Zvýšenou expresi receptoru pro epidermální růstový faktor (EGFR) nacházíme až u 90 % spinocelulárních karcinomů hlavy a krku. Nadměrná exprese EGFR je spojena s horším přežitím. Inhibitory EGFR, jako je cetuximab, prokázaly významný protinádorový účinek. Režim EXTREME (cetuximab a cisplatina + 5-fluorouracil) byl zlatým standardem v 1. linii R/M HNSCC od roku 2008. Nahrazení 5-fluorouracilu taxany využívá jejich potenciální imunogenní synergie s cetuximabem. Režim TPEx se jeví jako přijatelná alternativa k režimu EXTREME, s kratší chemoterapeutickou fází a příznivým bezpečnostním profilem. Recentní klinická studie KEYNOTE-048 prokázala lepší výsledky léčby samotným pembrolizumabem a pembrolizumabem plus chemoterapií oproti předchozímu standardu s cetuximabem. Účinnost pembrolizumabu u R/M HNSCC se výrazně liší podle exprese PD-L1. Cetuximab zůstává metodou volby v 1. linii u R/M HNSCC neexprimujících PD-L1 nebo u pacientů nevhodných k imunoterapii.

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of squamous cell carcinoma of the head and neck. The overexpression of EGFR is associated with poorer survival. EGFR inhibitors such as cetuximab have shown a significant antitumoral effect. The EXTREME regimen (cetuximab and cisplatin + 5-fluorouracil) has been the gold standard of care in first-line R/M HNSCC since 2008. Replacing 5-FU with a taxane seeks to take advantage of the potential immunogenic synergy between cetuximab and taxane. The TPEx regimen appears to be a acceptable alternative to EXTREME regimen, with a shorter chemotherapeutic phase and a favourable safety profile. Recent clinical study KEYNOTE-048 demonstrated better treatment outcomes with pembrolizumab alone or pembrolizumab plus chemotherapy than previous standard treatment with cetuximab. However, the effectiveness of pembrolizumab vary significantly according to PD-L1 status. Cetuximab remains the method of choice in the first-line R/M HNSCC that does not express PD-L1 or in patients unsuitable for immunotherapy.

• Publikační typ
• abstrakty MeSH

Approximately 90 % of head and neck cancers are squamous cell carcinomas (HNSCC), and the overall 5-year survival rate is not higher than 50 %. There is much evidence that human papillomavirus (HPV) infection may influence the expression of commonly studied HNSCC markers. Our study was focused on the possible HPV-specificity of molecular markers that could be key players in important steps of cancerogenesis (MKI67, EGF, EGFR, BCL-2, BAX, FOS, JUN, TP53, MT1A, MT2A, VEGFA, FLT1, MMP2, MMP9, and POU5F). qRT-PCR analysis of these selected genes was performed on 74 biopsy samples of tumors from patients with histologically verified HNSCC (22 HPV-, 52 HPV+). Kaplan-Meier analysis was done to determine the relevance of these selected markers for HNSCC prognosis. In conclusion, our study confirms the impact of HPV infection on commonly studied HNSCC markers MT2A, MMP9, FLT1, VEGFA, and POU5F that were more highly expressed in HPV-negative HNSCC patients and also shows the relevance of studied markers in HPV-positive and HPV-negative HNSCC patients.

• MeSH
• DNA virů genetika   MeSH
• dospělí MeSH
• infekce papilomavirem komplikace   virologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   MeSH
• nádory hlavy a krku etiologie   patologie   MeSH
• následné studie MeSH
• Papillomaviridae genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom etiologie   patologie   MeSH
• staging nádorů MeSH
• stanovení celkové genové exprese MeSH
• studie případů a kontrol MeSH
• stupeň nádoru MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

• MeSH
• imunoterapie MeSH
• infekce papilomavirem MeSH
• klinické zkoušky jako téma MeSH
• kongresy jako téma MeSH
• monoklonální protilátky MeSH
• nádory hlavy a krku epidemiologie   terapie   MeSH
• sexuální chování MeSH
• vakcíny proti papilomavirům MeSH

• Publikační typ
• abstrakt z konference MeSH

BACKGROUND AND AIMS: There is evidence of differences in p63 expression in HNSCC (head and neck squamous cell carcinoma) tumours of different sub-sites within the oral cavity which appear to have an important role in CD44 regulation. The aim of this study was to investigate CD44 expression in HNSCC tumours in different areas of the oral cavity. METHODS: Formalin-fixed and paraffin-embedded oral squamous cell carcinoma specimens from 29 patients were investigated. Expression of CD44s was detected by immunohistochemistry with specific CD44 antibodies and analysed using the H-score. The samples were classified by anatomic location (tongue; floor of the mouth; gingiva and other group included hard palate, tonsils, naso- and oropharynx) and histological tumour grade (G1 and G2-G3). Fischer's exact test with a Bonferroni correction was used for the statistical analysis. RESULTS: Positive immunostaining for CD44s in carcinomas of the tongue was significantly lower (0%) than that of the floor of the mouth (85%; P=0.003) or other group (100%; P=0.003). No statistically significant differences in CD44s expression were found for different histological tumour grades. CONCLUSIONS: The results indicate that CD44 expression is strongly reduced in tongue tumours compared with other sub-sites within the oral cavity. This should be taken into consideration in assessing the prognostic value of CD44s in this tumour group.

• MeSH
• antigeny CD44 biosyntéza   MeSH
• lidé MeSH
• nádory hlavy a krku metabolismus   MeSH
• nádory úst metabolismus   MeSH
• spinocelulární karcinom metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential.

• MeSH
• dospělí MeSH
• epigenomika * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové buněčné linie MeSH
• nádory hlavy a krku genetika   patologie   MeSH
• pohyb buněk genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory Notch genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• RNA interference MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• shluková analýza MeSH
• signální transdukce genetika   MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• tumor supresorové geny * MeSH
• ubikvitinligasy genetika   MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.

• MeSH
• biologické markery MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky imunologie   metabolismus   patologie   MeSH
• dlaždicobuněčné karcinomy hlavy a krku etiologie   metabolismus   patologie   MeSH
• exprese genu MeSH
• infekce papilomavirem komplikace   virologie   MeSH
• interferon alfa imunologie   metabolismus   MeSH
• lidé MeSH
• náchylnost k nemoci MeSH
• nádorové mikroprostředí * imunologie   MeSH
• regulační T-lymfocyty imunologie   metabolismus   MeSH
• studie případů a kontrol MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• virová transformace buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Head and neck squamous cell carcinoma (HNSCC) is a group of malignancies with serious impact on patient quality of life due to a reduced rate of response to chemotherapy or radiation therapy. MiR-21 has been identified as one of the most common proto-oncogenes. It is hypothesized that upregulated miR-21 could serve as a potential biomarker for human cancer diagnosis. Considering the target genes identified for miR-21 in HNSCC, this transcript is an important player in several cellular processes that control carcinogenesis. The abnormal expression of miR-21 in this group of pathologies has been assessed in several publications, but given the heterogeneity of the published results, a meta-analysis and proper bioinformatics analysis of expression databases are needed to correctly establish the prognostic potential of this molecule. The present meta-analysis comprises the published survival data on HNSCC patients, reported as HR and 95% CI, in association with the expression levels of miR-21. Our investigation revealed that miR-21 could be used successfully as a prognostic biomarker in HNSCC patients, confirming its oncogenic potential. Specifically, the upregulation of miR-21 in these patients predicts a worse outcome in terms of survival rate.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH