Publications by authors named "Michał Jarząb"

66 Publications

Thyroid nodules with indeterminate cytopathology: a constant challenge in everyday practice. The effectiveness of clinical decisions using diagnostic tools available in Poland.

Pol Arch Intern Med 2021 Oct 11. Epub 2021 Oct 11.

Introduction: A crucial issue in the management of thyroid nodules is to estimate, as accurately as possible, the malignancy risk in thyroid lesions. The key tool for risk stratification is fine needle aspiration biopsy. Unfortunately, approximately 20 % of biopsy results are indeterminate. The malignancy risk assigned to these categories does not allow unequivocal further management.

Objectives: We aimed to assess the malignancy risk in indeterminate thyroid nodules in the Polish population, and to analyze the effectiveness of clinical decisions after an indeterminate cytological diagnosis in Polish clinical practice.

Patients And Methods: The retrospective analysis included 222 indeterminate thyroid nodules in 222 patients. The ultrasound features were assessed from scans preceding a thyroid biopsy. Cytology results were classified according to the Bethesda system. The nature of the thyroid nodule was determined on the basis of a histopathological analysis or follow up.

Results: The analyzed cohort included 82 lesions in Bethesda category III, 75 in Bethesda category IV and 65 in Bethesda category V. The malignancy risk, estimated on the basis of histological verification and surveillance was 6.7% for Bethesda III, 11.3% for Bethesda IV and 70.3%for Bethesda V category. An ultrasound pattern was not effective enough for refining the malignancy risk after obtaining an indeterminate cytopathology result. In the case of surgery, postoperative hypoparathyroidism was significantly more frequent following more extensive surgical procedures.

Conclusions: Majority of Polish patients with thyroid nodules assigned to cytological categories Bethesda III and IV is overtreated using diagnostic tools currently available in Poland.
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http://dx.doi.org/10.20452/pamw.16117DOI Listing
October 2021

Two professions against two killer diseases: the rationale, organization, and initial experience of a cardio-oncology service.

Kardiol Pol 2021 02 4;79(2):139-146. Epub 2020 Nov 4.

Background: Cardiovascular diseases are the most common factor affecting prognosis in cancer survivors. Cardio‑oncology (CO) services have been developed to solve this issue. The outcomes regarding patient demographics and clinical findings are limited and the available data include CO services evaluating patients undergoing only chemotherapy as opposed to those also undergoing radiation therapy.

Aims: We aimed to show initial experiences of the CO service implemented in a tertiary oncology center.

Methods: The CO service was designed to include 2 major domains, general CO and electrotherapy consultations. This observational study included patients referred to the CO service with the following data: baseline demographics, cancer type, reasons for referral, cardiac evaluation, and initial clinical outcomes.

Results: All patients with cancer referred to our CO service between March 2016 and December 2019 were included in the study. A total of 2762 patients (77% women) at the mean (SD) age of 62 (12) years were referred (63% on an out‑patient basis) for general consultations. The most frequent diagnosis was breast cancer (66%). A total of 18% of patients were referred to the CO service due to cardiovascular complications related to cancer treatment. The CO-cardiac implantable electronic device (CIED) team evaluated 652 patients (515 patients with CIEDs who were qualified for radiotherapy, 48 patients with CIEDs who were assessed with magnetic resonance imaging, and 89 patients with CIEDs who underwent cancer surgery). In the total of 5872 radiotherapy sessions, there were 2 harmful interactions; no other complications during magnetic resonance imaging and surgery were recorded.

Conclusions: The CO‑service established within the cancer center seems to be safe and feasible.
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http://dx.doi.org/10.33963/KP.15674DOI Listing
February 2021

New RNA Structural Elements Identified in the Coding Region of the Coxsackie B3 Virus Genome.

Viruses 2020 10 30;12(11). Epub 2020 Oct 30.

Institute of Bioorganic Chemistry Polish Academy of Sciences, Zygmunta Noskowskiego 12/14, 61-704 Poznań, Poland.

Here we present a set of new structural elements formed within the open reading frame of the virus, which are highly probable, evolutionarily conserved and may interact with host proteins. This work focused on the coding regions of the CVB3 genome (particularly the V4-, V1-, 2C-, and 3D-coding regions), which, with the exception of the -acting replication element (CRE), have not yet been subjected to experimental analysis of their structures. The SHAPE technique, chemical modification with DMS and RNA cleavage with Pb, were performed in order to characterize the RNA structure. The experimental results were used to improve the computer prediction of the structural models, whereas a phylogenetic analysis was performed to check universality of the newly identified structural elements for twenty CVB3 genomes and 11 other enteroviruses. Some of the RNA motifs turned out to be conserved among different enteroviruses. We also observed that the 3'-terminal region of the genome tends to dimerize in a magnesium concentration-dependent manner. RNA affinity chromatography was used to confirm RNA-protein interactions hypothesized by database searches, leading to the discovery of several interactions, which may be important for virus propagation.
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http://dx.doi.org/10.3390/v12111232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692623PMC
October 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

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

The Association of SNPs Located in the CDKN2B-AS1 and LPA Genes With Carotid Artery Stenosis and Atherogenic Stroke.

Front Neurol 2019 22;10:1170. Epub 2019 Nov 22.

Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland.

The aim of this project was to assess the prevalence of four selected SNPs rs4977574 and rs7857345 (CDKN2B-AS1 gene) and rs3798220 and rs10455872 polymorphisms (the LPA gene) in the subpopulation of patients with symptomatic and asymptomatic carotid stenosis. This study included 623 individuals (244 patients with symptomatic carotid artery stenosis, 176 patients with asymptomatic carotid artery stenosis and 203 healthy people. All the participants underwent neurological examination, duplex Doppler ultrasound examination and molecular procedures. In the first part of the analysis the assiociation of SNPs with stroke/TIA was investigated. The association was seen in symptomatic vs. control group for two SNPs: rs4977574 and rs7857345 (CDKN2B-AS1 gene); genotype distributions for rs4977574 and rs7857345 showed the statistically significant differences between patients and controls ( = 0.043 and 0.017, respectively). No association was observed for rs3798220 and rs10455872 located in the LPA gene. There were statistically significant differences between asymptomatic patients vs. control group in genotype distribution for the SNPs located in CDKN2B-AS1: rs4977574 and rs7857345 ( = 0.031 and 0.0099, respectively); and for the rs3798220 (LPA gene; = 0.003); however, statistically significant differences did not occur for the rs10455872 polymorphism located in the LPA gene. In the next part of the evaluation, a comparison between symptomatic and asymptomatic patients was performed. Significant differences in genotype distribution were seen only for the rs3798220 polymorphism located in the LPA gene ( = 0.0015). The analysis of the prevalence of the polymorphisms in the total group (symptomatic and asymptomatic) patients in comparison with the control group showed significant differences for three polymorphisms: rs4977574 and rs7857345 (CDKN2B-AS1 gene; = 0.015 and 0.0046, respectively) and rs3798220 (LPA gene, = 0.044). The present research on the carotid artery stenosis patient cohort suggests the significant association between the rs4977574, rs7857345 and rs3798220 polymorphisms and carotid artery stenosis as well as between the rs4977574 and rs7857345 polymorphisms and atherogenic stroke. The rs4977574 and rs7857345 polymorphisms in patients with carotid artery stenosis appear to affect a person's susceptibility to atherogenic brain ischemia. Our results need to be replicated in future studies.
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http://dx.doi.org/10.3389/fneur.2019.01170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883000PMC
November 2019

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

Association of breast cancer grade with response to neoadjuvant chemotherapy assessed postoperatively.

Pol J Pathol 2019 ;70(2):91-99

Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong Province, People's Republic of China.

Currently, breast cancer chemotherapy response can be predicted based on various parameters, with common reporting of tumour grade and Ki67 proliferation index. We analysed their association with pathological complete response (pCR) in a multivariate approach. The study was carried out in a group of 353 patients, treated by preoperative chemotherapy and prospectively observed. In selected patients, parallel to routing core needle biopsy assessment, gene expression profile of tumour was analysed by oligonucleotide microarrays. Tumour parameters associated with pCR in univariate analysis were: tumour grade, nuclear grade, mitotic index, Ki67, oestrogen and progesterone receptor (all p < 0.0001), and triple-negative status (p = 0.0032). The highest increase of pCR chance was observed in patients with high-grade tumours and with Ki67 ≥ 20%. In multivariate analysis, only tumour grade and oestrogen receptor status were predictive for pCR independently of other variables, with high grade increasing the odds of pCR 2.42 fold, and high ER decreasing the chance of pCR 0.41 fold. Tumour grading reflects important biological features of breast cancer and is not inferior to proliferation markers, including Ki67. It should be taken into account in decision-making for preoperative chemotherapy in parallel to breast cancer biologic subtypes, because grade 3 tumours exhibit a higher proportion of pCR.
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http://dx.doi.org/10.5114/pjp.2019.87101DOI Listing
October 2019

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

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

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

Pancreatic neuroendocrine neoplasms - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):169-197

This article presents updated diagnostic and therapeutic guidelines for the management of pancreatic neuroendocrine tumours (PNEN), proposed by the Polish Network of Neuroendocrine Tumours. The guidelines contain new data received in the years 2013-2016, which confirm previous recommendations, and have led to modification of previous guidelines or have resulted in the formulation of new guidelines. Biochemical and imaging (anatomical and functional) tests are of great importance in diagnostics, as well as histopathological diagnosis to determine the management of PNEN patients, but they must be confirmed by an immunohistochemical examination. PNEN therapy requires collaboration among the members a multidisciplinary team of specialists experienced in the management of these neoplasms. Surgery is the basic form of treatment in many cases. Further therapy requires a multidirectional procedure; therefore, the rules of biotherapy, peptide receptor radionuclide therapy, molecular targeted therapy, and chemotherapy are discussed.
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http://dx.doi.org/10.5603/EP.2017.2016DOI Listing
July 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

Brain Metastasis Prediction by Transcriptomic Profiling in Triple-Negative Breast Cancer.

Clin Breast Cancer 2017 Apr 8;17(2):e65-e75. Epub 2016 Sep 8.

Department of Pathology, Medical University of Gdańsk, Gdańsk, Poland.

Background: Triple-negative breast cancer (TNBC) lacks expression of steroid hormone receptors (estrogen receptor α and progesterone) and epidermal growth factor receptor type 2. This phenotype shows high metastatic potential, with particular predilection to lungs and brain. Determination of TNBC transcriptomic profiles associated with high risk of brain metastasis (BM) might identify patients requiring alternative, more aggressive, or specific preventive and therapeutic approaches.

Patients And Methods: Using a cDNA-mediated annealing, selection, extension, and ligation assay, we investigated expression of 29,369 gene transcripts in primary TNBC tumor samples from 119 patients-71 in discovery cohort A and 48 in independent cohort B-that included best discriminating genes. Expression of mRNA was correlated with the occurrence of symptomatic BM.

Results: In cohort A, the difference at the noncorrected P < .005 was found for 64 transcripts (P = .23 for global test), but none showed significant difference at a preset level of false-discovery rate of < 10%. Of the 30 transcripts with the largest differences between patients with and without BM in cohort A, none was significantly associated with BM in cohort B.

Conclusion: Analysis based on the primary tumor gene transcripts alone is unlikely to predict BM development in advanced TNBC. Despite its negative findings, the study adds to the knowledge on the biology of TNBC and paves the way for future projects using more advanced molecular assays.
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http://dx.doi.org/10.1016/j.clbc.2016.08.008DOI Listing
April 2017

Somatic mutation profiling of follicular thyroid cancer by next generation sequencing.

Mol Cell Endocrinol 2016 09 6;433:130-7. Epub 2016 Jun 6.

Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland; Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Warsaw, Poland. Electronic address:

The molecular etiology of follicular thyroid tumors is largely unknown, rendering the diagnostics of these tumors challenging. The somatic alterations present in these tumors apart from RAS gene mutations and PAX8/PPARG translocations are not well described. To evaluate the profile of somatic alteration in follicular thyroid tumors, a total of 82 thyroid tissue samples derived from 48 patients were subjected to targeted Illumina HiSeq next generation sequencing of 372 cancer-related genes. New somatic alterations were identified in oncogenes (MDM2, FLI1), transcription factors and repressors (MITF, FLI1, ZNF331), epigenetic enzymes (KMT2A, NSD1, NCOA1, NCOA2), and protein kinases (JAK3, CHEK2, ALK). Single nucleotide and large structural variants were most and least frequently identified, respectively. A novel translocation in DERL/COX6C was detected. Many somatic alterations in non-coding gene regions with high penetrance were observed. Thus, follicular thyroid tumor somatic alterations exhibit complex patterns. Most tumors contained distinct somatic alterations, suggesting previously unreported heterogeneity.
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http://dx.doi.org/10.1016/j.mce.2016.06.007DOI Listing
September 2016

Mouse models of papillary thyroid carcinoma - short review.

Endokrynol Pol 2016 ;67(2):212-23

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

Thyroid carcinoma (TC) is the most common endocrine malignancy, and its frequency is still rising. Papillary thyroid carcinoma (PTC) accounts for 80% of all TCs and usually is related to a very good prognosis. However, the standard therapeutic approaches are not always sufficient and disease progression is sometimes observed. These data highlight the limitation of our understanding of molecular mechanisms underlying tumorigenesis and how they vary between individual patients. Over the last 19 years mouse models of thyroid cancers have been developed in order to give answers to questions about their genetic background, relations of key molecular events with pathways fundamental for cancer, and many others. Among these models genetically engineered mice were of utmost importance regarding the input of knowledge about human tumorigenesis. In the present review the most significant mouse models of PTC are described with particular emphasis on BRAFV600E-induced ones, for the sake of its frequency in PTC, relation to factors of poor prognosis, and the fact that, since its identification, it became an attractive target in novel therapies. For the presented mouse models phenotype consequences of particular genetic alterations are described as well as the limitations of the used methods.
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http://dx.doi.org/10.5603/EP.a2016.0042DOI Listing
March 2017

Molecular classification of pituitary adenomas: in search for criteria useful for high-throughput studies.

Endokrynol Pol 2016 17;67(2):148-56. Epub 2016 Feb 17.

Department of Nuclear Medicine and Endocrine Oncology; MSC Cancer Center and Institute of Oncology, Gliwice Branch.

Introduction: The mechanism of pathogenesis of pituitary adenomas is still unknown, and it shows differences in pituitary cells of different origin. The aim of our study was to analyse the gene expression profile of pituitary hormones and their precursor genes: PRL, GH, POMC, TSHb, LHb, FSHb, and CGA by QPCR in particular types of pituitary adenomas, and to evaluate the results in the context of sample selection for microarray studies.

Material And Methods: Analysis of the gene expression profile was performed in 84 samples of pituitary adenomas, by real-time quantitative PCR (QPCR).

Results: As expected, expression of GH gene was significantly higher in somatotropinomas than in prolactinomas (p < 0.05). For POMC gene we noticed lower expression in all pituitary adenomas, except adrenocorticotropinomas (p < 0.05). In the case of PRL gene, the highest expression was observed; PRL+ adenomas were in third place. LHb and FSHb genes showed the highest expression, respectively, in LH-producing and FSH-producing pituitary adenomas; however, our analysis did not show statistically significant differences between LH-producing and FSH-producing adenomas.

Conclusions: Our study showed that GH is a characteristic gene for somatotropinomas. We drew a similar conclusion for POMC gene and adrenocorticotropinomas. However, the results that we obtained for PRL, TSHb, LHb, FSHb, and CGA genes indicate that evaluation of gene expression is not sufficient for classification of particular subtypes of pituitary adenomas.
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http://dx.doi.org/10.5603/EP.a2016.0024DOI Listing
March 2017

Ongoing risk stratification for differentiated thyroid cancer (DTC) - stimulated serum thyroglobulin (Tg) before radioiodine (RAI) ablation, the most potent risk factor of cancer recurrence in M0 patients.

Endokrynol Pol 2016 ;67(1):2-11

Nuclear Medine and Endocrine Oncology Department; M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch.

Introduction: Adequate postoperative risk assessment currently constitutes the principle of DTC treatment and further management. The aim of the study - a retrospective assessment of risk factors influencing DTC relapse.

Material And Methods: The study group consisted of 510 DTC staged pT1b-T4N0-N1M0, in whom total thyroidectomy and complementary radioiodine (RAI) treatment were carried out. In 71% papillary thyroid cancer was diagnosed, whereas in the remaining 29% - follicular thyroid carcinoma. Based on TNM classification from 1997, T1 feature was diagnosed in 11.6%, T2 in 35.1%, T3 in 8.4%, T4 in 9,4%, while in 35.5% - Tx. Lymph node metastases were present in 24.7% of cases. Median follow-up was 12.1 years (1.5-15.2).

Results: Age at DTC diagnosis, tumour diameter (T), lymph node metastases (N1), stimulated thyroglobulin, and RAI uptake in thyroid bed at qualification for RAI ablation significantly influenced freedom from progression time (FFP) in a multivariate analysis. When postoperative stimulated Tg was > 30 ng/mL the risk of relapse increased nearly six-fold, whereas the presence of N1 feature - four-fold. The total risk of relapse in the whole group was 12.55% while median FFP was 154.8 months. Five-year and 10-year FFP was 90.1% and 87.5%, respectively.

Conclusions: Postoperative stimulated thyroglobulin level was the most potent, independent risk factor influencing FFP in DTC patients. Age above 60 years, an initial DTC stage (T and N features), and low RAI uptake in thyroid bed ( < 1%) were related to a higher risk of DTC relapse, whereas the investigated histopathological features were insignificant.
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http://dx.doi.org/10.5603/EP.2016.0001DOI Listing
February 2017

Gene signature of the post-Chernobyl papillary thyroid cancer.

Eur J Nucl Med Mol Imaging 2016 Jul 26;43(7):1267-77. Epub 2016 Jan 26.

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

Purpose: Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC.

Methods: We investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized.

Results: There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p < 0.01), with 300 differently expressed probe sets (p < 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples.

Conclusion: Significant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure.
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http://dx.doi.org/10.1007/s00259-015-3303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869750PMC
July 2016

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma.

PLoS One 2015 1;10(12):e0143688. Epub 2015 Dec 1.

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

Background: The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation--its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior.

Methods: In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset.

Results: Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(-) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project.

Conclusion: The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143688PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666467PMC
July 2016

Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features.

BMC Cancer 2015 Oct 24;15:778. Epub 2015 Oct 24.

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland.

Background: Pilocytic astrocytoma is the most common type of brain tumor in the pediatric population, with a generally favorable prognosis, although recurrences or leptomeningeal dissemination are sometimes also observed. For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features, and the clinical pattern of the disease.

Methods: Eighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in this study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples).

Results: Bioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression.

Conclusions: Here we have shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease.
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http://dx.doi.org/10.1186/s12885-015-1810-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619381PMC
October 2015

The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors.

PLoS One 2015 15;10(7):e0132821. Epub 2015 Jul 15.

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

Introduction: The risk of over-treatment in low-advanced PTC stages has prompted clinicians to search for new reliable prognostic factors. The presence of BRAF mutation, the most frequent molecular event in PTC, seems to be a good candidate. However, there is still lack of randomised trials and its significance has been proved by retrospective analyses, involving a large group of patients. The question arises whether this factor is useful in smaller populations, characterised for specialised centres. Thus, the aim of the study was to evaluate the use of BRAF mutation as a potential predictive marker in PTC patients.

Material: 233 PTC subjects treated between 2004-2006, were retrospectively analysed. Stage pT1 was diagnosed in 64.8% patients and lymph node metastases in 30.9%. Median follow-up was 7.5 years. BRAFV600E mutation was assessed postoperatively in all cases.

Results: BRAF V600E mutation was found in 54.5%. It was more frequent in patients > 45 years (p=0.0001), and associated with larger tumour size (p=0.004). Patients with tumours <= 10 mm were over-represented among BRAF negative population (p=0.03). No association between BRAF mutation and other clinicopathological factors was observed. BRAF status was associated neither with relapse nor with disease-free survival (DFS) (p=0.76). Nodal status, extrathyroidal invasion and tumour size significantly influenced DFS.

Conclusion: The risk of PTC recurrence is mainly related to the presence of lymph node metastases and extrathyroidal invasion, whereas no impact of BRAF V600E mutation has been demonstrated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132821PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503446PMC
May 2016

Global gene expression profiling in three tumor cell lines subjected to experimental cycling and chronic hypoxia.

PLoS One 2014 14;9(8):e105104. Epub 2014 Aug 14.

Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.

Hypoxia is one of the most important features of the tumor microenvironment, exerting an adverse effect on tumor aggressiveness and patient prognosis. Two types of hypoxia may occur within the tumor mass, chronic (prolonged) and cycling (transient, intermittent) hypoxia. Cycling hypoxia has been shown to induce aggressive tumor cell phenotype and radioresistance more significantly than chronic hypoxia, though little is known about the molecular mechanisms underlying this phenomenon. The aim of this study was to delineate the molecular response to both types of hypoxia induced experimentally in tumor cells, with a focus on cycling hypoxia. We analyzed in vitro gene expression profile in three human cancer cell lines (melanoma, ovarian cancer, and prostate cancer) exposed to experimental chronic or transient hypoxia conditions. As expected, the cell-type specific variability in response to hypoxia was significant. However, the expression of 240 probe sets was altered in all 3 cell lines. We found that gene expression profiles induced by both types of hypoxia were qualitatively similar and strongly depend on the cell type. Cycling hypoxia altered the expression of fewer genes than chronic hypoxia (6,132 vs. 8,635 probe sets, FDR adjusted p<0.05), and with lower fold changes. However, the expression of some of these genes was significantly more affected by cycling hypoxia than by prolonged hypoxia, such as IL8, PLAU, and epidermal growth factor (EGF) pathway-related genes (AREG, HBEGF, and EPHA2). These transcripts were, in most cases, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our results indicate that experimental cycling hypoxia exerts similar, although less intense effects, on the examined cancer cell lines than its chronic counterpart. Nonetheless, we identified genes and molecular pathways that seem to be preferentially regulated by cyclic hypoxia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133353PMC
March 2016

Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa.

Folia Histochem Cytobiol 2014 ;52(2):79-89

Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch.

Epidermal differentiation complex (EDC) comprises a number of genes associated with human skin diseases including psoriasis, atopic dermatitis and hyperkeratosis. These genes have also been linked to numerous cancers, among them skin, gastric, colorectal, lung, ovarian and renal carcinomas. The involvement of EDC components encoding S100 proteins, small proline-rich proteins (SPRRs) and other genes in the tumorigenesis of head and neck squamous cell cancer (HNSCC) has been previously suggested. The aim of the study was to systematically analyze the expression of EDC components on the transcript level in HNSCC. Tissue specimens from 93 patients with HNC of oral cavity and 87 samples from adjacent or distant grossly normal oral mucosawere analyzed. 48 samples (24 tumor and 24 corresponding surrounding tissue) were hybridized to Affymetrix GeneChip Human 1.0 ST Arrays. For validation by quantitative real-time PCR (QPCR) the total RNA from all180 samples collected in the study was analyzed with Real-Time PCR system and fluorescent amplicon specific-probes. Additional set of samples from 14 patients with laryngeal carcinoma previously obtained by HG-U133 Plus 2.0 microarray was also included in the analyses. The expression of analyzed EDC genes was heterogeneous. Two transcripts (S100A1 and S100A4) were significantly down-regulated in oral cancer when compared to normal mucosa (0.69 and 0.36-fold change, respectively), showing an opposite pattern of expression to the remaining S100 genes. Significant up-regulation in tumors was found for S100A11, S100A7, LCE3D, S100A3 and S100A2 genes. The increased expression of S100A7 was subsequently validated by QPCR, confirming significant differences. The remaining EDC genes, including all encoding SPRR molecules, did not show any differences between oral cancer and normal mucosa. The observed differences were also assessed in the independent set of laryngeal cancer samples, confirming the role of S100A3 and LCE3D transcripts in HNC. In HNC of oral cavity only one family of EDC genes (S100 proteins) showed significant cancer-related differences. A number of other transcripts which showed altered expression in HNC require further validation.
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http://dx.doi.org/10.5603/FHC.2014.0018DOI Listing
April 2015

Gene expression analysis in ovarian cancer - faults and hints from DNA microarray study.

Front Oncol 2014 28;4. Epub 2014 Jan 28.

Department of Pathology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland.

The introduction of microarray techniques to cancer research brought great expectations for finding biomarkers that would improve patients' treatment; however, the results of such studies are poorly reproducible and critical analyses of these methods are rare. In this study, we examined global gene expression in 97 ovarian cancer samples. Also, validation of results by quantitative RT-PCR was performed on 30 additional ovarian cancer samples. We carried out a number of systematic analyses in relation to several defined clinicopathological features. The main goal of our study was to delineate the molecular background of ovarian cancer chemoresistance and find biomarkers suitable for prediction of patients' prognosis. We found that histological tumor type was the major source of variability in genes expression, except for serous and undifferentiated tumors that showed nearly identical profiles. Analysis of clinical endpoints [tumor response to chemotherapy, overall survival, disease-free survival (DFS)] brought results that were not confirmed by validation either on the same group or on the independent group of patients. CLASP1 was the only gene that was found to be important for DFS in the independent group, whereas in the preceding experiments it showed associations with other clinical endpoints and with BRCA1 gene mutation; thus, it may be worthy of further testing. Our results confirm that histological tumor type may be a strong confounding factor and we conclude that gene expression studies of ovarian carcinomas should be performed on histologically homogeneous groups. Among the reasons of poor reproducibility of statistical results may be the fact that despite relatively large patients' group, in some analyses one has to compare small and unequal classes of samples. In addition, arbitrarily performed division of samples into classes compared may not always reflect their true biological diversity. And finally, we think that clinical endpoints of the tumor probably depend on subtle changes in many and, possibly, alternative molecular pathways, and such changes may be difficult to demonstrate.
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http://dx.doi.org/10.3389/fonc.2014.00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904181PMC
January 2014

Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2013 ;64(6):418-43

Division of Endocrinology, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland.

An increased interest in gastro-entero-pancreatic neuroendocrine neoplasms (GEP NENs) has recently been observed. These are rare neoplasms and their detection in recent years has improved. Over 50% of GEP NENs are carcinoids, and they are usually found incidentally during surgery in the small intestine and appendix and at diagnosis in distant metastases, mainly to the liver. There is a need for co-operation between specialists in various disciplines of medicine in order to work out the diagnostic and therapeutic guidelines. In this publication, we present general recommendations of the Polish Network of Neuroendocrine Tumours for the management of patients with GEP NENs, developed at the Consensus Conference which took place in Kamień Śląski in April 2013. Members of the guidelines working groups were assigned sections of the 2008 guidance to update. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - neuroendocrine neoplasms of the stomach and duodenum (including gastrinoma); - pancreatic neuroendocrine neoplasms; - neuroendocrine neoplasms of the small intestine and the appendix; - colorectal neuroendocrine neoplasms. The proposed recommendations by Polish and foreign experts representing different fields of medicine (endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathology) will be helpful in the diagnosis and treatment of GEP NENs patients.
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http://dx.doi.org/10.5603/EP.2013.0028DOI Listing
September 2015

Unsupervised analysis of follicular thyroid tumours transcriptome by oligonucleotide microarray gene expression profiling.

Endokrynol Pol 2013 ;64(5):328-34

Introduction: Mechanisms driving the invasiveness of follicular thyroid cancer (FTC) are not fully understood. In our study, we undertook an unsupervised analysis of the set of follicular thyroid tumours (adenomas (FTA) and carcinomas) to verify whether the malignant phenotype influences major sources of variability in our dataset.

Material And Methods: The core set of samples consisted of 52 tumours (27 FTC, 25 FTA). Total RNA was analysed by oligonucleotide microarray (HG-U133 Plus 2.0). Principal Component Analysis (PCA) was applied as a main method of unsupervised analysis.

Results: An analysis of biological character of genes correlated to the first six PCs was performed. When genes correlated to the first PC were used to cluster FTC and FTA, they appeared in two branches; one, relatively enriched in adenomas, with homogenous expression of subset of genes, and the other containing mainly carcinomas, with down-regulation of these genes and heterogeneous up-regulation in a smaller cluster of transcripts. Genes highly up-regulated in adenomas included some thyroid-specific transcripts. The second cluster of genes, up-regulated in carcinomas, contained mainly immunity-related transcripts. Immune response genes were found in the first, third and sixth principal components, improving the discrimination between carcinomas and adenomas.

Conclusions: Our unsupervised analysis indicates that invasiveness of follicular tumours might be considered as the major source of variability in transcriptome analysis. However, the distance between both groups is small and the clusters are overlapping, thus, unsupervised analysis is not sufficient to properly classify them.
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http://dx.doi.org/10.5603/EP.2013.0013DOI Listing
December 2014

Molecular differential diagnosis of follicular thyroid carcinoma and adenoma based on gene expression profiling by using formalin-fixed paraffin-embedded tissues.

BMC Med Genomics 2013 Oct 7;6:38. Epub 2013 Oct 7.

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

Background: Differential diagnosis between malignant follicular thyroid cancer (FTC) and benign follicular thyroid adenoma (FTA) is a great challenge for even an experienced pathologist and requires special effort. Molecular markers may potentially support a differential diagnosis between FTC and FTA in postoperative specimens. The purpose of this study was to derive molecular support for differential post-operative diagnosis, in the form of a simple multigene mRNA-based classifier that would differentiate between FTC and FTA tissue samples.

Methods: A molecular classifier was created based on a combined analysis of two microarray datasets (using 66 thyroid samples). The performance of the classifier was assessed using an independent dataset comprising 71 formalin-fixed paraffin-embedded (FFPE) samples (31 FTC and 40 FTA), which were analysed by quantitative real-time PCR (qPCR). In addition, three other microarray datasets (62 samples) were used to confirm the utility of the classifier.

Results: Five of 8 genes selected from training datasets (ELMO1, EMCN, ITIH5, KCNAB1, SLCO2A1) were amplified by qPCR in FFPE material from an independent sample set. Three other genes did not amplify in FFPE material, probably due to low abundance. All 5 analysed genes were downregulated in FTC compared to FTA. The sensitivity and specificity of the 5-gene classifier tested on the FFPE dataset were 71% and 72%, respectively.

Conclusions: The proposed approach could support histopathological examination: 5-gene classifier may aid in molecular discrimination between FTC and FTA in FFPE material.
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http://dx.doi.org/10.1186/1755-8794-6-38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852913PMC
October 2013
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