Dissertations / Theses on the topic 'Oral cancer diagnosis'

El càncer oral és considerat, globalment, un problema de salut pública. Aquest té una taxa de supervivència al cap de 5 anys del 50%, ja que el seu diagnòstic es realitza, en general, en estadis avançats. Pel que fa al seu tractament, normalment, hi participa un equip multidisciplinari per tal de proporcionar una atenció integral als individus que pateixen aquesta malaltia. Actualment, hi ha un nombre considerable de publicacions científiques que suggereixen l’ús de diferents opcions terapèutiques; però, la qualitat d’aquesta evidència es desconeix. Per tant, es requereix una avaluació crítica de l’evidència sobre el diagnòstic i el tractament del càncer oral. Es van realitzar tres estudis independents que utilitzaven diferents dissenys metodològics. Per descriure i avaluar la qualitat de l’evidència científica sobre el diagnòstic i els tractaments per al càncer oral, es va dissenyar i realitzar: i) un estudi de mapatge de l’evidència per tal de descriure l’evidència disponible sobre les principals intervencions terapèutiques per a càncer oral; ii) un estudi d’avaluació critica sistemàtica per determinar la qualitat de guies de pràctica clínica sobre tractaments de càncer oral, i iii) un estudi d’avaluació critica sistemàtica per determinar la qualitat de guies de pràctica clínica sobre diagnòstic de càncer oral, i descriure les seves recomanacions. L’estudi de mapatge de l’evidència va incloure 15 revisions sistemàtiques que incloïen 118 estudis primaris; d’aquests, el 55,1% van ser assaigs clínics controlats aleatoritzats. Deu revisions sistemàtiques van tenir una qualitat metodològica “summament baixa”. Es van extreure trenta preguntes PICOs, les quals es van enfocar en intervencions com ara cirurgia, radioteràpia, quimioteràpia, teràpia dirigida i immunoteràpia; 18 PICOs eren per càncer oral operable, de les quals vuit van ser reportades com a “beneficiosa”. Hi va haver 12 PICOs per càncer oral inoperable, de les quals només dos van ser reportades com a “beneficiosa”. En el segon estudi, es van incloure 12 guies de pràctica clínica. La mitjana de la puntuació per a cada domini de l’AGREE II van ser: “abast i propòsit”, 88,4% ± 12,4%; “Participació dels interessats”, 60,4% ± 25%; “Rigor de desenvolupament”, 60,9% ± 25,3%; “Claredat de presentació”, 76,5% ± 19,8%; “Aplicabilitat”, 32,2% ± 30,7%; i “independència editorial”, 61,6% ± 35,5%. Tres guies van ser classificades com a “recomanada”, sis com a “recomanada amb modificacions”; i tres com a “no recomanada”. En l’últim estudi, es van seleccionar vuit guies de pràctica clínica. La mitjana de la puntuació per als sis dominis de l’AGREE II van ser: “abast i propòsit”, 97,9% (RIC: 96,2-100,0%); “Participació dels interessats”, 86,1% (RIC: 69,8-93,1%); “Rigor de desenvolupament”, 75,3% (RIC: 64,2-94,3%); “Claredat de presentació”, 91,7% (RIC: 82,6-94,4%); “Aplicabilitat”, 53,1% (RIC: 19,3-74,2%); i “independència editorial”, 83,3% (RIC: 67,2-93,8%). Quatre guies van ser classificades com a “recomanada”, quatre com a “recomanada amb modificacions” i cap com a “no recomanada”. Es van identificar 23 recomanacions, majoritàriament basades en nivell d’evidència “baixa” o “molt baixa”. En general, l’evidència científica sobre els tractaments de càncer oral és limitada i la seva qualitat és summament baixa. Així mateix, la qualitat metodològica de guies de pràctica clínica sobre diagnòstic i tractaments per al càncer oral va ser considerada des de subòptima fins a moderada. A més, la majoria de les seves recomanacions es van basar en un nivell d’evidència “baixa”. Aquestes troballes ressalten la necessitat de realitzar futures investigacions sobre nous tractaments i buits del coneixement identificats en aquesta àrea; així mateix, són necessaris més esforços per permetre el desenvolupament de guies basades en evidència d’alta qualitat per al càncer oral.
El cáncer oral es considerado un problema de salud pública globalmente. Este tiene una tasa de supervivencia a los 5 años del 50%, debido a que su diagnóstico se realiza comúnmente en estadios avanzados. En su tratamiento usualmente participa un equipo multidisciplinario para proporcionar una atención integral a los individuos que padecen esta enfermedad. Actualmente, existe un número considerable de publicaciones científicas que sugieren el uso de diferentes opciones terapéuticas y recomendaciones para su diagnóstico; sin embargo, la calidad de esta evidencia se desconoce. Por lo tanto, se requiere una evaluación crítica de la evidencia sobre el diagnóstico y tratamiento de cáncer oral. Tres estudios independientes fueron realizados usando diferentes diseños metodológicos. Para describir y evaluar la calidad de la evidencia científica sobre el diagnóstico y tratamientos para el cáncer oral, se diseñó y realizó: i) un estudio de mapeo de la evidencia para describir la evidencia disponible sobre principales intervenciones terapéuticas para cáncer oral; ii) un estudio de evaluación crítica sistemática para determinar la calidad de guías de práctica clínica sobre tratamientos de cáncer oral, y iii) un estudio de evaluación critica sistemática para determinar la calidad de guías de práctica clínica sobre diagnóstico de cáncer oral, y describir sus recomendaciones. El estudio de mapeo de la evidencia incluyó 15 revisiones sistemáticas abarcando 118 estudios primarios; de estos 55,1% fueron ensayos clínicos controlados aleatorizados. Diez revisiones sistemáticas tuvieron una calidad metodológica “muy baja”. Treinta preguntas PICOs fueron extraídas, las cuales se enfocaron en intervenciones como cirugía, radioterapia, quimioterapia, terapia dirigida e inmunoterapia; 18 PICOs eran para cáncer oral operable, de las cuales ocho fueron reportadas como beneficiosa. Hubo 12 PICOs para cáncer oral inoperable, de las cuales solo dos fueron reportadas como beneficiosas. En el segundo estudio se incluyeron 12 guías de práctica clínica. Los puntajes promedio para cada dominio del AGREE II fueron: “alcance y propósito” 88,4%±12,4%; “participación de los interesados” 60,4%±25%; “rigor de desarrollo” 60,9%±25,3%; “claridad de presentación” 76,5%±19,8%; “aplicabilidad” 32,2%±30,7%; y “independencia editorial” 61,6%±35,5%. Tres guías fueron clasificadas como “recomendada”, seis como “recomendada con modificaciones”; y tres como “no recomendada”. En el último estudio ocho guías de práctica clínica fueron seleccionadas. Los puntajes en mediana para los seis dominios del AGREE II fueron: “alcance y propósito” 97,9% (RIC: 96,2-100%); “participación de los interesados” 86,1% (RIC: 69,8-93,1%); “rigor de desarrollo” 75,3% (RIC: 64,2-94,3%); “claridad de presentación” 91,7% (RIC: 82,6-94,4%); “aplicabilidad” 53,1% (RIC: 19,3-74,2%); y “independencia editorial” 83,3% (RIC: 67,2-93,8%). Cuatro guías fueron clasificadas como “recomendada”, cuatro como “recomendada con modificaciones” y ninguna como “no recomendada”. Se identificaron 23 recomendaciones, en su mayoría basadas en nivel de evidencia “baja” o “muy baja”. En general, la evidencia científica sobre los tratamientos de cáncer oral es limitada y su calidad es muy baja. Asimismo, la calidad metodológica de guías de práctica clínica sobre diagnóstico y tratamientos para el cáncer oral fue considerada desde subóptima hasta moderada. Además, la mayoría de sus recomendaciones fueron basadas en un nivel de evidencia “baja”. Estos hallazgos resaltan la necesidad de realizar futuras investigaciones sobre nuevos tratamientos y vacíos del conocimiento identificados en esta área; asimismo mayores esfuerzos son necesarios para permitir el desarrollo de guías basadas en evidencia de alta calidad para cáncer oral.
Oral cancer is considered a public health problem worldwide. It has a 5-year survival rate of 50% due to diagnosis are commonly performed at advanced stage of the disease. Its treatment usually involves a multidisciplinary team to provide comprehensive healthcare to people that suffer from this disease. Nowadays, there is a vast number of scientific publications suggesting the use of different therapeutic interventions and recommendations for its diagnosis, but their quality is unknown. Thus, a critical appraisal of evidence about diagnosis and treatments for oral cancer is needed. Three independent studies were carried out using different methodology designs. In order to describe and assess the quality of scientific evidence on diagnosis and treatments for oral cavity cancer, we designed and conducted: i) an evidence mapping study to describe the available evidence about the main therapeutic interventions for oral cancer; ii) a systematically critical assessment study to determine the quality of clinical practice guidelines on treatments for oral cavity cancer; and iii) a systematically critical assessment study to assess the quality of clinical practice guidelines on oral cancer diagnosis, and to describe their recommendations. The evidence mapping study included 15 systematic reviews involving 118 primary studies, of which 55.1% were randomized controlled clinical trials. Ten systematic reviews scored “critically low” methodological quality. We extracted 30 PICOs focusing on interventions such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy; 18 PICOs were for resectable oral cancer, of which 8 were reported as beneficial. There were 12 PICOs for unresectable oral cancer, of which only 2 interventions were reported as beneficial. In the second study, 12 clinical practice guidelines were included. The mean scores for each AGREE II domain were the following: “scope and purpose” 88.4%±12.4%; “stakeholder involvement” 60.4%±25%; “rigor of development” 60.9%±25.3%; “clarity of presentation” 76.5%±19.8%; “applicability” 32.2%±30.7%; and “editorial independence” 61.6%±35.5%. Three guidelines were rated as “recommended”; six as “recommended with modifications”; and three as “not recommended”. In the last study, eight clinical practice guidelines were selected. The median scores of the six AGREE II domains were as follows: “scope and purpose” 97.9% (IQR: 96.2-100.0%); “stakeholder involvement” 86.1% (IQR: 69.8-93.1%); “rigor of development” 75.3% (IQR: 64.2-94.3%); “clarity of presentation” 91.7% (IQR: 82.6-94.4%); “applicability” 53.1% (IQR: 19.3-74.2%); and “editorial independence” 83.3% (IQR: 67.2-93.8%). Four guidelines were assessed as “recommended”, four “recommended with modifications”, and none “not recommended”. Twenty-three recommendations were provided, mostly with a low or very low level of evidence. Overall, the scientific evidence about treatments for oral cancer is limited and its quality is critically low. Likewise, the methodological quality of clinical practice guidelines on diagnosis and treatments for oral cancer was rated from suboptimal to moderate. Moreover, most recommendations were based on a low level of evidence. These findings highlight the need to address future research focused on new treatments and knowledge gaps identified in this field, and increased efforts are required to enable the development of high-quality evidence-based guidelines for oral cancer.

Objectives: Intact cell peptidome profiling (ICPP) with MALDI-ToF Mass-Spectrometry holds promise as a non invasive method to detect head and neck squamous cell carcinoma (HNSCC) objectively, which may improve the early diagnosis of oral cancer tremendously. The present study was designed to discriminate between tumour samples and non-cancer controls (healthy mucosa and oral lesions) by analysing complete spectral patterns of intact cells using MALDI-ToF MS. Material and Methods: In the first step, a data base consisting of 26 patients suffering from HNSCC was established by taking brush biopsy samples of the diseased area and of the healthy buccal mucosa of the respective contralateral area. After performing MALDI-ToF MS on these samples, classification analysis was used as a basis for further classification of the blind study composed of additional 26 samples including HNSCC, oral lesions and healthy mucosa. Results: By analyzing spectral patterns of the blind study, all cancerous lesions were defined accurately. One incorrect evaluation (false positive) occurred in the lesion cohort, leading to a sensitivity of 100%, a specificity of 93% and an overall accuracy of 96.5%. Conclusion: ICPP using MALDI-ToF MS is able to distinguish between healthy and cancerous mucosa and between oral lesions and oral cancer with excellent sensitivity and specificity, which may lead to a more impartial early diagnosis of HNSCC.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide. It is a result of numerous aetiological factors such as genetic predisposition, smoking, excessive alcohol consumption and viruses such as the human papilloma virus. Due to late diagnosis it has a high mortality and morbidity rates which has remained unchanged over the last 5 decades. Currently no screening is available for high risk patients for better monitoring. Diagnosing OSCC relies on histopathology of biopsy tissue, reviewed for dysplasia and advancing lesions. Although the technique has been used for decades for successful diagnosis it fails to identify the molecular signature of OSCC which appears much before the visual signs. It also falls short in predicting the malignant transformation of pre-malignant oral lesions. Identifying the molecular and genetic changes leading to OSCC lesion will aid in more specific (quantitative) and early diagnosis of the disease reducing the financial burden of treating late-stage OSCC patients on the healthcare system. This study focuses on developing new adjuncts which can be used alongside histopathology for early diagnosis. There is a need to monitor high risk patients through non-invasive methods causing less patient discomfort. We therefore explored the potentials of exosomes which are extracellular vesicles secreted by normal and tumour cells. They can be isolated from body fluids such as blood and saliva. In cancer biology exosomes offer both diagnostic and therapeutic advantage. Their involvement in cell-cell communication indicates their influence in tumour development, progression, metastasis and therapeutic efficacy. Exosomes released by cancerous cells carry numerous biomarkers, which are passed on to healthy cells via microenvironment, causing stromal and angiogenic activation along with immune escape. In this study exosomes were successfully isolated from body fluids (blood, saliva and plasma) and cell line supernatant through ultracentrifugation and characterised by visual and particle size quantification techniques including Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM), Zetasizer and Nanosight Tracking Analysis (NTA). Exosomal specific membrane proteins were identified through Western blotting. 5 We report the presence of a potential protein biomarker located exclusively on the outer membrane of cancer exosomes. Since body fluids consist of a heterogeneous population of exosomes derived from multiple cell types, such surface biomarker can potentially be used to isolate OSCC exosomes. Characterisation of exosomal mRNA cargo was done using Agilent Bioanalyzer (for RNA quantity and quality assurance) and reverse transcription-quantitative PCR (RT-qPCR; for gene specific quantitation). Functional significance of exosomes was studied by transfecting normal oral keratinocyte cells with self and cancer-derived exosomes. Through gene-expression microarray and subsequent RT-qPCR verification, we report a panel of differentially expressed genes involved in essential cellular functions being modulated by exosome transfection. A previously developed molecular diagnostic system by our research group called quantitative malignancy index diagnostic system (qMIDS) based on FOXM1 oncogene and its downstream targets was validated on archival formalin fixed paraffin embedded OSCC patient biopsy samples. We report that qMIDS index successfully correlates with the disease stages including dysplasia, tumour and lymph node metastasis. Furthermore, through meta-analysis of 8 OSCC microarray studies we identified a panel of six genes including PLAU, FN1, CDCA5, CRNN, CLEC3B and DUOX1 (q6) which are able to identify two clinically distinct sub-groups of OSCC patient population. Through RT-qPCR the expression of q6 biomarkers was established in 100 OSCC biopsy samples. This information can be of immense importance in developing personalized treatment strategies based on the molecular makeup of the presenting tumour.

Oral cancer is the 6th most common cancer in the world, with a poor prognosis and frequent late-stage diagnosis, which significantly impacts survival and quality of life. The key to better control of this disease is early detection, preferably at a precancerous stage. In order to facilitate this early detection and diagnosis, it is critical to identify the factors potentially impacting on the time lag from initial detection to diagnostic biopsy. The overall goal is to develop effective strategies for early identification of oral cancers in order to achieve better control over this disease. There are 2 components in this thesis: the objectives of part I (personal interview) were 1) to develop an interview-style questionnaire, 2) to collect data from patients with high-risk oral lesions (HRL’s) and 3) to characterize the experiences of these individuals that may have impacted the time interval leading up to diagnosis. The objectives of Part II (focus group discussion) were 1) to gather feedback regarding the questionnaire developed in Part I, 2) to obtain recommendations for future planning and delivery of province-wide questionnaire and 3) as a group, to share information on patients’ experiences to diagnosis and patients’ perspectives on their interactions with health professionals (HP’s) throughout this journey. An interview-style questionnaire was developed to collect both qualitative and quantitative data on patients’ experiences. Forty patients with HRL’s diagnosed within 12 months were recruited and interviewed in the Dysplasia Clinic of the BC Oral Cancer Prevention Program. Two focus groups were conducted and feedback from participants regarding the questionnaire and patients’ experiences was recorded. Among 40 patients interviewed, 21 (53%) initially self-identified their lesions (SIG) and 19 (47%) were identified by health professional screening (PSG; 84% by dental professionals). The SIG showed higher rates of invasive SCC at diagnosis as compared to those in the PSG (76% vs. 32%, P = 0.01) and SIG took twice as long to have the initial biopsy performed as the PSG (23 ± 52 vs. 11 ± 28 months). Notably, the main symptom of patients in SIG was pain or presence of non-healing ulcers (18/21; 86%). In contrast, all lesions in PSG were asymptomatic. The mean time from detection to diagnosis was 17.5 ± 42.3 months (range: 0-240 months). Fourteen patients (35%) experienced a time lag of greater than 6 months from first detection of an oral lesion until the first diagnostic biopsy was performed. Both patient and professional factors impact on the time lag. The main contributing factors for this time lag include both patient factors (a lack of concern, fear, and a lack of oral cancer awareness) and the professional factors (lack of knowledge in differentiating high-risk lesions, delay in initiating the referral or ‘watch and wait’, and delay in scheduling of referral appointments to the specialists). Focus group results supported the format and content of the questionnaire, provided input in designing of future province-wide survey and emphasized that patients require continued post-diagnostic and treatment care. A general lack of awareness of oral cancer in general population and in HP’s in addition to a lack of screening activities have been brought forward as critical factors that result in delay to diagnosis. In conclusion, these results suggest HP’s, especially dental professionals, can play a critical role in early identification of HRL’s at an asymptomatic, pre-invasive stage through regular screening. Strategies in raising awareness of oral cancer in both the general population and among HP’s are essential for early identification of oral cancers in order to achieve better control over this disease.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina Dentária
Introdução: O cancro oral em Portugal no passado era diagnosticado tardiamente, porém atualmente, existe um número elevado de profissionais de saúde com capacidades de realizarem o diagnóstico de cancro oral. O objetivo principal deste estudo foi conhecer o perfil de referenciação dos doentes com cancro oral, no ano de 2013 no Instituto Português de Oncologia do Porto, com o intuito de avaliar se o diagnóstico é realizado mais precocemente. Materiais e Métodos: O estudo descritivo de caso efetuado envolveu 215 doentes com neoplasias orais, a colheita de dados foi realizada através do recurso à base de dados do IPO-Porto (Registo Oncológico Hospitalar), onde foram selecionados os doentes com neoplasias orais, do ano 2013. Resultados: Dos 215 doentes com neoplasias orais, (74%) são do género masculino. Em relação à idade média foi de 61,5 anos (SD 13,7), esta era no género masculino significativamente mais baixa que no género feminino. A língua foi a localização topográfica mais prevalente com (33,0%) dos casos. Em 207 casos as neoplasias eram malignas, apenas 8 doentes tinham neoplasias benignas. O tipo histológico o mais observado foi o carcinoma espinocelular com (86%). O profissional que referenciou mais doentes com cancro oral ao IPO-Porto foi a especialidade de otorrinolaringologia (29,8%). No que diz respeito ao estádio, a maioria dos doentes encontrava-se no estádio IV (48,4%). Conclusão: Apesar de existir um número considerável de profissionais potencialmente habilitados para o diagnóstico do cancro oral, os resultados obtidos mostram que o diagnostico do cancro oral em 2013, foi realizado na maior parte dos casos tardiamente.
Introduction: Oral Cancer in Portugal last was diagnosed late, but currently, there is a high number of health professionals with capabilities to conduct the diagnosis of oral cancer. The aim of this study was to know the profile referral of patients with oral cancer in 2013 at the Portuguese Institute of Oncology of Porto, in order to assess whether the diagnosis is made earlier. Materials and Methods: The descriptive case study carried out involving 215 patients with oral cancers, the data collection was performed through the IPO-Porto database to use (Hospital Cancer Registry), where patients were selected with oral cancers, the year 2013. Results: Of the 215 patients with oral cancers, (74%) are males. Compared to the average age was 61.5 years (SD 13.7), this was significantly lower in males than in females. The language was the most prevalent topographical location with (33.0%) of cases. In 207 cases the tumors were malignant, only 8 patients had benign tumors. The histological type as squamous cell carcinoma was observed with (86%).The professional referenced more patients with oral cancer to IPO-Porto was the specialty of otolaryngology (29,8%). With respect to the stage, most of the patients was at the stage IV (48.4%). Conclusion: Although there is a potentially large number of qualified professionals in the diagnosis of oral cancer, the obtained results show that the diagnosis of oral cancer in 2013 was carried out in most cases later.

Communication about medications can be one-sided, leaving the patient to take a passive role in discussions about medications. In relation to oral chemotherapy, there is a paucity of research in this area, which is surprising given the extremely narrow therapeutic index of oral chemotherapy and subsequent high risk of toxicity. The aim of this ethnographic study was to illuminate the processes of communication between healthcare professionals, patients and informal carers during oral cancer drug therapy in order to identify factors that promote or inhibit concordance and appropriate medication administration. Observations were conducted on interactions between healthcare professionals and eight patients. These observations occurred over a period of six months, in outpatient departments where prescriptions were explained and supplied, and on follow-up consultations where treatment regimens were monitored and assessed. Semi-structured interviews were conducted with patients and their informal carers during and after their six-month treatment. Focus-groups were carried out with healthcare professionals at the conclusion of the study. These data were analysed using thematic analysis. The results of this study are divided into two sections. The first relates to the patient journey to their first consultation appointment, which includes two broad themes of the shock of the lifeworld and the waiting room experience. The second explores the patient’s six-month journey of receiving communication about oral chemotherapy and this includes the three broad themes of colonization of the lifeworld, mutual system lifeworld and detachment of the system. Communication processes within oncology are complex. This study found that the main communication priority for patients, their family members and healthcare professionals, was medical management of side-effects. Importantly, communication about oral chemotherapy is not an isolated event. It occurs over a long period, is preceded by important communication processes through the diagnosis period and succeeded by supportive communication in the period after treatment.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina Dentária
A terapia fotodinâmica (PDT, do inglês, photodynamic therapy) é uma opção terapêutica recente e valiosa, dirigida para a destruição das células tumorais, com potencial para ser incluída no tratamento principal de combate ao cancro, bem como adjuvante de outras terapêuticas. Atualmente é considerada uma estratégia terapêutica de sucesso, clinicamente, aprovada para o tratamento de lesões potencialmente malignas (LPM) e malignas da cavidade oral. A PDT envolve a administração de um fotossensibilizador (PS, do inglês, photosensitizer) que, por si só, não possui efeito farmacológico. Contudo, este é, posteriormente ativado por irradiação, com luz visível de comprimento de onda (λ) adequado ao local a tratar. Com a foto-ativação do PS ocorre a produção de espécies reativas de oxigénio (ROS, do inglês, reactive oxygen species) que dão inicio à morte celular. O processo está associado com a indução de uma forte reação inflamatória local, potenciando a resposta imunitária e conduzindo à destruição efetiva das células tumorais. O efeito citotóxico ocorre, apenas, no local de ativação da luz e o PS acumula-se preferencialmente nas células malignas, pelo que esta terapêutica apresenta elevada seletividade e um baixo número de efeitos secundários. No contexto clínico, a PDT é utilizada em diversas áreas da medicina como a oftalmologia, a dermatologia e a oncologia, entre outras. No entanto, a sua utilização no tratamento do cancro ainda é limitada.
Photodynamic therapy (PDT) is a new and valuable therapeutic option, directed to the destruction of tumor cells, with the potential to be included in the primary treatment to combat cancer, as well as an adjunct to other therapies. A successful therapeutic strategy, clinically approved for the treatment of premalignant lesions (LPM) and malignant oral cavity is considered currently. PDT involves the administration of a photosensitizer (PS) which, by itself, does not possess pharmacological effect. However, this is subsequently activated by irradiation with visible light of wavelength (λ) appropriate to the site to be treated. With the photo-activation of the PS occurs the production of reactive oxygen species (ROS, English, reactive oxygen species) that give beginning to cell death. The process is associated with the induction of a strong local inflammatory response, enhancing the immune response and leading to the effective destruction of tumor cells. The cytotoxic effect occurs only in the light activation site and the PS accumulates preferentially in malignant cells, whereby this treatment has high selectivity and a low number of side effects. In the clinical context, PDT is used in many areas of medicine such as ophthalmology, dermatology and oncology, among others. However, their use in cancer treatment is still limited.

O câncer bucal é uma doença que afeta principalmente homens acima de 40 anos com hábito de fumar e beber. Em geral, esses pacientes têm o diagnóstico da enfermidade realizado tardiamente, acarretando tratamentos complexos, mutilantes e de alto custo tanto financeiro como social e de prognóstico sombrio a ponto do câncer bucal apresentar uma taxa de sobrevida em 5 anos inferior a 50%. O diagnóstico precoce representa uma alternativa importante para alterar esse panorama. Os recursos de que os profissionais da área da saúde, principalmente os cirurgiões-dentistas, dispõem são o diagnóstico clínico de lesões estabelecidas acompanhado da biópsia com exame histopatológico.Outra alternativa para o diagnóstico precoce dos carcinomas espinocelulares ocorre quando estes são precedidos de lesões cancerizáveis. Nas duas últimas décadas, a utilização da citopatologia como método de diagnóstico de danos celulares prévios ao aparecimento de lesões clínicas possibilitou sua utilização em mucosa bucal. Os estudos apresentados tratam especificamente desta aplicação clínica, abordando: a) os aspectos genéticos do câncer bucal; b) a correlação histocitopatológica de lesões cancerizáveis em câncer bucal e na mucosa normal exposta aos carcinógenos; c) a validação das amostras citopatológicas; d) a padronização da técnica de extração de DNA em células esfoliadas da mucosa bucal.
Oral cancer affects mainly men over 40 years who are exposed to tobacco and alcohol. These patients usually receive a late diagnosis, which results in complex, mutilating treatments with high financial and social costs, poor prognosis, and, therefore, a 5-year survival rate lower than 50%. Early diagnosis is critical to change this situation. The resources currently available to healthcare professionals, particularly dentists, are the clinical diagnosis of lesions and biopsies for histopathologic examination. Another alternative for the early diagnosis of squamous cell carcinomas is the identification of precursor lesions. In the last two decades, cytopathology has been used as a method to diagnose cell damage that precedes the appearance of clinical lesions, and this use can be extended to the oral mucosa. The studies reported here deal specifically with this clinical application, and discuss: A) the genetic factors in oral cancer; B) the cytohistologic correlation of cancer precursor lesions and the normal mucosa exposed to carcinogens; C) the validation of cytopathologic samples; D) the standardization of the technique to extract DNA of cells exfoliated from the oral mucosa.

Este estudo teve como objetivo conhecer as ações que os cirurgiões-dentistas das unidades básicas de saúde do município de São Paulo têm desenvolvido quanto à prevenção e ao diagnóstico precoce do câncer bucal, além de suas percepções para a realização de tais ações, a fim de analisar o comportamento destes profissionais a cerca das questões relativas a esta morbidade. A maioria dos diagnósticos de câncer bucal é feita em estágios avançados em São Paulo, cidade que possui as maiores taxas de incidência nacionais, semelhantes a de outras regiões do mundo. O cirurgião-dentista exerce um papel fundamental e estratégico no combate aos fatores ligados ao aparecimento desse agravo. Foram enviados, em março de 2005, 885 questionários aos cirurgiões-dentistas das 286 unidades básicas de saúde de São Paulo, via Correio. Foi feito um banco de dados utilizando o software de informática Epi Info – versão 6.04b. Participaram da pesquisa 282 profissionais, (taxa de resposta de 32%), em sua maioria do sexo feminino, com mais de 20 anos de graduação, com perfil generalista e que possui outros vínculos empregatícios. Além do baixo grau de conhecimento constatado quanto aos fatores de risco ligados à etiologia e às condições bucais em relação a possível evolução para um câncer bucal, a maioria dos participantes expôs limitações relevantes quanto às práticas relativas ao apoio à cessação do hábito do tabagismo e etilismo e às aptidões para executarem citologia esfoliativa e biópsia. Verifica-se a necessidade de se propor políticas públicas de enfrentamento do câncer bucal em São Paulo, que considere o aprimoramento dos cirurgiões-dentistas das unidades básicas de saúde em relação a esse problema e a melhor estruturação desses locais para a pronta realização dos exames complementares para fins diagnósticos.
The purpose of this study was to know the actions that dentists from basic health units of the city of São Paulo have been developing for the prevention and early diagnosis of oral cancer, besides their perceptions for the accomplishment of such actions, in order to analyze the behavior of these professionals about these subjects in relation to this morbidity. Most of the diagnosis of oral cancer is made in advanced stages in São Paulo that possesses the largest national incidence taxes, similar to other areas of the world. The primary health care dental professional plays a fundamental and strategic role against the linked factors related to the greater appearance of this malignant neoplasm. Eight hundred and eighty-five dentists from 286 basic health units of the city of São Paulo were surveyed in march 2005. It was made a database using the computer software Epi Info, version 6.04b. Two hundred and eighty-two professionals have answered the questionnaires (a response rate of 32% was obtained) and their majority composed by female general dental practitioners, with more than 20 years of graduation and that have other kinds of employment. Besides the low degree of knowledge verified for the risk factors linked to the etiology and the oral conditions in relation to a possible evolution for an oral cancer, most of the participants exposed relevant limitations as for the relative practices to support tobacco and alcohol cessation as for the accomplishment of esfoliative cytology and biopsy. It is verified the need of proposing public policies to face the problem of oral cancer in São Paulo, which considers not only the technical improvement of the primary health care dental practitioners but also the best structuring of those places for the ready accomplishment of the complemental exams to leading final diagnosis.

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The oral cancer is a problem of public health in the world, including in Brazil. Most cases of the disease are detected in an advanced phase, in low-income individuais, those with little access to the health services. This neoplasia can be preventable, since the main related factors of risk related to the development of the disease are, in general, from social/environmental basis. The treatment, in the advanced period, turns out to be of high economic and social cost, with unfavorable prognostic. The purpose of this study was to verify the knowledge of the dentists from Feira de Santana- Bahia on the oral cancer. An exploratory study was carried out in which a questionnaire was applied to a random sample of 240 dentists. After the procedure of data collection, the statistics analysis proceeded through the program SPSS 10,0 for Windows, making use of Pearson's chi squared test, in the analysis of correlation of frequencies. The results have disclosed that, among the professionals who have participated in the research, 151 (62,9%) were female, 148 (62,9%) were up to 37 years of age, 125 (53,2%) up to ten years who had graduated and 122 (50,8%) were specialists. The levei of reliability to carry out the diagnostic procedures of oral cancer was considered low for 69,5% of the professionals. The professionals have reported not to investigate the presence of injuries in the first consultation in 21,1 % of the cases. Only 58.3% indicated the spinocellular carcinoma as the most frequent type of oral cancer. Tobacco consumption (100%), alcoholic beverage ingestion (89,2%), solar exposition (83,3%) and family history (93,3%) have been the most reported risk factors. Nevertheless, (96,3%) and (71,3%), respectively, believed that the use of badly adapted prosthesis and uncared teeth presence made up risk factors for the disease. Only 3.75% of the interviewed ones have gotten the highest results concerning the knowledge. The findings agree with the results disclosed in other studies and indicate the need of educational reshaping, in order to enable the professionals for an early diagnosis, and for the investment in healthful public policies in the city, which enable the adoption of strategies of primary prevention for reduction of the morbimortality of the disease.
O c?ncer bucal ? um problema de sa?de p?blica no mundo, inclusive no Brasil. A maioria dos casos da doen?a ? detectada em fase avan?ada, em indiv?duos de baixa renda e com pouco acesso aos servi?os de sa?de. Esta neoplasia pode ser prevenida, pois os principais fatores de risco relacionados ao desenvolvimento da doen?a s?o, em sua maioria, de ordem s?cio-ambiental. O tratamento, nos est?gios avan?ados, revela-se de alto custo econ?mico e social, com progn?stico desfavor?vel. O objetivo deste estudo foi verificar o n?vel de conhecimento dos cirurgi?es-dentistas de Feira de Santana -Bahia sobre o c?ncer bucal. Foi realizado um estudo explorat?rio em que se aplicou um question?rio a uma amostra de 240 cirurgi?es-dentistas. Ap?s o procedimento de coleta de dados, procedeu-se a an?lise estat?stica por meio do programa SPSS 10.0 for Windows, empregando-se o teste do qui-quadrado de Pearson, na an?lise de correla??o de frequ?ncias. Os resultados revelaram que dos profissionais que participaram da pesquisa, 151 (62,9%) eram do g?nero feminino, 148 (62,9%) tinham at? 37 anos, 125 (53,2%) at? dez anos de formados e 122 (50,8%) eram especialistas. O n?vel de confian?a para realizar procedimentos de diagn?stico de c?ncer bucal foi considerado baixo para 69,5% dos profissionais. Os profissionais relataram n?o investigar a presen?a de les?es na primeira consulta em 21' 1% dos casos. Somente 58,3% apontaram o carcinoma espinocelular como o tipo de c?ncer bucal mais frequente. O consumo de tabaco (100%), o uso de bebidas alco?licas (89,2%), a exposi??o solar (83,3%) e a hist?ria familiar (93,3%) foram os fatores de riscos mais apontados. Entretanto, (96,3%) e (71,3%) acreditavam que o uso de pr?teses mal adaptadas e a presen?a de dentes em mau estado constitu?am-se em fatores de risco para a doen?a, respectivamente. Apenas 3, 75% dos entrevistados obtiveram o maior conceito em rela??o ao conhecimento. Os achados condizem com os resultados revelados em outros estudos e apontam para a necessidade de reformula??o do ensino, de forma a capacitar os profissionais para o diagn?stico precoce, e para o investimento em pol?ticas p?blicas saud?veis no munic?pio que possibilitem a ado??o de estrat?gias de preven??o prim?ria para redu??o da morbimortalidade da doen?a.

In the UK in 2008 over 1,800 people died from oral cancer. Despite advances in surgery and therapy the survival rates for those diagnosed with oral cancer have not significantly improved over the past 20 years. There is a need for both better detection and treatment. Early detection could reduce these mortality rates but unfortunately diagnosing oral cancer, which is often symptomless, in the early stages of the disease is incredibly challenging. More targeted treatments for oral cancer are also needed which can be administered to the site of disease with higher efficiency and accuracy to reduce side effects and allow higher concentrations of therapeutic agents to be delivered to tumour cells. This project used a tissue engineered oral mucosa model to develop models of oral cancer progression. These oral cancer models incorporated many pathological features of oral cancer progression including features seen in dysplastic epithelia, carcinoma in situ and early invasive squamous cell carcinomas. Multi-cellular tumour spheroids were created from an oral cancer cell line to model solid expanding tumour masses. The tissue engineered models of oral mucosa and the multi-cellular tumour spheroids were used to test the behaviour of polymersomes, a novel drug delivery system, in three dimensional tissues. Polymersome distribution and penetration in the tissue engineered models was examined over time, to investigate the potential of polymersomes to deliver therapeutic agents into and/or across the oral mucosa and into solid expanding tumours. Drug delivery agents that are able to reach the central hypoxic region of solid expanding tumours are particularly important as these cells are often resistant to both radio- and chemotherapy and correlate with poor patient prognosis. In addition, we explored the potential of polymersomes to cross the oral epithelial permeability barrier and act as delivery vehicles for topical delivery of therapies for oral mucosal diseases and as an alternative to parenteral administration for the systemic delivery of drugs. Results showed good penetration of polymersomes into the oral mucosa and the multi-cellular tumour spheroids demonstrating the potential to develop these drug delivery vehicles to deliver anti-cancer drugs and other therapeutic agents in the future. The tissue engineered models of cancer were next utilised to test four non-invasive diagnostic technologies. These included a cell metabolism marker, impedance spectroscopy, Fourier transform infra-red and optical coherence tomography. The results obtained from these different techniques showed varying degrees of promise with the images from OCT demonstrating that this technology has real diagnostic potential. The 3D models proved useful test-beds for some but not all of these diagnostic imaging techniques. They provide convenient models to tackle some of the key issues in the preclinical development of novel diagnostic technologies for oral cancer and oral dysplastic lesions.

Inledning:Oral cancer är ett allvarligt tillstånd med hög dödlighet, särskilt vid sen diagnostisering. Brasilien är ett av de länder i världen som har högst prevalens och dödlighet i oral cancer och det är den femte vanligaste cancerformen I landet. Ett hjälpmedel för tidig diagnostisering är önskvärd.Syfte:Att utvärdera skillnaden i diagnostisk tillförlitlighet mellan konventionell oral undersökning och användning av multispektralt ljus (Identafi®) som en metod för tidig upptäckt av potentiellt maligna och maligna lesioner i munslemhinnan i en brasiliansk befolkning.Material och metod:Screening av en befolkning med förhöjd risk för att utveckla oral cancer i Goiânia, Goiás, Brasilien, för att upptäcka potentiellt maligna (PML) eller maligna lesioner (ML). Patienter med misstänkta PML eller ML upptäckta under screeningen undersöktes med multispektralt ljus (Identafi®). Tre oberoende observatörer genomförde bedömning med Identafi® och slutgiltig beslut avseende PML/ML togs i konsensus. Biopsier användes som diagnostisk referensstandard. Interobservatörs överensstämmelse beräknades som procentuell överensstämmelse och kappa-värde (κ).Resultat:Undersökning med Identafi® genererade tolv biopsier. Resultaten blev tre sant positiva, fem falskt positiva, två sant negativa och noll falskt negativa. Sensitiviteten beräknades till 0,29. Specificiteten var inte möjlig att beräkna, då det inte fanns några falska negativa resultat. Interobservatörs överensstämmelse för par av observatörer varierade mellan 78-86% och κ-värden mellan 0,46-0,60.Slutsats:Slutsatsen är att multispektralt ljus, Identafi® inte har inga fördelar jämfört med konventionell klinisk undersökning i fråga om diagnostisk träffsäkerhet för PML eller ML. Dock kan det vara till hjälp för en tandläkare eller oral kirurg som stöd i sitt beslutsfattande. Det kan också hjälpa kirurgen att ta en biopsi från det mest misstänkta delen av lesionen. Det finns inte tillräckligt publicerade studier som tyder på att Identafi® kan skilja mellan normal slemhinna och PML eller ML och denna studie bekräftar detta. Användning av Identafi® som ett hjälpmedel vid screening och undersökning för PML eller ML behöver utredas ytterligare, men baserat på denna studie kan Identafi® inte rekommenderas.
Introduction: Oral cancer is a severe condition with high mortality rate, in particular if diagnosed late. Brazil is one of the countries in the world with high prevalence and mortality from oral cancer and it is the fifth most common cancer there. An aid in early detection of oral cancer as an adjunct to health promotion is desirable.Purpose:The aim of this study was to evaluate the diagnostic accuracy of conventional oral examination and the use of multi spectral light (Identafi®) as an approach for early detection of potentially malignant or malignant lesions in the oral mucosa in a Brazilian population.Material and method:Screening of high-risk population in Goiania, Goias, Brazil, for oral potentially malignant lesions (PML) or malignant lesions (ML) as a selection phase. Patients collected from the screening were examined with multi spectral light (Identafi®) to evaluate diagnostic accuracy. Three observers independently assessed all lesions with Identafi® and the final decision if a lesion was present was taken in consensus. Inter observer agreement was calculated as overall agreement and as kappa value (κ). Biopsies were used as diagnostic reference standard.Results:Identafi® generated, from twelve biopsies, three true positive, five false positive, two true negative and zero false negative. Sensitivity was calculated to 0.29 and specificity was not possible to calculate since there were no false negative results.Inter observer agreement for the use of Identafi® was calculated as overall agreement and as kappa value (κ). The overall agreement for the three pairs of observers varied between 78-86% and κ-values between 0.46 and 0.60.Conclusion:The conclusion of this study is that Identafi® does not have any benefits over conventional oral examination in diagnostic accuracy for potentially malignant or malignant lesions in the oral mucosa. It might, however, be an aid for a dentists or oral surgeons that are unsure whether to take a biopsy or not. It can also aid the surgeon when taking a biopsy to take the most suspicious part of the lesion. There are not enough published evidence that Identafi® can discriminate between normal mucosa and PML or ML, and this study confirms previous results. The use of Identafi® as an aid in screening and examination for PML or ML needs further investigation.

RESUMO O objetivo deste estudo foi avaliar o conhecimento de cirurgiões dentistas inscritos em cursos de estética quanto aos fatores predisponentes e de diagnóstico do câncer bucal, a partir de um questionário previamente testado. O desenvolvimento de materiais e técnicas odontológicas e o anseio cada vez maior do ser humano em busca da beleza têm levado um número crescente de pacientes aos consultórios odontológicos. Julgamos este momento oportuno para informar a população e diagnosticar precocemente o câncer de boca. Com relação às características gerais dos 465 participantes, houve predominância de uma população jovem, com idade inferior a 39 anos, maior participação feminina e quase 1/3 formados de 10 a 20 anos. As características clínicas da ocorrência desta neoplasia não estão claras para os entrevistados, uma vez que somente metade indicou o carcinoma espinocelular como o tipo mais comum, e aproximadamente metade tem conhecimento das características do linfonodo em metástase cervical. Cerca de 20% desconhece a região da boca e a faixa etária de maior ocorrência deste tumor, e também o seu aspecto inicial. Entretanto, 75,7% reconhecem a leucoplasia como a condição mais comumente associada ao câncer bucal. Com relação aos fatores de risco, o consumo de tabaco, história familiar e consumo de álcool estão claros para quase todos os participantes, mas, em se tratando das demais condições apresentadas como fatores de risco, as dúvidas e contradições estão evidentes. Na prática clínica relacionada ao câncer de boca, observa-se que 14,2% não realizam exames para identificar lesões bucais, sendo que, destes, 80,3% não sabem como fazê-lo. Apenas 5,8% realizam procedimentos de diagnóstico, com a grande maioria considerando regular ou insuficiente seu conhecimento na área. Somente 16,6% têm confiança para realizar o diagnóstico. Mais da metade está há mais de 5 anos sem realizar um curso de atualização em câncer de boca, apesar de terem interesse em faze-lo no futuro. Concluindo, os cirurgiões dentistas ainda não apresentam conhecimento e treinamentos ideais para difundir os meios de prevenção e detecção precoce do câncer de boca.
ABSTRACT The purpose of this paper is assessing the knowledge of dentists who are registered at aesthetics courses as for predisposing and diagnosis factors of oral cancer, through a previously tested questionnaire. The development of odontological materials and techniques allied to a longing of a human being who is more and more in search of beauty, has taken an increasing number of patients to odontoligical consultation rooms. We consider this an opportune moment to inform the population and to do the early diagnosis of oral cancer. On what concerns the general characteristics of the 465 participants, there was a predominance of a young population, whose age was under 39 years, more female participation and almost 1/3 who had been graduated for 10 to 20 years. The clinical characteristics of this neoplasia occurrence are not clear for the persons interviewed, since only half of them have indicated the spinocellular carcinoma as the most common one and approximately half of them are aware of the lymph node characteristics in cervical metastasis. Around 20%, ignores the region of the mouth and the age group where this tumor occurs more frequently, and also its initial aspect. Notwithstanding, 75,7% recognizes the leucoplasia as the condition more frequently associated with oral cancer. On what concerns risk factors, the use of tobacco, family history and alcohol intake are clear for almost all the participants, but on what refers to the other conditions presented as risk factors, the doubts and contradictions are evident. On the clinical practice related to oral cancer, it is observed that 14,2% don’t do examinations for identifying buccal lesions, and among these ones, 80,3% don’t know how to do it. Only 5,8% does diagnosis procedures, and the great majority considers their knowledge in the area, regular or insufficient. Only 16,6% has enough confidence to do the diagnosis. In spite of being interested in doing courses in the future, more than half of them have not taken any upgrading course on oral cancer for more than 5 years. Concluding, the dentists still don’t present ideal knowledge and training to diffuse the means for prevention and early detection of mouth cancer.

Les Papillomavirus Humains (HPV) sont responsables de près de 100% des cancers du col utérin. Récemment, ces HPV sont apparus comme étant aussi la cause de certaines tumeurs des voies aérodigestives supérieures, et particulièrement des carcinomes épidermoïdes de l’oropharynx. En France, la proportion des tumeurs oropharyngées HPV-induites est mal connue, notamment parce que le dépistage viral n’est pas recommandé. De plus, il est difficile d’évaluer la proportion de tumeurs HPV positives dans les tumorothèques car les échantillons tumoraux sont fixés dans du formol puis inclus en paraffine (FFIP), ce qui complexifie les techniques de détection. Nous avons, au cours de nos travaux, testé une méthode de détection des HPV à haut risque oncogène indiquée pour le traitement des frottis en phase liquide. Nous l’avons mise à l’épreuve sur des prélèvements FFIP et comparée à la technique de référence qu’est la PCR (Polymerase Chain Reaction) suivie d’une électrophorèse sur gel. Nos résultats indiquent que cette technique est applicable aux prélèvements tissulaires et apparaît même comme étant plus sensible. En France, deux tiers des patients atteints de tumeurs des VADS sont pris en charge à des stades tardifs. Ceci s’explique en partie par l’absence de dépistage organisé de ces cancers. Nous avons donc mené une étude prospective sur des patients atteints d’une tumeur des VADS afin de tester le frottis oral comme technique de dépistage des cancers mais également des infections par les HPV. Nos résultats indiquent que le frottis a une spécificité proche de celle de la biopsie (94,4%) pour le dépistage des cancers des VADS, mais une moindre sensibilité (66,7%). Cette étude nous a permis de mettre en évidence une tumeur HPV-induite dans 12,2% des cas. Parmi eux, nous avons détecté grâce à un frottis buccal (en zone saine) une infection par un HPV à haut risque oncogène dans 53,3% des cas. L’OMS a classé les HPV comme agents carcinogènes depuis 1995, et a établi que les patientes ayant développé un cancer du col utérin avaient un risque 6 fois plus élevé de développer une autre tumeur HPV-induite. Dans ce contexte, nous avons prévu une étude prospective multi-centrique visant à dépister une infection orale par un HPV oncogène chez des patientes porteuses d’une lésion pré-néoplasique ou néoplasique du col utérin. Le taux de co-infection des deux sites anatomiques est inconnu chez les femmes infectées au niveau génital. Dans la mesure où l’infection orale pourrait être à l’origine d’une seconde localisation tumorale, il semble important d’en connaître la proportion afin de proposer par la suite un suivi particulier aux populations « à risque ». Au-delà des traitements des cancers avérés se pose la question de la vaccination préventive, qui existe contre les HPV 16 et 18 dans la prévention des cancers du col utérin. Le type 16 étant retrouvé dans 90% des tumeurs épidermoïdes de l’oropharynx HPV-induites, l’extension des recommandations vaccinales apparaît comme une nouvelle question de santé publique
The Human Papillomavirus (HPV) are involved in almost 100% of cervical cancers. Recently, HPVs have been recognized as the cause of tumors of the upper aerodigestive tract, especially of squamous cell carcinoma of the oropharynx. In France, the proportion of oropharyngeal HPV-related tumors is unknown, partly because viral testing is not in guidelines. Moreover, assess the proportion of HPV-positive tumors in tumor banks is difficult because the tumor samples were fixed in formalin and embedded in paraffin (FFPE), which complicates detection techniques. We tested a high risk HPV detection method, indicated for liquid based pap smear, on FFPE samples. We compared this technique to the gold-standard : PCR (Polymerase Chain Reaction) followed by electrophoresis. Our results indicate that this technique is applicable to FFPE samples and even appears to be more sensitive. The majority of French patients (2/3) with head and neck consult with an advanced stage of disease. This is explained in part by the lack of organized screening of these cancers, contrary to breast, prostate, cervical, or colorectal cancers. But an early treatment is essential to increase the survival rate. We therefore conducted a prospective study on patients with head and neck tumors to test the oral brushing as screening cancer and HPV detection. We found tumor and/or dystrophic cells in 97.8% of patients with biopsy, and in 88.9% of patients by brushing. Compared with biopsy, our results suggested that smear has similar specificity for HPV detection in tumors (94.4%), but lower sensitivity (66.7%). This study has shown an HPV-related tumor in 12.2% of cases. Among them, we detected by brushing (in healthy area) an oral infection by high-risk HPV in 53.3% of cases. WHO has classified HPV as carcinogenic agents since 1995, and determined that patients who developed cervical cancer are six-times more likely to develop another HPV-related tumor. In this context, we have planned a multicenter prospective study to detect oral HPV infection in patients with a pre-neoplastic or neoplastic lesion of the cervix. Co-infection rate of the two anatomical sites is unknown in women infected with genital level. Insofar oral infection could be the cause of a second tumor location, it seems important to know how much women are co-infected to propose thereafter a special monitoring. The preventive vaccination, which exists against HPV 16 and 18 in the prevention of cervical cancer, is a future perspective. Because HPV 16 is found in 90% of HPV-related squamous cell carcinoma of the oropharynx, extending vaccine recommendations emerge as a new public health issue

FundaÃÃo de Amparo à Pesquisa do Estado do CearÃ
BACKGROUND: Oral malignant and potentially malignant lesions (LPM) are commom in oral cavity and diagnosis network health structure is required to improve early diagnosis. OBJECTIVE: This research had evaluated primary and secondary health care integration in oral cancer diagnosis evaluating contact with risk factors and presence of LPM and Oral squamous cell carcinoma (OSCC) in two different Cearà geographic regions. STUDY DESIGN: People served at two regions basic health unit (UBS) were examined. The coastal region was defined as Group 1, and the interior region as Group 2. Data collected: gender, age, tobacco and/or alcohol use, radiation and present lesions. When lesions were present patients were forwarded to dental centers (CEO) where diagnosis was made. RESULTS: 3.809 were examined, 285 lesions found, 43% in males and 57% in females. Risk factors analysis show: 31% smokers, 24% alcoholics, 53% exposed solar radiation, and 1% with sexually disease. Biopsies were performed in 76 lesions, with 7 OSCC (9,2%), 06 in Group 2 and 15 PMD (19,7%), 10 in Group 1. Most of OSCC (71,4%) occurred in females and 60% LPM in males. Lower lip was the most frequently localization with 57% of OSCC and 87% of LPM. Majority OSCC individuals (71,4%) and LPM individuals (86,6%) had solar exposition. CONCLUSION: Our data illustrate greater number of OSCC in Group 2, and LPM in Group 1, and warn that oral cancer diagnosis network structure need improve, and continuous prevention policy policy is necessary to access high risk population for OSCC
INTRODUÃÃO: LesÃes malignas e potencialmente malignas sÃo comuns na cavidade oral, sendo necessÃria a estruturaÃÃo de redes em saÃde para o estabelecimento do diagnÃstico precoce dessas alteraÃÃes. OBJETIVO: Neste trabalho foi avaliada a integraÃÃo entre AtenÃÃo PrimÃria e SecundÃria no diagnÃstico de cÃncer oral, observando-se o contato com fatores de risco e ocorrÃncia de LesÃes Potencialmente Malignas (LPM) e Carcinoma de CÃlulas Escamosas (CEC), em duas regiÃes geogrÃficas distintas do Estado do CearÃ. METODOLOGIA: IndivÃduos atendidos nas Unidades BÃsicas de SaÃde das duas regiÃes foram examinados. A regiÃo litorÃnea foi classificada como grupo 1, enquanto a regiÃo de sertÃo foi identificada como grupo 2. VariÃveis de sexo, idade, contato com fumo, Ãlcool, sol, DoenÃa Sexualmente TransmissÃvel (DST) e presenÃa/ausÃncia de lesÃo oral foram coletadas. Pacientes portadores de lesÃes foram encaminhados aos Centros de Especialidades OdontolÃgicas (CEO), para estabelecimento de diagnÃstico. RESULTADOS: Foram examinadas 3.809 pessoas, nas quais foram encontradas 285 alteraÃÃes orais, sendo 43% destas observadas em homens e 57% no sexo feminino. Quanto aos fatores de risco, 53%, 31%, 24% e 1% de indivÃduos expostos à radiaÃÃo, fumantes, etilistas e portadores de DST foram observados respectivamente. Foram biopsiadas 76 lesÃes, sendo 07 CEC (9,2%), com 06 tumores diagnosticados no grupo 2 e 15 LPM (19,7%), sendo 10 dessas lesÃes encontradas no grupo 1. O sexo feminino foi identificado em 71,4% dos CEC e 60% LPM foram observadas em homens. O lÃbio inferior foi a localizaÃÃo mais frequente de CEC (57%) e de LPM (87%). Quanto aos fatores de risco, a exposiÃÃo solar esteve presente em 71,4% dos CEC e 86,6% das LPM. CONCLUSÃO: Os dados desta pesquisa apontaram um maior acometimento de Carcinomas no grupo 2, enquanto as LPM foram mais frequentes no grupo 1, sendo necessÃria a implementaÃÃo de redes de diagnÃstico em cÃncer oral, bem como uma polÃtica de prevenÃÃo permanente frente Ãs populaÃÃes vulnerÃveis a estas neoplasias.

En partant des rencontres faites pendant l'étude A. S. E. D sur les patients atteints des cancers des Voies-Aérodigestives Supérieures, ce travail propose de partir du discours du patient afin de montrer que les cancers des VADS sont des maladies d'une grande complexité qui ne sont pas réductibles à la causalité des facteurs. La combinaison des facteurs est tellement complexe que nous ne pouvons pas affirmer par exemple que c'est la toxicomanie ou la précarité des patients qui retardent leurs prises en charge. Une corrélation est à penser entre les facteurs. Une lecture des 4 cas, mettra en exergue les incidences psychiques et physiques d'une telle maladie et de sa prise en charge
Starting from the meetings with patients suffering from head and neck cancer, this research shows that this disease is much more complicated that we think. Cancers are diseases with a such complexity that do not allow us to think that it is a result of factors that leeds to this disease. We can assume for example that a head and neck cancer is due to a drug addiction or a precariousness, but those two factors are not the unique reason. A lecture of the 4 cases, will highlight the psychical and physical effects of such a disease and the way we take care of those patients

La première partie de la thèse traite de la recherche de biomarqueurs du cancer. Lors de la transcription, il apparaît que certains nucléotides peuvent être remplacés par un autre nucléotide. On s'intéresse alors à la comparaison des probabilités de survenue de ces infidélités de transcription dans des ARNm cancéreux et dans des ARNm sains. Pour cela, une procédure de tests multiples menée sur les positions des séquences de référence de 17 gènes est réalisée via les EST (Expressed Sequence Tag). On constate alors que ces erreurs de transcription sont majoritairement plus fréquentes dans les tissus cancéreux que dans les tissus sains. Ce phénomène conduirait ainsi à la production de protéines dites aberrantes, dont la mesure permettrait par la suite de détecter les patients atteints de formes précoces de cancer. La deuxième partie de la thèse s'attache à l'étude de l'allergie à l'arachide. Afin de diagnostiquer l'allergie à l'arachide et de mesurer la sévérité des symptômes, un TPO (Test de Provocation Orale) est réalisé en clinique. Le protocole consiste à faire ingérer des doses croissantes d'arachide au patient jusqu'à l'apparition de symptômes objectifs. Le TPO pouvant se révéler dangereux pour le patient, des analyses discriminantes de l'allergie à l'arachide, du score du TPO, du score du premier accident et de la dose réactogène sont menées à partir d'un échantillon de 243 patients, recrutés dans deux centres différents, et sur lesquels sont mesurés 6 dosages immunologiques et 30 tests cutanés. Les facteurs issus d'une Analyse Factorielle Multiple sont également utilisés comme prédicteurs. De plus, un algorithme regroupant simultanément en classes des intervalles comprenant les doses réactogènes et sélectionnant des variables explicatives est proposé, afin de mettre ensuite en compétition des règles de classement. La principale conclusion de cette étude est que les mesures de certains anticorps peuvent apporter de l'information sur l'allergie à l'arachide et sa sévérité, en particulier ceux dirigés contre rAra-h1, rAra-h2 et rAra-h3.

Les carcinomes épidermoïdes des voies aéro-digestives supérieures (VADS) se situent au sixième rang des cancers les plus fréquents dans le monde. Ces tumeurs sont liés à deux facteurs de risque : l’intoxication éthylo-tabagique (80% des cas) et l’infection de l’épithélium des VADS par les papillomavirus humain (HPV) à haut risque oncogène (20% des cas). Ces derniers définissent une sous-population de patients de meilleur pronostic. Une des hypothèses actuellement étudiées, afin d’expliquer la survie améliorée des patients HPV positifs, serait une hypoxie moindre dans ces tumeurs. En effet, les tumeurs des VADS sont fréquemment hypoxiques, et l’hypoxie intratumorale est un facteur de mauvais pronostic. Dans une première partie de cette thèse, nous avons entrepris une caractérisation moléculaire de l’hypoxie intratumorale dans les tumeurs humaines oropharyngées en fonction du statut HPV. Il apparaît que les tumeurs HPV positives présentent un statut hypoxique moindre comparées aux tumeurs HPV négatives. Ces tumeurs se caractérisent également par une abondante vascularisation intratumorale, qui pourrait être à l’origine de ce statut hypoxique moindre. Dans une deuxième partie, nous avons étudié l’adaptation à l’hypoxie de la lignée cellulaire HPV négative SQ20B et la lignée cellulaire HPV positive SCC90. De plus, des modèles de xénogreffes ont été établis à partir de ces mêmes lignées cellulaires et ont été analysés du point de vue de l’hypoxie intratumorale. De façon comparable aux tumeurs HPV positives, les xénogreffes obtenus à partir de la lignée SCC90 montre un statut hypoxique réduit comparés aux xénogreffes SQ20B. Les deux lignées cellulaires s’adaptent également différemment en hypoxie in vitro. La réponse à l’hypoxie dans la lignée SCC90 semble plus dynamique. En effet, la lignée SCC90 tente de s’adapter et de répondre à cet environnement hypoxique en induisant de fort niveau d’expression de gènes comparée à la lignée SQ20B
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy worldwide. The major risk factors for HNSCC identified are tobacco use and alcohol consumption (80% of all HNSCC), which seem to have a synergistic effect. A subgroup of HNSCCs (20% of cases), particularly those of the oropharynx, is caused by infection with high-risk types of human papillomavirus (HPV). Human papillomavirus HPV-related oropharyngeal squamous cell carcinoma defines a distinct clinical subgroup of head and neck cancer patients with improved prognosis. Currently, one of the several hypothesis studied to account for their improved survival outcomes could be a distinct hypoxia status compared to their HPV-negative counterpart. Indeed, tumour hypoxia is common in solid tumours including head and neck tumours, and hypoxia is a well-known poor prognosis factor. In first part of this thesis, we have performed a molecular characterisation of tumor hypoxia on cohort of oropharyngeal tumours according to HPV status of the patients. The results support the hypothesis that HPV-related tumours display a lesser hypoxia status compared to HPV-negative oropharyngeal tumours. These HPV-related tumours also characterize by an abundant tumour vascularisation, which could be responsible for a lesser hypoxia status. In a second part, we have studied the ability of the adaptation to hypoxia of the HPV-positive SCC90 cell line and HPV-negative SQ20B cell line. Furthermore, HPV-positive and HPV-negative HNSCC xenograft models have been established and have been analysed about tumor hypoxia. Similar to HPV-related HNSCC, tumours-derived HPV positive cell lines display a reduced hypoxic status compared to tumours-derived HPV negative cell lines. The two cell lines adapt also differently to in vitro hypoxia. In the HPV-positive cell line, the hypoxia response pathways could be more dynamics. Indeed, SCC90 cell lines attempt to adapt and to reply to hypoxic environment inducing highly expression of all of the hypoxia related genes compared to SQ20B cell lines

碩士
國立交通大學
電控工程研究所
101
Many clinical results and literatures revealed that the hyper-spectral imaging was widely applied to biomedical diagnosis. Nowadays, the operative steps of hyper-spectral devices for cancer detection were slicing the region of suspected lesions, and the pathologist observed the image information through the analysis of hyper-spectral instruments. The process must slice the lesions and caused the pain of patients. This thesis proposes an in vivo diagnostic method that utilizes the fiber endoscopic to capture the image of the oral tissue and then the image information is transmitted to the hyper-spectral instrument through the endoscope. The research develops two sets of diagnostic systems. The high-resolution fiber endoscopy combined with Embedding Relay Lens Hyper-spectral Image system (ERL-HSI). The system can simultaneous acquire 400nm to 1000nm spectral information and spatial image for analysis. For the clinical fast diagnosis, this study proposes a simple handheld device. The fluorescent image is excited by the UV light source and then passes through the selected spectral filter. Finally, the sensor acquires the specific band image for diagnosis. This study eventually develops the algorithm for diagnosing the oral cancer with high accuracy. In the experimental data of the fiber endoscope combined with hyper-spectral system, we find the spectral index of oral cancer using for algorithm. It reached 94% sensitivity and 93% specificity.

博士
國立臺灣大學
光電工程學研究所
96
Oral cavity cancer has recently become the fourth leading cancer for men in Taiwan. The main causes include the habits of alcoholconsumption, chewing betel nuts (Areca catechu) and smoking cigarettes.For patients with ocalized diseases (earlier phases) at diagnosis, the 5-yr survival rate is as high as 75%, which reveals the significances of earlydiagnosis. Oral cancer study including lesion canning and diagnosisindicator analysis are demonstrated.In the dissertation, we first demonstrate the ex vivo imaging of oralcancerous samples with a SS-OCT system. With the axial resolution of 8um in free space and system sensitivity of 108 dB in this system, we can well differentiate normal and abnormal oral tissue samples. We analyze the lateral variation of A-mode scanning profiles to show two parameters of SS-OCT signal including decay constant in the exponential fitting and standard deviation of the SS-OCT signal intensity for determining the lateral expansion range of abnormal oral tissue. Then, the SS-OCT system is equipped with a probe for clinical oral cavity scanning. In clinical diagnosis, three indicators, including the standard deviation (SD) of an A-mode scan signal profile, the exponential decay constant (α) of an A-mode-scan spatial-frequency spectrum, and the epithelium thickness (T) when the boundary between epithelium and iii lamina propria can still be identified, are proposed. The sensitivity and specificity of the three indicators are discussed based on universal and individual relative criteria. It is found that SD and α are good diagnosisindicators for MD and SCC. On the other hand, T is a good diagnosisindicator for EH and MD. The SS-OCT system is also used to clinically scan oral cancerpatients for tracking the progress of photodynamic therapy. The progresses of two patient cases are reported based on the calibrations of the variation trends of three indicators mentioned above.

碩士
國立臺灣大學
光電工程學研究所
93
Recently, a lot of research groups around the world have focused their research on the biomedical applications of optical coherence tomography, covering from the diagnosis of human eyes and skin to gastrointestinal with endoscope. Among such research, the major efforts include optical system improvement, real-time imaging process, and probe design. Little research focused on a specific disease to build up image database for medical usage. However, except the diseases of the eyes. In our research, we develop an OCT system and suitable probes to diagnose oral cavity cancer, which has a high population rate than other developed countries. We will demonstrate the images of oral mucosa and compare the differences between the normal tissues with diseased ones. In this study, to reach tissues at different location in a oral cavity, we develop three probes of the features of miniature, convenience, and fast-scanning. Besides, by choosing a superluminescent diode as the light source, designing a fiber-based system, and integrating the whole system on a damping handcart, we can move this OCT system easily to meet the clinical environment. Before the application to oral cavity cancer, we use a human skin as the sample for test. From our human skin images, we can clearly distinguish the structures such as stratum corneum, epidermis, papilla, and dermis. The scanning depth of 0.5 mm can be reached. In our OCT imaging on oral cavity tissues, we first scan normal tissues located at several different positions such as masticatory mucosa and lining mucosa. We can clearly distinguish the epithelium, lamina propria, and submucosa. The scanning depth of 0.9 mm can be reached. In clinical scanning, the oral cancer tissues on several patients have been imaged. From the comparison between the cancerous and normal tissues, we find that the backscattered intensities of diseased tissues are stranger. Also, the interface between epithelium and lamina propria is more unclear.

碩士
中國醫藥大學
醫務管理學系碩士在職專班
101
PURPOSE: Prevalence of betel nut chewing culture in Taiwan, the incidence of oral cancer increasing year by year. In Taiwan’s top 10 cancers in men, oral cancer’s incidence and mortality both are ranked the fourth, while delay diagnosis may affect the survival of patients with oral cancer. Purpose of this study was to understand delay diagnosis of oral cancer cases in Taiwan, and to investigate the important factors. METHODS: This study used cross-sectional study, is a secondary data adopted from a medical center, the “oral cancer cases for medical treatment” data in May 2007 to October 2012, which is located in the central part of Taiwan. A total of 416 valid samples using SAS software to conduct descriptive, inferential and multiple regression analysis. RESULTS: Patients with symptoms of oral cancer whose average delay diagnosis days were accounted for 36.36 days. Delay diagnosis days less than 30 days accounted for 79.55% (n = 315).Delay diagnosis days between 31 to 180 days and 181 to 365 days were accounted for 15.90% (n = 63) and 4.55% (n = 18).The highest perceptive early symptoms of oral cancer patients is oral / throat leukoplakia(36.54%), followed by pain(25.91%). Delay diagnosis days correlated with hospital grade of oral cancer patients’ initial visit (p < 0.01), first examination (p < 0.01), the number of hospitals patients visit (p < 0.01), symptoms of swallowing difficulties / drinking choked easily(p < 0.01), and other symptoms(p < 0.01).Finally, multiple regression show that delay diagnosis days correlated with age(p = 0.042), first examination including biopsy (p = 0.026), the number of hospitals patients visit 2 times (p = 0.044) or more(p = 0.014), symptoms of oral / throat leukoplakia (p = 0.028). CONCLUSION: The Results show that delay diagnosis days increase while the number of hospitals patients visit increase, which could provide policy in improving delay diagnosis for medical and health administrative units in the future. KEYWORDS: Oral Cancer; Delay Diagnosis; Early Symptoms

碩士
長庚大學
生物醫學研究所
98
Oral squamous cell carcinoma (OSCC), one of the prevalent epithelial malignancies worldwide, is ranked as the 5th-most common cancers in Taiwan with a high mortality rate. Currently, however, there is no non-invasive biomarker which can reliably detect and monitor the progression of OSCC. MicroRNAs (miRNAs) are small (~22nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. In this study, we aim to identify microRNAs in circulation as potential biomarkers for OSCC diagnosis. We first established a method to prepare total RNA from small volume of serum samples and demonstrated that miRNAs indeed present in human serum in a remarkably stable form. To identify serum miRNAs showing differential abundance in normal and OSCC samples, we analyzed the expression levels of 270 miRNAs in serum samples from 7 OSCC patients and 6 normal controls. We identified a subset of 40 microRNAs whose expression levels were significantly altered in normal and OSCC sera. To validate the utility of these serum miRNAs for OSCC detection, we conducted a large scale validation using serum samples from 40 OSCC and 40 age- and gender-matched controls and validated that five microRNAs, including two up-regulated and three down-modulated, were significantly (p-value and fold-change) altered in OSCC serum. To determine the best miRNA or miRNA panel for OSCC detection, we conducted Receiver Operating Characteristic (ROC) Curve analyses to evaluate the predicting power of individual serum miRNAs, either alone or in combination. Our data demonstrated that combination of two serum miRNAs significantly improved the specificity and sensitivity in OSCC detection. In conclusion, our study found that circulating microRNAs or microRNA panel have the potential to serve as non-invasive biomarkers for OSCC diagnosis.

This dissertation focuses on the development of algorithms for analyzing and modeling of the signals from optical spectroscopy. This dissertation is motivated by the detection of oral cancer, but some of the methods developed can be generalized to epithelial cancers of other sites. Two main topics are covered in this dissertation: Analysis and Modeling. For analysis, the focus is on developing algorithms to make diagnostic predictions. The analysis methods are empirically tested using an oral cancer dataset. Statistical analyses show that polarized reflectance spectroscopy has the potential to aid screening and diagnosis of oral cancer. Also, a novel adaptive windowing technique is developed to extract spectral features with fewer windows that retain the diagnostic information. For modeling, a Monte Carlo model simulating light-tissue interactions is presented to aid in the design of diagnostic instrumentation.
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碩士
國立臺灣大學
光電工程學研究所
94
In this research, a fiber-based optical coherence tomography (OCT) system is built, which utilized the broadband SLD light source with the central wavelength at 1300 nm and the spectral width at 100 nm. In the OCT system, an optical phase delay line is implemented for the fast scanning requirement with the scanning frequency up to 250 Hz. The axial resolution of the OCT system is 8 microns. Its sensitivity is 80 dB. A compact rotation-type probe specially designed for the oral cavity scanning is fabricated. The lateral resolution of the system is 14 microns. With this hand-held probe, the in vivo scanning results of human skin are first obtained. In such scanning, three major layers, including stratum corneum, epidermis, and dermis, can be clearly identified. The penetration depth of human skin scanning images is 600~800 μm. The image size of human skin scanning of 1 mm x 1mm can be completed in less than one second. To test the clinical application, in vivo scanning of oral mucosa was performed. In such scanning, two types of oral mucosa, including labial mucosa (lip) and specialized mucosa (the dorsal surface of tongue) are scanned. In the labial scanning images, three major layers, including epithelium, lamina propria, and submucosa, can be identified. The scanning depth of labial mucosa was 600~700 μm. In scanning the images of specialized mucosa, some glands inside the layer of lamina propria can be observed. This OCT system will be used for clinical diagnosis of oral cavity cancer at the National Taiwan University Hospital.

碩士
臺北醫學大學
牙醫學系碩博士班
103
Background and Purpose : Latest AD 2014, the Ministry of Health and Welfare reported Taiwan''s cancer registration showed that there are more than six thousand new cases of oral cancer (including oropharynx , hypopharynx ) occurred each year. The positive rate of oral cancer screening for high-risk group who smoke or chew betel nut was 8.5% , but the referral rate was 52.3% .To promote all level medical institutions to enhance the positive referrals rate, this study combined the data of positive cases in oral cancer screening, impact on the prognosis of cancer treatment and care patterns , impact on the diagnosis between the positive cases and various medical institutions , the positive cases and the treatment of resource distribution and so on.. Methods and procedures : In medical institutions of oral cancer screening have implemented, we extract the random cluster sampling clinic samples , issued questionnaire to North 615, Central 267 , Southern 370 , East 34 , a total of 1,286 medical institutions in Taiwan, began in August 2012. In this study, the main analysis.method was the multi -class model (Hierarchical Model). Results: In the northern of Taiwan, referral rates was higher in Medical Center and other level hospitals than the national average. In central and southern of Taiwan, other level hospitals and local health bureau had higher referral rate than the national average. In eastern of Taiwan, the medical center and local health bureau had higher referral rate than the national average. Oral cancer screening worker except of local health bureau, the dentist is a majority. Positive cases in other hospitals are up to a total of 12,740, followed by the Medical Center 9360. In oral cancer screening, other hospitals have the highest benefits are 1:24, then medical center are lower 1:18. For every positive case in every-singleday outpatient number, medical centers had the proportion of 1:18, then other hospital is about 1:68. That efficiency of positive cases screening in the medical center outpatient is highest. The average referral positive cases in the medical center are highest 234 positive cases. If the medical institutions implemented of adult health prevention and smoking cessation classes, there has higher referral rate. Difference between referrals successful and failed is the factor of family support. In the group of successful referrals, 83.2% of screening case family noticed the oral lesion and suggested received medical treatment as soon as possible, on the contrary, group of failed referral was only 28.3% supported by their families and 22.5% of the cases are deliberately concealed reluctant family to know that condition. Conclusion: This study found that levels of medical institutions influence on referral rates include oral cancer therapy equipment, community area screening, adult health care and consultation before referrals. Individual level factors that influence the rate of referral are family support, younger age, betel nut chewing habit and repeated screening. In addition, adult preventive care and smoking cessation classes related to the referral rate. Cases of unsuccessfully referred told that the most common reasons include disease-insight and the time factor (too busy, prolong waiting time) ; if the hospital to facilitate referral program or encourage to receive local clinics follow. Suggestion are setting referral reward, encourage medical institutions refer positive actively , providing practice management resources of cases, assisting other clinic referral resource, setting up referral service primary care centers to improve the current plight of low referral .

Objectives: Intact cell peptidome profiling (ICPP) with MALDI-ToF Mass-Spectrometry holds promise as a non invasive method to detect head and neck squamous cell carcinoma (HNSCC) objectively, which may improve the early diagnosis of oral cancer tremendously. The present study was designed to discriminate between tumour samples and non-cancer controls (healthy mucosa and oral lesions) by analysing complete spectral patterns of intact cells using MALDI-ToF MS. Material and Methods: In the first step, a data base consisting of 26 patients suffering from HNSCC was established by taking brush biopsy samples of the diseased area and of the healthy buccal mucosa of the respective contralateral area. After performing MALDI-ToF MS on these samples, classification analysis was used as a basis for further classification of the blind study composed of additional 26 samples including HNSCC, oral lesions and healthy mucosa. Results: By analyzing spectral patterns of the blind study, all cancerous lesions were defined accurately. One incorrect evaluation (false positive) occurred in the lesion cohort, leading to a sensitivity of 100%, a specificity of 93% and an overall accuracy of 96.5%. Conclusion: ICPP using MALDI-ToF MS is able to distinguish between healthy and cancerous mucosa and between oral lesions and oral cancer with excellent sensitivity and specificity, which may lead to a more impartial early diagnosis of HNSCC.

Dissertação de Mestrado em Biologia Celular e Molecular apresentada à Faculdade de Ciências e Tecnologia
O cancro oral encontra-se entre os 10 cancros mais comuns, com 405,000 novos casos esperados anualmente, a nível mundial. A sua taxa de sobrevivência a cinco anos é de aproximadamente 80% no estadio I, mas desce para 20% no estadio IV. Apesar do progresso na área terapêutica, as suas taxas de incidência e de sobrevivência permanecem preocupantes, principalmente devido ao diagnóstico tardio e a altas taxas de recidiva. As biópsias de tecido continuam a ser o gold standard para o diagnóstico e para a determinação do perfil genético dos tumores. No entanto, para além de não serem de fácil obtenção e de estarem associadas a riscos e a dor para o doente, as biópsias de tecido apenas oferecem uma caracterização momentânea da heterogeneidade tumoral, não consideram a plasticidade fenotípica das células cancerígenas, e não podem ser obtidas repetidamente para a monitorização dos doentes. Dada a necessidade de desenvolver métodos não invasivos para a deteção precoce, o diagnóstico, e a monitorização de doentes oncológicos, as biópsias líquidas surgiram recentemente como uma potencial abordagem na medicina de precisão. As biópsias líquidas consistem na deteção de componentes derivados dos tumores, incluindo DNA tumoral em circulação (do inglês, ctDNA), em biofluidos, como o sangue e a urina, ultrapassando várias limitações impostas pelas biópsias de tecido, uma vez que são minimamente invasivas, fáceis de repetir durante o acompanhamento clínico do doente, e capazes de detetar a heterogeneidade tumoral. No entanto, o impacto clínico das biópsias líquidas no cancro oral ainda é muito limitado quando comparado com outros tipos de cancro, requerendo mais estudos de validação para a sua implementação com sucesso. Deste modo, o principal objetivo deste estudo piloto foi explorar o potencial das biópsias líquidas no diagnóstico e na monitorização de doentes com cancro oral. Em suma, procurámos monitorizar as concentrações de DNA livre em circulação (do inglês, cfDNA) no plasma e na urina durante o acompanhamento clínico de doentes com cancro oral, e avaliar e comparar as caraterísticas mutacionais do ctDNA e dos tecidos tumorais correspondentes por sequenciação de nova geração (do inglês, NGS). Ambas as análises quantitativas e qualitativas do cfDNA foram correlacionadas com as caraterísticas clinicopatológicas dos doentes. Para além disso, como um objetivo secundário, estudámos os perfis genómicos e epigenéticos dos tumores orais pelas técnicas de a-CGH e MS-MLPA. Foi possível obter informações preliminares interessantes relativamente à cinética do cfDNA durante o tratamento dos doentes com cancro oral, nomeadamente, que os níveis de cfDNA no plasma parecem aumentar em resposta ao tratamento. Para além disso, a identificação de mutações específicas do cancro em genes como TP53 e SMAD4 no ctDNA revelou que as biópsias líquidas podem ser uma fonte de informação relativamente ao perfil genético dos tumores e à resposta terapêutica no cancro oral. Adicionalmente, a combinação das técnicas MS-MLPA e a-CGH permitiu encontrar alterações frequentes na variação do número de cópias e na metilação em tumores, e identificar um conjunto de genes associados a vias celulares comumente alteradas na carcinogénese que poderão ter potencial como biomarcadores.
Oral cancer ranks within the top 10 most common cancers, with 405,000 new cases being anticipated each year, worldwide. Its five-year survival rate is approximately 80% in stage I but decreases to 20% in stage IV. Despite the improvements made in the therapeutic area, its incidence and survival rates are still concerning, mainly due to late diagnosis and high rates of recurrence. Tissue biopsies are still the gold standard for diagnosis and for the genetic profiling of tumors. However, besides not being easily obtained and implying risk and pain to the patient, tissue biopsies only provide a snapshot of tumor heterogeneity, do not consider the phenotypic plasticity of cancer cells, and cannot be obtained repeatedly for patient follow-up. Given the need to develop non-invasive tools for early detection, diagnosis and monitoring of cancer patients, liquid biopsies have recently emerged as a potential approach in precision medicine. Liquid biopsies consist in the detection of cancer-derived components, including circulating tumor DNA (ctDNA), in biofluids, such as blood and urine, overcoming many limitations presented by tissue biopsies, since they are minimally invasive, easily repeated during patient follow-up, and able to detect tumoral heterogeneity. However, the clinical impact of liquid biopsies in oral cancer is still very limited when compared to other cancers, requiring further validation studies for its successful implementation. In this sense, the main objective of this pilot study was to explore the potential of liquid biopsies for the diagnosis and monitoring of oral cancer patients. In sum, we aimed to monitor plasma and urine cell-free DNA (cfDNA) concentrations before and during the treatment course of oral cancer patients, and to assess and compare mutational characteristics of ctDNA and corresponding tumor tissues by Next Generation Sequencing (NGS). Both quantitative and qualitative analysis of cfDNA were correlated with the patient’s clinicopathological features. Moreover, as a secondary objective, we aimed to establish the genomic and epigenetic profiles of oral tumor tissues by array-Comparative Genomic Hybridization (a-CGH) and Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). We were able to obtain interesting preliminary data on the kinetics of cfDNA during the treatment course of oral cancer patients, namely that plasma cfDNA levels seem to increase in response to treatment. Moreover, the identification of cancer-specific mutations in genes such as TP53 and SMAD4 in ctDNA revealed that liquid biopsies could be a source of information regarding the tumors’ genetic profile and therapeutic response in oral cancer. Additionally, the combination of the MS-MLPA and a-CGH techniques allowed us to find common CNVs and methylation alterations in oral tumors and to identify a set of genes related to commonly altered cellular pathways in carcinogenesis that could have potential as biomarkers.

碩士
國立陽明大學
牙醫學系
106
Research background: Oral Squamous Cell Carcinoma is the sixth common cancer in the world. According to the latest statistics of the Ministry of Health and Welfare Cancer Registry Report (2015), oral cancer incidence rate ranked as the sixth and mortality the fifth in Taiwan. The incidence and mortality among men both ranked as the fourth. There are approximately 7,000 newly diagnosed oral cancer cases each year and nearly 3,000 deaths due to oral cancer. Oral cancer became the most common cancer among adults age between 25-44 years old. Of these patients with oral cancer, as many as 88% had the habit of chewing betel quids, and accompanying cigarette-smoking and alcohol-drinking behaviors, the incidence of oral cancer in Taiwan remains high. Oral cancer affects not only the patient’s own health, but also the physical aspects and psychological aspects (the appearance is impaired, the inability to continue work, and the lack of financial resources, etc.). At the peak of work, it will also cause social productivity and economic derogation, and the impact will be enormous. Research methods: The subjects of this study was male oral cancer patient at the Oral Surgery Department of Taichung Veterans General Hospital, who completed the questionnaire to understand the patient's medical treatment behavior and why they delay in diagnosis or treatment. The questionnaire was based on health belief models, PRECEDE-PROCEED model , health literacy, and other factors combined with the characteristics of oral cancer in Taiwan and was calculated using the Likert Scale. Mainly to discuss male oral cancer patients. After consciously having abnormalities in the oral cavity, do they immediately go to the hospital for medical diagnosis; or if they are diagnosed with oral cancer, why they don’t receive treatment immediately. Results: A total of 50 male patients who had undergone oral cancer surgery for the first time were recruited from the oral surgery section of a medical center at central Taiwan The patient gave the questionnaire information after agreeing and signing the informed consent form. For all study subjects, the mean age was 51.8 years old, and most of them had an education level as high school or junior high school(both were 17, 34%) . Forty-one (82%) subjects were married. Thirteen (26%) subjects did not have a job when interviewed. The economic conditions are mostly ordinary (56%). Twenty-nine (58%) subjects had quit smoking, but 19 (38%) still kept smoking habits. Thirty-eight (76%) subjects had quit chewing betel quid. Twenty-three (46%) subjects had quit drinking habits and still thirteen (26%) continued to drink. Most of the study subjects were with other chronic diseases: 15 patients (30%) have high blood pressure and 12 patients (24%) have diabetes. Divided into three groups at intervals to conduct cross-sectional analysis to see the patient's health beliefs and self-efficacy, propensity factors, enhancement factors, and enabling factors. Patients worried about the surgery would do damage to their faces (P=0.026). Discussion: Oral cancer can be diagnosed at its early stage. If soon to diagnosis, the five-year survival rate can reach 80%. However, the current incidence of oral cancer and the mortality in Taiwan are the fourth among men. In addition to the lack of cancer awareness, in the face of suffering from oral cancer and delaying treatment or treatment due to various factors, it may be because there is still working, there is no income without work, the family has elders or children to take care of, etc., but also from the questionnaire results The patient's family will support the patient to treatment. Instead, the patient will be more willing to face the treatment and subsequent side effects. Family support is also an important factor. Conclusion: This study shows that although there are no statistically significant differences in the health beliefs, health education diagnostic evaluation, and health awareness among male oral cancer patients, they can know that oral cancer patients have a positive attitude toward treatment, with family support and assistance. Oral cancer patients can be actively treated. It is also suggested that high-risk groups should have the ability to self-inspect the oral cavity and hope to reduce the incidence of oral cancer so as to improve people's health.

博士
國立陽明大學
生醫光電研究所
104
Raman spectroscopic tissue characterization for cancer diagnosis has been explored extensively. It is yet to be developed, however, as a routine tool for everyone’s use. Complexity of tissue Raman spectra requires specialized spectral analysis, impeding development of an automatic and objective method for cancer diagnosis. Here we adopt a multivariate curve resolution analysis to unequivocally detect the Raman spectroscopic signature of keratin, a well-established molecular biomarker of oral squamous cell carcinoma (OSCC). We successfully diagnose OSCC with excellent accuracy and specificity by measuring 196 independent Raman spectra from 196 different points from one oral tissue sample and globally analyze these spectra using a Multivariate Curve Resolution (MCR) analysis. Discrimination of OSCC tissues was automatically and objectively made by spectral matching comparison of the MCR decomposed Raman spectra and the standard Raman spectrum of keratin. We used a total of 24 tissue samples, 10 OSCC and 10 normal tissues from the same 10 patients, 3 OSCC and 1 normal tissues from four independent different patients. Following the newly developed protocol presented here, we have been able to detect OSCC tissues with 77 to 92 % sensitivity (depending on how to define positivity) and 100 % specificity. All procedures are automatic and objective, and do not require any specialized spectroscopic knowledge, making a highly practical new method for general use in disease diagnosis. It lends itself to a reliable clinical diagnosis of OSCC substantiated by the “molecular fingerprint” of keratin.

Autofluorescence spectroscopy can improve the early detections of oral cancer. Biochemical and structural changes associated with dysplastic progression alter the optical properties of oral mucosa and cause diagnostically significant differences in spectra from normal and neoplastic sites. This dissertation describes experimental and modeling studies aimed at revealing biological reasons for the diagnostically significant differences observed in depth-resolved fluorescence spectra from normal and neoplastic oral mucosa. An experimental approach, based on high-resolution fluorescence imaging, is used to study the autofluorescence patterns of oral tissue. At UV excitation, most of the epithelial autofluorescence originates from cells occupying the basal and intermediate layers, while stromal signal originates from collagen and elastin crosslinks. With dysplasia, epithelial autofluorescence increases, while autofluorescence from subepithelial stroma drops significantly. Benign lesions also display a drop in autofluorescence from subepithelial stroma, but have different epithelium fluorescence patterns compared to dysplasia. Optical probes that measure mostly stromal fluorescence, may reveal a similar loss of fluorescence intensity and thus fail to distinguish benign inflammation from dysplasia. These results emphasize the importance of using probes with enhanced detection of epithelial fluorescence for improved diagnosis of different types of oral lesions. The second part of this work presents a Monte Carlo model that predicts fluorescence spectra of oral mucosa obtained using a depth-selective probe as a function of tissue optical properties. A model sensitivity analysis determines how variations in optical parameters associated with neoplastic development influence the intensity and shape of spectra, and elucidates the biological basis for differences in spectra from normal and premalignant oral mucosa. Spectra of oral mucosa collected with the depthselective probe, are affected by variations in epithelial optical properties and to a lesser extent by changes in superficial stromal parameters, but not by changes in the optical properties of deeper stroma. Changes in parameters associated with dysplastic progression lead to a decreased fluorescence intensity and a shift of the spectra to longer emission wavelengths. Decreased fluorescence is due to a drop in detected stromal photons, whereas the shift of spectral shape is attributed to an increased fraction of detected photons arising in the epithelium.

碩士
國立臺灣科技大學
管理學院MBA
105
The present study explores the knowledge diffusion and developmental trajectories in the scientific literature on biomarkers of oral malignancies. We have utilized the Main Path software to analyze the citation data of 2210 relevant scientific papers obtained from Scopus database. The data was composed by papers published from 1983 to 2016. Additionally, we have applied the edge-betweenness clustering analysis to reveal the most relevant subgroups inside the citation network which can further explain the developmental trajectories that have taken place in this scientific field. Finally, we have used indicators such as g-index and h-index to identify the most influential countries, journals and researchers in the literature related to biomarkers for oral cancer diagnosis management (BOCM). The results of the Main Path analysis have portrayed a variation in the portfolio of biomarkers used to detect oral cancer. The initial biomarkers contemplated were chromosomic alterations at 3p, 9p, 17p and 18q, as well as changes in molecular expression such as those in phosphoproteins p53, p16 and p21. The final stage of the Main Path shows the use of micro-RNAs as potential BOCM due to their role in carcinogenesis. This variation goes along with the emergence of novel technologies such as proteomics and genomics that allows to isolate various types of molecular markers from less-invasive samples. Additionally, five different clusters were identified in the citation network of this research. Furthermore, this study ranks the contribution of countries in the field of BOCM and found that traditional countries devoted to science such as the US, Japan or UK are the most influential in this field, but there are new players from developing economies such as Taiwan, India and China. Finally, the geographical distribution in this knowledge field is mainly loco-regional in accordance with the “localization” theory of knowledge flow maybe due to the great uncertainty associated with new technologies to do diagnosis. Based on the results obtained, it is possible to state that the methodology applied in the present study is a very viable and beneficial fashion to methodically organize, classify and analyze the evolution course of the literature data related to BOCM.

博士
國立陽明大學
牙醫學系
106
Background: Glutamine has a very important role in the human body, including pH balance in an acidic environment, as well as supporting the TCA cycle in cancer cell growth. One from two of the isoforms in catabolism of glutamine is initiated by the kidney type glutaminase (GLS1). This GLS1 modulate cellular acidity by catalytic activities where produces ammonia and showed TG-2 is up-regulated, helps protect cells from acid-induced cell death and decrease cellular pH. However, the expression of transglutaminase-2 (TG-2) in oral cancer growth related to renal function is unknown. Here we examined TG-2 and its expression as a prognostic tool. Methods: Fifty-six oral squamous cell carcinoma (OSCC) tissues were collected with the inclusion of tumor in any region of oral area, and patients with creatinine (Cr) and blood urea nitrogen (BUN) results. The tissues were stained using immunohistochemistry (IHC) with a TG-2 antibody [N3C3], then observed under the microscope. The TG-2 expressions were calculated using Adobe Photoshop CS software and statistical analyses using SPSS ver. 21. Results: We found that TG-2 expression showed a significant difference in the expression levels between tumor and the adjacent groups without disease-free survival, disease-specific survival, and recurrence with p<0.05. The average staining intensity with 25th percentile of TG-2 becomes a vital score for the diagnosis in OSCC. Furthermore, our study demonstrated a good prognosis outcome if the intensity score showed a higher difference in TG-2 expression between the adjacent and tumor tissue. Conclusion: To our knowledge, this is the only clinical study on TG-2 expression in OSCC and patient with good renal function, and it demonstrates that TG-2 can serve as a predictor of tumorigenesis and prognosis outcome.

A qualidade de vida é proporcionalmente influenciada pelo estado de saúde geral, da qual faz parte a saúde oral. Um exame oral cuidadoso revela informações sobre inúmeras condições sistémicas, deficiências nutricionais, infecções e cancro. O diagnóstico precoce é essencial para evitar a evolução da doença. O objetivo deste trabalho foi discutir a importância do diagnóstico de patologias orais não dentárias pelos médicos especialistas em Medicina Geral e Familiar e, posteriormente compreender com base num questionário aplicado aos profissionais referidos, qual a real necessidade para a formação específica sobre as doenças com comprometimento oral. Foi possível concluir que o profissional em Medicina Geral e Familiar possuiu grande alcance populacional relativamente aos médicos de outras especialidades. A maioria dos estudos consultados revela um baixo conhecimento na área das patologias orais não dentárias por parte dos especialistas em medicina geral e familiar. Paralelamente enfatizam a necessidade de formação na área da saúde oral.
The quality of life is proportionally influenced by the general health, which includes oral health. An oral exam shows information about various systemic conditions, nutritional deficiencies, infections and cancer. Early diagnosis is essential to prevent disease progression. The objective of this work was to discuss the importance of the diagnosis of non-dental oral pathologies by Physicians and, later, based on a survey applied to the professionals mentioned, what is the real need for specific training on diseases with oral impairment. It was possible to conclude that the Physicians had a large population range in relation to doctors in other specialties. Most of the studies revealed a lack of knowledge in the area of non-dental oral pathologies by specialists in general and family medicine. At the same time, they highlight the need for training in oral health area.

Introdução: Atualmente o cancro oral é o sexto cancro mais comum em todo o mundo. A sua elevada taxa de morbilidade e consequente mortalidade está relacionada com uma deteção da doença em estádios de malignidade avançados. Esta conjuntura acaba por levar ao aumento de complicações no tratamento, o que o torna mais agressivo consoante o grau de malignidade. Por isso o diagnóstico precoce combinado com o tratamento adequado é a chave fundamental para o controlo da doença. Face a esta realidade os profissionais de saúde têm um papel fulcral na deteção precoce de lesões potencialmente malignas ou malignas, sendo por isso um objetivo prioritário na saúde. Para avaliação deste tipo de lesões o diagnóstico definitivo, histopatologicamente fornecido pela biópsia convencional, continua a ser o método imprescindível e de eleição para os profissionais de saúde, no entanto novas técnicas não-invasivas têm surgido como auxiliares de diagnóstico. Objetivos: Esta monografia teve como objetivo obter um conhecimento detalhado acerca do cancro oral, nomeadamente as suas principais particularidades e especificidades de forma a obter uma deteção precoce e consequentemente um prognóstico favorável. Conjuntamente, foi realizado um estudo que recolheu informações sobre o conhecimento geral dos médicos dentistas e estomatologistas portugueses relativamente ao cancro oral, a utilização de modalidades auxiliares de diagnóstico hoje em dia disponíveis, assim como a colheita de dados face ao protocolo de atuação dos clínicos aquando suspeita de lesões potencialmente malignas ou malignas. Materiais e Métodos: Este trabalho teve como base as palavras-chave delineadas e critérios de inclusão e exclusão específicos, com o objetivo de angariar e debater o máximo de informação acerca desta grande associação entre oncologia e medicina dentária, o cancro oral. De forma a dar resposta aos objetivos enunciados associou-se a esta monografia um estudo quantitativo do tipo descritivo e transversal. A recolha de dados foi realizada através de um inquérito em que participaram 324 profissionais de saúde oral. O inquérito, com a totalidade de vinte e uma perguntas, teve como principal objetivo a recolha de informação sobre o conhecimento geral do médico dentista ou estomatologista relativamente ao cancro oral. Após colheita de dados, estes foram tratados e analisados recorrendo a programas informáticos como o Microsoft Office Excel (2010) e o programa Statistical Package for the Social Sciences (IBM© SPSS© Statistics) vs. 22.0 para Windows. Resultados: A amostra selecionada demonstrou ter os conhecimentos necessários e fundamentais quando abordados sobre este tema, estando conscientemente alerta caso suspeitem de uma lesão potencialmente maligna ou maligna. Cerca de 78% dos inquiridos preferem encaminhar o paciente quando perante uma lesão suspeita. Relativamente aos indivíduos que realizam biópsia, 66.7% prefere a técnica excisional. 96% discute com colegas quando suspeita de uma lesão maligna. A maioria dos profissionais (88.9%) refere que nunca utilizou outros métodos auxiliares para além da biópsia. Dos 11.1% que admitem ter utilizado outro método auxiliar de diagnóstico, 58.8% indica o azul de toluidina como método preferencial. 27.2% dos profissionais não considera a biópsia como elemento fundamental. Discussão e Conclusão: Através da pesquisa realizada verificou-se que é fundamental um conhecimento dos sinais e sintomas e a realização de rastreio em consultas de rotina para detetar precocemente lesões potencialmente malignas ou malignas. Por consenso geral dos inquiridos, constatou-se que a história clínica, o exame clínico e a biópsia são os métodos mais eficazes e comummente utilizados a fim de reduzir a morbilidade e mortalidade associada a esta doença. Ainda assim, 27.2% dos profissionais não considera a biópsia como elemento fundamental o que revela ser preocupante. Contudo corroborou-se que a maioria dos inquiridos, mesmo aptos teoricamente, prefere encaminhar ao invés de realizar biópsia.
Introduction: Currently oral cancer is the sixth most common cancer worldwide. Its high rate of morbidity and consequent mortality, is related with the detection of this disease already in advanced stages of malignancy. In this context, it ends up leading to increased complications in treatment that becomes more aggressive according to the degree of malignancy. Therefore early diagnosis along with suitable treatment is the fundamental key to control the disease. Due to this reality, health professionals have a key role in early detection of potential malignant or malignant lesions making it a priority goal in health. To evaluate this kind of lesions, the definitive histopathologic diagnosis provided by conventional biopsy, still remains the crucial method of choice for health professionals, although new non-invasive techniques have emerged as auxiliary diagnosis methods. Objective: This paper aims to obtain a detailed knowledge of oral cancer, including its main particularities and specificities in order to obtain an early detection and consequently a favorable prognosis. It has also have been conducted a study that collected information on the general knowledge of portuguese dentists and stomatologists regarding oral cancer, the use of auxiliary diagnostic tools nowadays available, as well as data collection concerning the clinical performance protocol when suspected potentially malignant or malignant lesions. Materials and Methods: This study was based on the keywords and outlined specific inclusion and exclusion criteria, in order to raise and discuss as much information about this great association between oncology and dentistry, which is oral cancer. In order to meet the stated goals, it was associated with this monography a quantitative study of a descriptive and cross-sectional type. Data collection was conducted through a survey involving 324 dental professionals. The survey, with a total of twenty-one questions, aimed to collect information on the general knowledge of dentists regarding oral cancer. After data collection, these were processed and analyzed using computer programs such as Microsoft Office Excel (2010) and the Statistical Package for Social Sciences (SPSS IBM © © Statistics) vs. 22.0 for Windows. Results: The selected sample has demonstrated the necessary and basic knowledge when approached about the subject, consciously being alert if suspected a potentially malignant or malignant lesion. About 78% of respondents prefer to refer the patient when faced with a suspected lesion. Regarding the individuals that perform biopsy, 66.7% prefer the excisional technique. 96% approaches other colleagues when suspects of a malignant lesion. Most professionals (88.9%) reported ever used other auxiliary methods in addition to biopsy. Of the 11.1% who admit to having used an auxiliary diagnostic tool, 58.8% indicates the toluidine blue as the preferred method. 27.2% of professionals do not consider the biopsy as a fundamental element. Discussion and Conclusion: Through the research made, it was found that it is essential to have knowledge of signs and symptoms and provide screening in routine consults aiming for an early detection of potentially malignant or malignant lesions. By general consensus of those surveyed, it was found that the clinical history, clinical examination and biopsy are the most effective methods and commonly used to reduce morbidity and mortality associated with this disease. Still, 27.2% of the respondents do not consider the biopsy as a fundamental element, which is concerning. However it was corroborated that the majority of respondents although theoretically able, prefer to refer instead of performing biopsy.