Orientador: Antonio Santos Martins / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T06:49:57Z (GMT). No. of bitstreams: 1 ScanaviniJunior_RuiCarlos_M.pdf: 989083 bytes, checksum: 9b013db47c9ffb39e508299508218360 (MD5) Previous issue date: 2005 / Resumo: O carcinoma espinocelular ou de células escamosas constitui a segunda neoplasia de pele mais freqüente e apresenta índice de cura superior a 90%, quando tratado na fase mais inicial. Tumores maiores e uma pequena fração dos tumores iniciais costumam apresentar evolução desfavorável, representada pelas recidivas loco-regional e a distância, apesar do tratamento inicial. Objetivo: Identificar, por análise retrospectiva, os fatores histológicos e clínicos associados à evolução adversa, identificando os tumores de alto risco. Material e método: Foram analisados trinta e cinco prontuários de pacientes submetidos ao tratamento cirúrgico do carcinoma espinocelular (CEC) cutâneo de cabeça e pescoço, sendo coletadas informações sobre espessura (milímetros), invasão perineural, grau de diferenciação e invasão angiolinfática. Realizou-se a análise estatística da associação desses fatores com as variáveis da evolução do CEC (recidiva local, metástase linfática, metástase a distância e óbito). Procedeu-se de forma similar na comparação das variáveis da evolução do CEC entre si. Admitiu-se diferença estatística de 5%. Resultados: Ocorreu associação estatística entre a recidiva local e invasão perineural; metástase linfática e invasão angiolinfática, espessura e invasão perineural; metástase a distância e invasão angiolinfática; óbito e invasão perineural, invasão angiolinfática, espessura tumoral. Entre as variáveis do CEC, verificou-se que a metástase linfática e a metástase a distância estiveram associadas ao óbito. Conclusão: Os fatores histológicos e clínicos observados na evolução permitem definir pacientes de alto risco para os quais o seguimento e novos protocolos terapêuticos prospectivos devem ser melhor estabelecidos. Unitermos: Carcinoma de células escamosas, pele, prognóstico / Abstract: Squamous cell carcinoma represents the second most common cancer of the skin. Most of the patients, especially with the small tumors, can be cured at rates that exceed 90%. Larger tumors and a subset of the small ones will present substantial risk of recurrence. Objective: To identify, by retrospective analysis, histological and clinical features associated with recurrence and metastasis. Material and method: There were analyzed thirty five records of patients treated by surgery for squamous cell carcinoma of the skin of the head and neck. From them we collected information about: tumor depth (millimeters), perineural invasion, grade (Broders) and angiolymphatic invasion. After that we verified the association of these features with the variants of prognosis: local recurrence, lymph node metastasis, distant metastasis and death caused by the disease. In a similar fashion we compared these variants of prognosis between them. Statistical significance was admitted at the level of 5%. Results: We found statistical significance between: local recurrence and perineural invasion; lymph node metastasis and perineural invasion, angiolymphatic invasion and depth; distant metastasis and angiolymphatic invasion; death and perineural invasion, depth and angiolymphatic invasion. Between the variants of prognosis we found association of death with distant and lymph node metastasis. Conclusion: Histological and clinical features of squamous cell carcinoma of the skin of the head and neck may help to define high risk patients. Prospective protocols should be established for better treatment results in these patients / Mestrado / Cirurgia / Mestre em Cirurgia

Squamous cell carcinomas of the head and neck (SCCHN) is a diverse group of tumours includingtumours of the mouth, of which most are manifested in the tongue. Previous studies have shown that assessment of histological risk factors including worstpattern of invasion (WPOI) and lymphocytic response (LR) is of clinical relevance in treating SCCHN. It hasalsobeen suggested that evaluation of the inflammatory infiltrate could be of prognostic importance.The purpose of this study was to further investigate, analyze and map histological factors associated with TSCC.A total of 58biopsies fromtwo different ethnic groups,Swedish and Italian,were evaluated regarding factors like WPOI andLR. Results were thencorrelated to clinical data.Approximately halfof the patients, 53%, displayed patches ofdense lymphocytic infiltrate at the tumour interface. There was,however,no statistically relevant correlation seen between LR, recurrence of disease, survival rate or ethnicity. Considering WPOI, 83% of patients showed a tumour growth pattern withsmall invasive islands <15 cells (WPOI 4). No correlationbetween WPOI, recurrence of disease, survival rate, ethnicity or lymphocyticresponse was found.Our findings confirm that SSC of the tongue hasa very split patternof invasion. No conclusive result was found concerning inflammatory response and prognostic factors. Data collected showed that ethnic differences could potentiallybe of interest for further study of the prevalence of tongue SCC.

Abstract Traditional clinicopathological factors are not accurate enough to predict the behavior of head and neck squamous cell carcinoma (HNSCC). The most powerful indicator of prognosis is the stage of the disease. New prognostic markers have, however, been searched for in order to better identify patient groups in need of different treatments or follow-up. Gelatinases (MMP-2, -9) are endopeptidases associated with tumor invasion and angiogenesis, and their tissue inhibitors (TIMP-1, -2) are also linked to cancer cell invasion and metastasis formation. In some cancer types they are even prognostic and relate with a more aggressive clinical course of the disease. In the present work the expression and the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2, -9, TIMP-1 and -2 were assessed in HNSCC. The study group included 74 patients with HNSCC and 44 healthy controls. The expression of immunoreactive proteins was examined in paraffin-embedded tumor sections by immunohistochemical staining using specific antibodies, and the pretreatment serum levels of those proteins were quantitatively measured by ELISA assay. Immunohistochemical overexpression of MMP-9 in tumor was for the first time found to predict the prognosis for shortened survival in HNSCC, the cause-specific survival rates being 45% and 92% and relapse-free survival being 42% and 79% in MMP-9 positive or negative cases, respectively. Additionally, tissue TIMP-1, MMP-2 and TIMP-2 positivity were all also linked with poorer survival of patients with HNSCC. However, these differences remained less distinct than with MMP-9. The expression of gelatinases and their inhibitors in tumor tissue was also an indicator for later lymph node or hematogenic relapses in HNSCC patients. Circulating MMP-9 and TIMP-1 levels were significantly higher in HNSCC patients than in healthy controls. Further, the cause-specific and relapse-free survival rates were lower among HNSCC patients with high MMP-9 and TIMP-1 serum levels compared to patients with low levels of circulating MMP-9 and TIMP-1. A significant correlation was shown between circulating MMP-9 and MMP-9 immunohistochemical staining in the corresponding tumors. No correlation was found between tissue or circulating levels of gelatinases or their inhibitors and the traditional clinical or histopathological factors, except for the association between tissue and circulating TIMP-1 and the size of the primary tumor. Taken together, these results suggest that tissue expression of gelatinases and their inhibitors as well as pretreatment circulating MMP-9 and TIMP-1 levels could be prognostic in estimation of the clinical course of HNSCC. The results indicate further studies are needed with larger patient materials.

Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced in the past decade as a promising therapeutic option in Head and Neck Squamous Cell Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result, RTK inhibitors require a combination based therapeutic approach with other treatment modalities. To uncover such a combination of agents, we performed a high throughput Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.

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Diagnosis of two distinct malignant entities existing concurrently and at the same location (synchronous malignancy) by fine-needle aspiration (FNA) is unusual but may occur. Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) in particular is associated with an increased incidence of secondary tumor, likely due to associated immunodeficiency. Co-occurrence of some carcinomas such as squamous cell carcinoma (SCC), may show especially aggressive behavior. A 57-year-old Caucasian male presented with recurrent upper extremity lymphedema and diffuse lymphadenopathy ofthe axillary and cervical regions. FNA ofa large cervical lymph node was diagnostic for both atypical lymphocytic proliferation and SCC. Flow cytometric analysis showed the atypical lymphocytic proliferation to be positive for CD5, CD23, CD19, CD20, HLA-DR, CD38, and the population was kappa light chain restricted. These cells were negative for CD-10 and FMC-7 antigens, suggesting a phenotype of B-cell SLL/CLL. We report a rare occurrence of metastatic SCC to a lymph node infiltrated by SLL/CLL. The diagnosis was achieved by a combination of cytomorphologic examination of FNA smears, immunohistochemical staining of cell block material, and flow cytometry on the sample obtained by FNA. To the best of our knowledge, only three cases of SCC metastasis to SLL/CLL diagnosed by FNA have been reported in the English literature. Though rare, awareness of such a possibility and careful cytological examination under the appropriate clinical conditions is warranted.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21417号 / 医博第4407号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 小川 誠司, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21699号 / 医科博第103号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 妹尾 浩, 教授 渡邊 直樹, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Early investigations of the urokinase type plasminogen activator (uPA) receptor (uPAR) and its ligand, uPA, were limited to their role in degradation of the extracellular matrix (ECM) and invasion. Emerging evidence revealed that uPAR and its relationship with uPA and/or transmembrane proteins, such as the integrins, affects cell-ECM adhesion events and proliferation. These events are tightly coordinated and essential for epithelial tissue development. However, unregulated expression of molecules involved in cell adhesion and proliferation plays a significant role in tumour development and metastasis. The overexpression of uPAR is linked to several cancer types, including human oesophageal squamous cell carcinoma (HOSCC). This study examines the contribution of uPAR, and its communication with extracellular components, to cell-ECM adhesion and/or proliferation of HOSCC cells. The confirmation of the uPAR and 1-integrin expression as well as uPA secretion in the HOSCC cells lines, established these lines as excellent models for further investigation. In all the HOSCC cell lines, uPAR associated with integrin-linked kinase, a scaffolding protein in cell-ECM adhesion events. Data presented in this investigation confirmed that the interaction of uPAR with uPA or 1-integrin contributed to adhesion of the HOSCC cell lines on collagen type I and vitronectin. It was clearly established that uPAR also played a part in the proliferation of all the HOSCC cell lines. The uPAR role in proliferation is influenced by: a) The absence or presence of collagen type I or vitronectin substrates; b) The activation of uPAR by endogenous uPA; c) The uPAR/1-integrin interaction; d) the presence of transforming growth factor  and epidermal growth factor. In the current study, it was successfully demonstrated that uPAR, and its relationship with the ECM and growth factors, contributes to adhesion and proliferation during the progression of HOSCC. This gives uPAR a considerable value as a therapeutic target for HOSCC.