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Impact of pattern and functional properties of tumor-infiltrating immune cells for clinical outcome of head and neck cancer
Hladíková, Kamila ; Špíšek, Radek (advisor) ; Plzák, Jan (referee) ; Reiniš, Milan (referee)
Head and neck squamous cell carcinoma encompasses a complex and heterogeneous group of malignant diseases. Originally, this tumor type was associated with tobacco and alcohol consumption. However, a significantly expanding subset of tumors associated with oncogenic human papillomavirus infection arising in deep tonsillar crypts was identified within the last decades. Due to the essential role of the immune system in antiviral and anticancer immune response, the prognosis of patients is significantly influenced by the volume, composition and functional capacity of the immune infiltrate. The immunosuppressive landscape of head and neck cancer leads to unfavorable outcome of patients and decreased efficacy of immunotherapy. The response rate to standard treatment is high, however, standard therapy is accompanied by considerable toxicity influencing the quality of life. In 2016, the first immunotherapeutics for the treatment of patients with recurrent squamous cell carcinoma of the head and neck were approved - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab. This type of therapy, based on mitigation of immunosuppression, shows strong efficacy and less toxicity in combination with other therapies. Therefore, anti-PD-1 immunotherapy was recently approved in the first-line...
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The cochlea and vestibular apparatus in man-physiological and pathophysiological mechanisms that condition the diagnostic and therapeutic procedure
Holý, Richard ; Hahn, Aleš (advisor) ; Plzák, Jan (referee) ; Jeřábek, Jaroslav (referee)
The issue of the cochleovestibular disorders is part of otoneurology. The scope of the etiopathogenesis of these lesions is wide. The examination of an otoneurological profile using the cochleovestibular diagnostic tests and imaging techniques can distinguish an organic lesion - mostly a vestibular schwannoma - from idiopathic lesions. The treatment of idiopathic and organic lesions is vastly different. The return to the original state takes precedence in the treatment of idiopathic sensorineural hearing impairment. Hyperbaric oxygen therapy plays an important role. This, however, is not the case with a vestibular schwannoma. The removal of a tumor or its radiosurgical treatment to stop its growth is given priority. Observation of tumor growth is an independent method. Preservation of hearing in the state as before the treatment is considered a success. Revealing the etiology of hearing impairment by means of examining a patient's otoneurological profile determines totally different medical procedures and diverse outcomes of the treatments for idiopathic and organic lesions, and this is what the thesis is focusing on. The introductory chapters give an overview of the current knowledge of the anatomy and physiology of the vestibular apparatus in relation to an otoneurological profile. This is...
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Genetical analysis of head and neck squamous cell carcinomas
Čapková, Markéta ; Plzák, Jan (advisor) ; Smilek, Pavel (referee) ; Čelakovský, Petr (referee)
Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. They are associated with high morbidity and mortality. Despite considerable advances in surgical and oncological treatment over the past two decades, overall treatment outcome has only slightly improved. In my thesis I focused on serum gene expression analysis of head and neck cancer patients, which followed the tissue gene expression analysis in same patients. Further we investigated gene expression analysis in tumour stroma, which is now considered as significant factor in cancer initiation and progression. We revealed several candidate genes, which are involved in signalling pathways connected with cell differentiation and proliferation and are involved in apoptotic pathway (BCl-2, BCl-XL a MAX). As well we detected down-regulation of the main tumour suppressor p 53 protein. In peritumoural tissue we detected overexpression of cytokines typical for embryonal development and ectoderm differentiation - IGF-2 and BMP-4, which significantly influence the phenotype of normal keratinocytes. Further we identified several candidate genes relating with overexpression of Gal-1 in stromal myofibroblasts rich tissue (SPIN1, FUSIP1, TRIM23, SLC25A40, PTPLAD1, MP3K2). HNSCC is a heterogeneous disease despite the presence of...
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Impact of pattern and functional properties of tumor-infiltrating immune cells for clinical outcome of head and neck cancer
Hladíková, Kamila ; Špíšek, Radek (advisor) ; Plzák, Jan (referee) ; Reiniš, Milan (referee)
Head and neck squamous cell carcinoma encompasses a complex and heterogeneous group of malignant diseases. Originally, this tumor type was associated with tobacco and alcohol consumption. However, a significantly expanding subset of tumors associated with oncogenic human papillomavirus infection arising in deep tonsillar crypts was identified within the last decades. Due to the essential role of the immune system in antiviral and anticancer immune response, the prognosis of patients is significantly influenced by the volume, composition and functional capacity of the immune infiltrate. The immunosuppressive landscape of head and neck cancer leads to unfavorable outcome of patients and decreased efficacy of immunotherapy. The response rate to standard treatment is high, however, standard therapy is accompanied by considerable toxicity influencing the quality of life. In 2016, the first immunotherapeutics for the treatment of patients with recurrent squamous cell carcinoma of the head and neck were approved - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab. This type of therapy, based on mitigation of immunosuppression, shows strong efficacy and less toxicity in combination with other therapies. Therefore, anti-PD-1 immunotherapy was recently approved in the first-line...
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Prognostic and predictive markers of the head and neck tumors
Kalfeřt, David ; Vokurka, Jan (advisor) ; Brychtová, Svetlana (referee) ; Plzák, Jan (referee)
Prognostic and predictive markers of the head and neck tumors Introduction. Head and neck squamous cell carcinoma (HNSCC) is aggressive tumor with unfavorable prognosis despite the improved therapy in the last decades. HNSCC with its clinicopathological and biological heterogeneity remains difficult to be clinically managed. Therefore, a better understanding its molecular pathobiology is required. The aim of our studies was to analyze the expression profile and possible prognostic and predictive role of selected matrix metalloproteinases (MMP), microRNAs (miR) and proteins p16, p53 and galectin-3 in HNSCC with respect to tumor location (oropharynx, larynx, hypopharynx) and clinicopathological parameters. Material and Methods. Three studies were performed (1. study: prospective, 46 patients, analysis of preoperative serum levels of MMP-1, MMP-2 and MMP-9 by multiplex method MAGPIX (Luminex, TX, USA); 2. study: retrospective, 58 patients, immunohistochemical analysis of p16, p53 and galectin-3; 3. study: retrospective, 51 patients, analysis of tissue let- 7a, miR-21, miR-34a, miR-200c, and miR-375 by real-time quantitative PCR method. Results. Statistically significant differences in serum levels of MMPs between cancers of different locations were not found. Significant correlations were confirmed...
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The cochlea and vestibular apparatus in man-physiological and pathophysiological mechanisms that condition the diagnostic and therapeutic procedure
Holý, Richard ; Hahn, Aleš (advisor) ; Plzák, Jan (referee) ; Jeřábek, Jaroslav (referee)
The issue of the cochleovestibular disorders is part of otoneurology. The scope of the etiopathogenesis of these lesions is wide. The examination of an otoneurological profile using the cochleovestibular diagnostic tests and imaging techniques can distinguish an organic lesion - mostly a vestibular schwannoma - from idiopathic lesions. The treatment of idiopathic and organic lesions is vastly different. The return to the original state takes precedence in the treatment of idiopathic sensorineural hearing impairment. Hyperbaric oxygen therapy plays an important role. This, however, is not the case with a vestibular schwannoma. The removal of a tumor or its radiosurgical treatment to stop its growth is given priority. Observation of tumor growth is an independent method. Preservation of hearing in the state as before the treatment is considered a success. Revealing the etiology of hearing impairment by means of examining a patient's otoneurological profile determines totally different medical procedures and diverse outcomes of the treatments for idiopathic and organic lesions, and this is what the thesis is focusing on. The introductory chapters give an overview of the current knowledge of the anatomy and physiology of the vestibular apparatus in relation to an otoneurological profile. This is...
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Systemic inflammatory and immune response in the treatment of tumor diseases
Holečková, Petra ; Melichar, Bohuslav (advisor) ; Macháček, Jindřich (referee) ; Plzák, Jan (referee)
Systémová a zánětlivá imunitní odpověď při léčbě nádorových onemocnění Imunitní a zánětlivá odpověď je organizmem rozvíjena při každém vnitřním či vnějším inzultu, proto hraje významnou úlohu také při vzniku, růstu a terapii karcinomů. Neméně důležitým mechanismem je oxidační stres. Snížená hladina vitamínu E a A koreluje se zvýšenou hladinou markerů systémového zánětu u pokročilých karcinomů a je špatným prognostickým faktorem. Neopterin je produkován z guanosin - trifosfátu aktivovanými makrofágy v reakci katalyzované GTP - cyklohydrolázou I a je jedním z biomarkerů imunitní odpovědi a reprezentuje molekulu asociovanou s antioxidační rovnováhou. Jeho vysoká koncentrace je asociována se špatnou prognózou maligního onemocnění Karcinomy ORL oblasti jsou relativně časté nádory s vysokou mortalitou. V jejich léčbě jsou uplatňovány multimodální přístupy. Tato intenzivní léčba indukuje řadu specifických akutních i pozdních nežádoucích účinků, které zhoršují kvalitu života nejen v průběhu léčby, ale i po ní. Poznatky o neopterinu, retinolu a - tokoferolu u pacientů s karcinomem ORL oblasti jsou velmi omezené. U nemocných s karcinomy ORL oblasti byl měřen neopterin v moči, retinol a - tokoferol v séru pomocí HPLC. Vysoká hladina neopterinu v moči a nízká hladina retinolu v séru predikovala špatnou...
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Molecular genetic examination of Czech patients and families with hereditary hearing loss and with excluded mutations in GJB2 gene
Pourová, Radka ; Seeman, Pavel (advisor) ; Gaillyová, Renata (referee) ; Plzák, Jan (referee)
Hearing loss is the most common sensory deficit and it affects 1 of 300 newborns. Genetic causes are responsible for 50-75% of cases. The most common cause of hereditary hearing loss (HHL) are mutations of GJB2 gene, which account for 43 % of non-syndromic hearing loss (NSHL) in the Czech Republic. According to literature, the second most common genetic cause of HHL are mutations in SLC26A4 gene. Bialelic mutations in this gene cause NSHL of type 4 (DFNB4) and Pendred syndrome (PS), which means a hearing loss associated with thyroid impairment. A typical symptom of both units is Enlarged Vestibular Aqueduct (EVA) and Mondini dysplasia (MD) on the HRCT of temporal bone. Sequencing of SLC26A4 gene was used to examine 315 patients with NSHL where bialelic mutations in GJB2 gene were dismissed, out of that 30 familiar and 285 sporadic cases. At least one pathogenic mutation in SLC26A4 gene was found in 6.9% patients and bialelic pathogenic mutations in 2.6% patients, however for familial cases it was 14.8% patients with at least one mutation, or 7.4% patients with both identified mutations. In the group of cochlear implant users with no GJB2 mutations at least one pathogenic mutation was found in 13.0% and bialelic mutation in 7.6%. The SLC26A4 mutations appear to represent the second most common cause...
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Genetical analysis of head and neck squamous cell carcinomas
Čapková, Markéta ; Plzák, Jan (advisor) ; Smilek, Pavel (referee) ; Čelakovský, Petr (referee)
Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. They are associated with high morbidity and mortality. Despite considerable advances in surgical and oncological treatment over the past two decades, overall treatment outcome has only slightly improved. In my thesis I focused on serum gene expression analysis of head and neck cancer patients, which followed the tissue gene expression analysis in same patients. Further we investigated gene expression analysis in tumour stroma, which is now considered as significant factor in cancer initiation and progression. We revealed several candidate genes, which are involved in signalling pathways connected with cell differentiation and proliferation and are involved in apoptotic pathway (BCl-2, BCl-XL a MAX). As well we detected down-regulation of the main tumour suppressor p 53 protein. In peritumoural tissue we detected overexpression of cytokines typical for embryonal development and ectoderm differentiation - IGF-2 and BMP-4, which significantly influence the phenotype of normal keratinocytes. Further we identified several candidate genes relating with overexpression of Gal-1 in stromal myofibroblasts rich tissue (SPIN1, FUSIP1, TRIM23, SLC25A40, PTPLAD1, MP3K2). HNSCC is a heterogeneous disease despite the presence of...
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