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HPV Asociované karcinómy hlavy a krku: morfologická, klinická a molekulovo biologická korelácia
Švajdler, Marián ; Skálová, Alena (advisor) ; Vošmik, Milan (referee) ; Rychlý, Boris (referee)
This doctor thesis comprises two studies. (i) A retrospective study was performed on 22 patients who presented with cystic head and neck squamous cell carcinoma (SCC) metastases. The purpose of the study was to find out whether histomorphology, p16 protein expression, HPV and EBVstatus could be useful in predicting the localization of the primary tumor. The primary site was identified in 20 of 22 patients and included the oropharynx in 14 patients (63.6%), the nasopharynx in 3 patients (13.6%), the lungs in 2 cases (9%), and the skin of the auricle in one case (4.5%). No primary was found in two patients (9%). Sixteen of 17 cases (94.1%) originating in Waldayer's ring, and both cases with an unknown primary showed morphology of non-keratinizing SCC or non-keratinizing SCC with maturation. All tumors with oropharyngeal primary and both cases with unknown primary showed diffuse p16 staining and presence of HPV DNA. All three cystic metastases of nasopharyngeal carcinoma (NPCa) were EBV-positive and p16/HPV negative. In contrast, cutaneous and pulmonary metastases showed morphology of a well differentiated keratinizing SCC and poorly differentiated keratinizing SCC, respectively, and were HPV/EBV-negative. We confirmed that cystic SCC lymph node metastases of the head and neck region are strongly...
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Histological Quantification of MicrovesselsStereology of Vasa Vasorum and Brain Microvessels
Tomášek, Petr ; Tonar, Zbyněk (advisor) ; Skálová, Alena (referee) ; Kachlík, David (referee)
Considering the current knowledge on histology of microvessels suggested that quantification of the tissue microvessels itself should be accompanied by a description of the surrounding tissue components supplied by these microvessels. However, the microscopic anatomy of this tissue context can vary considerably on the scale of large-sized organs, such as the aorta of large mammals or the human brain. Given that the present knowledge on the variability of densities, spatial arrangement, and orientation of microvessels is usually limited to macroscopically small areas of these large organs, we consider mapping of the microvessels on a large macroscopic scale to be a matter of great importance. This became the unifying element of this thesis. The main findings based on six studies presented in the thesis were as follows: Finding #1: The density and the penetration depth of the vasa vasorum has a considerable segmental variability in the porcine aorta. The density of the vasa vasorum was greatest in thoracic aortic segments, as was the depth of penetration into the tunica media, which exceeded previously published findings. The vasa vasorum density declined with age, but the relative depth of their penetration did not. The individual segments of the porcine aorta were not interchangeable for being used...
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Immunohistochemical and Molecular Genetic Methods in the Head and Neck Pathology
Baněčková, Martina ; Skálová, Alena (advisor) ; Stárek, Ivo (referee) ; Laco, Jan (referee)
Current doctoral thesis is dealing with morphology, immunohistochemistry, molecular genetics and biological behavior of head and neck tumors with a particular emphasis on salivary gland and sinonasal lesions. Dr. Martina Baneckova has focused on this topic during her postgraduate studies at Charles University, Medical Faculty in Pilsen, in the years 2017 - 2020. In her publication activity, the author focused on rare tumors of the head and neck. A total of 9 publications were published over a span of three years are presented in a form of a commentary. Four of them are first-author papers and these are introduced briefly below. The first study entitled "Mammary analog secretory carcinoma of the nasal cavity: Characterization of 2 cases and their distinction from other low-grade sinonasal adenocarcinomas" deals with the relationship of newly described entities, secretory carcinoma (SC) of the nasal cavity and ETV6-rearranged low-grade sinonasal adenocarcinoma (LG SNAC). It is important to distinguish these 2 entities because of different clinical behaviors. Low-grade non-ITAC, including ETV6-rearranged LG SNAC mostly behave in an indolent manner, whereas SC is a malignancy with metastatic potential. It is important to be aware of the possible occurrence of SC in the sinonasal region, as in this area...
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Correlation of Immunohistochemical and Molecular Methods in Diagnostics of Salivary Gland Tumors
Horáková, Markéta ; Skálová, Alena (advisor) ; Laco, Jan (referee) ; Dušková, Jaroslava (referee)
This doctoral thesis is dealing with the correlation of morphological, immunohistochemical and genetical findings in malignant tumors of salivary glands. The first half of the thesis comprises the summary of current knowledge about salivary malignancies. The second half is presenting the research itself. The research results are divided into three parts. The first part is presenting the method of "2-step diagnostic test" of malignant tumors. This screening test aims to find new, so far not described gene aberrations with a focus on malignant tumors of salivary glands. This method takes place in two consecutive steps. In the first step the material is examined by an immunohistochemical mixture of antibodies, which non-specifically detects aberration in the genes NTRK1-3, ALK and ROS1. In the second step all positive cases are subjected to highly sensitive and specific molecular-genetic examination by the method of next generation sequencing (NGS) using the Archer kit. In the second part of the work there has been designed the approach to the cytological diagnosis of salivary secretory carcinoma by the fine-needle aspiration (FNA). This part is describing to the details the cytomorphology of secretory carcinoma in both, Pap smears and cell blocks, from which additional immunocytochemical and genetic...
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Clinical-pathological correlations of immunohistochemical and molecular classification of salivary duct carcinoma.
Andrle, Pavel ; Skálová, Alena (advisor) ; Stárek, Ivo (referee) ; Slouka, David (referee)
Thesis is focused on correlation of immunohistochemical, molecular genetic and clinical features of salivary duct carcinomas. Clinicopathological and follow-up information of 29 patients originally diagnosed as SDC who were treated at Faculty Hospital in Plzen from 1987 to 2018, were collected. Clinical findings: The patient group comprised 22 males and 4 females, aged between 24-95 years with a mean age at diagnosis of 66 years and median of 64 years. at stage IV . 54 % patients were diagnosed at cervical metastasis and 58 % had tumor T3 or T4. Five-year survival rate was 33%. Immunohistochemical and molecular findings: After analysis of immunohistochemical results, the SDC cases were classified according to revised classification into five subtypes (Apocrine A (AR+/HER2-/MIB1-low); Apocrine B (AR+/HER2-/MIB1-high); Apocrine HER2 (AR+/HER2+); HER2-enriched (AR-/HER2+); and double negative (AR-/HER2-). Apocrine HER2 and HER2 enriched subtypes were significantly associated with lower OS (p < 0.05). NGS analysis revealed one case harboring an ETV6-NTRK3 fusion, therefore it was reclassified as a high-grade secretory carcinoma. Five likely pathogenic mutations were detected in 5 SDC cases (HRAS: c.182A>G p.Gln61Arg, 2x HRAS: c.37G>C p.Gly13Arg, AKT1: c.49G>A p.Glu17Lys, PTEN c.1003C>T p.Arg335Ter)....
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Correlation of Immunohistochemistry and Molecular Biologic Methods in The Diagnosis of Tumors
Michal, Michael ; Skálová, Alena (advisor) ; Rychlý, Boris (referee) ; Zambo, Iva (referee)
This thesis is a collection of commentaries on altogether 13 first-authored and 20 co- authored publications where morphology, immunohistochemistry (IHC) and molecular genetic methods were used to provide novel clues for arriving at an accurate diagnosis of tumors, as well as to propose novel approaches and refinement of classification of certain tumors. The presented manuscripts are the result of the postgraduate studies of MUDr. Michael Michal at the Charles University in Prague, Faculty of Medicine in Pilsen in the period between 2015-2018. The author focused the main part of his research, particularly his first-authored manuscripts, on soft tissue tumors but also largely participated in research activities focusing on other body systems. Over the course of his studies, four main areas of interests within the topic of soft tissue pathology emerged. The first is oriented on soft tissue tumors of presumed (but unconfirmed) fibroblastic lineage. First two publications regard two related low-grade sarcomas called Myxoinflammatory fibroblastic sarcoma (MIFS) and Pleomorphic hyalinizing angiectatic tumor (PHAT). In the first manuscript, a high-grade variant of the former is described. The latter publication is focused on the morphological and IHC similarities between both MIFS and PHAT. The third and...
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Correlation of Molecular-Genetic and Morphological Markers of Rare Salivary Gland Tumors
Šteiner, Petr ; Skálová, Alena (advisor) ; Laco, Jan (referee) ; Šíma, Radek (referee)
Thesis deals with relationship between histomorphological and molecular-genetic findings of selected salivary gland tumors. Author, as a molecular-cytogeneticist mainly focused on detection of tumor-specific translocations of the salivary gland tumors which can serve as differential diagnostic markers. The thesis is composed as a commented files of authors own publications, and it is divided into four parts. First part deepens the knowledge of salivary adenoid cystic carcinoma. It was proved, that t(6;9)(q22-23;p23-24) resulting in fusion of transcription factors MYB-NFIB, or more rarely t(8;9) resulting in MYBL1-NFIB fusion represent robust differential diagnostic marker of adenoid cystic carcinoma. Further it was proved, that the 1p36 deletion can serve as an unfavorable prognostic indicator of adenoid cystic carcinoma, as the patients with 1p36 deletion had significantly lower survival. Second part summarizes new developments about mammary analogue secretory carcinoma (MASC), which was described by our group as a new salivary tumor entity characterized by translocation t(12;15)(p13;q25) resulting in ETV6-NTRK3 fusion. Another novel observation is a discovery of ETV6-RET fusion in a subset of MASC cases. Further, the first two MASCs of nasal mucosa origin have been described. Third part consists...
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HPV Asociované karcinómy hlavy a krku: morfologická, klinická a molekulovo biologická korelácia
Švajdler, Marián ; Skálová, Alena (advisor) ; Vošmik, Milan (referee) ; Rychlý, Boris (referee)
This doctor thesis comprises two studies. (i) A retrospective study was performed on 22 patients who presented with cystic head and neck squamous cell carcinoma (SCC) metastases. The purpose of the study was to find out whether histomorphology, p16 protein expression, HPV and EBVstatus could be useful in predicting the localization of the primary tumor. The primary site was identified in 20 of 22 patients and included the oropharynx in 14 patients (63.6%), the nasopharynx in 3 patients (13.6%), the lungs in 2 cases (9%), and the skin of the auricle in one case (4.5%). No primary was found in two patients (9%). Sixteen of 17 cases (94.1%) originating in Waldayer's ring, and both cases with an unknown primary showed morphology of non-keratinizing SCC or non-keratinizing SCC with maturation. All tumors with oropharyngeal primary and both cases with unknown primary showed diffuse p16 staining and presence of HPV DNA. All three cystic metastases of nasopharyngeal carcinoma (NPCa) were EBV-positive and p16/HPV negative. In contrast, cutaneous and pulmonary metastases showed morphology of a well differentiated keratinizing SCC and poorly differentiated keratinizing SCC, respectively, and were HPV/EBV-negative. We confirmed that cystic SCC lymph node metastases of the head and neck region are strongly...
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Molecular genetic characteristics of salivary gland tumors in differential diagnosis and prognosis prediction
Hauer, Lukáš ; Skálová, Alena (advisor) ; Laco, Jan (referee) ; Mazánek, Jiří (referee)
Molecular genetic characteristics of salivary gland tumors in differential diagnosis and prognosis prediction Abstract: In the presented manuscript the author summarizes the current knowledge on molecular biomarkers of salivary gland cancer, focusing on tumor-type specific fusion oncogenes and their use as diagnostic, prognostic and therapeutic biomarkers. In detail, the author deals with adenoid cystic carcinoma (AdCC), the second most common salivary gland cancer. New facts of its biological behavior as well as new fusion oncogenes probably responsible for its carcinogenesis were described in the last few years. A retrospective case series evaluating 27 patients suffering from AdCC, who were treated at the University Hospital in Pilsen in the last 30 years (1986- 2016), is presented in this study. The following characteristics were observed: age, gender, tumor location, clinical stage at diagnosis, presence of regional and distant metastases, tumor grade, duration of follow-up, treatment and outcomes. Detection of the 1p36 deletion and the t(6;9)(q22-23;p23-24) chromosomal translocation resulting in the MYB-NFIB gene fusion were performed. The incidence of AdCC in minor salivary glands, submandibular gland, parotid gland and sublingual gland was 41 %, 26 %, 22 % and 11% respectively. The following staging...
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Game Theory for Gifted Secondary School Students
Skálová, Alena ; Hykšová, Magdalena (advisor) ; Staněk, Jakub (referee)
The thesis contains a textbook for gifted secondary school students. Its aim is to give to these students (or to their teachers) a Czech-written text covering fundamental principles in the field of game theory. In the first part we introduce the combinatorial games and some elementary methods of their solution. The second part is devoted to the game of Nim, to the Sprague-Grundy function and to the sums of the combinatorial games. It also contains a necessary introduction to the binary numeral system. In the third part we present the concept of matrix and bimatrix games. There is a lot of exercises and examples in the textbook. At the end we bring solutions to the most of them, providing the active reader with the opportunity of checking their own solutions.
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