Carcinoma de Células Renais (CCR) representa uma família de tumores distintos com evolução clínica imprevisível. Uma variedade de moléculas tem sido avaliada como marcadores prognósticos para CCR. Ciclina D1, uma proteína reguladora do ciclo celular, encontra-se superexpressa em vários tumores primários. Nosso objetivo é avaliar sua expressão como marcador prognóstico em CCR. Antes disso, traçamos um perfil clínico e histopatológico da amostra e verificamos sua relação com os fatores prognósticos considerados clássicos pela literatura. 109 espécimes de pacientes diagnosticados com CCR foram obtidos entre 2005 e 2010 no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto USP e submetidos à análise imunoistoquímica juntamente com 07 amostras de tecido renal normal. A maior parte das características epidemiológicas e clínicas de nossa amostra foi similar àquelas descritas na literatura mundial. Houve predomínio do gênero masculino, da raça branca, com idade próxima a 60 anos, frequência de pacientes assintomáticos em torno de 36% e grande prevalência do CCR de células claras (71,55%). A mortalidade específica da doença foi de 13,76%, sendo o CCR de células claras o tipo mais frequente entre os óbitos e casos metastáticos. Os casos que exibiram má evolução clínica, definida pela ocorrência de metástase e/ou óbito por CCR (22,01%), estiveram associados à presença de sintomas ao diagnóstico, maior tamanho tumoral, grupo de estágio alto (III ou IV), grau nuclear de Fuhrman alto (3 ou 4), presença de necrose e de diferenciação sarcomatóide no tumor, além de outros fatores histológicos desfavoráveis (p < 0,01). Isso indica que as variáveis utilizadas na avaliação de prognóstico em países desenvolvidos podem ser aplicadas aos nossos pacientes. Não houve expressão imunoistoquímica de Ciclina D1 nos casos de tecido renal normal. Observou-se heterogeneidade de marcação nuclear intratumoral no total de casos e menor expressão proteica entre os CCR papilífero e cromófobo. Pacientes com tumores com Ciclina D1baixa (até 30% de células positivas) apresentaram má evolução clínica (p = 0,03), maior tamanho tumoral (p = 0,01), presença de sintomas ao diagnóstico (p = 0,04), grau nuclear alto (p = 0,001), presença de necrose (p = 0,004) e de diferenciação sarcomatóide (p = 0,04) no tumor, além de menor sobrevida sem metástase e/ou óbito por CCR (p = 0,03). Após análise multivariada, a expressão de Ciclina D1 não apresentou valor prognóstico independente para má evolução clínica, embora tenha aumentado levemente a acurácia prognóstica do modelo adotado. Em todas as análises realizadas para o CCR de células claras isoladamente, observamos significância estatística semelhante à do total de casos (CCR). Nosso estudo demonstrou que: a proteína Ciclina D1 encontra-se superexpressa em CCR; os tipos de CCR parecem exibir diferentes padrões de marcação imunoistoquímica da Ciclina D1; alta marcação da proteína (acima de 30% de células positivas) esteve associada à boa evolução clínica e à maioria dos fatores prognósticos favoráveis bem estabelecidos na literatura. Novas investigações são necessárias para descobrir que mecanismos levam a seu acúmulo nas células neoplásicas e quais outros eventos podem estar contribuindo para a progressão da doença. / Renal Cell Carcinoma (RCC) is a family of distinct tumors with unpredictable clinical outcome. A variety of molecules have been evaluated as prognostic markers for RCC. Cyclin D1, a cell cycle regulatory protein, is overexpressed in several primary tumors. Our purpose is to evaluate its expression as a prognostic marker in RCC. Before that, we drew a clinical and histopathological profile of the sample and verified its relationship with prognostic factors regarded as classics in literature. 109 specimens from patients diagnosed with RCC were obtained between 2005 and 2010 at Hospital das Clínicas - Ribeirão Preto School of Medicine USP and submitted to immunohistochemical analysis, along with 07 normal kidney tissue samples. Most epidemiological and clinical characteristics of our sample were similar to those described in the literature. There was a predominance of male, Caucasian, aged about 60 years, the frequency of asymptomatic patients around 36%, and high prevalence of clear cell RCC (71.55%). The disease-specific mortality was 13.76%, being the clear cell RCC the most frequent type among deaths and metastatic cases. Cases that exhibited poor clinical outcome, defined by the occurrence of metastasis and/or death by RCC (22.01%), were related to the presence of symptoms at diagnosis, larger tumor size, high stage group (III or IV), high Fuhrman nuclear grade (3 or 4), presence of necrosis and sarcomatoid differentiation in the tumor and other unfavorable histological factors (p < 0.01). This indicates that the variables used in the assessment of prognosis in developed countries can be applied to our patients. There was no immunohistochemical expression of Cyclin D1 in cases of normal kidney tissue. There was intratumoral heterogeneity in nuclear staining in all cases and lower protein expression among papillary and chromophobe RCC. Patients with Cyclin D1low tumors (up to 30% positive cells) showed poor clinical outcome (p = 0.03), larger tumor size (p = 0.01), presence of symptoms at diagnosis (p = 0.04), high nuclear grade (p = 0.001), presence of necrosis (p = 0.004) and sarcomatoid differentiation (p = 0.04) in the tumor and lower survival without metastasis and/or death by RCC (p = 0.03). After multivariate analysis, the expression of Cyclin D1 showed no independent prognostic value for poor clinical outcome, although it has slightly increased the prognostic accuracy of the model adopted. In all analyzes performed for clear cell RCC alone, we observed statistical significance similar to that of the total cases (RCC). Our study showed that: Cyclin D1 protein is overexpressed in RCC; RCC types seem to exhibit different patterns of immunohistochemical staining for Cyclin D1; high protein expression (over 30% positive cells) was related to good clinical outcome and to most favorable prognostic factors well established in the literature. Further investigations are necessary to reveal which mechanisms lead to its accumulation in neoplastic cells and what other events might be contributing to the progression of the disease.

A radioterapia de fracionamento convencional (6000 cGy/6 semanas) oferece pequena chance de cura para os pacientes com diagnóstico de carcinoma brônquico não de pequenas células estádio m (localmente avançado). Recentemente, vários protocolos de pesquisa passaram a testar radioterapia com fracionamento alterado de dose e novas associações terapêuticas COIll o objetivo de tentar melhorar este resultado. Porém, como a radioterapia de fracionamento convencional ainda é a modalidade mais utilizada, toma-se importante conhecer com mais profundidade os fatores prognósticos nesse grupo de pacientes para uma adequada comparação dos resultados com as deIllais fonnas de tratamento. Com o objetivo de avaliar a expressão clínica, o comportamento quando submetido a radioterapia e os eventuais fatores prognósticos do carcinoma brônquico não de pequenas células estádio III, foram admitidos prospectivamente 43 pacientes inicialmente encaminhados para radioterapia exclusiva no Hospital São Lucas da Pontifícia Universidade Católica do RGS, em POlio Alegre, no período de abril de 1991 a maio de 1994. O tratamento foi realizado com feixe de fótons de megavoltagem (Acelerador Linear de 8 MeV e Tele Cobalto6o ) na dose lnínitna de 6000 cGy enl 6 selnanas (30 sessões). Foram estudados 39 homens e 4 luulheres com idade mediana de 67,0 anos. O carcinoma epidenllóide foi o lualS freqüente (81,40/0), seguido do adenocarcinolua (14,0%) e carcinoma indiferenciado de grandes células (4,70/0). O diâmetro mediano do tumor foi de 6,7 em, havendo uma localização preferencial no lobo superior direito (46,5%). Cerca de 80% dos pacientes apresentaram peiformance status (Zubrod) de 1 ou 2. Em 76,7% deles a taxa de hemoglobina foi superior a 12g/100 m1. O estádio III A contou com 48,90/0 e o III B com 51,10/0. Ao final de 18 lueses, 850/0 dos pacientes estavalU mOlios. A sobrevida mediana foi de 13,0 meses. Doze fatores clínicos foram estudados por análise univariada (sexo, idade, tipo histológico, localização do tumor primário, maior diâmetro do tumor, peiformance status, hemoglobinemia, estádio clínico, características relacionadas aos fatores T3 e T4, metástases linfáticas, significado do fator N2 em relação ao tamanho do tumor e resposta ao tratamento) As correlações mais relevantes foram com a invasão da parede torácica (p=0,04) e o grau de resposta à radioterapia (p=O,OOO 1). A presença de invasão de grandes vasos mediastinais e estádio 111 B também influenciaram significativamente a sobrevida; porém, a validação destes resultados pode ainda requerer estudos com maior número de pacientes. Não foi possível demonstrar que determinados fatores anatôlnicos, tais como a presença e localização de metástases linfáticas, e níveis de invasividade do tumor primário, exerçam influência prognóstica. Os delnais resultados apresentados, com poucas exceções, são similares aos de outros trabalhos da literatura estrangeira sobre o carcinoma brônquico não de pequenas células estádio III tratado com radioterapia exclusiva. / Novel combined treatments as well as radiation therapy with altered fractionation have been designed in the last recent years ailning an improvement of the poor results achieved by the current treatment of stage III non-small cell lung cancer. Since irradiation alone with conventional fractionation (6000 cGy/6 weeks) continues to be the most utilized treatment, it is important to know in detail the prognostic factors involved in this subgroup of patients for a better comparison of the results. The clinicaI expression, the behavior when treated by radiation therapy and the eventual prognostic factors of stage fi non-small cell lung cancer were prospectively studied in 43 selected patients referred for treatment to the Hospital Sao Lucas da Pontificia Universidade Catolica do RGS, in Porto Alegre, Brazil, between April, 1991 and May, 1994. The treatment was delivered with photons of megavoltage units (8 MeV Linear Accelerator and Cobalt60 ) with minimal tumor dose of 6000 cGy in 6 weeks (30 fractions). Thirty nine patients were Inale and 4 were female. The Inedian age was 69,5 years. Epidermoid carcinoma was the lnost frequent histological type (81.4010), follo\ved by adenocarcinoIna (14.0%) and undifferentiated large cell carcinoma (4.7%). Upper right lobe accounted to be the most frequent site involved by the primary tumor (46.50/0). The median dialneter of the lesions was 6.7 cm. About 80% of the patients had Zubrod's peiformance status of I and 11. In 76.70/0 of the patients the median rate of hemoglobin was upper than 12g/100 ml. Stage 111 A was ascertained in 48.9% of the patients and III B, in 51.1 %. At the end of 18 months of follow up 85% of the patients had died and no one survived 30 months. The median survival was 13.0 months. From twelve clinicaI factors studied (sex, age, histological type, tumor location, major diameter, performance status, hemoglobin, clinicaI stage, characteristics related to T3 and T4 tumors, lymphatic metastasis, significance of N2 factor related to the size of the tumor, and response to treatment), the most reIevant were thoracic wall invasion (p=0.04) and response to radiation therapy (p=0.0001). The presence of great mediastinal vessels invasion and stage III B also significant1y influenced survival, but further studies with larger number of patients may be required for validating these findings. It was not possible to demonstrate that detennined anatomical factors - such as the presence and location of lymphatic metastasis and leveI of tumor invasiveness - have some influence on the prognosis. The relnaining results presented, with few exceptions, are similar to the data of other series reported in the literature on stage 111 non-slnall cell lung cancer treated with radiotherapy alone.

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Sze, Siu Ching. / Thesis M.Phil. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 109-124). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016).

He, Mian. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 165-188). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016).

Magnetic resonance imaging is utilized as an important tool in radiation oncology for delineation of healthy and cancerous tissues, and evaluating the functionality of those tissues, structures, and organs. Currently, the clinical imaging protocol at Virginia Commonwealth University includes anatomical imaging for tissue and structure delineation, and to observe treatment induced changes. Diffusion weighted imaging (DWI) is also acquired for calculation of apparent diffusion coefficient (ADC) values to provide quantitative information on tissue diffusivity and microstructure. However, anatomical images and ADC values may not display the true extent of changes in tissue. This work seeks to further utilize the capabilities of MRI and expand its role in treatment response monitoring for liver cancer patients treated with stereotactic body radiotherapy (SBRT). To do so, an imaging protocol and image analysis methodology to evaluate treatment changes on pre- and post-treatment image sets was developed. An extension of DWI, termed intravoxel incoherent motion (IVIM) imaging, was utilized to quantitatively assess levels of perfusion and diffusion within the liver and tumor. Acquisition of high-quality diffusion weighted images of the liver necessitated the development of an MR safe respiratory motion management device, which was designed, constructed and evaluated in this work. An imaging protocol was developed providing anatomical and functional images of the liver, acquired under breath hold, utilizing the respiratory motion management device. An IVIM parameter calculation and texture analysis workflow was developed using MATLAB, and applied to acquired data sets from multiple studies, including past clinical cases, investigator, healthy volunteer, and liver cancer patient . Differences in IVIM and texture analysis parameters were investigated for healthy and diseased tissue, and for select dose regions from pre- and post-treatment imaging sessions. Significant differences, at a voxel level, were found between healthy and diseased tissue, and pre- and post-treatment volumes, for multiple parameters, including apparent diffusion coefficient, pure diffusion, and perfusion, as well as for various texture features. Overall, this study showed the potential of IVIM and texture analysis to be used for discriminating between healthy and diseased tissues in the liver, and for indication of treatment response.

Tesis Magister En Ciencias Odontológicas Con Mención En Patología Y Medicina Oral / El carcinoma de celulas escamosas es el tipo histológico más prevalente en tumores de la cavidad oral. Además de ser un cáncer altamente agresivo e infiltrante, tiende a generar compromiso linfático y metástasis con mucha rapidez. MMP-9, ha sido asociada a destrucción del colageno IV y promotora de la angiogénesis y, a la densidad de vasos linfáticos y sanguíneos han sido asociados en su progresión, metástasis y sobrevida. El objetivo de este estudio fue determinar la relación existente entre la expresión inmunohistoquímica de MMP-9, densidad de vasos linfáticos (D2-40) y densidad de vasos sanguíneos (CD34) en COCE. Se obtuvieron 37 biopsias de carcinoma espinocelular, desde la base de datos del Servicio de Anatomía Patológica, diagnosticadas entre los años 2000- 2008, que cumplieron con los criterios de inclusión. Estas biopsias fueron procesadas para el estudio histopatológico y teñidas con los anticuerpos monoclonales anti-MMP-9, anti-D2-40 y anti-CD34 y evaluadas mediante microscopía óptica. En nuestro estudio no se encontró asociación entre los niveles de expresión de MMP-9 y la densidad de vasos linfáticos y sanguíneos. Del los 37 casos analizados, todas las muestras presentaron algún grado de inmunoreactividad para MMP-9, en promedio un 80,3% de las células epiteliales neoplásicas fueron positivas por caso. No se observó asociación con otras varaibles clinico-patológicas excepto edad. En relación al componente vascular se determinó una mayor densidad promedio de vasos sanguíneos (128,0 vasos/mm2) que linfáticos (42,9 vasos/mm2) y además, una correlación positiva entre la DVL y la DVS en los casos COCE. La densidad de vasos linfáticos no presentó diferencias significativas con variables clinico-patológicas, pero evidenció que lengua tienen en promedio 23,4 vasos/mm2 más que la localización reborde alveolar. / Esta tesis forma parte de los proyectos FONDECYT No. 1120248 y FONDEF No. D11/1096

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Renal cell carcinoma (RCC) accounts for 85% of kidney cancer incidence in the US. Since 1950 there has been a 126% increase in kidney cancer incidence in the US. Thirty percent of new patients present with a localized easily treatable carcinoma while 30% of patients present with a high-grade metastatic carcinoma. Five-year survival rates for metastatic RCC is 6-12 months (Lipworth et al, 2006). Current disease treatment options for metastasis include chemotherapy and radiation (8% response rate), immunotherapy (15-30% response rate) and newly developed angiogenesis inhibitors which are in phase III trials (Staehler et el, 2005). In RCC cells, it has been shown that PPARγ agonists inhibit cell proliferation, induce apoptosis, and induce anti-angiogenic effects in vitro. Unlike most tumor types, PPARγ is downregulated in tissue samples from 47 RCC patients. However, in cell culture studies PPARγ expression does not correlate with growth inhibitory or apoptotic effects of PPARγ agonists in renal cell lines indicating that PPARγ independent responses may play a large role in actions associated with the PPARγ agonists (Yuan et al, 2006). 1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl, p-t-butyl and p-phenyl substituents activate peroxisome proliferator-activated receptor (PPAR) and inhibit growth of ACHN and 786-0 renal cell carcinoma cell lines. PPAR is overexpressed in ACHN cells and barely detectable in 786-0 cells, and treatment with the t-butyl analog (DIM-C-pPhtBu) induces cell cyle inhibition. DIM-C-pPhtBu also induced several common PPAR-independent proapoptotic responses in ACHN and 786-0 cells, including increased expression of nonsteroidal antiimflammatory drug-activated gene-1 (NAG-1) and endoplasmic reticulum stress which activates death receptor 5 and the extrinsic pathway of apoptosis. In addition, DIM-C-pPhtbu (40 mg/kg/d) also inhibited tumor growth in an orthotopic mouse model for renal carcinogenesis, and this was accompanied by induction of apoptosis in renal tumors treated with DIM-C-pPhtBu but not in tumors treated with the corn oil vehicle (control). Thus, DIM-C-pPhtBu and related compounds represent a novel class of mechanism-based drugs that have potential for treatment of renal adenocarcinoma for which there are currently limited options for successful chemotherapy.

In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown. In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes. In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade. In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence. In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.