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      The value of thyroperoxidase as a prognostic factor for differentiated thyroid cancer -- a long-term follow-up study

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          Abstract

          Background

          Thyroperoxidase (TPO) is a membrane-bound protein essential for the production of thyroid hormones; because of this, TPO expression may be impaired in selected thyroid diseases. The goal of this study is to analyze TPO immune expression in differentiated thyroid cancer, and to determine whether TPO has any prognostic value.

          Methods

          A total of 139 patients who required surgery due to a thyroid nodule with signs or symptoms suspicious for malignancy during their physical, ultrasound and/or cytology examination were consecutively selected for the study. A study of TPO immunohistochemical expression was carried out on these patients using the MoAb47 monoclonal antibody. In addition, cell proliferation marker Ki67 and tumor suppressor p53 were also measured for comparison.

          Results

          A total of 139 cases, 43 benign tumors, 42 papillary carcinomas, 38 follicular carcinomas, 8 undifferentiated carcinomas, and 8 sporadic medullary carcinomas were analyzed. The relationship between TPO expression and disease was statistically significant ( p <0.001), and decreased with tumor dedifferentiation extent. Increased TPO expression in benign lesions as compared to decreased expression in papillary carcinomas and undifferentiated tumors is outstanding. Differences in TPO expression were observed in minimally invasive follicular carcinoma (MIFC) compared to widely invasive follicular carcinoma (WIFC). TPO expression decreases in undifferentiated malignancies in contrast with p53 and Ki67 expression, which increases in that setting. TPO, p53 and Ki67 expression was significantly related to TNM stage ( p <0.001). Survival rate was 72 % after a 20-year follow-up, and 100 % for subjects with higher TPO expression.

          Conclusions

          TPO may be useful in confirming or ruling out benign diseases from differentiated thyroid carcinoma, with the exception of low-risk carcinoma such as MIFC. It could be used as a prognostic factor for differentiated thyroid cancer and patient follow-up, together with other markers.

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          Most cited references25

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          Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers.

          Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.
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            Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy.

            Heat shock proteins (Hsps) are induced in vitro by several cytotoxic drugs; in human breast cancer cells these proteins appear to be involved in anti-cancer drug resistance. The present report was designed to analyze whether chemotherapy affects in vivo the expression of Hsp27, Hsp70, Hsc70 and Hsp90 in breast cancer patients treated with induction chemotherapy and whether these proteins may be determinants of tumor resistance to drug administration. We have analyzed 35 biopsies from breast cancer patients treated with induction chemotherapy. Expression of the Hsps in the tumors was compared with (i) histological and clinical responses to chemotherapy, (ii) tumor cell proliferation measured by proliferating cell nuclear antigen (PCNA) immunostaining and nucleolar organizer regions (AgNORs) staining and (iii) the expression of estrogen and progesterone receptors. We also compared disease-free survival (DFS) and overall survival (OS) with the expression of the Hsps studied. After chemotherapy, nuclear Hsp27 and Hsp70 expression was increased and Hsp70 and Hsc70 cytoplasmic expression was decreased. A high nuclear proportion of Hsp70 in tumor cells (>10%) correlated significantly with drug resistance. We also observed that patients whose tumors expressed nuclear or a high cytoplasmic proportion (>66%) of Hsp27 had shorter DFS. The combination of Hsp27 and Hsp70 levels showed a strong correlation with DFS. Neither the cellular proliferation nor the levels of steroid receptors showed any significant difference before or after drug administration or during follow-up of patients. Our results suggest that Hsp27 and Hsp70 are involved in drug resistance in breast cancer patients treated with combination chemotherapies.
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              BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer.

              A low sodium iodide symporter (NIS) expression has been shown in papillary thyroid carcinomas (PTCs) harboring the BRAFV600E mutation. In the present study, we analyzed the mRNA expression of thyroid differentiation genes, glucose transporter (GLUT)-1 and GLUT-3, in 78 PTCs according to the presence of BRAFV600E or RET/PTC rearrangements. We found BRAFV600E and RET/PTC rearrangements in 35.8 and 19.4% of PTCs respectively. The mRNA expression of NIS and thyroperoxidase (TPO) genes were significantly lower (P<0.0001 and P=0.004 respectively) in BRAFV600E-positive PTC with respect to non-mutated samples. In support of this result, immunohistochemistry showed that the percentage of NIS-positive cells was significantly lower (P=0.005) in BRAFV600E-mutated PTC (mean 53.5%) than in negative cases (mean 72.6%). In contrast, no difference either in NIS or in any other thyroid differentiation genes' mRNA expression was found in PTC with or without RET/PTC rearrangements. When GLUT-1 and GLUT-3 mRNA expression was considered, no correlation was found either in BRAFV600E- nor in RET/PTC-mutated cases. In conclusion, this study confirmed the presence of a genetic alteration of BRAF and/or RET oncogenes in 64% of PTC cases and revealed a significant correlation of BRAFV600E mutation with a lower expression of both NIS and TPO. This latter finding could indicate that an early dedifferentiation process is present at the molecular level in BRAFV600E-mutated PTC, thus suggesting that the previously demonstrated poor prognostic significance of BRAFV600E mutation could be related to the dedifferentiation process more than to a more advanced stage at diagnosis.
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                Author and article information

                Contributors
                +34 669653808 , yure_hop@hotmail.com
                dretomassetti@gmail.com
                julianfavre@hotmail.com
                jrsantana@telefonica.net
                jjcabreracabrera@hotmail.com
                jurahh@yahoo.es
                Journal
                Thyroid Res
                Thyroid Res
                Thyroid Research
                BioMed Central (London )
                1756-6614
                13 August 2015
                13 August 2015
                2015
                : 8
                : 12
                Affiliations
                [ ]General Surgery Department, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Las Palmas, Spain
                [ ]Pathology Department, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Las Palmas, Spain
                Article
                22
                10.1186/s13044-015-0022-6
                4546101
                26300979
                1605bdd6-683d-44a1-9b27-ac43b5c3e4aa
                © Caballero et al. 2015

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 June 2015
                : 23 June 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Endocrinology & Diabetes
                thyroid cancer,thyroperoxidase,ki67,p53
                Endocrinology & Diabetes
                thyroid cancer, thyroperoxidase, ki67, p53

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