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Sijin Li Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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Zhen Chen Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Mengchu Liu School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, China

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Liang Li Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Wensong Cai Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Zhe-Xiong Lian Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Haixia Guan Department of Endocrinology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Bo Xu Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1CD103 plus CD39PD-1CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.

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Julia Beck ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Alexander Siebenhüner Hirslanden Zurich AG, Clinic for Hematology and Oncology, Zurich, Switzerland

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Damian Wild ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland

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Emanuel Christ ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Julie Refardt ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Sex differences affect the management of several diseases in both male and female patients. However, the influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from July 2014 to September 2022. The analysis included 1985 patients (46% female and 54% male). No significant difference in tumor grading was found between male and female patients. However, male patients presented with higher staging at time of diagnosis and with more lymph node and bone metastases. Surgery was performed more often in female compared to male patients (73.4% vs 68.7%, P = 0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, P = 0.003). The median overall survival was significantly shorter for male compared to female patients (male: 18 years, female: not reached, P < 0.001, hazard ratio (HR) 1.55 (1.19–2.01), P = 0.001). Multivariable analyses revealed advanced age (HR 1.02 (1.01–1.04)), cancer of unknown origin (HR 2.01 (1.09–3.70)), higher grading (G3: HR 6.74 (4.22–10.76)), having metastases at the time of diagnosis (HR 2.11 (1.47–3.02)), and surgical treatment (HR 0.67 (0.48–0.93)) as independent predictors for overall survival. In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.

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Yihao Chen Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Jiahong Chen Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Yongcheng Shi Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Xiaohui Ling Reproductive Medicine Center, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Shumin Fang Science Research Center, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Chuanfan Zhong Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Fengping Liu State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China

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Weide Zhong State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, Guangdong

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Xuecheng Bi Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Zhong Dong Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China

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Jianming Lu Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China

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Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

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Andreas Machens Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

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Uriel Clemente-Gutierrez Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Carolina R C Pieterman Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

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Michael S Lui Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Thomas Szabo Yamashita Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Andrés Tame-Elorduy Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Bernice L Huang Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Aditya S Shirali Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Derek J Erstad Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Jeffrey E Lee Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Sarah B Fisher Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Paul H Graham Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Elizabeth G Grubbs Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Steven G Waguespack Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Chaan S Ng Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Nancy Perrier Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients’ clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3–123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion’s growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

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Roger Harty The Ohio State University College of Medicine, Columbus, Ohio, USA

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Joshua D Safer Mount Sinai Center for Transgender Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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Graphical abstract

Abstract

With the increasing number of transgender and gender diverse (TGD) individuals who are seeking gender-affirming care, there is a clear need for the development and collection of evidence-based data to establish guidelines for patient care. TGD individuals are estimated to represent 0.3 to 4.5% of the world population. Gender-affirming care that includes hormone therapy helps to align the body of a transgender person with their gender identity. Hormone therapy requires monitoring for both safety and efficacy. The extent to which gender-affirming hormone therapy alters cancer risk remains unknown. Because of a lack of comprehensive data collection pertaining to this patient population, endocrine cancer data including incidence and outcomes is limited. Dedicated research is needed to help address the gap in knowledge pertaining to the risk of cancer in the TGD population.

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Valdemar Máximo i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal

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Miguel Melo i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Medical Faculty, University of Coimbra, Coimbra, Portugal

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Yingjie Zhu Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, USA

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Andrea Gazzo Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, USA

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Manuel Sobrinho Simões i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal
Department of Pathology, Hospital São João, Porto 4200-319, Portugal

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Arnaud Da Cruz Paula i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal

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Paula Soares i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal

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The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.

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Isabella Albuquerque Pinto Rebello Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Vinícius Loures de Oliveira Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Luís Felipe Holzwarth Abbud Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Tales Aprígio Camargos Ferreira Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Ana Paula Aguiar Vidal Department of Pathology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Brazil

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Patrícia de Fátima dos Santos Teixeira Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Few studies have focused on reclassifying follicular adenomas (FAs) as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), but none have been conducted in America or Europe. The aims of this study were to analyze the prevalence of NIFTP reclassified from follicular variant of papillary thyroid carcinomas (FVPTCs) and FAs before NIFTP was defined in the literature, the rate of NIFTP among PTC (papillary thyroid carcinomas) established in real time between 2017 and 2022, and demographic, ultrasonographic, and cytologic characteristics of NIFTPs compared with FVPTCs and FAs. This was a retrospective cohort study of tumors diagnosed as PTCs (n = 247) and FAs (n = 144) at a Brazilian hospital. Overall, 13.4% of PTCs and 7% of FAs were reclassified as NIFTPs. The rate of real-time diagnosed NIFTPs among PTC was 12.3%. The median tumor size was larger among NIFTPs (3.0 cm) than FVPTCs (1.1 cm; P < 0.01). A high-risk ultrasonographic pattern was rare in NIFTPs (5.6%). The cytologic classifications differed between FVPTCs and NIFTPs (P < 0.01), and the most frequent category among NIFTPs was ‘follicular neoplasm’ (52.6%). The category ‘suspicious for malignancy’ was frequent in FVPTCs and rare (5.3%) in NIFTPs. In conclusion, FVPTCs and FAs may be reclassified as NIFTPs. The prevalence of NIFTPs reclassified from FAs was lower in our cohort than in Asian studies. The rate of NIFTPs reclassified from PTC was similar to that of NIFTPs diagnosed in real time and was aligned with rates reported in studies from America and Europe. Preoperative features could not differentiate NIFTPs from FVPTCs or FAs.

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Andres Elía Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Leo Saldain Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Silvia Lovisi Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Paula Martínez Vazquez Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Javier Burruchaga Hospital de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina

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Caroline A Lamb Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Isabel Alicia Lüthy Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Federico Diez University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Natalie Z M Homer University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Ruth Andrew University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Paola Rojas Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Claudia Lanari Instituto de Biología y Medicina Experimental (IBYME), CONICET, Argentina

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Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

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