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PubMed | University of Belgrade, Center for Endocrine Surgery and Clinical Center Dr Dragisa Misovic
Type: | Journal: International journal of endocrinology | Year: 2014

Background. Anaplastic thyroid cancer (ATC) is a form of thyroid cancer with very poor prognosis, but is fortunately quite rare. Its aetiology is unknown and not well researched. Aim. The aim of this study was to identify potential risk factors for ATC. Material and Method. Case-control study of 126 ATC patients (77 females and 49 males) and 252 controls individually matched by gender, age, and place of abode. In statistical analysis we used a Cox regression model. Results. Univariate logistic regression showed that the risk factors for ATC are low education level, type B blood group, goitre, other nonthyroid malignancies, diabetes, late menarche, and an early first pregnancy. Multivariate logistic regression analysis showed that independent risk factors for ATC are low education level (OR=1.42, 95% CI=1.09-1.86), type B blood group (OR=2.41, 95% CI=1.03-5.66), and goitre (OR=25-33, 95% CI=5.66-126.65). Conclusion. Independent risk factors for ATC are: low education level, type B blood group, and goitre.


Isic Dencic T.,University of Belgrade | Cvejic D.,University of Belgrade | Paunovic I.,Center for Endocrine Surgery | Tatic S.,University of Belgrade | And 2 more authors.
Medical Oncology | Year: 2013

Cytokeratin19 (CK19) has been reported as a useful marker of thyroid tumors. We evaluated its value for differential diagnosis of thyroid neoplastic lesions and assessed its usefulness for predicting aggressive behavior of papillary thyroid carcinomas by correlating immunohistochemical results with clinicopathological features of the patients. A total of 351 thyroid tissue samples included 27 follicular adenomas (FTA), 18 follicular carcinomas (FTC), 147 papillary carcinomas (71 of follicular type-PTCfv and 76 of classical type-PTCcl) and 33 cases of anaplastic carcinoma with 126 adjacent thyroid tissues. Diagnostic usefulness of CK19 was determined by ROC analysis, while its value as a predictive marker of PTC was tested by univariate and multivariate analysis. According to ROC analysis, CK19 can discriminate both types of PTC from other neoplasias of the thyroid gland (p < 0.05). Although greatest accuracy was gained for the identification of PTCcl (91.07 %), this marker was also helpful for distinguishing PTCfv from FTA and FTC (accuracy 71.43 and 65.17 %, respectively). Regarding the univariate set of tests, high expression of CK19 correlated significantly with age, multifocality, extrathyroidal extension, pT status and pTNM stage of PTC (p < 0.05 for all). Multivariate analyses confirmed the significant association of high CK19 expression with extrathyroidal extension of PTC as well as with pTNM stage (p < 0.05 and p < 0.01, respectively). CK19 is a useful marker for the identification of both types of PTC. High expression of this protein predicts the aggressive behavior of PTC and can help in the identification of a particular subgroup of PTC patients with a potentially worse prognosis. © 2012 Springer Science+Business Media New York.


Selemetjev S.,University of Belgrade | Dencic T.I.,University of Belgrade | Marecko I.,University of Belgrade | Jankovic J.,University of Belgrade | And 3 more authors.
Pathology Research and Practice | Year: 2014

Overexpression of survivin, an inhibitor of apoptosis protein, has been found in a variety of human cancers, and is associated with tumor aggressiveness. In this study, we analyzed the expression of survivin in papillary thyroid carcinoma (PTC) and evaluated its clinical significance for predicting an aggressive course of disease at the time of diagnosis. Survivin expression was determined by immunohistochemistry in 104 tissue specimens of PTC, confirmed by Western blot and correlated with clinicopathological parameters. Of the tumors examined, 74 (71.15%) showed high cytoplasmic survivin expression. There was no association between high survivin expression and age, gender or tumor size. On the other hand, it was closely correlated with the presence of lymph node metastasis (P= 0.009), and there was a tendency for correlation with extrathyroidal invasion (P= 0.062). The high risk PTC group (TNM stage III-IV) was associated with high levels of survivin (P= 0.027). These results indicate that survivin is an unfavorable molecule for PTC prognosis, and that its high expression may indicate a subset of PTC patients with a more aggressive disease course. Evaluation of its expression in fine needle aspiration samples could be a useful tool for the identification of those PTC patients who require more extensive surgery, careful follow-up and therapeutic strategy. © 2013 Elsevier GmbH.


PubMed | University of Belgrade, Institute for the application of nuclear energy and Center for Endocrine Surgery
Type: | Journal: Diagnostic pathology | Year: 2015

Nodular follicular lesions of thyroid gland comprise benign and malignant neoplasms, as well as some forms of hyperplasia. Follicular refers to origin of cells and in the same time to growth pattern - building follicles. Nodular follicular thyroid lesions have in common many morphological features, therefore attempts were made to define additional criteria for distinction between follicular adenoma, follicular carcinoma and follicular variant of papillary carcinoma. Increasing number of immunohistochemical markers is in the continual process of evaluation.Tissue microarrays incorporating, total 201 cases, out of which 122 malignant and 79 benign follicular lesions, including neoplastic and non-neoplastic, were constructed and immunostained with antibodies to CD56, CK19, Galectin-3, HBME-1. Tissue cores were exclusively being acquired from tumour/lesion on interface with normal thyroid tissue. A systematic review of literature was done for period from the year 2001 to present time.All analysed markers may make a difference between benign lesions/tumours from differentiated thyroid carcinomas (p=<0.01, for all markers). Expression of all markers is significantly higher in papillary carcinoma than in follicular adenoma (p<0.01). Statistically significant difference in expression of Galectin-3 and CD56 between follicular carcinoma and follicular adenoma was registered (p=0.043; p=0.028, respectively). The only marker which expression showed statistically significant difference between adenoma and carcinoma of Hurthle cells was Galectin 3 (p=0.041). CK19 and HBME-1 were significantly expressed more in papillary carcinoma as compared to follicular carcinoma.Galectin 3 is most sensitive marker for malignancy, while loss of expression of CD56 is very specific for malignancy. Expected co-expression for combination of markers in diagnosis of follicular lesions decreases sensitivity and increases specificity for malignancy.


PubMed | University of Belgrade and Center for Endocrine Surgery
Type: Journal Article | Journal: Pathology, research and practice | Year: 2014

Overexpression of survivin, an inhibitor of apoptosis protein, has been found in a variety of human cancers, and is associated with tumor aggressiveness. In this study, we analyzed the expression of survivin in papillary thyroid carcinoma (PTC) and evaluated its clinical significance for predicting an aggressive course of disease at the time of diagnosis. Survivin expression was determined by immunohistochemistry in 104 tissue specimens of PTC, confirmed by Western blot and correlated with clinicopathological parameters. Of the tumors examined, 74 (71.15%) showed high cytoplasmic survivin expression. There was no association between high survivin expression and age, gender or tumor size. On the other hand, it was closely correlated with the presence of lymph node metastasis (P=0.009), and there was a tendency for correlation with extrathyroidal invasion (P=0.062). The high risk PTC group (TNM stage III-IV) was associated with high levels of survivin (P=0.027). These results indicate that survivin is an unfavorable molecule for PTC prognosis, and that its high expression may indicate a subset of PTC patients with a more aggressive disease course. Evaluation of its expression in fine needle aspiration samples could be a useful tool for the identification of those PTC patients who require more extensive surgery, careful follow-up and therapeutic strategy.


The aim of our study was to investigate the incidence of papillary thyroid microcarcinoma (PTMC) in patients operated for benign thyroid diseases (BTD) and its relation to age, sex, extent of surgery and type of BTD.Retrospective study of 2466 patients who underwent thyroid surgery for BTD from 2008 to 2013. To determine independent predictors for PTMC we used three separate multivariate logistic regression models (MLR).There were 2128 (86.3%) females and 338 (13.7%) males. PTMC was diagnosed in 345 (16.2%) females and 58 (17.2%) males. Age ranged from 14 to 85 years (mean 54 years). Sex and age were not related to the incidence of PTMC. The overall incidence of PTMC was 16.3%. The highest incidence was in Hashimoto thyroiditis (22.7%, (2)=10.80, p<0.001); and in patients with total/near-total thyroidectomy (17.7%, (2)=7.05, p<0.008). The lowest incidence (6.6%, (2)=9.96, p<0.001) was in a solitary hyperfunctional thyroid nodule (SHTN). According to MLR, Hashimoto thyroiditis (OR 1.54, 95% CI 1.15-2.05, p<0.003) and SHTN (OR 0.43, 95% CI 0.21-0.87, p<0.019) are independent predictors. Since the extent of surgery was an independent predictor (OR 1.45, 95% CI 1.10-1.92, p=0.009) for all BTD, and sex and age were not; when the MLR model was adjusted for them, Graves disease (OR 0.72, 95% CI 0.53-0.99, p<0.041) also proved to be an independent predictor.Sex and age are not statistically related to the incidence of PTMC in BTD. The incidence of PTMC is higher in Hashimoto thyroiditis and patients with total/near-total thyroidectomy; and lower in patients with a SHTN and Graves disease.


PubMed | Institute of Public Health of Serbia, University of Belgrade and Center for Endocrine surgery
Type: Journal Article | Journal: Hippokratia | Year: 2016

In the past decade, the incidence of thyroid cancer (TC) has shown a stable increase, for both sexes, in many parts of the world at a rate faster than for any other type of malignancy. The aim of our study was to analyze and report changes in TC incidence in Serbia, as well as to evaluate potential reasons for these changes. So far, the incidence of TC in Serbia has not been reported.This is a retrospective descriptive epidemiological study of TC data from the Cancer Register for Serbia for a ten year period, from 1999 to 2008. Crude rates (CR), age-specific rates (ASR), age-adjusted rates (AAR), linear trends and average annual percentage changes (AAPC) were calculated and analyzed.TC incidence increased substantially for both genders with the highest increase in 2007 for the age group 50-59 (females 14.2, males 10.3). TC was three times more common in females (CR 4.7:1.5). The AAR for females ranged 1.9-4.8 (3.3, 95% CI 2.6-4.0), for males 1.0-2.6 (1.0, 95% CI 0.8-1.2) and for both sexes combined 1.4-3.2 (2.2, 95% CI 1.7-2.6). The incidence trend for males showed an increase (y =0.05x + 0.70, p =0.058). It was highly statistically significant for females (y =0.31x + 1.61, p <0.001) and both genders combined (y =0.18x + 1.18, p <0.001). AAPC was highest for ages 20-29 and 30-39, for females (+25.2%) and males (+17.3%), respectively.We found a substantial increase in TC incidence in Serbia for both genders. The highest increase in TC incidence was found in females aged 20 to 29 years while the highest incidence was found in the age group 50 to 59.


PubMed | University of Belgrade, Center for Endocrine Surgery and Clinical Center Nis
Type: | Journal: BMC surgery | Year: 2015

Graves disease represents an autoimmune disease of the thyroid gland where surgery has an important role in its treatment. The aim of our paper was to analyze the results of surgical treatment, the frequency of microcarcinoma and carcinoma, as well as to compare surgical complications in relation to the various types of operations performed for Graves disease.We analysed 1432 patients (221 male and 1211 female) who underwent surgery for Graves disease at the Centre for Endocrine Surgery in Belgrade during 15years (1996-2010). Average age was 34.8years. Frequency of surgical complications within the groups was analyzed with nonparametric Fishers test.Total thyroidectomy (TT) was performed in 974 (68%) patients, and Dunhill operation (D) in 221 (15.4). Carcinoma of thyroid gland was found in 146 patients (10.2%), of which 129 (9%) were a microcarcinoma. Complication rates were higher in the TT group, where there were 31 (3.2%) patients with permanent hypoparathyroidism, 9 (0.9%) patients with unilateral recurrent nerve paralysis and 10 (1.0%) patients with postoperative bleeding. Combined complications, such as permanent hypoparathyroidism with bleeding were more common in the D group where there were 2 patients (0,9%), while unilateral recurrent nerve paralysis with bleeding was more common in the TT group where there were 3 cases (0,3%).Frequency of complications were not significantly statistically different in relation to the type of surgical procedure. Total thyroidectomy represents a safe and efficient method for treating patients with Graves disease, and it is not followed by a greater frequency of complications in relation to less extensive procedures.


Klubo-Gwiezdzinska J.,Washington Hospital Center | Jensen K.,Uniformed Services University of the Health Sciences | Costello J.,Uniformed Services University of the Health Sciences | Patel A.,Uniformed Services University of the Health Sciences | And 5 more authors.
Endocrine-Related Cancer | Year: 2012

Medullary thyroid cancer (MTC) is associated with activation of mammalian target of rapamycin (mTOR) signaling pathways. Recent studies showed that the antidiabetic agent metformin decreases proliferation of cancer cells through 5′-AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR. In the current study, we assessed the effect of metformin on MTC cells. For this purpose, we determined growth, viability, migration, and resistance to anoikis assays using two MTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined in MTC cell lines and in 14 human MTC tissue samples. We found that metformin inhibited growth and decreased expression of cyclin D1 in MTC cells. Treatment with metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and downregulation of pERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined. Metformin-inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (compound C) or AMPK silencing did not prevent growth inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration but reduced the ability of cells to form multicellular spheroids in nonadherent conditions. Immunostaining of human MTC showed over-expression of cyclin D1 in all tumors compared with corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1%) examined tumors. Together, these findings indicate that growth inhibitory effects in MTC cells are associated with downregulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin's molecular targets in human MTC cells suggests its potential utility for the treatment of MTC in patients. © 2012 Society for Endocrinology.


Sabljak V.,Center for Endocrine Surgery
Acta chirurgica Iugoslavica | Year: 2011

Preoperative evaluation of patients with thyroid land disease, in any kind of surgery, should include the possibility of difficult intubation caused by thyromegaly, the hormonal status (its disbalance), as well as the screening, and therapy of consequences of thyroid imbalance on specific organ systems, especially cardiovascular. It is necessary to select the adequate anesthetics and other pharmacological agents, according to current hormonal status. It is also necessary to select the adequate medications and other therapeutic measures for prevention and treatment of possible complications in perioperative period, some of which are life-threatening (thyroid storm and mixedema coma).

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