Publications by authors named "Dariusz Lange"

105 Publications

The incidence and clinical analysis of non-melanoma skin cancer.

Sci Rep 2021 Feb 22;11(1):4337. Epub 2021 Feb 22.

Department of Dermatology, Paediatric Dermatology and Oncology Clinic, Medical University of Łódź, Łódź, Poland.

Non-melanoma skin cancers (NMSCs) are the most common malignancies diagnosed in Caucasian populations. Basal cell carcinoma (BCC) is the most frequent skin cancer, followed by squamous cell carcinoma (SCC). Unfortunately, most European cancer registries do not record individual types of NMSC. To evaluate the incidence of primary BCCs and SCCs regarding age, sex, tumour site and tumour subtype to determine trends in epidemiology of both cancers. Retrospective analysis of BCCs and SCCs diagnosed and treated across seven sites in Poland from 1999 to 2019. We recorded 13,913 NMSCs occurring in 10,083 patients. BCC represented 85.2% of all cases. SCC patients were older than BCC patients (77.1 ± 11.3 years vs. 70.1 ± 12.3 years, p < 0.01). The nodular subtype was the most common subtype of BCC, followed by the superficial and infiltrative subtypes. The superficial BCC subtype was more common on photoprotected areas (p < 0.01), whereas the nodular BCC subtype occurred on the face (p < 0.01). The high-risk SCC subtypes were more common on face compared to low-risk SCC subtypes (p < 0.01). BCC and SCC are common malignancies developing at various ages and anatomical sites. These data underline the need for better registration policies regarding NMSC in order to improve prevention and treatment strategies for these tumours.
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http://dx.doi.org/10.1038/s41598-021-83502-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900109PMC
February 2021

Clinical and epidemiological analysis of basosquamous carcinoma: results of the multicenter study.

Sci Rep 2020 10 28;10(1):18475. Epub 2020 Oct 28.

Department of Dermatology, Paediatric Dermatology and Oncology Clinic, Medical University of Łódź, Łódź, Poland.

Basosquamous carcinoma (BSC) is a rare non-melanoma skin cancer that shares the characteristic features of both basal and squamous cell carcinomas (BCC, SCC). Our research enables better characterization of BSC in comparison to high-risk subtypes of BCC and SCC. Paper includes a retrospective analysis of BSC cases regarding sex, age, number of tumors and anatomical distribution in comparison to BCC and SCC evaluating the differences and defining the implications. Histologically confirmed carcinomas recorded between 1999 and 2019 were studied. 181 diagnosed BSC cases were identified, making this study the largest cohorts of BSC patients reported worldwide. Most cases were reported on head and neck. Analysis of facial anatomic distribution shows that most commonly affected sites were the nose (43%) and the cheek (25%). The age at excision of metatypical BCC was higher than those of low-risk BCC (P < 0.05), however similar to high-risk BCC (P = 0.20). We revisited that the concept of BSC is the most similar to high-risk subtypes of BCC. Patients with diagnosed BSC have higher risk of second nonmelanoma skin cancer. Therefore, the frequency of follow-up examination should be adjusted to the individual risk of another skin cancer.
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http://dx.doi.org/10.1038/s41598-020-72732-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595159PMC
October 2020

hMTH1 and GPX1 expression in human thyroid tissue is interrelated to prevent oxidative DNA damage.

DNA Repair (Amst) 2020 11 20;95:102954. Epub 2020 Aug 20.

Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland.

Oxidative stress (OS) is recognized as disturbance of cellular equilibrium between reactive oxygen species (ROS) formation and their elimination by antioxidant defense systems. One example of ROS-mediated damage is generation of potentially mutagenic DNA precursor, 8-oxodGTP. In human cells genomic 8-oxodGTP incorporation is prevented by the MutT homologue 1 (MTH1 or hMTH1 for human MTH1) protein. It is well established that malignant cells, including thyroid cancer cells, require hMTH1 for maintaining proliferation and cancerous transformation phenotype. Above observations led to the development of hMTH1 inhibitors as novel anticancer therapeutics. In the current study we present extensive analysis of oxidative stress responses determining sensitivity to hMTH1 deficiency in cultured thyroid cells. We observe here that hMTH1 depletion results in downregulation of several glutathione-dependent OS defense system factors, including GPX1 and GCLM, making some of the tested thyroid cell lines highly dependent on glutathione levels. This is evidenced by the increased ROS burden and enhanced proliferation defect after combination of hMTH1 siRNA and glutathione synthesis inhibition. Moreover, due to the lack of data on hMTH1 expression in human thyroid tumor specimens we decided to perform detailed analysis of hMTH1 expression in thyroid tumor and peri-tumoral tissues from human patients. Our results allow us to propose here that anticancer activity of hMTH1 suppression may be boosted by combination with agents modulating glutathione pool, but further studies are necessary to precisely identify backgrounds susceptible to such combination treatment.
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http://dx.doi.org/10.1016/j.dnarep.2020.102954DOI Listing
November 2020

The Spectroscopic Similarity between Breast Cancer Tissues and Lymph Nodes Obtained from Patients with and without Recurrence: A Preliminary Study.

Molecules 2020 Jul 21;25(14). Epub 2020 Jul 21.

Institute of Physics, University of Rzeszow, College of Natural Sciences, PL-35959 Rzeszow, Poland.

Lymph nodes (LNs) play a very important role in the spread of cancer cells. Moreover, it was noticed that the morphology and chemical composition of the LNs change in the course of cancer development. Therefore, finding and monitoring similarities between these characteristics of the LNs and tumor tissues are essential to improve diagnostics and therapy of this dreadful disease. In the present study, we used Raman and Fourier transform infrared (FTIR) spectroscopies to compare the chemical composition of the breast cancer tissues and LNs collected from women without (I group-4 patients) and with (II group-4 patients) recurrence. It was shown that the similarity of the chemical composition of the breast tissues and LNs is typical for the II group of the patients. The average Raman spectrum of the breast cancer tissues from the I group was not characterized by vibrations in the 800-1000 cm region originating from collagen and carbohydrates, which are typical for tumor-affected breast tissues. At the same time, this spectrum contains peaks at 1029 cm, corresponding to PO from DNA, RNA and phospholipids, and 1520 cm, which have been observed in normal breast tissues before. It was shown that Raman bands of the average LN spectrum of the II group associated with proteins and carbohydrates are more intensive than those of the breast tissues spectrum. The intensity of the Raman spectra collected from the samples of the II group is almost three times higher compared to the I group. The vibrations of carbohydrates and amide III are much more intensive in the II group's case. The Raman spectra of the breast cancer tissues and LNs of the II group's samples do not contain bands (e.g., 1520 cm) found in the Raman spectra of the normal breast tissues elsewhere. FTIR spectra of the LNs of the I group's women showed a lower level of vibrations corresponding to functional group building nucleic acid, collagen, carbohydrates, and proteins in comparison with the breast cancer tissues. Pearson's correlation test showed positive and more significant interplay between the nature of the breast tissues and LN spectra obtained for the II group of patients than that in the I group's spectra. Moreover, principal component analysis (PCA) showed that it is possible to distinguish Raman and FTIR spectra of the breast cancer tissues and LNs collected from women without recurrence of the disease.
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http://dx.doi.org/10.3390/molecules25143295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397234PMC
July 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

The clinical value of the routine analysis of cardiac implantable electronic devices after the patient's death in a tertiary cardiovascular center.

Pol Arch Intern Med 2020 06 7;130(6):492-500. Epub 2020 May 7.

3rd Department of Cardiology, School of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland

Introduction: The postmortem interrogation of cardiac implantable electronic devices (CIEDs) has not been regularly practiced yet. We presumed that it can provide data not only on the mechanism of the patient's death but also on possible device malfunctions contributing to its occurrence.

Objectives: The study aimed to determine the usefulness of the explantation and interrogation of CIEDs after the patient's death in routine clinical practice, when combined with autopsy findings and clinical follow‑up starting from the time after device implantation.

Patients And Methods: Between August 24, 2008 and August 30, 2018, all patients who underwent autopsy in the tertiary cardiovascular center or partner facilities had the device explanted and interrogated by the qualified electrophysiologist. Clinical characteristics obtained at the time of device implantation and patients' death were obtained from medical records. Device interrogation results were then combined with autopsy report and clinical data.

Results: Out of 1200 autopsied patients, the device was removed and analyzed in 61 individuals. Clinical characteristics from the time of implantation and patients' death were available in 53 (86.7%) and 49 (80.3%) patients, respectively. Device‑related concerns, undetected during patients' hospital stay, were noted in 6 cases (6.1%) and included 3 programming and 3 hardware issues.

Conclusions: To our knowledge, this is the first study to date to combine the clinical follow‑up of patients before death and on admission at the end of life, autopsy results, and postmortem CIED interrogation. Having implemented the device interrogation, we found 6 CIED‑related events potentially associated with patients' death, which were not detected before its occurrence.
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http://dx.doi.org/10.20452/pamw.15343DOI Listing
June 2020

Significance of HPV16 Viral Load Testing in Anal Cancer.

Pathol Oncol Res 2020 Oct 7;26(4):2191-2199. Epub 2020 Apr 7.

Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102, Gliwice, Poland.

Human papilloma virus (HPV) is highly frequent among patients with anal squamous cell carcinoma, but the viral load (VL) differs between patients. This study aimed to compare the rate of HPV positivity, HPV16VL, p16 and p53 expression between treatment naive and recurrent anal cancer patients. HPV was genotyped via AmpliSens® HPV HCR-genotype-titre-FRT kit. HPV16 VL was determined via quantitative polymerase chain reaction-based in-house test. p16 and p53 expression was tested via immunohistochemistry. The cohort comprised 13 treatment-naive and 17 recurrent anal SCC patients. High-risk HPV was detected in 87% of cases, and HPV16 (73%) was the predominant genotype. The rate of HPV positivity was higher among women and nonsmokers, and majority of HPV-positive cases were also p16-positive. All p53-negative tumors were HPV16-positive. The most predominant p53 staining pattern in the HPV-positive group was scattered type, whereas it was diffuse type in the HPV-negative group. The HPV16 VL was higher in the treatment-naive group. Further, in the treatment-naive group, cases with scattered staining pattern of p53 had higher HPV16 VL than cases with diffuse staining pattern. The opposite result was noted in the recurrent cancer group. Moreover, p16-positive cases with scattered p53 staining pattern in the treatment naive group had higher HPV16 VL than their counterparts in the recurrent cancer group. In conclusion, the HPV VL, as is the association between VL and p16 /p53, is in an inversed trend in treatment naive and recurrent cancer patients, highlighting the importance of HPV VL measurement in anal SCC.
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http://dx.doi.org/10.1007/s12253-020-00801-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471158PMC
October 2020

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

Spectroscopic identification of benign (follicular adenoma) and cancerous lesions (follicular thyroid carcinoma) in thyroid tissues.

J Pharm Biomed Anal 2019 Jun 28;170:321-326. Epub 2019 Mar 28.

Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, PL-35959, Rzeszow, Poland.

Thyroid follicular nodules are quite common in the population, however only a small proportion is malignant. Thyroid cancer differs from adenoma by features of cellular atypia, angioinvasiveness and possibility of metastasis via blood vessels mainly in the lungs and bones. Pathomorphological examination of the postoperative material plays a significant role in the diagnosis of cystic thyroid lesions. De facto, there is no possibility to determine with certainty whether the lesion is benign or malignant before surgery, therefore new methods are being sought to meet clinical needs. The study aimed to investigate if Fourier-transform infrared spectroscopy (FTIR) spectroscopy and Raman spectroscopy combined with multidimensional analysis can be a useful tool in distinguishing between thyroid adenomas and carcinomas. The obtained results indicate quantitative and qualitative alterations within proteins and fats derived from patients' tissues samples. Raman spectroscopy additionally shows significant changes in the amount of tissue collagen due to the pathogenic process. In the spectra of the second FTIR derivative, shifts of vibrations corresponding to the β-sheet and α-helix structure are observed towards the lower rates of wave numbers in the case of neoplastic tissues. Using the leave-one-out cross-validation, sensitivity and specificity calculated with Principal Component Analysis-Linear Discriminant Analysis (PCA-LDA) clearly shows the possibility to distinguish between pathologically changed and normal thyroid tissue as well as differentiate follicular thyroid adenoma (FTA) from widely invasive follicular thyroid carcinoma (WI-FTC) tissues.
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http://dx.doi.org/10.1016/j.jpba.2019.03.061DOI Listing
June 2019

Spectroscopic analysis of normal and neoplastic (WI-FTC) thyroid tissue.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Nov 7;204:18-24. Epub 2018 Jun 7.

Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, PL-35959 Rzeszow, Poland.

Thyroid cancer holds the first place of the malignant tumors of the endocrine system. One of the less common thyroid cancers is follicular thyroid carcinoma (FTC), which is very difficult to diagnose because it gives the same image as adenoma, which is benign. Certainty of the diagnosis is gained only when FTC gives metastases. Therefore, it was decided to compare normal and neoplastic (FTC) thyroid tissues with Fourier Transform Infrared (FTIR) spectroscopy. The obtained FTIR spectra and Principal Component Analysis (PCA) allowed us to conclude that there are differences in the FTIR spectrum between normal tissues and those affected by cancer. In addition, the results indicate that there is a decrease in the number of functional groups that build cellular and tissue structures in tumoral tissues. The shifts of wave numbers corresponding to the protein and lipid function group vibrations, as well as the calculated second derivative of the FTIR spectra showed the structural changes in neoplastic tissues. Moreover, the deconvolution of the amide I massif indicates that in cancerous tissues the prevailing secondary structure is β-sheet structure, while in normal tissues it is α-helix. The obtained results allow us to conclude that infrared spectroscopy, in addition to providing information on the composition of tested samples, can be an excellent diagnostic tool contributing to understanding the FTC substrate.
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http://dx.doi.org/10.1016/j.saa.2018.06.010DOI Listing
November 2018

Enhanced intratumoral expression of RNF2 is a favorable prognostic factor for patients with cutaneous melanoma?

Oncotarget 2018 Apr 3;9(25):17656-17663. Epub 2018 Apr 3.

Department of Medical Biology, Faculty of Biology and Environment Protection, Nicolaus Copernicus University, Toruń, Poland.

Recent studies involving melanoma cell lines suggest that enhanced expression of epigenetic regulator RNF2 supports proliferation and promotes metastasis. However, it is not clear to what extent those data apply to disease progression and prognosis for melanoma patients. Therefore the aim of the present study was to assess the prognostic power of RNF2 intratumoral expression by melanoma cells. RNF2 was detected immunohistochemically in standard formalin-fixed paraffin-embedded samples of 9 benign nevi, 60 melanomas and 24 nodal metastases. The lowest percentage of RNF2-positive melanocytes found in nevi was comparable to expression levels in normal skin. The RNF2 expression found in melanomas was significantly higher and it was even more enhanced in metastases. The increased occurrence of RNF2 expressing cells was positively correlated with longer patients' overall survival. Moreover, a negative correlation was found between intratumoral RNF2 expression and number of generated metastatic lesions. Our data indicate that development of melanoma is associated with significant changes in RNF2 intratumoral expression and imply that at least for some patients the enhancement of the expression levels of RNF2 in both primary and metastatic lesions may be considered a favorable prognostic factor in melanoma.
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http://dx.doi.org/10.18632/oncotarget.24825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915146PMC
April 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

Prognostic significance of RBP2-H1 variant of JARID1B in melanoma.

BMC Cancer 2017 Dec 15;17(1):854. Epub 2017 Dec 15.

Department of Medical Biology, Faculty of Biology and Environment Protection, Nicolaus Copernicus University, Lwowska 1, 87-100, Toruń, Poland.

Background: Histone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients' prognosis have been reported.

Methods: We investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients.

Results: Expression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients.

Conclusions: Such results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness.
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http://dx.doi.org/10.1186/s12885-017-3836-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731204PMC
December 2017

Proteome profiles of different types of thyroid cancers.

Mol Cell Endocrinol 2018 09 26;472:68-79. Epub 2017 Nov 26.

Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, ul. Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland. Electronic address:

Proteomics profiling of tissue specimens representative for major types of thyroid cancers: papillary (classical and follicular variant), follicular, anaplastic and medullary, as well as benign follicular adenoma, was performed using shotgun LC-MS/MS approaches. A combination of Orbitrap and MALDI-TOF approach allowed to identify protein products of 3700 unique genes and revealed large differences between medullary, anaplastic and epithelium-derived differentiated cancers (papillary and follicular). Proteins characteristic for medullary and anaplastic cancers included factors associated with neuroendocrine functions and factors typically associated with advanced malignancies, respectively. Proteomes of different types of epithelium-derived differentiated cancers and follicular adenoma were compared using multi-enzyme LC-MS/MS approach, which revealed products of 4800 unique genes. A comparable overall similarity of follicular cancers to both variants of papillary cancers was found. Moreover, follicular adenoma showed higher overall similarity to follicular cancer than to either variant of papillary cancer. Proteins discriminating differentiated thyroid neoplasms included factors associated with lipid and hormone metabolism, regulation of gene expression and maintenance of DNA structure. Importantly, proteome data matched several features of transcriptome and metabolome profiles of thyroid cancers contributing to systems biology of this malignancy.
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http://dx.doi.org/10.1016/j.mce.2017.11.020DOI Listing
September 2018

Oral and oropharyngeal papillomas are not associated with high-risk human papillomavirus infection.

Eur Arch Otorhinolaryngol 2017 Sep 21;274(9):3477-3483. Epub 2017 Jun 21.

Department of Laryngology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.

The role of different types of human papillomavirus (HPV) in the development of oral and oropharyngeal papillomas remains unclear. High-risk HPV (HR-HPV) was shown to be involved in the pathogenesis of significant proportion of squamous cell carcinomas of the oropharynx. In this study, we hypothesized that in some oropharyngeal papillomas, low-risk HPV (LR-HPV) and HR-HPV infection could co-exist, similar to what is observed in genital warts, and thus contribute to the elevated risk of malignancy. To test this hypothesis, we used real-time PCR to assess the presence of HPV DNA of 16 types (2 LR-HPV and 14 HR-HPV), in 75 formalin-fixed and paraffin-embedded histopathological samples of oral and oropharyngeal papillomas and in 57 squamous cell carcinomas from the same regions. We investigated the biological activity of HPV by demonstrating accumulation of P16(INK4A) protein in the viral-infected tissue samples. The presence of the LR-HPV genome from the HPV6 or HPV11 types was confirmed in 42 (56%) papillomas and in no carcinomas. HPV6/HPV11 co-infection was detected in 17 (22.7%) of the papillomas. HR-HPV DNA presence and HR-HPV activity hallmarks were not observed in any of the investigated papillomas. Thus, a causative role for HR-HPV or its contribution to LR/HR-HPV co-infection in the pathogenesis of oral or oropharyngeal papillomas is unlikely. Additionally, HR-HPV and LR-HPV infections seem to be mutually exclusive in papillomas and squamous cell carcinomas of the oral cavity and oropharynx.
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http://dx.doi.org/10.1007/s00405-017-4649-xDOI Listing
September 2017

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

Endokrynol Pol 2017 ;68(2):79-110

Klinika Endokrynologii i Nowotworów Neuroendokrynnych, Katedra Patofizjologii i Endokrynologii, Śląski Uniwersytet Medyczny.

Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechów near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.
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http://dx.doi.org/10.5603/EP.2017.0015DOI Listing
July 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

The association of tumor lymphocyte infiltration with clinicopathological factors and survival in breast cancer.

Pol J Pathol 2017;68(1):26-32

Recent studies have confirmed the role of tumor-infiltrating lymphocytes (TILs) in carcinogenesis and cancer progression. The aim of this study was to evaluate the correlation between the level of tumor lymphocyte infiltration and well-known clinicopathological factors in breast cancer patients. We also evaluated the influence of TILs on overall survival. Paraffin sections were retrospectively evaluated in 76 cases in early stage breast cancer patients who underwent surgery followed by systemic treatment. Tumor-infiltrating lymphocytes were classified as absent (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3). Tumor-infiltrating lymphocytes were found in 87% of patients (severe grade in 8% of them). Higher grade (grades 2-3) TILs were present more frequently in younger patients (under 65 years) than older women (47% vs. 24%; p = 0.099). Higher grades of tumor-infiltrating lymphocytes (grades 2-3) appear to be associated with clinicopathological factors such as negative steroid receptor status (p = 0.001), HER2 overexpression (p = 0.016) and higher histological grade (G3) (p = 0.095). Tumor-infiltrating lymphocytes were not a significant prognostic factor for overall survival in our group. Only HER2 overexpression significantly increases the risk of death (HR = 4.3, p = 0.020). In the subgroup of patients who had tumors with HER2 overexpression there was non-significantly worse OS independently of TIL grade (p = 0.086).
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http://dx.doi.org/10.5114/pjp.2017.67612DOI Listing
July 2017

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

Endokrynol Pol 2017 ;68(2):250-260

Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer-tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358-368.
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http://dx.doi.org/10.5603/EP.2017.0019DOI Listing
July 2017

Neuroendocrine neoplasms of the small intestine and appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):223-236

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.
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http://dx.doi.org/10.5603/EP.2017.0018DOI Listing
July 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

Gastroduodenal neuroendocrine neoplasms, including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):138-153

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.
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http://dx.doi.org/10.5603/EP.2017.0016DOI 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

Molecular profiles of thyroid cancer subtypes: Classification based on features of tissue revealed by mass spectrometry imaging.

Biochim Biophys Acta Proteins Proteom 2017 Jul 17;1865(7):837-845. Epub 2016 Oct 17.

Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, ul. Wybrzeze Armii Krajowej 15, 44101 Gliwice, Poland. Electronic address:

Determination of the specific type of thyroid cancer is crucial for the prognosis and selection of treatment of this malignancy. However, in some cases appropriate classification is not possible based on histopathological features only, and it might be supported by molecular biomarkers. Here we aimed to characterize molecular profiles of different thyroid malignancies using mass spectrometry imaging (MSI) which enables the direct annotation of molecular features with morphological pictures of an analyzed tissue. Fifteen formalin-fixed paraffin-embedded tissue specimens corresponding to five major types of thyroid cancer were analyzed by MALDI-MSI after in-situ trypsin digestion, and the possibility of classification based on the results of unsupervised segmentation of MALDI images was tested. Novel method of semi-supervised detection of the cancer region of interest (ROI) was implemented. We found strong separation of medullary cancer from malignancies derived from thyroid epithelium, and separation of anaplastic cancer from differentiated cancers. Reliable classification of medullary and anaplastic cancers using an approach based on automated detection of cancer ROI was validated with independent samples. Moreover, extraction of spectra from tumor areas allowed the detection of molecular components that differentiated follicular cancer and two variants of papillary cancer (classical and follicular). We concluded that MALDI-MSI approach is a promising strategy in the search for biomarkers supporting classification of thyroid malignant tumors. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
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http://dx.doi.org/10.1016/j.bbapap.2016.10.006DOI Listing
July 2017

Two-miRNA classifiers differentiate mutation-negative follicular thyroid carcinomas and follicular thyroid adenomas in fine needle aspirations with high specificity.

Endocrine 2016 Nov 29;54(2):440-447. Epub 2016 Jul 29.

Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Diagnosis of thyroid by fine needle aspiration is challenging for the "indeterminate" category and can be supported by molecular testing. We set out to identify miRNA markers that could be used in a diagnostic setting to improve the discrimination of mutation-negative indeterminate fine needle aspirations. miRNA high-throughput sequencing was performed for freshly frozen tissue samples of 19 RAS and PAX8/PPARG mutation-negative follicular thyroid carcinomas, and 23 RAS and PAX8/PPARG mutation-negative follicular adenomas. Differentially expressed miRNAs were validated by quantitative polymerase chain reaction in a set of 44 fine needle aspiration samples representing 24 follicular thyroid carcinomas and 20 follicular adenomas. Twenty-six miRNAs characterized by a significant differential expression between follicular thyroid carcinomas and follicular adenomas were identified. Nevertheless, since no single miRNA had satisfactory predictive power, classifiers comprising two differentially expressed miRNAs were designed with the aim to improve the classification. Six two-miRNA classifiers were established and quantitative polymerase chain reaction validated in fine needle aspiration samples. Four out of six classifiers were characterized by a high specificity (≥94 %). The best two-miRNA classifier (miR-484/miR-148b-3p) identified thyroid malignancy with a sensitivity of 89 % and a specificity of 87 %. The high-throughput sequencing allowed the identification of subtle differences in the miRNA expression profiles of follicular thyroid carcinomas and follicular adenomas. While none of the differentially expressed miRNAs could be used as a stand-alone malignancy marker, the validation results for two-miRNA classifiers in an independent set of fine needle aspirations are very promising. The ultimate evaluation of these classifiers for their capability of discriminating mutation-negative indeterminate fine needle aspirations will require the evaluation of a sufficiently large number of fine needle aspirations with histological confirmation.
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http://dx.doi.org/10.1007/s12020-016-1021-7DOI Listing
November 2016