Head and neck cancer (HNC) makes up 6 ¢H of the cancer patients in the world every year. This disease usually occurs in males and the incidence is increasing year by year. According to statistical analysis, HNC has less than 50 ¢H five-year survival rate. Therefore, the research of HNC seems imminent so that may lead to the development of new approaches of diagnosis and therapy. Recent research had shown that expression of podoplanin caused cellular proliferation, and may be associated with tumor invasion, metastasis and malignant prognosis. Podoplanin, a mucin-type transmembrane sialoglycoprotein, is highly expressed in lymphatic endothelial cells but not expressed in vascular endothelial cells. The purpose of this study was to determine the clinical and pathological significance of podoplanin in oral squamous cell carcinoma (OSCC). Therefore, we collected clinical specimen and associated patient history of OSCC. Further, we used the human cell lines of HNSCC (Fadu, Hep2) to investigate the molecular regulation of podoplanin. Podoplanin expression was analyzed by RT-PCR and Western blot assay firstly. As shown, podoplanin was found to be overexpressed in tumors compared with normal adjacent tissues. Further, immunohistochemical analysis revealed the location of podoplanin expression in OSCC tissues. The results showed that podoplanin had higher expression in T4 stage tumor section than in normal adjacent tissues of OSCC samples, or in T1 stage. Here, podoplanin was highly expressed in the OSCC tumor cell and lymphatics of stage T4 OSCC tissue. Furthermore, we found that overexpression of podoplanin in OSCC patients was associated with decreased five-years survival rate. In the univariate analysis, several factors were statistically significantly associated with disease-specific survival rate, including Tumor stage, Nodal stage, and podoplanin expression. In the subsequent multivariate analysis, only Tumor stage and Nodal stage showed a trend toward worse disease-specific survival. To further investigate the regulatory mechanism of podoplanin and its position of expression within the cell, immunofluorescence and transfection were utilized to assay. The results showed that podoplanin was expressed in the nuclear membrane of the Fadu and Hep2 cell lines, and the PI3K/AKT signaling pathway was involved. We suggest that the role of podoplanin in OSCC should be further investigated for potential future treatment.

There is some evidence to suggest that human papilloma virus (HPV) may play a causal role in head and neck carcinoma (HNSCC). The aim of this study was to investigate the prevalence of HPV DNA in HNSCC and to determine whether any correlation exists with p16 or survival. An initial pilot study of sixty formalin-fixed HNSCC was carried out in order to optimise the methodology for the PCR and immunohistochemistry. A further 84 benign lesions, 12 dysplasias and additional 80 HNSCC were also included. In the pilot study the prevalence of all HPV types was 67% of which 18% were high risk-HPV (HR-HPV) and for the combined carcinoma sample it was 59% of which 25% were HR-HPV. The overall HPV prevalence was 51% and 42% for benign lesions and dysplasias with HR-HPV accounting for 14% and 8% respectively. A total of four alpha HPV types were identified and eleven beta HPV types. Multiple HPV types co-existed in the same tissue and in some cases both alpha and beta HPV. The results may suggest that HR-HPV may play a role in a small subset of HNSCC. An association was found between HPV status and gender, age group, survival, nodal metastasis and T3 tumour size and smoking. HPV16 was predominantly present in female patients and was associated with an improved overall survival and recurrence free survival. p16 positivity varied from 76-78% in carcinomas, 51% in benign lesions and 66% in dysplasias. p16 status was not associated with disease recurrence or nodal metastasis. Positive p16 staining and high staining intensity was associated with a poorer overall survival and the male gender, an older age group, anatomic site, and T2 tumour size. Overall HPV status was not correlated with p16 expression but a correlation found between p16 and HPV16 may suggest that p16 could potentially act as a surrogate marker of HPV16. However, the lack of concordance would suggest that in isolation p16 may not be a reliable marker for HR-HPV and should not be relied upon in isolation. Our findings could suggest that HPV16 and p16 status may be independent predictors for prognosis and disease recurrence.

A systems biology approach was adopted in order to assess various aspects of the disease oral squamous cell carcinoma. Three main aims were addressed; assess the ability of CoCl2 to mimic the hypoxic response in a eukaryotic cell line, assess the role of PDE4D in oral squamous cell carcinoma (OSCC) and the construction of a normoxic/hypoxic mathematical model to identify therapeutic targets.Cancer cells often acquire a revised metabolism which aids in initiation, survival and progression of the tumour. This is predominantly due to the transcription factor HIF-1 which is activated under hypoxic conditions. Certain compounds such as cobalt chloride (CoCl2) have been used extensively to inhibit the degradation of HIF-1α and simulate hypoxia. CoCl2 is likely to have off-target effects on metabolism; these effects were examined when exposing human telomerase reverse transcriptase (hTERT) cells to 100μM CoCl2. Gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS) based metabolomics were utilised in combination with ELISA assays for HIF-1α and ATP. Central metabolism was accurately mimicked when hTERT cells were subjected to 100μM CoCl2, however; it was apparent that this concentration of CoCl2 does not induce an equal extent of hypoxia as 1% oxygen. A number of off-target effects of CoCl2 were observed in secondary metabolism, specifically in lipids and fatty acids. In conclusion, CoCl2 should be used with caution as a hypoxic mimicker with the caveat that interpretation of results should be restricted to its effects on central metabolism.The transcription factor CREB has the ability to regulate approximately 4000 genes, a number of which are associated with cancer initiation and progression. Cyclic adenosine monophosphate (cAMP) is required to activate CREB and is partially regulated through its degradation via the enzyme phosphodiesterase type 4D (PDE4D). A homozygous deletion of PDE4D has been associated with OSCC; however; the exact consequence of this deletion has not been fully elucidated. PDE4D was knocked down in the OSCC cell line BicR16 and cellular proliferation, migration, resistance to ionising radiation and central metabolism was investigated using MTT, scratch, clonogenic and GC-MS, respectively. The knockdown resulted in an increase in proliferation, migration and radiation resistance suggesting the role of PDE4D as a TSG. Amino acids, cholesterol, fatty acids, carbohydrates and TCA intermediates were found to be altered in concentration.A mathematical model of glycolysis, TCA and glutaminolysis under normoxia and hypoxia was constructed through the amalgamation of two established models from the literature. New reactions, parameters and metabolite concentrations were added and unnecessary entities were deleted. COmplex PAthway SImulator (COPASI) was utilised to construct the model before validating the model using experimental data from the literature and steady state and flux analyses. Sensitivity analysis and a reduction in external glucose and glutamine were mimicked and the alterations in hypoxic and normoxic metabolism analysed. The reactions vCSII, vGS, vPGK and vGII were identified as potential therapeutic targets which may affect metabolism in hypoxia only. However, certain validation methods proved unsuccessful and hence the model requires further work before attempting the analyses again.

Magister Chirurgiae Dentium (MChD) / Oral Squamous Cell Carcinoma (OSCC) patients suffer from the terrible consequences of the disease and its treatment modalities, and as a result, their Quality of Life (QoL) and Oral Health-related Quality of Life (OHRQoL) is badly affected, especially due to functional limitation, physical disability and psychological disability that they encounter before, during and after treatment. There is a need for more research on OHRQoL of OSCC patients at various treatment intervals. The present study focused on investigating OHRQoL of OSCC patients at the post-treatment phase.

O carcinoma epidermóide da cavidade oral (CEO) é o tumor maligno mais frequente da região da cabeça e pescoço. O Chk2 (Checkpoint kinase 2) é considerado um supressor tumoral que atua na resposta celular ao dano do DNA. Entretanto, a relação do Chk2 entre CEO ainda não está compreendida. O objetivo deste estudo foi avaliar a imunoexpressão do Chk2 nos CEOs e associar sua expressão com parâmetros clínico-patológicos de importância prognóstica, incluindo a sobrevida global, sobrevida livre de doença e livre de metástase. A expressão de Chk2 foi analisada em 104 amostras de pacientes com CEO por meio da técnica de imunoistoquímica e foi positiva em 97,11% dos nossos casos com CEO, com isso, estratificamos apenas os casos de marcação positiva, e dividimo-los em alta expressão (> 66%) e baixa expressão (<66%), e excluímos os casos negativos de nossa análise, pois o número de casos com expressão negativa para Chk2 seria inclusivo para realizarmos as análises estatísticas. A positividade de Chk2 na maioria dos nossos casos sugere que o Chk2 possa estar envolvido na patogênese desses tumores, porém em nosso trabalho, a expressão de Chk2 não se associou com os parâmetros prognósticos. Não houve diferença entre a sobrevida global, sobrevivência livre de metástases e sobrevida livre de doença de acordo com a marcação de Chk2. Em conclusão, em nossos achados, o Chk2 não pode ser considerado como um biomarcador prognóstico do carcinoma de células epidermóides da cavidade oral. / Squamous cell carcinoma of the oral cavity (CEO) is the most frequent malignant tumor of the head and neck region. Chk2 (Checkpoint kinase 2) is considered a tumor suppressor that acts on the cellular response to DNA damage. However, the Chk2 relationship between CEO is not yet understood. The objective of this study was to evaluate the Chk2 immunoexpression in the CEOs and to associate their expression with clinical-pathological parameters of prognostic importance, including global survival, disease-free survival, and metastasis-free. The expression of Chk2 was analyzed in 104 samples of patients with CEO using the immunohistochemistry technique and was positive in 97.11% of our cases with CEO, with that, we stratified only the cases of positive marking, and we divided them into high expression (> 66%) and low expression (<66%), and we excluded the negative cases from our analysis, since the number of cases with negative expression for Chk2 would be inclusive for the statistical analysis. The positivity of Chk2 in most of our cases suggests that Chk2 may be involved in the pathogenesis of these tumors, but in our study, the expression of Chk2 was not associated with the prognostic parameters. There was no difference between overall survival, metastasis-free survival, and disease-free survival according to the Chk2 labeling. In conclusion, in our findings, Chk2 cannot be considered as a prognostic biomarker of oral squamous cell carcinoma.

O carcinoma epidermóide da cavidade oral (CEO) é o tumor maligno mais frequente da região da cabeça e pescoço. O Chk2 (Checkpoint kinase 2) é considerado um supressor tumoral que atua na resposta celular ao dano do DNA. Entretanto, a relação do Chk2 entre CEO ainda não está compreendida. O objetivo deste estudo foi avaliar a imunoexpressão do Chk2 nos CEOs e associar sua expressão com parâmetros clínico-patológicos de importância prognóstica, incluindo a sobrevida global, sobrevida livre de doença e livre de metástase. A expressão de Chk2 foi analisada em 104 amostras de pacientes com CEO por meio da técnica de imunoistoquímica e foi positiva em 97,11% dos nossos casos com CEO, com isso, estratificamos apenas os casos de marcação positiva, e dividimo-los em alta expressão (> 66%) e baixa expressão (<66%), e excluímos os casos negativos de nossa análise, pois o número de casos com expressão negativa para Chk2 seria inclusivo para realizarmos as análises estatísticas. A positividade de Chk2 na maioria dos nossos casos sugere que o Chk2 possa estar envolvido na patogênese desses tumores, porém em nosso trabalho, a expressão de Chk2 não se associou com os parâmetros prognósticos. Não houve diferença entre a sobrevida global, sobrevivência livre de metástases e sobrevida livre de doença de acordo com a marcação de Chk2. Em conclusão, em nossos achados, o Chk2 não pode ser considerado como um biomarcador prognóstico do carcinoma de células epidermóides da cavidade oral. / Squamous cell carcinoma of the oral cavity (CEO) is the most frequent malignant tumor of the head and neck region. Chk2 (Checkpoint kinase 2) is considered a tumor suppressor that acts on the cellular response to DNA damage. However, the Chk2 relationship between CEO is not yet understood. The objective of this study was to evaluate the Chk2 immunoexpression in the CEOs and to associate their expression with clinical-pathological parameters of prognostic importance, including global survival, disease-free survival, and metastasis-free. The expression of Chk2 was analyzed in 104 samples of patients with CEO using the immunohistochemistry technique and was positive in 97.11% of our cases with CEO, with that, we stratified only the cases of positive marking, and we divided them into high expression (> 66%) and low expression (<66%), and we excluded the negative cases from our analysis, since the number of cases with negative expression for Chk2 would be inclusive for the statistical analysis. The positivity of Chk2 in most of our cases suggests that Chk2 may be involved in the pathogenesis of these tumors, but in our study, the expression of Chk2 was not associated with the prognostic parameters. There was no difference between overall survival, metastasis-free survival, and disease-free survival according to the Chk2 labeling. In conclusion, in our findings, Chk2 cannot be considered as a prognostic biomarker of oral squamous cell carcinoma.

Made available in DSpace on 2014-12-17T15:32:25Z (GMT). No. of bitstreams: 1 AndreaFS_tese.pdf: 610478 bytes, checksum: 22934e3fba7a401686d3b0057e0e7f35 (MD5) Previous issue date: 2007-07-11 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The expression of bone morphogenetic proteins (BMPs) is altered in a variety of human canceres. The BMP-2/4 and BMPR-IA were recently shown to be overexpressed in high-risk premalignant and malignant lesions of oral epithelium. The present study analysed the expression of BMP-2/4 and BMPR-IA in Oral Squamous Cell Carcinoma (OSCC) such as their implications in disease prognostic using munohistochemistry. Ten cases of Oral Fibroepithelial Hiperplasia were selected as a control group. The experimental group included 16 cases of OSCC without metastases and 7 cases of OSCC metastatic. The presence or absence of nodal metastases was used as parameter to evaluated the disease prognostic. The results demonstrated weak immunoreactivity for BMP-2/4 and BMPR-IA in every case of the control group. In the cases of OSCC with metastases an overexpression of BMP-2/4 (71,4%) was observed while the BMPR-IA showed weak expression (85,7%). In the cases of OSCC without metastases BMP-2/4 (62,5%) and BMPR-IA showed strong immunostaining standing out an overexpression of the receptor in all the specimens. Observed statistical significance for correlation between the oral cancer prognostic and the staining intensity of the BMP-2/4 (p=0,002). There wasn t statistical significance for association between the staining intensity of the BMPR-IA and the disease prognostic (p<0,001). In conclusion, this findings suggest that the overexpression of BMP-2/4 associated with the loss of expression of the BMPR-IA in OSCC metastatic has prognostic relevance, as the loss of sensitivity to BMPs can be an indicative of metastases development in OSCC / A express?o das prote?nas morfogen?ticas ?sseas (BMPs) est? alterada em v?rios c?nceres humanos. A BMP-2/4 e o BMPR-IA foram recentemente encontrados superexpressos em les?es malignas e pr?-malignas de alto risco em epit?lio oral. Este estudo analisou a express?o da BMP-2/4 e seu receptor BMPR-IA em 23 esp?cimes de Carcinoma Epiderm?ide Oral (CEO), utilizando a imuno-histoqu?mica. O grupo controle constou de 10 casos de Hiperplasia Fibro-epitelial da mucosa oral. O grupo experimental foi constitu?do por 16 casos de CEO n?o metast?tico e 7 casos de CEO metast?tico. Utilizou-se o par?metro presen?a ou aus?ncia de met?stase nodal para avaliar o progn?stico da doen?a. Os resultados demonstraram imunorreatividade fraca para a BMP-2/4 e o BMPR-IA em todos os esp?cimes do grupo controle. No grupo experimental com met?stase, a BMP-2/4 exibiu forte expressividade (71,4%), enquanto que o BMPR-IA mostrou fraca express?o (85,7%). No grupo experimental sem met?stase, evidenciou-se forte express?o para a BMP-2/4 (62,5%) e para o BMPR-IA (100%). Encontrou-se signific?ncia estat?stica para a associa??o entre o progn?stico do CEO e a intensidade de marca??o da BMP-2/4 (p=0,002). Para o BMPR-IA n?o houve signific?ncia estat?stica ? sua associa??o com o progn?stico da doen?a (p<0,001), em fun??o do tamanho da amostra. Portanto, os resultados sugerem que a fraca expressividade do BMPR-IA associada ? forte express?o da BMP-2/4, no grupo experimental com met?stase, tem relev?ncia progn?stica, j? que a perda de sensibilidade ?s BMPs, atrav?s da perda de express?o de seus receptores pode ser indicativo de desenvolvimento de met?stase em CEO

No description available.

Background: Standardized staging procedures and presentation of oral squamous cell carcinoma (OSCC) patients in multidisciplinary tumor boards (MDTB) before treatment and utilization of elective neck dissection (ND) are expected to improve the outcome, especially in local advanced LAOSCC (UICC stages III–IVB). As standardized diagnostics but also increased heterogeneity in treatment applied so far have not been demonstrated to improve outcome in LAOSCC, a retrospective study was initiated. Methods: As MDTB was introduced into clinical routine in 2007, 316 LAOSCC patients treated during 1991-2017 in our hospital were stratified into cohort 1 treated before (n=104) and cohort 2 since 2007 (n=212). Clinical characteristics, diagnostic procedures and treatment modality of patients were compared using Chi-square tests and outcome analyzed applying Kaplan-Meier plots and log-rank tests as well as Cox proportional hazard regression. Propensity scores (PS) were used to elucidate predictors for impaired distant metastasis-free survival (DMFS) in PS-matched patients. Results: Most patient characteristics and treatment modalities applied showed insignificant alteration. Surgical treatment included significantly more often resection of the primary tumor plus neck dissection, tracheostomy and percutaneous endoscopic gastrostomy tube use. Cisplatin-based chemo-radiotherapy was the most frequent. Only insignificant improved disease- (DFS), progression- (PFS) and event-free (EFS) as well as tumor-specific (TSS) and overall survival (OS) were found after 2006 as local (LC) and locoregional control (LRC) were significantly improved but DMFS significantly impaired. Cox regression applied to PS-matched patients elucidated N3, belonging to cohort 2 and cisplatin-based chemo-radiotherapy as independent predictors for shortened DMFS. The along chemo-radiotherapy increased dexamethasone use in cohort 2 correlates with increased DM. Conclusions: Despite standardized diagnostic procedures, decision-making considering clear indications and improved therapy algorithms leading to improved LC and LRC, shortened DMFS hypothetically linked to increased dexamethasone use had a detrimental effect on TSS and OS.

Objective: In many countries the access to high quality medical service depends on socioeconomic factors. Therefore, these factors are associated with the treatment and prognosis of many diseases. In Germany health care is claimed to be independent from such factors due to obligatory health insurance and a well-developed medical infrastructure. Thus, socioeconomically caused health disparities should be absent. The aim of this study was to analyze the association between socioeconomic factors and the survival of oral cavity cancer in Germany. Patients and methods: In this descriptive cohort study socioeconomic status related factors as well as demographic, tumor-specific, and comorbidity factors of 500 patients treated for oral cavity cancer were obtained in the university hospital of Dresden. Pearson correlation was used to describe associations between continuous variables. Associations between categorical variables were assessed using the chi-square test. Overall and recurrence-free survival were studied using the Kaplan-Meier method. Log-rank test was carried out to test between-group differences. Cox proportional hazard models were used to estimate the risk of death and the risk of recurrence. Results: Significant differences in overall survival were found between the different educational levels and sex. Seventy-nine percent of the patients did not have a university degree or master craftsman/craftswoman. Less discrepancy was observed according to the marital status (49.4% married/engaged vs. 47.8% single, divorced, or widowed). In the multivariable analysis only sex, age at diagnosis, the Charlson score, the number of positive lymph nodes, and the nodal status were identified as independent predictors for overall survival whereas sex and the age at diagnosis were identified as independent predictors for recurrence-free survival. Conclusion: Despite the equitable health system in Germany, significant associations between overall survival of oral cavity cancer and different socioeconomic factors could be found. For elimination of these disparities, health education programs should be established in socially deprived areas. Furthermore, clinicians should keep these factors in mind when determining recall periods for dental check-ups.