytic neoplasms, non-neoplastic nodules (hyperplastic and adenomatoid), and classic papillary thyroid cancers (PTC) were extracted from enterprise data warehouses. We independently reviewed each ultrasound and recorded nodule dimensions to identify nodules that were TTW and determine if the proportion of TTW nodules is different in benign and malignant thyroid nodules of various histologies. We also evaluated the sphericity index and sphericity ratio, two quantitative measures of how close the 3D shape of the nodule is to a sphere. <b><i>Results:</i></b> In total, 1110 nodules were analyzed: 209 non-neoplastic nodules (hyperplastic and adenomatoid), 398 benign neoplasms (follicular and oncocytic adenomas), and 503 malignant neoplasms (FTC, OCA, PTC, and follicular variant-PTC [FV-PTC]) and noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP). There was no statistical difference for the TTW feature when follicular and oncocytic adenomas were compared with FV-PTC, OCA, FTC, and NIFTP (χ², <i>p</i> = 0.08, sensitivity of 28% [confidence interval 23-24%]), when follicular adenoma was compared with FTC (χ², <i>p</i> = 0.64) or when oncocytic adenoma was compared with OCA (χ², <i>p</i> = 0.08). Benign and malignant neoplasms were more likely than non-neoplastic nodules to be TTW (χ², <i>p</i> = 0.02). In contrast, the sphericity index and sphericity ratio were significantly different in most comparisons of benign and malignant nodules (Wilcoxon, <i>p</i> < 0.03) except for oncocytic tumors. <b><i>Conclusions:</i></b> TTW shape has limited utility in distinguishing benign follicular and oncocytic neoplasms from malignancy. This sonographic feature was more common among all benign and malignant neoplasms when they were compared as a group to non-neoplastic nodules, which suggests this sonographic feature is an indicator of neoplastic growth (benign or malignant) but not cancer. Alternative methods, such as measures of sphericity, are needed to distinguish benign and malignant oncocytic and follicular neoplasms.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"291-297"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Response to the Letter:</i> Addressing Surgical Difficulty and Pathological Findings in Thyroidectomy Post-Thermal Ablation.","authors":"Ting-Chun Kuo, Ming-Hsun Wu","doi":"10.1089/thy.2025.0029","DOIUrl":"10.1089/thy.2025.0029","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"340-341"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two Novel <i>SLC5A5</i> Variants (Q263L and G350D) Causing Congenital Hypothyroidism.","authors":"Kiyomi Abe, Mikiko Koizumi, Takahiko Kogai, Shinobu Ida, Chiho Sugisawa, Masanobu Kawai, Tomonobu Hasegawa, Satoshi Narumi","doi":"10.1089/thy.2024.0716","DOIUrl":"10.1089/thy.2024.0716","url":null,"abstract":"<p><p><i>SLC5A5</i> encodes sodium-iodide symporter (NIS), which transports inorganic iodide into thyroid cells. Biallelic loss-of-function variants in <i>SLC5A5</i> cause thyroid dyshormonogenesis due to iodide transport defect (ITD). We report a Japanese sibling with ITD carrying novel compound heterozygous <i>SLC5A5</i> variants (p. [Gln263Leu]; [Gly350Asp]). The elder brother was diagnosed with congenital hypothyroidism (CH) through newborn screening (NBS), while the younger brother, with a negative NBS result, developed CH-related symptoms at age 3 months. We characterized the two variant NIS proteins <i>in vitro</i> and negligible iodide transport capacity of both proteins. These findings provide unique evidence for the structure-function relationship of the NIS protein.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"335-337"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytologic and Molecular Assessment of Isthmus Thyroid Nodules and Carcinomas.","authors":"Sina Jasim, Allan Golding, David Bimston, Mohammed Alshalalfa, Yang Chen, Ruochen Jiang, Yangyang Hao, Jing Huang, Joshua P Klopper, Richard T Kloos, Taylor C Brown","doi":"10.1089/thy.2024.0254","DOIUrl":"10.1089/thy.2024.0254","url":null,"abstract":"<p><p><b><i>Background:</i></b> Isthmic thyroid nodules are more likely to be malignant and isthmic differentiated thyroid cancer demonstrates less favorable behavior compared with lobar locations. The goal of this study was to assess molecular differences of thyroid nodules and carcinomas from the isthmus relative to the lobes. <b><i>Methods:</i></b> The Afirma thyroid nodule database (<i>n</i> = 177,227) was assessed for cytologic and molecular differences between isthmus and lobar nodules in this observational cohort study. Genome-wide differential expression analysis was conducted to decipher transcriptomic differences. Histopathology reports (<i>n</i> = 583) of papillary thyroid cancer (PTC) (<i>n</i> = 389) and infiltrative follicular subtype of PTC (IF-PTC) (<i>n</i> = 194) from Afirma discovery cohorts and from thyroid cancer patients managed at an integrative endocrine surgery community care practice were analyzed for molecular differences between isthmic and lobar cancers. <b><i>Results:</i></b> In the Afirma database, 8527 (4.8%) isthmus nodules were identified. Bethesda V-VI nodules were almost twice as prevalent from the isthmus as compared with the lobes (8.2% vs. 4.3%, <i>p</i> < 0.0001). Isthmus nodules had twice the frequency of <i>BRAFp.^V600E</i> (21% vs. 10.6%, <i>p</i> < 0.0001), an increased frequency of <i>ALK</i>/<i>NTRK</i>/<i>RET</i> fusions (4.6% vs. 2.5%, <i>p</i> < 0.0001) and <i>SPOP</i> variants (1.5% vs. 0.8%, <i>p</i> < 0.0001), and a lower frequency of <i>NRAS</i> mutations (7.8% vs. 13.2%, <i>p</i> < 0.0001), and <i>PAX8::PPARy</i> fusions (1.1% vs. 2.3%, <i>p</i> < 0.0001) than lobar nodules. Transcriptome analysis of molecular signatures and genome-wide analysis showed that isthmus nodules have higher <i>BRAF</i>-like scores, ERK activity, follicular mesenchymal transition scores (FMT), and lower inflammation activity scores. Pathway enrichment analysis revealed genes downregulated in isthmus tumors are enriched in immune response regulation. IF-PTC from the isthmus (<i>n</i> = 13) were more <i>BRAF</i>-like and had increased ERK and FMT scores compared with those from the lobes (<i>n</i> = 181) (<i>p</i> < 0.01 for all). <b><i>Conclusions:</i></b> These data suggest isthmic nodules are more likely to have malignant cytology and increased rates of higher risk molecular alterations compared with lobar nodules. IF-PTC from the isthmus is molecularly different compared with IF-PTC from the lobes. More data are needed to know if a change in surgical therapy is warranted in isthmic thyroid cancers relative to lobar cancers and if this molecular data should influence isthmic thyroid cancer management and monitoring.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"255-264"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Association Between Thyrotropin and Clinically Relevant Depression: A Retrospective Cross-Sectional Study.","authors":"Balwinder Singh, Amanda V Bakian, Michael Newman, Vishnu Sundaresh","doi":"10.1089/thy.2024.0428","DOIUrl":"10.1089/thy.2024.0428","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> Thyroid dysfunction and mood disorders are chronic health conditions with a significant impact on quality of life. This study aimed to investigate the association between thyrotropin (TSH) and clinically relevant depression (CRD) in patients with and without mood disorders, in a population-based sample. <b><i>Methods:</i></b> This retrospective cross-sectional study included all consecutive adults (≥18 years) who had TSH and completed the Patient Health Questionnaire (PHQ-9) within 6 months of the index visit, between October 2016 and May 2021, at the University of Utah Health. Data on demographics, hypothyroidism diagnoses, TSH, thyroid hormone replacement (THR), PHQ-9, antidepressant (AD) medications, and mood disorder diagnoses (using the International Classification of Diseases, 10th Revision, Clinical Modification codes; Major depressive disorder single episode-F32, recurrent-F33, persistent mood disorder-F34, bipolar disorder-F30+F31, and mood disorder not otherwise specified-F39) were extracted electronically. CRD was defined as PHQ-9 ≥ 10. <i>t</i>-Test and chi-square test were used to compare continuous and categorical variables, respectively. Logistic regression models were formulated to evaluate the association between TSH and CRD, after adjusting for covariates. <b><i>Results:</i></b> The cohort included 33,138 patients, mean age 42.41 ± 16.10 years, 80.67% Caucasian, 69.10% females, and mean PHQ-9 score 10.11 ± 6.94. A total of 45.23% (<i>n</i> = 14,989) patients had a diagnosis of mood disorders, and 49.70% had CRD. Patients with mood disorders were more likely to be female, Caucasian, non-Hispanic/Latino, on AD, had hypothyroidism diagnoses, on thyroid medications, had higher mean PHQ-9 scores, and had CRD. TSH level was associated with an increased odds of CRD (odds ratio [OR] = 1.01, confidence interval [CI], 1.01-1.02, <i>p</i> < 0.009) after adjusting for age, sex, body mass index, Charlson Comorbidity Index, and use of THR and AD. Both the low TSH and high TSH groups showed increased odds of CRD, with respective ORs of 1.19 (CI: 1.04-1.37) and 1.26 (CI: 1.13-1.40). <b><i>Conclusions:</i></b> Thyroid dysfunction is associated with an increase in the odds of depression. Future longitudinal cohort studies are recommended to investigate the association between thyroid function and incident depression.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"245-254"},"PeriodicalIF":5.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composition and Priorities of Multidisciplinary Pediatric Thyroid Programs: A Consensus Statement.","authors":"Ronik Kothari, Julia R Donner, Karthik Balakrishnan, Gary Hartman, Adina Alazraki, Zoltan Antal, Andrew Bauer, Daniel Chelius, Christine Cherella, John P Dahl, Amy Dimachkieh, Larry A Fox, Sara Helmig, Wen Jiang, Ken Kazahaya, Theodore W Laetsch, Maya Lodish, Priya Mahajan, Lauren Parsons, Kara Prickett, Lourdes Quintanilla-Dieck, Jeffrey Rastatter, David H Rothstein, Jeffrey Simons, Anthony Sheyn, Amy Wagner, Steven G Waguespack, Jonathan D Wasserman, Ari J Wassner, Hilary Seeley, Kara D Meister","doi":"10.1089/thy.2024.0496","DOIUrl":"https://doi.org/10.1089/thy.2024.0496","url":null,"abstract":"<p><p><b><i>Background:</i></b> The incidence of pediatric thyroid cancer has been increasing, and care varies due to socioeconomic disparities or differing practice patterns. Clinical guidelines call for care in multidisciplinary teams to minimize variance and provide protocols. Based on expert opinion, we hope to describe the form and function of such multidisciplinary teams for pediatric thyroid programs. <b><i>Methods:</i></b> A modified Delphi method to reach consensus statements over two rounds. Twenty-one experts with varying backgrounds responded to each statement on a 9-point Likert scale. Upon completion of the survey, the panel reviewed and shared the results and comments from participants and modified the statements accordingly. This process was repeated such that statements reached consensus, were deemed no consensus, or had no change in the mean. <b><i>Results:</i></b> There was an 88% and 83% completion rate for Rounds 1 and 2, respectively. A consensus was observed that there is a distinct definable model of care for pediatric thyroid patients. No consensus was reached for the age range of patients, but programs should care for children with medullary thyroid cancer, differentiated thyroid cancer, and patients with genetic predisposition syndromes. A comprehensive team includes, but is not limited to, a thyroid surgeon, a pediatric endocrinologist, a high-volume fine-needle aspiration (FNA) proceduralist, an oncologist, a nuclear medicine physician, a pediatric pathologist, a pediatric radiologist, and a nurse coordinator. Necessary support services involve care coordination, access to a multidisciplinary tumor board, ability to perform ultrasound-guided FNA, and access to molecular testing. The panel emphasized cross-institutional collaborative research prioritizing guidelines development, disease-specific outcomes, treatment toxicity, and the molecular landscape of thyroid cancer. <b><i>Conclusions:</i></b> These consensus statements can be beneficial in improving multidisciplinary care, by describing which elements of pediatric thyroid programs should be consistent across institutions. Overall, the panel agreed that pediatric thyroid centers should provide integrated care with defined team members, services, resources, and research priorities. This model has the potential to standardize various aspects of clinical care and enhance our ability to study patient outcomes, improve health care delivery, and increase scholarly collaboration.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Clinical Nomogram to Predict Survival Outcomes in Patients with Well-Differentiated Thyroid Cancer.","authors":"Cristina Valero, Alana Eagan, Dauren Adilbay, Danielli Matsuura, Victoria Harries, Ashok R Shaha, Jatin P Shah, R Michael Tuttle, Darkhan Akhmedin, Renan Aguera Pinheiro, Leandro Luongo Matos, Luiz P Kowalski, Galym Adilbayev, Rabiga Kadyrbayeva, Snehal G Patel, Ian Ganly","doi":"10.1089/thy.2024.0486","DOIUrl":"https://doi.org/10.1089/thy.2024.0486","url":null,"abstract":"<p><p><b><i>Background:</i></b> The current American Joint Committee on Cancer 8th edition staging system on thyroid cancer describes outcomes for populations of patients with well-differentiated thyroid cancer (WDTC) and not individual patients. The aim of this study was to create a clinical nomogram that can be used to predict survival in individual patients with WDTC. <b><i>Methods:</i></b> A single institutional cohort of 8535 patients with WDTC treated with primary surgery at the Memorial Sloan Kettering Cancer Center was used to create a predictive nomogram for disease-specific survival (DSS) as a retrospective cohort study. The nomogram was created using DSS as the dependent variable, and the independent variables used were sex, age, pathology subtype, and TNM stage. An external validation cohort of 519 patients from three different international centers was used to assess the accuracy and generalizability of the nomogram. <b><i>Results:</i></b> Sex, age, pathology subtype, T stage, N stage, and M stage were significant predictors of DSS on univariable analysis. The nomogram created using all these variables showed an extremely high concordance index (0.963; SE 0.012). This nomogram was validated on the external patient cohort with a high concordance index (0.810; SE: 0.070). <b><i>Conclusions:</i></b> We describe a predictive nomogram that accurately predicts DSS in individual patients with WDTC. The external validation illustrates its generalizability. This nomogram will help in counseling individual patients on prognosis and may identify patients who could benefit from more aggressive therapy.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Usefulness of the International Grading System in the Management of Sporadic Medullary Thyroid Carcinoma.","authors":"Alessandro Prete, Liborio Torregrossa, Carla Gambale, Raffaele Ciampi, Teresa Ramone, Cristina Romei, Virginia Cappagli, Paolo Piaggi, Clara Ugolini, Gabriele Materazzi, Rossella Elisei, Antonio Matrone","doi":"10.1089/thy.2024.0444","DOIUrl":"https://doi.org/10.1089/thy.2024.0444","url":null,"abstract":"<p><p><b><i>Background:</i></b> The international medullary thyroid carcinoma (MTC) grading system (IMTCGS) has been proposed as an independent tool to predict disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS). We aimed to evaluate the performance of IMTCGS in our series of sporadic MTCs and to compare its predictive power with conventional prognostic factors. <b><i>Methods:</i></b> In a retrospective cohort study, we evaluated data from 314 patients with sporadic MTC, all managed at the Pisa University Hospital. We divided patients according to the extent of the disease at diagnosis into localized (183/314, 58.3%) (confined to the thyroid), regional (100/314, 31.8%) (limited to the neck, involving surrounding thyroid tissues and/or regional lymph nodes), and distant (31/314, 9.9%) (distant metastases) disease. Data about somatic mutations were available in 212/314 (67.5%) patients. Expert pathologists differentiated high- and low-grade tumors. <b><i>Results:</i></b> According to the IMTCGS, 115/314 (36.6%) had high- and 199/314 (63.4%) patients had low-grade tumors. Patients with high-grade tumors showed higher preoperative calcitonin levels compared with low-grade (542 vs. 76 pg/mL, <i>p</i> < 0.01) as well as larger tumor size (2.3 vs. 1.1 cm, <i>p</i> < 0.01) and more frequent multifocality (22.6 vs. 12.1%, <i>p</i> = 0.01), minimal extrathyroidal extension (30.4 vs. 9.5%, <i>p</i> < 0.01), and lymph node metastases (63.5 vs. 27.6%, <i>p</i> < 0.01). Overall, patients with high-grade showed lower DSS, LRFS, and DMFS (<i>p</i> < 0.01). Grouping the whole cohort according to different disease extent at diagnosis, only in the case of localized disease, patients with high-grade tumors had significantly lower LRFS compared with low-grade. Similarly, in the other subgroups, we did not identify any difference in DSS, LRFS, and DMFS. Moreover, in the case of <i>RET</i> aggressive mutations, no differences in DSS, LRFS, and DMFS were observed between high- and low-grade tumors. <b><i>Conclusions:</i></b> We confirmed the usefulness of IMTCGS in predicting DSS, LRFS, and DMFS. However, it finds the best utility in patients with a lower risk of recurrence and mortality, identifying those rare cases with more aggressive clinical behavior. Conversely, when laterocervical lymph nodes (N1), distant metastasis (M1), or <i>RET</i> mutations, particularly <i>M918T</i> or <i>indels</i>, are already present at diagnosis, the role of IMTCGS in predicting DSS, DMFS, and LRFS becomes less relevant.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Profiling of Medullary Thyroid Cancer Identifies CAPN1 as a Key Regulator of NF1 and RET Fueled Growth.","authors":"Eshan Khan, Hannah Hylton, Neel Rajan, Stephanie J Bouley, Jalal K Siddiqui, Swetha Rajasekaran, Ganesh R Koshre, Hayden Storts, Anisley Valenciaga, Misbah Khan, Sandya Liyanarachchi, Francisco Fernandez, Xuguang Zheng, John Phay, Priya H Dedhia, Jing Wang, James A Walker, Matthew D Ringel, Wayne O Miles","doi":"10.1089/thy.2024.0102","DOIUrl":"10.1089/thy.2024.0102","url":null,"abstract":"<p><p><b><i>Background:</i></b> Medullary thyroid cancer (MTC) is a frequently metastatic tumor of the thyroid that develops from the malignant transformation of C-cells. These tumors most commonly have activating mutations within the RET or RAS proto-oncogenes. Germline mutations within RET result in C-cell hyperplasia, and cause the MTC pre-disposition disorder, multiple endocrine neoplasia, type 2A (MEN2A). Single-agent therapies for MTC, including vandetanib (VAN) and cabozantinib for all MTCs and selpercatinib (SEL) for RET-mutated MTC, lead to partial responses but are not curative. <b><i>Methods:</i></b> To identify new therapeutic targets for MTC, we conducted proteomic profiling of normal C-cells, MTC cells, pre-malignant MEN2A patient samples, and MTC tumors. <b><i>Results:</i></b> From this analysis, we identified CAPN1, a member of the CALPAIN (CAPN) family endopeptidases, as widely upregulated in MTC samples. We found that short hairpin RNA-mediated depletion of CAPN1 or inhibitors of CAPN1 significantly reduced MTC cell growth, colony formation, and xenograft tumor growth <i>in vivo</i>. In addition, we show that CAPN1 inhibitors synergize with VAN and SEL <i>in vitro</i>, maximizing apoptosis. Mechanistic experiments implicate CAPN1 in inhibiting neurofibromin, encoded by NF1, and CAPN1 inhibitors stabilize NF1 protein levels and diminish downstream RAS/RET activation of AKT and ERK. <b><i>Conclusions:</i></b> Our data suggest that increased CAPN1 levels support RET and RAS-fueled growth by reducing NF1 levels. We find that combinatorial therapies between CAPN1 inhibitors and VAN or SEL show maximal efficacy in MTC cells.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"177-187"},"PeriodicalIF":5.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}