Thyroid最新文献

{"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":"Is Radioactive Iodine Contraindicated in Patients with Moderate-to-Severe and Active Graves' Orbitopathy?","authors":"Luigi Bartalena, Maria Laura Tanda","doi":"10.1089/thy.2025.0059","DOIUrl":"https://doi.org/10.1089/thy.2025.0059","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399864","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":"<i>Letter to the Editor:</i> Does Thermal Ablation of Thyroid Nodules Increase the Complexity of Subsequent Thyroidectomy?","authors":"Xinxin Zhao, Ye Yang","doi":"10.1089/thy.2025.0002","DOIUrl":"https://doi.org/10.1089/thy.2025.0002","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190715","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":"Controversies Surrounding IGF-I Receptor Involvement in Thyroid-Associated Ophthalmopathy.","authors":"Terry J Smith","doi":"10.1089/thy.2024.0606","DOIUrl":"https://doi.org/10.1089/thy.2024.0606","url":null,"abstract":"<p><p><b><i>Background:</i></b> Thyroid-associated ophthalmopathy (TAO, aka thyroid eye disease [TED], Graves' orbitopathy) remains poorly understood and inadequately treated since its initial description. It is disfiguring, can threaten vision, and represents an autoimmune process closely associated with thyroid disease. Unambiguous connections linking TAO to the glandular maladies of Graves' disease (GD) remain incompletely clarified. Detecting the thyrotropin receptor (TSHR) in periocular tissues suggests that this cell-surface protein represents a shared autoantigen with the thyroid gland, but we now know that its expression is ubiquitous. Most patients with TAO have relatively high circulating levels of activating anti-TSHR autoantibodies. Emerging more recently is the importance of insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of TAO. The TSHR/IGF-IR signaling complex apparently drives circulating fibrocytes and the unique phenotypes of fibroblasts inhabiting the TAO orbit (GD-OF). <b><i>Methods:</i></b> The PubMed database was scanned for articles dating back to the earliest time periods covered. Keywords used for primary searches included thyroid-associated ophthalmopathy, Graves' orbitopathy, TED, orbit, TSH receptor, IGF-I receptor, and autoimmune thyroid disease. Secondary searches used numerous other search terms. <b><i>Results:</i></b> GD-OF have been characterized extensively as being particularly responsive to the immunological factors and key effectors in TAO pathogenesis. Both TSHR and IGF-IR are overexpressed by GD-OF and CD34⁺ fibrocytes and form a signaling complex. They are activated through this TSHR/IGF-IR complex to produce large amounts of hyaluronan and express multiple cytokines. This complex mediates cellular responses to pathogenic IgGs in TAO. CD34⁺ fibrocytes and CD34⁺ OF also express relatively high levels of multiple thyroid autoantigens. Identifying IGF-IR as a key component of a receptor complex and its intertwining signaling activities with those of TSHR has led to a targeted medical therapy for TAO. This therapy involves the selective systemic inhibition of IGF-IR. <b><i>Conclusions:</i></b> Much has been learned over the preceding decades about the pathogenesis of TAO. Among these is the identification of IGF-IR as a pivotal component underpinning the disease. This has led directly to development of an effective targeted therapy. Important gaps in our understanding persist, and current therapies have limitations. Thus, despite these advancements, considerably more remains to be achieved.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256671","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":"Ablative Versus Conservative Approach for Hyperthyroidism Treatment in Patients with Graves' Orbitopathy: A Retrospective Cohort Study.","authors":"Giada Cosentino, Giulia Lanzolla, Simone Comi, Maria Novella Maglionico, Chiara Posarelli, Dalì Antonia Ciampa, Francesca Menconi, Roberto Rocchi, Francesco Latrofa, Michele Figus, Ferruccio Santini, Michele Marinò","doi":"10.1089/thy.2024.0633","DOIUrl":"https://doi.org/10.1089/thy.2024.0633","url":null,"abstract":"<p><p><b><i>Background:</i></b> Treatment for Graves' hyperthyroidism (GH) in patients with Graves' orbitopathy (GO) remains a topic of debate. This study aimed to investigate the outcome of GO following glucocorticoids, depending on the chosen thyroid treatment. <b><i>Methods:</i></b> This retrospective cohort study included 49 consecutive patients with GH and moderate-to-severe, active GO, as defined by the European Group on Graves' Orbitopathy guidelines. Twenty-four patients were treated with radioactive iodine (RAI) and 25 with methimazole (MMI). All patients were administered intravenous methylprednisolone. Follow-up visits occurred at weeks 24, 48, and 72. The primary endpoint was the overall outcome of GO at week 24. Response was defined as a change in at least two of the following eye features: reduction ≥1 point in clinical activity score; proptosis reduction ≥2 mm; eyelid aperture reduction ≥2 mm; increase in eye ductions ≥8 degrees. <b><i>Results:</i></b> Follow-up duration was 72 weeks for both groups (interquartile range 66-72 for RAI and 48-72 for MMI). The proportion of responders for week 24 overall GO outcome was greater in RAI (54.1% vs. 16%; odds ratio [OR] 6.2 [confidence interval (CI): 1.6-23.6], <i>p</i> = 0.0075), but it increased in MMI at weeks 48 and 72, with no differences between groups. There was a trend indicating a better response in RAI regarding individual eye features. Improvement in GO-specific quality of life questionnaire at week 24 was trendily more pronounced in RAI (responders 50% vs. 28% in MMI; OR = 2.5 [CI: 0.7-8.4], <i>p</i> = 0.11), although results were similar in both groups at later time points. At week 24, only one patient (4%) in RAI and three (12%) in MMI experienced worsening of GO. Fifty-nine adverse events were recorded among 36 patients, with no differences between groups, except for infections, which were more frequent in RAI (53.8% vs. 15.3% in MMI; OR = 6.41 [CI: 1.7-23.9], <i>p</i> = 0.0056). <b><i>Conclusions:</i></b> RAI appears to be associated with an earlier response of GO to intravenous glucocorticoids. In the long term, a conservative approach also seems to be effective. RAI appears to be relatively safe when patients are concurrently treated with glucocorticoids. However, randomized clinical trials are necessary to confirm these findings.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256668","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":"https://doi.org/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":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-05","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":"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":"https://doi.org/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":""},"PeriodicalIF":5.8,"publicationDate":"2025-02-03","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":"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}