Publications by authors named "Agnieszka Czarniecka"

59 Publications

The assessment of risk factors for long-term survival outcome in ypN0 patients with rectal cancer after neoadjuvant therapy and radical anterior resection.

World J Surg Oncol 2021 May 21;19(1):154. Epub 2021 May 21.

The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-100, Gliwice, Poland.

Background: The main negative prognostic factors in patients with rectal cancer after radical treatment include regional lymph node involvement, lymphovascular invasion, and perineural invasion. However, some patients still develop cancer recurrence despite the absence of the above risk factors. The aim of the study was to assess clinicopathological factors influencing long-term oncologic outcomes in ypN0M0 rectal cancer patients after neoadjuvant therapy and radical anterior resection.

Methods: A retrospective survival analysis was performed on a group of 195 patients. We assessed clinicopathological factors which included tumor regression grade, number of lymph nodes in the specimen, Charlson comorbidity index (CCI), and colorectal anastomotic leakage (AL).

Results: In the univariate analysis, AL and CCI > 3 had a significant negative impact on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). After the division of ALs into early and late ALs, it was found that only patients with late ALs had a significantly worse survival. The multivariate Cox regression analysis showed that CCI > 3 was a significant adverse risk factor for DFS (HR 5.78, 95% CI 2.15-15.51, p < 0.001), DSS (HR 7.25, 95% CI 2.25-23.39, p < 0.001), and OS (HR 3.9, 95% CI 1.72-8.85, p = 0.001). Similarly, late ALs had a significant negative impact on the risk of DFS (HR 5.05, 95% CI 1.97-12.93, p < 0.001), DSS (HR 10.84, 95% CI 3.44-34.18, p < 0.001), and OS (HR 4.3, 95% CI 1.94-9.53, p < 0.001).

Conclusions: Late AL and CCI > 3 are the factors that may have an impact on long-term oncologic outcomes. The impact of lymph node yield on understaging was not demonstrated.
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http://dx.doi.org/10.1186/s12957-021-02262-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140444PMC
May 2021

A Woman with a 27-Year History of Hyperparathyroidism and Hypercalcemia Who Was Diagnosed with Low-Grade Parathyroid Carcinoma.

Am J Case Rep 2021 Mar 11;22:e930301. Epub 2021 Mar 11.

Department of General, Endocrine and Vascular Surgery, Medical University of Warsaw, Warsaw, Poland.

BACKGROUND Parathyroid carcinoma (PC), accounting for 0.005% of all cancers, is responsible for less than 1% of all cases of primary hyperparathyroidism, and equally affects males and females, usually in 4th or 5th decades of life. PC can occur sporadically and can be associated with congenital genetic syndromes such as hyperparathyroidism-jaw tumor syndrome (HPT-JT), isolated familial hyperparathyroidism, or multiple endocrine neoplasia 1 and 2 syndromes. Surgery is the main treatment, with a limited role of radio- and chemotherapy, which allows 49-77% of patients to survive 10 years. In this work we report the case of a patient with parathyroid carcinoma, whose treatment required 13 surgeries over a period of 27 years, together with radiotherapy and pharmacological treatment. CASE REPORT A 51-year-old woman was first diagnosed with primary hyperparathyroidism in 1993 at the age of 23. From 1993 to present, she underwent 13 surgeries and 33 courses of radiotherapy due to recurrent lesions, which initially had a character of parathyroid adenomas, then parathyromatosis, and finally were diagnosed as parathyroid carcinoma. The patient also required and currently requires complex pharmacological treatment to control the calcemia and manage the complications of the primary disease. Supervision by the multidisciplinary professional medical team allows the patient to lead a normal life with good control of the disease. CONCLUSIONS Parathyroid carcinoma is a rare disease with a number of complications; however, obtaining satisfactory long-term survival with acceptable quality of life is achievable.
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http://dx.doi.org/10.12659/AJCR.930301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957837PMC
March 2021

Shared and unique metabolic features of the malignant and benign thyroid lesions determined with use of H HR MAS NMR spectroscopy.

Sci Rep 2021 Jan 14;11(1):1344. Epub 2021 Jan 14.

Department of Medical Physics, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102, Gliwice, Poland.

The purpose of this work was to investigate the distinct and common metabolic features of the malignant and benign thyroid lesions in reference to the non-transformed tissue from the contralateral gland (chronic thyroiditis and colloid goiter). H HR MAS NMR spectra of 38 malignant lesions, 32 benign lesions and 112 samples from the non-tumoral tissue (32 from chronic thyroiditis and 80 samples from colloid goiter) were subjected both to multivariate and univariate analysis. The increased succinate, glutamine, glutathione, serine/cysteine, ascorbate, lactate, taurine, threonine, glycine, phosphocholine/glycerophosphocholine and decreased lipids were found in both lesion types in comparison to either colloid goiter or chronic thyroiditis. The elevated glutamate and choline, and reduced citrate and glucose were additionally evident in these lesions in reference to goiter, while the increased myo-inositol-in comparison to thyroiditis. The malignant lesions were characterized by the higher alanine and lysine levels than colloid goiter and thyroiditis, while scyllo-inositol was uniquely increased in the benign lesions (not in cancer) in comparison to both non-tumoral tissue types. Moreover, the benign lesions presented with the unique increase of choline in reference to thyroiditis (not observed in the cancerous tissue). The metabolic heterogeneity of the non-tumoral tissue should be considered in the analysis of metabolic reprogramming in the thyroid lesions.
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http://dx.doi.org/10.1038/s41598-020-79565-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809111PMC
January 2021

Laparoscopic cortical-sparing adrenal surgery in pheochromocytomas associated with hereditary neoplasia syndromes.

Endokrynol Pol 2020 30;71(6):518-523. Epub 2020 Oct 30.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland.

Introduction: Pheochromocytomas in hereditary syndromes tend to grow multifocal with adrenal involvement on both sides. Surgical treatment with bilateral adrenalectomy inevitably leads to life-long hormonal dependence, which significantly affects quality of life. The development of minimally invasive adrenal surgery has created a chance to preserve adrenal cortex function in these patients. The aim of the present study was to evaluate the safety of laparoscopic cortical-sparing adrenal surgeries and their efficacy in the prevention of postoperative adrenal insufficiency in patients with hereditary pheochromocytomas.

Material And Methods: We retrospectively analysed the medical histories of 10 patients, who underwent 10 laparoscopic cortical sparing adrenal surgeries from January 2015 to January 2019 in our centre. The decision to perform sparing surgery was based on preoperative diagnosis of hereditary syndrome in line with the result of DNA analysis or its diagnosis based on the clinical appearance. All surgeries were performed laparoscopically from transperitoneal access in the lateral decubitus position, with preserving 1/3-1/4 adrenal tissue. The sufficiency of remnant adrenal tissue was assessed in all patients. The median time of follow-up was three years (ranged 0.5-4 years).

Results: No intraoperative complications were observed. One case of acute heart failure was the only early postoperative adverse event. There were no late postoperative complications and no local recurrences observed. In one out of three patients undergoing sparing surgery as a second procedure after former total adrenalectomy, adrenal cortex failure occurred. In all patients after unilateral surgery or after bilateral surgery performed simultaneously (total adrenalectomy at one side and sparing surgery contralaterally), function of remnant adrenal tissue was preserved.

Conclusions: In hereditary pheochromocytomas, with minimal risk of malignant process, laparoscopic cortical sparing adrenal surgeries are the safe approach and provide the chance to preserve adrenal cortex function.
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http://dx.doi.org/10.5603/EP.a2020.0075DOI Listing
October 2020

Current status of the prognostic molecular markers in medullary thyroid carcinoma.

Endocr Connect 2020 Dec;9(12):R251-R263

Nuclear Medicine and Endocrine Oncology Department, M. Sklodowska-Curie Institute National Research Institute of Oncology Gliwice Branch, Gliwice, Poland.

Medullary thyroid cancer (MTC) is a rare thyroid malignancy, which arises from parafollicular C-cells. It occurs in the hereditary or sporadic form. Hereditary type is a consequence of activation of the RET proto-oncogene by germline mutations, whereas about 80% of sporadic MTC tumors harbor somatic, mainly RET or rarely RAS mutations. According to the current ATA guidelines, a postoperative MTC risk stratification and long-term follow-up are mainly based on histopathological data, including tumor stage, the presence of lymph node and/or distant metastases (TNM classification), and serum concentration of two biomarkers: calcitonin (Ctn) and carcinoembryonic antigen (CEA). The type of RET germline mutation also correlates with MTC clinical characteristics. The most common and the best known RET mutation in sporadic MTC, localized at codon 918, is related to a more aggressive MTC course and poorer survival. However, even if histopathological or clinical features allow to predict a long-term prognosis, they are not sufficient to select the patients showing aggressive MTC courses requiring immediate treatment or those, who are refractory to different therapeutic methods. Besides the RET gene mutations, there are currently no other reliable molecular prognostic markers. This review summarizes the present data of genomic investigation on molecular prognostic factors in medullary thyroid cancer.
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http://dx.doi.org/10.1530/EC-20-0374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774764PMC
December 2020

Evaluation of risk factors for postoperative complications in rectal cancer patients.

Pol Przegl Chir 2020 Jul;92(5):1-5

Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology.

<b>Introduction:</b> The complications of surgical treatment for rectal cancer, particularly anastomotic leaks after anterior resection, are a significant clinical problem. We retrospectively analysed preoperative factors that may affect the occurrence of complications. <br><b>Meterial and Methods:</b> A total of 392 rectal cancer patients were included in a retrospective analysis. A total of 257 anterior resections (AR) and 135 abdominoperineal resections (APR) were performed. The risk factors for early postoperative complications were analysed by logistic regression and receiver operating characteristic curves. <br><b>Results:</b> The significant risk factors for severe complications (grade 3B and higher on the Clavien-Dindo scale) in the multivariate analysis were neutrophil to lymphocyte ratio > 5 (P = 0.047) in the AR group, age of the patients (P = 0.031) in the APR group, and coronary artery disease in both groups (P = 0.03, P = 0.011, respectively). There were no risk factors for anastomotic leaks in the AR group before the analysis was divided into early and late leaks. In the univariate analysis, the statistically significant risk factors for early leaks were preoperative neutrophil to lymphocyte ratio > 5 and peripheral blood platelet count, while late leaks were associated with coronary artery disease; however, in the multivariate analysis, these factors were not statistically significant. <br><b>Conclusions:</b> The risk factors for severe postoperative complications were neutrophil to lymphocyte ratio > 5, advanced age of the patients and coronary artery disease. The different risk factors for early and late anastomotic leaks after anterior resection may indicate their different aetiologies.
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http://dx.doi.org/10.5604/01.3001.0014.2871DOI Listing
July 2020

Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients.

World J Surg Oncol 2020 Aug 14;18(1):207. Epub 2020 Aug 14.

The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-100, Gliwice, Poland.

Background: One of the most severe complications of low anterior rectal resection is anastomotic leakage (AL). The creation of a loop ileostomy (LI) reduces the prevalence of AL requiring surgical intervention. However, up to one-third of temporary stomas may never be closed. The first aim of the study was to perform a retrospective assessment of the impact of LI on the risk of permanent stoma (PS) and symptomatic AL. The second aim of the study was to assess preoperative PS risk factors in patients with LI.

Methods: A total of 286 consecutive patients who underwent low anterior rectal resection were subjected to retrospective analysis. In 101 (35.3%) patients, diverting LI was performed due to low anastomosis, while in the remaining 185 (64.7%) patients, no ileostomy was performed. LIs were reversed after adjuvant treatment. Analyses of the effect of LI on symptomatic AL and PS were performed. Among the potential risk factors for PS, clinical factors and the values of selected peripheral blood parameters were analysed.

Results: PS occurred in 37.6% and 21.1% of the patients with LI and without LI, respectively (p < 0.01). Symptomatic ALs were significantly more common in patients without LI. In this group, symptomatic ALs occurred in 23.8% of patients, while in the LI group, they occurred in 5% of patients (p < 0.001). In the LI group, the only significant risk factor for PS in the multivariate analysis was preoperative plasma fibrinogen concentration (OR = 1.007, 97.5% CI 1.002-1.013, p = 0.013).

Conclusions: Although protective LI may reduce the incidence of symptomatic AL, it can be related to a higher risk of PS in this group of patients. The preoperative plasma fibrinogen concentration can be a risk factor for PS in LI patients and may be a useful variable in decision-making models.
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http://dx.doi.org/10.1186/s12957-020-01979-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427951PMC
August 2020

Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma-Do They Exist?

Int J Mol Sci 2020 Jun 29;21(13). Epub 2020 Jun 29.

Nuclear Medicine and Endocrine Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-101 Gliwice, Poland.

Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A-U133, set B-HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis (GSEA)). An additional independent set of 63 PTCs, including 9 M1 cases, was used to validate results by qPCR. The analysis on dataset A detected eleven transcripts showing significant differences in expression between metastatic and non-metastatic PTC. These genes were validated on microarray dataset B. The differential expression was positively confirmed for only two genes: (most significant) and . However, when analyzed on an independent dataset by qPCR, the gene showed no differences in expression. Gene group analysis showed differences mainly among immune-related transcripts, indicating the potential influence of tumor immune infiltration or signal within the primary tumor. The differences in gene expression profile between metastatic and non-metastatic PTC, if they exist, are subtle and potentially detectable only in large datasets.
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http://dx.doi.org/10.3390/ijms21134629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369779PMC
June 2020

Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma.

Cancers (Basel) 2020 Jun 17;12(6). Epub 2020 Jun 17.

Department of Genetic and Molecular Diagnostics of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland.

Background: Telomerase reverse transcriptase promoter (p) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of p mutations in PTC was the aim of our study.

Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. V600E, and p mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(-) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis.

Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(-) PTCs. Deregulation of pathways involved in key cell processes was observed.

Conclusions: p mutations are related to higher PTC aggressiveness. gene was validated as associated with p mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.
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http://dx.doi.org/10.3390/cancers12061597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352936PMC
June 2020

Impact of the Tumor Microenvironment on the Gene Expression Profile in Papillary Thyroid Cancer.

Pathobiology 2020 22;87(2):143-154. Epub 2020 Apr 22.

Nuclear Medicine and Endocrine Oncology Department, M. Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland.

Transcriptome of papillary thyroid cancer (PTC) is well characterized and correlates with some prognostic and genotypic factors, but data addressing the interaction between PTC and tumor microenvironment (TME) are scarce. Therefore, in the present study, we aimed to assess the impact of TME on gene expression profile in PTC. We evaluated the gene expression profile in PTC and normal thyroid cells isolated by laser capture microdissection and in whole tissue slides corresponding to the entire tumor. We included 26 microdissected samples for gene expression analysis (HG-U133 PLUS 2.0, Affymetrix, currently Thermo Fisher Scientific USA): 15 PTC samples, 11 samples of normal thyrocytes, and 30 whole slides (15 PTC and 15 normal thyroid). Transcripts were divided into three groups: differentially expressed both in microdissected and whole slides, transcripts differently expressed in microdissected samples and not changed in whole slides, and transcripts differentially expressed in whole slides and not changed in microdissected samples. Eleven genes were selected for validation in an independent set of samples; among them, four genes differentiated only microdissected PTC and normal cells. Two genes (PTCSC and CTGF) were confirmed. One gene (FOS) was not confirmed by the validation, whereas EGR1 was also significant in whole slide analysis. The other seven genes (TFF3, FN1, MPPED2, MET, KCNJ2, TACSTD2, and GALE) showed differentiated expression in microdissected thyrocytes and in whole tumor slides. Most of identified genes were related to the tumor-microenvironment interaction and confirmed the crosstalk between TME and cancer cells.
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http://dx.doi.org/10.1159/000507223DOI Listing
April 2021

Clinical validation of S-Detect mode in semi-automated ultrasound classification of thyroid lesions in surgical office.

Gland Surg 2020 Feb;9(Suppl 2):S77-S85

Department of Endocrine Surgery, Third Chair of General Surgery, Jagiellonian University Medical College, Kraków, Poland.

Background: In recent years well-recognized scientific societies introduced guidelines for ultrasound (US) malignancy risk stratification of thyroid nodules. These guidelines categorize the risk of malignancy in relation to a combination of several US features. Based on these US image lexicons an US-based computer-aided diagnosis (CAD) systems were developed. Nevertheless, their clinical utility has not been evaluated in any study of surgeon-performed office US of the thyroid. Hence, the aim of this pilot study was to validate s-Detect mode in semi-automated US classification of thyroid lesions during surgeon-performed office US.

Methods: This is a prospective study of 50 patients who underwent surgeon-performed thyroid US (basic US skills without CAD with CAD expert US skills without CAD) in the out-patient office as part of the preoperative workup. The real-time CAD system software using artificial intelligence (S-Detect for Thyroid; Samsung Medison Co.) was integrated into the RS85 US system. Primary outcome was CAD system added-value to the surgeon-performed office US evaluation. Secondary outcomes were: diagnostic accuracy of CAD system, intra and interobserver variability in the US assessment of thyroid nodules. Surgical pathology report was used to validate the pre-surgical diagnosis.

Results: CAD system added-value to thyroid assessment by a surgeon with basic US skills was equal to 6% (overall accuracy of 82% for evaluation with CAD 76% for evaluation without CAD system; P<0.001), and final diagnosis was different than predicted by US assessment in 3 patients (1 more true-positive and 2 more true-negative results). However, CAD system was inferior to thyroid assessment by a surgeon with expert US skills in 6 patients who had false-positive results (P<0.001).

Conclusions: The sensitivity and negative predictive value of CAD system for US classification of thyroid lesions were similar as surgeon with expert US skills whereas specificity and positive predictive value were significantly inferior but markedly better than judgement of a surgeon with basic US skills alone.
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http://dx.doi.org/10.21037/gs.2019.12.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044084PMC
February 2020

European perspective on the use of molecular tests in the diagnosis and therapy of thyroid neoplasms.

Gland Surg 2020 Feb;9(Suppl 2):S69-S76

The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice Branch, Gliwice, Poland.

Thyroid nodules are frequently observed, particularly in individuals of over 60 years of age. On the other hand, most of the detected changes are benign and they do not require surgery. Therefore, differentiation between benign and malignant lesions in preoperative diagnosis is of crucial importance. Currently, the use of fine-needle aspiration biopsy (FNAB) and cytological assessment are the gold standard in the diagnosis of thyroid nodules. This procedure significantly reduces the need for diagnostic surgical intervention. However, approximately 15-30% of cytological results are classified as indeterminate. This is mainly due to the lack of specific cytomorphologic features that would facilitate the diagnosis based on cell evaluation under microscopic assessment. For the diagnoses of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), the assessment of invasion is crucial. Such an evaluation is not possible in cytology. Recently, molecular tests have been developed. They improve cytological diagnosis, particularly in the case of indeterminate results. Commercially available tests are developed based on the North American population. It is important to assess whether such tests can be used in the evaluation of e.g., European population.
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http://dx.doi.org/10.21037/gs.2019.10.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044080PMC
February 2020

BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma.

Eur J Cancer 2020 01 29;124:161-169. Epub 2019 Nov 29.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management.

Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months).

Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC.

Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.
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http://dx.doi.org/10.1016/j.ejca.2019.10.017DOI Listing
January 2020

Postoperative Radioiodine Treatment within 9 Months from Diagnosis Significantly Reduces the Risk of Relapse in Low-Risk Differentiated Thyroid Carcinoma.

Nucl Med Mol Imaging 2019 Oct 5;53(5):320-327. Epub 2019 Sep 5.

Nuclear Medicine and Endocrine Oncology Department, M.Sklodowska-Curie Institute-Oncology Center, Gliwice Branch, Wybrzeze AK 15, 44-101 Gliwice, Poland.

Purpose: Although postoperative radioiodine (RAI) therapy has been used in patients with differentiated thyroid carcinoma (DTC) for many years, there is still lack of data defining the timing of RAI administration. A retrospective analysis was carried out to answer the question whether the time of postoperative RAI treatment demonstrated any impact on long-term outcomes, particularly in low-risk DTC.

Material: The analyzed group involved 701 DTC patients staged pT-TN-NM, who underwent total thyroidectomy and postoperative RAI therapy. According to the time interval between DTC diagnosis and RAI administration, patients were allocated to one of three groups: up to 9 months ( = 150), between 9 and 24 months ( = 323), and > 24 months ( = 228). Median follow-up was 12.1 years (1.5-15.2).

Results: Based on an initial DTC advancement and postoperative stimulated thyroglobulin concentration patients were stratified as a low-, intermediate-, and high-risk group. Low-risk patients, who received RAI therapy up to 9 months, demonstrated significantly lower risk of relapse comparing to those, in whom RAI was administered between 9 and 24 months and after 24 months since DTC diagnosis: 0%, 5.5%, and 7.1%, respectively. Regarding intermediate- and high-risk groups, the differences in the timing of postoperative RAI treatment were not significant.

Conclusion: If postoperative RAI treatment is considered in low-risk DTC, any delay in RAI administration above 9 months since diagnosis may be related to poorer long-term outcomes.
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http://dx.doi.org/10.1007/s13139-019-00608-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821904PMC
October 2019

Current surgical management in RET mutation carriers [Aktualne postępowanie chirurgiczne u nosicieli mutacji proto-onkogenu RET].

Endokrynol Pol 2019 ;70(4):367-379

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Centre Gliwice Branch, Gliwice, Poland.

Medullary thyroid carcinoma (MTC) still remains a rare endocrine tumor. 20-25% of MTC cases are genetically determined. The detection of the RET proto-oncogene mutation in 1993 allowed to understand the unique genotype-phenotype relationships in hereditary medullary thyroid carcinoma (HMTC) and formed the basis for therapeutic decisions based on the molecular results. Currently, prophylactic thyroidectomy is a commonly adopted and accepted therapeutic method. The decision on the time and extent of surgery should be made based on the results of molecular examination, the assessment of calcitonin (Ct) concentration and family history. Treatment of patients with HMTC requires the cooperation of a multidisciplinary team of experts and should be done in specialized centers only. The study is a review of the current guidelines for surgical management in the MEN2 syndrome.
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http://dx.doi.org/10.5603/EP.a2019.0021DOI Listing
February 2020

Surgical approach to differentiated thyroid cancers (DTC) in children [Specyfika leczenia chirurgicznego zróżnicowanych raków tarczycy (ZRT) u dzieci].

Endokrynol Pol 2019 ;70(4):357-366

Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Institute - Oncology Centre, Gliwice, Poland.

Thyroid cancer in children is rare and accounts for 1-3% of all malignant tumours. Differentiated thyroid cancers (DTC) and particularly papillary thyroid carcinoma (PTC) (90% of cases) are the most prevalent. Surgery is the mainstay of treatment in patients with DTC. The current recommendations are based not on prospective randomised clinical trials, but on retrospective trials and expert opinions. Therefore, it is not easy to choose the optimal therapeutic strategy to obtain the best treatment and to avoid serious complications and adverse events. In children and adolescents, the clinical presentation, course, and prognosis are different from those seen in adults. Children are generally at low risk of death but at higher risk of long-term harm due to overly aggressive treatment. Therefore, optimisation of the therapeutic strategy is particularly important. The present paper provides a summary of the current guidelines on surgical management in thyroid tumours and DTC in children and adolescents.
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http://dx.doi.org/10.5603/EP.a2019.0033DOI Listing
February 2020

Novel TG-FGFR1 and TRIM33-NTRK1 transcript fusions in papillary thyroid carcinoma.

Genes Chromosomes Cancer 2019 08 18;58(8):558-566. Epub 2019 Feb 18.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland.

Papillary thyroid carcinoma (PTC) is most common among all thyroid cancers. Multiple genomic alterations occur in PTC, and gene rearrangements are one of them. Here we screened 14 tumors for novel fusion transcripts by RNA-Seq. Two samples harboring RET/PTC1 and RET/PTC3 rearrangements were positive controls whereas the remaining ones were negative regarding the common PTC alterations. We used Sanger sequencing to validate potential fusions. We detected 2 novel potentially oncogenic transcript fusions: TG-FGFR1 and TRIM33-NTRK1. We detected 4 novel fusion transcripts of unknown significance accompanying the TRIM33-NTRK1 fusion: ZSWIM5-TP53BP2, TAF4B-WDR1, ABI2-MTA3, and ARID1B-PSMA1. Apart from confirming the presence of RET/PTC1 and RET/PTC3 in positive control samples, we also detected known oncogenic fusion transcripts in remaining samples: TFG-NTRK1, ETV6-NTRK3, MKRN1-BRAF, EML4-ALK, and novel isoform of CCDC6-RET.
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http://dx.doi.org/10.1002/gcc.22737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594006PMC
August 2019

Coexistence of Promoter Mutations and the V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients.

Int J Mol Sci 2018 Sep 6;19(9). Epub 2018 Sep 6.

Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie Institute, Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland.

promoter (p) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of p mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the V600E mutation. A total of 189 consecutive PTC specimens with known mutational status were evaluated. p mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional p alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the p hotspot mutations were highly correlated with the presence of the V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of p mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.
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http://dx.doi.org/10.3390/ijms19092647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163174PMC
September 2018

BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer.

J Clin Oncol 2018 09 2;36(27):2787-2795. Epub 2018 Aug 2.

Fei Wang, Shihua Zhao, and Yangang Wang, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Fei Wang, Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto Auxologico Italiano, Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Institute Oncology Center, Gliwice, Poland; Alfred K. Lam, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols" and Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
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http://dx.doi.org/10.1200/JCO.2018.78.5097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145834PMC
September 2018

Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update.

Endokrynol Pol 2018 ;69(1):34-74

Nuclear Medicine and Endocrine Oncology Department; M.Sklodowska-Curie Memorial Institute - Cancer Center, Gliwice Branch, Wybrzeze AK 15, 44-100 Gliwice, Poland; Zakład Medycyny Nuklearnej i Endokrynologii Onkologicznej, Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie, Oddział w Gliwicach, Wybrzeże AK 15, 44-100 Gliwice, Poland.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisła in November 2015 [1].
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http://dx.doi.org/10.5603/EP.2018.0014DOI Listing
July 2018

Heterogeneity of Thyroid Cancer.

Pathobiology 2018 6;85(1-2):117-129. Epub 2018 Feb 6.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, Gliwice, Poland.

There are 5 main histological types of thyroid cancers (TCs): papillary, follicular (also known as differentiated), poorly differentiated, anaplastic (the most aggressive form), and medullary TC, and only the latter arises from thyroid C cells. These different forms of TCs show significant variability, both among and within tumours. This great variation is particularly notable among the first 4 types, which all originate from thyroid follicular cells. Importantly, this heterogeneity is not limited to histopathological diversity only but is also manifested as variation in several genetic and/or epigenetic alterations, the numbers of interactions between the tumour and surrounding microenvironment, and interpatient differences, for example. All these factors contribute to the great complexity in the development of a tumour from cancer cells. In the present review, we summarise the knowledge accumulated about the heterogeneity of TCs. Further research in this direction should help to gain a better understanding of the underlying mechanisms contributing to the development and diversity of TCs, paving the way toward more effective treatment strategies.
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http://dx.doi.org/10.1159/000486422DOI Listing
October 2018

Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer.

J Clin Oncol 2018 02 14;36(5):438-445. Epub 2017 Dec 14.

Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; Alfred K. Lam, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, The University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh School of Medicine, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Ciberonc, Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
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http://dx.doi.org/10.1200/JCO.2017.74.5497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807010PMC
February 2018

BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment.

J Natl Cancer Inst 2018 04;110(4):362-370

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.

Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.

Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.

Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
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http://dx.doi.org/10.1093/jnci/djx227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658860PMC
April 2018

Current Advances in Thyroid Cancer Management. Are We Ready for the Epidemic Rise of Diagnoses?

Int J Mol Sci 2017 Aug 22;18(8). Epub 2017 Aug 22.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Institute-Cancer Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland.

A rising incidence of thyroid cancers (TCs) mainly small tumors, observed during recent years, lead to many controversies regarding treatment strategies. TCs represent a distinct molecular background and clinical outcome. Although in most cases TCs are characterized by a good prognosis, there are some aggressive forms, which do not respond to standard treatment. There are still some questions, which have to be resolved to avoid dangerous simplifications in the clinical management. In this article, we focused on the current advantages in preoperative molecular diagnostic tests and histopathological examination including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We discussed the controversies regarding the extent of thyroid surgery and adjuvant radioiodine therapy, as well as new treatment modalities for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Considering medullary thyroid cancer (MTC), we analyzed a clinical management based on histopathology and (ret proto-oncogene) mutation genotype, disease follow-up with a special attention to serum calcitonin doubling time as an important prognostic marker, and targeted therapy applied in advanced MTC. In addition, we provided some data regarding anaplastic thyroid cancer (ATC), a highly lethal neoplasm, which lead to death in nearly 100% of patients due to the lack of effective treatment options.
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http://dx.doi.org/10.3390/ijms18081817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578203PMC
August 2017

Age at diagnosis and gender modify the risk of 9q22 and 14q13 polymorphisms for papillary thyroid carcinoma.

Endokrynol Pol 2017 ;68(3):283-289

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Poland, Poland.

Introduction: Papillary thyroid cancer (PTC) shows familial occurrence, and some susceptibility single nucleotide polymorphisms (SNPs) have been identified in FOXE1 and near the NKX2-1 locus. The aim of our study was to analyse the association of PTC risk with SNPs in FOXE1 (rs965513, rs1867277, rs1443434) and near the NKX2-1 locus (rs944289) in a Polish population, and, in the second step, the interac-tion between SNPs and patient-related factors (age at diagnosis and gender).

Material And Methods: A total of 2243 DNA samples from PTC patients and 1160 controls were included in the study. The SNP analysis was performed with the allelic discrimination technique.

Results: There were significant associations of all SNPs with PTC (rs965513 odds ratio [OR] = 1.72, p = 8 × 10-7; rs1867277 OR = 1.59, p = 1 × 10-6; rs1443434 OR = 1.53, p = 1 × 10-5; rs944289 OR = 1.52, p = 4 × 10-5). Logistic regression analysis revealed an increased PTC risk in the interaction of rs944289 with age at diagnosis (OR = 1.01 per year, p = 6 × 10-4) and a decreased PTC risk in the interaction of male gender with the GGT FOXE1 protective haplotype (OR = 0.69, p = 0.01).

Conclusions: the association between PTC and all analysed SNPs was confirmed. It was also shown that patient-related factors modify the predisposition to PTC by increasing the risk for rs944289 per year of age, and by enhancing the protective effect of the FOXE1 GGT haplotype in men.
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http://dx.doi.org/10.5603/EP.2017.0021DOI Listing
December 2017

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer.

J Clin Endocrinol Metab 2017 09;102(9):3241-3250

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.

Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC.

Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation.

Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database.

Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.
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http://dx.doi.org/10.1210/jc.2017-00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587077PMC
September 2017

Gene Expression (mRNA) Markers for Differentiating between Malignant and Benign Follicular Thyroid Tumours.

Int J Mol Sci 2017 Jun 2;18(6). Epub 2017 Jun 2.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland.

Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (, , , , , , and ). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (, , , ). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin-fixed postoperative material.
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http://dx.doi.org/10.3390/ijms18061184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486007PMC
June 2017

Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations.

Sci Rep 2017 02 9;7:42074. Epub 2017 Feb 9.

Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland.

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.
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http://dx.doi.org/10.1038/srep42074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299608PMC
February 2017

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy.

Folia Histochem Cytobiol 2016 4;54(4):202-209. Epub 2017 Jan 4.

3rd Department of Radiotherapy and Chemotherapy, Breast Cancer Center, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.

Introduction: Prediction of response to preoperative breast cancer chemotherapy may offer a substantial optimization of medical management of this disease. The most efficient prediction would be done a priori, before the start of chemotherapy and based on the biological features of patient and tumor. Numerous markers have been proposed but none of them has been applied as a routine. The role of MKI67 and HSP90 expression has been recently suggested to predict treatment sensitivity in HER2-positive breast cancer. The aim of this study was to validate the utility of proliferation based markers (MKI67 and CDK1) and heat shock proteins (namely HSP90) to predict response to chemotherapy in cohort of breast cancer patients treated preoperatively.

Material And Methods: Ninety-three patients with breast cancer, all females, mean age 42.2 years, among them 32% T1-T2 patients, 49% T3 patients and 13% with T4 tumor stage, 27% N0, 42% N1, 16% N2, 15% N3 were subjected to initial chemotherapy. The majority of patients (86%) received anthracycline and taxane chemotherapy. Among the patients there were 9 individuals with metastatic disease (M1) at initial presentation, and 11 patients were not treated surgically after initial chemotherapy (no sufficient disease response). From 82 patients operated on, 20 patients (24%) showed pathological complete response (pCR), while in 62 patients there was no pCR. 42% of patients were hormone-sensitive HER2-negative, 20% hormone-sensitive HER2-positive, 9% only HER-positive and 29% with triple negative breast cancer. Four gene transcripts (MKI67, cyclin-dependent kinase 1 [CDK1], heat shock proteins HSP90AA1 and HSP- 90AB1) were analyzed in total RNA isolated from single core obtained during preoperative core needle biopsy by quantitative real-time PCR with fluorescent probes (Universal Probe Library, Roche). Results were normalized to the panel of reference genes.

Results: There were no statistically significant differences in MKI67 and CDK1 expression between pCR and no pCR groups (p = 0.099 and 0.35, respectively), although the median expression of both genes was slightly higher in pCR group. In contrast, both HSP90AA1 and HSP90AB1 transcripts showed decreased expression in pCR group (medians 0.77 and 0.55) when compared to no p CR group (median 0.86 and 0.73), statistically significant for HSP90AA1 (p = 0.031) and of borderline significance for HSP90AB1 (p = 0.054). The most significant predictor of pCR was the ratio of CDK1 transcript to HSP90AA transcript. This ratio was significantly higher in CR group (median 0.99) than in no CR group (median 0.68, p = 0.0023), and showed a potential diagnostic utility (area under receiver operating characteristic [ROC] curve 0.72).

Conclusions: HSP90AA1 and AB1 genes exhibit low expression in breast cancers highly sensitive to chemotherapy and may indicate the patients with higher probability of pathological complete response. The ratio of HSP90AA1 to proliferation-related markers (CDK1 or MKI67) may be even better predictor of pCR chance, with higher expression of proliferation genes and lower stress response in patients sensitive to chemotherapy.
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http://dx.doi.org/10.5603/FHC.a2016.0026DOI Listing
March 2017