A research report submitted to the Faculty of Medicine university of tho Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the Degree of Master of science in Medicine. / Breast cancer is a major health problem, afflicting up to 1 in 9 women in developed countries with Western diet and life style. While screening programs have led to earlier diagnosis, including diagnosis at a pre-invasive stage in a number of women, the majority of patients with breast cancer still present with clinically detectable, invasive breast cancer, which even if clinically localised still carries the risk of systemic micrometastases, Such patients have been shown to benefit both in terms of disease free as well as of overall survival from the addition of adjuvant systemic treatment. The identification of progostic factors which can be used to tailor specific forms of adjuvant treatment to the patient's disease has been an important goal of breast cancer research during the last 20 years. A particularly important goal is the early identification of poor risk patients, who may benefit from aggressive intervention with intensive chemotherapy, While many prognostic markers, including nodal status, hormone-receptor-status, ploidy and growth fraction and the expression of various oncogenes and proto-oncogenes by the tumor cells have been proposed as prognostic factors, the results, to date, have been equivocal for a number of these. Recently there has been much. interest in the prognostic importance of cerbB- 2 protein in breast cancer. Most of these studies have concentrated on immunohistochemically stainable e-erb-2 in tumor tissue. This dissertation focusses on the prognostic impact of the soluble c-erbB-2 protein in the serum of breast cancer patients treated at the Breast Clinic of tne Johannesburg Hospital and University of the Witwatersrand. The results of this investigation have been reported under the title "Soluble c-erhB-2 fragment in Serum Correlates With Disease Stage and Predicts for Shortened Survival in Patients with Early Stage and Advanced Breast Cancer" by H. Kandt, L. Seymour & W.R. Bezwoda, Published in British Journal of Cancer, Vo170 p739-742" 1994. / Andrew Chakane 2018

by Yu Xiongwen. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 74-84). / Abstract also in Chinese. / Acknowledgments --- p.i / Abstract --- p.ii / List of Tables --- p.iii / List of Figures --- p.iv / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Tumor Marker --- p.1 / Chapter 1.1.1 --- General concept of tumor marker --- p.1 / Chapter 1.1.2 --- Application of tumor marker --- p.2 / Chapter 1.1.3 --- Limitation of tumor markers --- p.5 / Chapter 1.2 --- Breast Cancer --- p.6 / Chapter 1.2.1 --- Incidence in Hong Kong Chinese --- p.6 / Chapter 1.2.2 --- Need for early diagnosis and prognosis --- p.8 / Chapter 1.3 --- Markers for Breast Cancer --- p.9 / Chapter 1.3.1 --- Usefulness of tumor marker for breast cancer --- p.9 / Chapter 1.3.2 --- Some tumor marker for breast cancer --- p.12 / Chapter 1.4 --- Selective Markers for Breast Cancer in this Study --- p.16 / Chapter 1.4.1 --- New TPA --- p.16 / Chapter 1.4.2 --- CA 15-3 --- p.19 / Chapter 1.4.3 --- Apolipoprotein(a) --- p.22 / Chapter 1.5 --- Objectives --- p.24 / Chapter Chapter 2 --- Materials and Methods --- p.25 / Chapter 2.1 --- Materials --- p.25 / Chapter 2.1.1 --- Patients and control subjects --- p.25 / Chapter 2.1.2 --- Sampling --- p.25 / Chapter 2.2 --- Methods --- p.26 / Chapter 2.2.1 --- CA 15-3: Cancer Antige 15-3 --- p.26 / Chapter 2.2.2 --- New TP A --- p.27 / Chapter 2.2.3 --- Apolipoprotein(a) --- p.28 / Chapter 2.3 --- Statistical Methods --- p.29 / Chapter Chapter 3 --- Results --- p.32 / Chapter 3.1. --- Precision Studies --- p.32 / Chapter 3.1.1 --- CA 15-3 --- p.32 / Chapter 3.1.2 --- TPA --- p.32 / Chapter 3.1.3 --- Apolipoprotein(a) --- p.32 / Chapter 3.2 --- CA 15-3 --- p.37 / Chapter 3.2.1 --- "CA 15-3 levels in healthy women, patients with benign breast disease and patients with breast cancer" --- p.37 / Chapter 3.2.2 --- "Sensitivity, specificity, and total accuracy of preoperative CA15-3 determination by cutoff value" --- p.42 / Chapter 3.3 --- TPA --- p.45 / Chapter 3.3.1 --- TPA levels in healthy women，patients with benign breast disease and patients with breast cancer --- p.45 / Chapter 3.3.2 --- "Sensitivity, specificity，and total accuracy of preoperative CA 15-3 determination by cutoff value" --- p.50 / Chapter 3.4 --- Apolipoprotein (a) --- p.53 / Chapter 3.4.1 --- Apo(a) levels in healthy women，patients with benign breast disease and patients with breast cancer --- p.53 / Chapter 3.5 --- Combination Test --- p.59 / Chapter 3.6 --- Study in Pairs --- p.64 / Chapter 3.6.1 --- Results of the pairs investigation --- p.64 / Chapter 3.6.2 --- Changes in post-operation compared with the pre- operation levels --- p.64 / Chapter Chapter 4 --- Discussion --- p.69 / Chapter Chapter 5 --- Conclusion --- p.73 / References --- p.74

A Dissertation submitted to the Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, to fulfil the requirement to acquire a degree of Master of Science in Medicine Johannesburg 30 September 2014 / Background In South Africa cervical cancer has an age standardised incidence rate of 23 per 100 000 in women below the age of 35 and 76 per 100 000 amongst women over 35. The National Department of Health (NDoH) introduced the national cervical cancer screening policy guidelines in 2000, with the aim to screen 70% of women aged between 30 and 59 over a 10-year period. Health managers at provincial and district level were expected to implement this policy at their respective levels. Research has shown that implementing national health policies is often challenging due to management weaknesses, including the lack of guidelines or tools on how managers should plan and allocate budget for services. Aim The aim of this study is to develop and test an approach to planning and budgeting that would assist health managers to follow a rational process to plan and estimate budget requirements for implementing the cervical cancer screening policy at subnational level. Method This study was conducted in three districts in South Africa. The study was conducted in four phases. A situational analysis of budgeting practices was conducted in the first phase, to describe existing planning and budget allocation practices for cervical cancer screening programmes in the study sites and identify any existing gaps. The process requirements for implementing a cervical cancer screening programme were then identified prospectively in the second phase. Informed by the situation analysis and the process requirements, a computer-based planning and budget estimation program was developed in the third phase and tested through interviews with key informants in the fourth phase of the study. Results The situational analysis revealed a lack of involvement of interviewed programme managers at all the levels, in planning and budgeting for implementing cervical cancer screening programmes. The participants’ descriptions of budget allocation processes indicated that there was no defined process for allocating budget to services and the allocations were not specifically informed by assessed programme needs in their respective areas of jurisdiction. Process requirements for cervical screening were identified and documented for the following aspects of a cervical screening programme: calculating target population to inform planning for service provision, staff and equipment audits, equipment and supplies, material required for systems functioning (e.g., tools, forms, guidelines), transport and communication systems, community information education and communication (IEC) strategies, staff training, laboratory services and services for the treatment of High grade Squamous Intraepithelial Lesions (HSIL). A computerbased planning and budget estimation program, which could enable managers to define and quantify resources needed to implement a cervical screening programme was developed, informed by the documented process requirements. The testing of the computerised planning and budget estimation program indicated that the program could improve planning and help managers to estimate budget requirements for implementing cervical screening. Respondents indicated that the program was relatively easy to use and also felt that it could potentially be useful for programme planning as follows: a) it could serve as a tool for programme needs assessment, b) it could facilitate rational budget estimations, c) managers could use it as a bottom-up tool to motivate for resources, and d) managers could use it to refute inadequate budget allocations where possible. Conclusion The findings of the situational analysis support existing literature in revealing very little if any change in relation to inherent challenges in implementing cervical cancer screening services in South Africa. The findings of this study are relevant for public health programme planning and budgeting beyond cervical screening. Since managers at sub-national level are delegated to implement policy, it is imperative that they are provided with tools that may guide them to plan and budget for services on the basis of needs in their areas of jurisdiction. This study provides one such tool.

Endometrial carcinoma is the most common gynaecologic cancer in the United States with about 41,200 new cases projected to occur in 2006. It often presents with abnormal uterine bleeding and spreads to the cervix in 10 to 20% of cases. Whilst early diagnosis is essential for optimal disease treatment, the best investigation for abnormal uterine bleeding remains uncertain. Although hysteroscopy has been reported to have high accuracy in predicting normal or abnormal endometrial histopathology, its accuracy varies with the underlying pathology. The highest accuracy occurs in the diagnosis of intrauterine anatomical pathology such as endometrial polyp whereas it is at its lowest in microscopic histopathology such as endometrial hyperplasia. Hysteroscopy is also potentially useful for detecting tumour spread to the uterine cervix that helps in staging and surgical planning. However, the role of hysteroscopy with guided biopsy in detecting endometrial cancer and the choice of distension medium remain to be determined. As the uterine cavity is a collapsed space, hysteroscopy requires its distension with a gaseous or liquid medium to allow complete visualization of the uterine cavity. The use of such media to rinse the uterine cavity raises the concern that when the endometrium harbours endometrial carcinoma cells, there is a potential risk of retrograde dissemination of these cells into the peritoneal cavity. The work in this thesis has addressed four major issues of diagnostic hysteroscopy in the management of patients with endometrial carcinoma. Firstly, the role of diagnostic hysteroscopy and guided biopsy is limited especially in microscopic tumours. Secondly, the role of diagnostic hysteroscopy to detect cervical invasion in preoperative staging of endometrial carcinoma is proven and the usage of normal saline is more accurate than that which uses carbon dioxide. Thirdly, hysteroscopic dissemination occurs more frequent when using normal saline as opposed to carbon dioxide as the distension medium. Lastly, complete occlusion of both fallopian tubes can effectively prevent the dissemination of endometrial carcinoma cells into the peritoneal cavity during diagnostic hysteroscopy. / Lo, Wing Kit Keith. / "May 2006." / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (167-193). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

目的：結直腸癌是世界上第三常見惡性腫瘤，結腸鏡檢查是診斷的金標准。但其創傷性、昂貴的設備以及人力的需求阻礙了廣泛應用。本研究評估了糞便miRNA作為非損傷性分子生物標記物篩查結直腸腺瘤和腫瘤的可行性，並深入探究了致癌miRNA的基因靶點。 / 方法：我們評估了糞便miRNAs的穩定性以及檢測的可重復性。糞便樣本收集自88例結腸直腸癌患者，57例結直腸息肉患者和101名健康對照，用實時定量逆轉錄PCR檢測miRNA水平。所有候選miRNA標記物在配對的癌及癌旁組織中進行驗証。我們共測試了糞便中7種miRNAs，包括前期報道在結直腸癌中上調的miR-21和miR-92a(第一部分)，以及在667個miRNA中在結直腸癌上調最高的5個miRNA(第二部分)。我們研究了它們的水平與腫瘤分期及位置的關系。並隨訪了病人經腫瘤或腺瘤切除術后其糞便miRNA水平，從而証實它們是否與腫瘤相關。我們應用了彗星試驗、細胞活力試驗、集落形成試驗，以及細胞凋亡分析試驗研究了miR-18a在腫瘤的發展過程中的作用(第三部分)。 / 結果：第一部分，我們確定糞便miRNA的穩定性，能被實時定量逆轉錄PCR檢測並顯示高重復性。糞便miR-92a標記物的靈敏度和特異性分別為71.6%和73.3%，miR-21分別為55.7%和73.3%。MiR-92a水平顯示遠端結直腸癌比近端結直腸癌的檢測具有更高靈敏度，晚期腺瘤比小息肉更具靈敏度。腫瘤切除后，miR-21和miR-92a水平顯著下降。 / 第二部分，基於結直腸腫瘤miRNA的表型，我們發現糞便miR-18a, miR-20a, miR-135b和miR-221能作為標記物鑒別結直腸癌，miR-18a (敏感度: 51.1%, 特異性: 90.1%); miR-20a (72.7%, 81.2%) ; miR-135b (81.8%, 68.3%); miR-221 (69.3%, 77.2%)。腫瘤切除后，這四種標記物會顯著下降。MiR-135b和miR-221也能鑒別腺瘤。四種標記物對遠近端結腸癌的檢測無顯著差異。 / 第三部分，通過程序和熒光素酶報告基因活性預測和驗証，我們發現一種重要的DNA修復蛋白---共濟失調毛細血管擴張突變(ATM)是miR-18a的靶蛋白。MiR-18a的異位表達減弱細胞DNA雙鏈損傷修復機制，導致腫瘤發生的易感性。 / 結論：我們發現糞便中miR-21, miR-92a, miR-18a, miR-20a, miR-135b 和miR-221標記物能夠鑒別結直腸癌。MiR-92a, miR-135b 和miR-221能鑒別結直腸腺瘤。MiR-18a抑制共濟失調毛細血管擴張突變基因表達並減弱細胞DNA雙鏈損傷修復機制。糞便miRNA是結直腸癌篩查的有效生物標記物。 / Objective: Colorectal cancer (CRC) is the third most common cancer worldwide. Colonoscopy is the current gold standard for diagnosing CRC. However, its invasive nature, the cost of equipment and the demand for manpower have hampered the wide application of this procedure. This study evaluated the feasibility of using stool-based miRNA as non-invasive biomarkers for the screening of colorectal adenoma and cancer, and investigated the gene target of a candidate oncogenic miRNA. / Methods: The reproducibility of detection and stability of stool-based miRNAs were first evaluated. Stool samples were collected from 88 CRC patients, 57 patients with colorectal polyp and 101 healthy controls MiRNA levels were detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). AII candidate miRNA markers were validated in a cohort of paired tumor and adjacent normal tissues. In total, we tested 7 miRNAs in the stool, including miR-21 and miR-92a which were reported to be up-regulated in CRC in previous studies (part one), and 5 miRNAs which were found to be the most up-regulated in colorectal tumor based on the profiling of 667 miRNAs (part two). Their levels with tumor stage and location were evaluated. Their change in level was followed up in a subset of patients after the removal of tumor or adenoma. We investigated miR-18a for its function in cancer development using comet assay, cell viability assay, colony formation assay, and analysis on apoptosis (part three). / Results: In part one, we found stool miRNAs stable and detectable with high reproducibility by qRT-PCR. In detecting CRC, stool miR-92a had a sensitivity of 71.6% and a specificity of 73.3%, stool miR-21 had a sensitivity of 55.7% and a specificity of 73.3%. Stool miR-92a level had higher sensitivity for distal CRC than proximal CRC, and a higher sensitivity for advanced adenoma than minor polyps. The removal of tumor resulted in reduced stool miR-21 and miR-92a levels. / In part two, based on miRNA profiling of CRC tumors, we found that stool-based miR-18a, miR-20a, miR-135b, and miR-221 can discriminate colorectal cancer patients from healthy individuals: miR-18a (sensitivity: 51.1%, specificitiy: 90.1%); miR-20a (72.7%, 81.2%); miR-135b (8 1.8%, 68.3%); miR-221 (69.3%, 77.2%). Levels of these 4 stool-based markers dropped after removal of tumors. Stool-based miR-135b and miR-221 also discriminated patients with adenoma from healthy individuals. MiR-18a, miR-20a, miR-135b and miR-221 showed no desparity in detecting proximal or distal colon cancer. / In part three, based on in silico prediction and validation with luciferase reporter activity, we identified Ataxia Telangiectasia Mutated (ATM ), a protein crucial to DNA repair, as a target of miR-18a. Ectopic expression miR-18a attenuates DNA double strand break repair mechanism, creating a genetic predisposition to the development of cancer. / Conclusion: Stool-based miR-21, miR-92a, miR-18a, miR-20a, miR-135b and miR-221 can discriminate patients with CRC from healthy individuals. Notably, a subset of these miRNAs (miR-92a, miR-135b, and miR-221) can discriminate patients with colorectal adenoma from healthy individuals MiR-18a suppressed ATM gene expression and attenuated cellular repair mechanism to DNA double strand breaks. Stool-based miRNAs are useful CRC screening biomarkers. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wu, Chung Wah. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 80-92). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Chapter CHAPTER ONE --- INTRODUCTION --- p.1 / Chapter 1.1 --- Colorectal cancer --- p.1 / Chapter 1.2 --- Current screening methods --- p.3 / Chapter 1.2.1 --- Colonoscopy --- p.3 / Chapter 1.2.2 --- Sigmoidoscopy --- p.4 / Chapter 1.2.3 --- Stool-based tests --- p.4 / Chapter 1.2.3.1 --- Fecal occult blood test --- p.5 / Chapter 1.2.3.2 --- Stool-based DNA test --- p.6 / Chapter 1.2.3.3 --- Stool-based RNA and protein test --- p.7 / Chapter 1.3 --- MiRNA and its role in cancer --- p.8 / Chapter 1.4 --- Aims of study --- p.9 / Chapter CHAPTER TWO --- METHODOLOGY --- p.10 / Chapter 2.1 --- Subjects and sample collection --- p.10 / Chapter 2.2 --- MiRNA extraction in tissue and stool samples --- p.13 / Chapter 2.3 --- MiRNA quantitation by quantitative reverse transcription quantitative reverse transcription polymerase chain reaction --- p.14 / Chapter 2.4 --- Determining the stability of miRNA in stool samples --- p.15 / Chapter 2.5 --- Determining the reproducibility of miRNA quantitation in stool samples --- p.16 / Chapter 2.6 --- Reverse transcription for miRNA array --- p.16 / Chapter 2.7 --- Quantitative polymerase chain reaction for miRNA array --- p.16 / Chapter 2.8 --- Cell culture, miRNA precursors and transfection --- p.17 / Chapter 2.9 --- Dual-luciferase reporter assay --- p.17 / Chapter 2.10 --- Quantitative reverse transcription polymerase chain reaction for mRNA --- p.19 / Chapter 2.11 --- Western blot analysis --- p.19 / Chapter 2.12 --- Comet assay --- p.19 / Chapter 2.13 --- Colony formation and cell viability assay --- p.20 / Chapter 2.14 --- Annexin V apoptosis assay --- p.21 / Chapter 2.15 --- Statistics --- p.21 / Chapter CHAPTER THREE --- RESULTS --- p.23 / Chapter 3.1 --- PART 1 --- p.23 / Chapter 3.1.1 --- Stability of miRNA detection in stool samples --- p.23 / Chapter 3.1.2 --- Reproducibility of miRNA quantitation in stool samples --- p.23 / Chapter 3.1.3 --- Detection and normalization of miRNA levels --- p.25 / Chapter 3.1.4 --- Expression of miR-21 and miR-92a in CRC tissue samples --- p.28 / Chapter 3.1.5 --- Levels of stool-based miR-21 and miR-92a in CRC and polyp patients --- p.30 / Chapter 3.1.6 --- Sensitivity of stool-based miR-21 and miR-92a towards colorectal cancer and polyps --- p.32 / Chapter 3.1.7 --- Association of stool-based miR-21 and miR-92a with clinicopathological features --- p.34 / Chapter 3.1.8 --- Follow-up on stool miR-21 and miR-92a levels after removal of lesion --- p.37 / Chapter 3.2 --- Part 2 --- p.39 / Chapter 3.2.1 --- MiRNA profiling in colorectal tumors --- p.39 / Chapter 3.2.2 --- Validation of miRNA profiling results --- p.41 / Chapter 3.2.3 --- Candidate miRNA levels in stool samples of CRC and adenoma patients --- p.44 / Chapter 3.2.4 --- Sensitivities and specificities of miRNA candidates for adenoma and CRC --- p.47 / Chapter 3.2.5 --- Sensitivties of miRNA candidates based on tumor location --- p.49 / Chapter 3.2.6 --- Follow-up on stool miRNA levels after removal of lesion --- p.51 / Chapter 3.2.7 --- Association of stool-based miRNAs with nodal involvement in CRC --- p.53 / Chapter 3.2.8 --- Establishing the miRNA marker panel --- p.55 / Chapter 3.3 --- Part 3 --- p.57 / Chapter 3.3.1 --- In Silico prediction of miR-18a target and validation by luciferase assay --- p.57 / Chapter 3.3.2 --- Expression and correlation between miR-18a and ATM in paired colorectal tumor tissue, cell lines and normal colon biopsies --- p.60 / Chapter 3.3.3 --- Regulation of double strand DNA damaga recovery by miR-18a --- p.62 / Chapter 3.3.4 --- Cell sensitization to genotoxin by miR-18a --- p.64 / Chapter 3.3.5 --- Effect of miR-18a on genotoxin induced apoptosis --- p.66 / Chapter CHAPTER FOUR --- DISCUSSION --- p.68 / Chapter 4.1 --- Stability and detection reproducibility of stool-based miRNA --- p.68 / Chapter 4.2 --- Stool-based miRNAs for screening colorectal cancer and polyps/adenomas --- p.69 / Chapter 4.2.1 --- MiR-21 --- p.69 / Chapter 4.2.2 --- MiR-18a, miR-20a and miR-92a --- p.70 / Chapter 4.2.3 --- MiR -135b and miR -221 --- p.71 / Chapter 4.2.4 --- MiR -31 --- p.72 / Chapter 4.3 --- Discriminating proximal and distal CRC --- p.73 / Chapter 4.4 --- Evaluation of stool-based miRNA level after removal of lesions --- p.74 / Chapter 4.5 --- MiRNA marker panel --- p.74 / Chapter 4.6 --- Advantages of stool-based miRNA tests --- p.75 / Chapter 4.7 --- Ataxia telangiectasia mutated as the direct target of miR -18a --- p.75 / Chapter 4.8 --- Future directions for study --- p.78 / Chapter 4.9 --- Conclusion --- p.78 / REFERENCES --- p.80 / PUBLICATIONS --- p.93

Abstract not available. / Pak Wai Martin. / Adviser: Charles Andrew van Hasselt. / Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 245-269). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Orientadores: Sophie Françoise Mauricette Derchain, Luis Otavio Zanatta Sarian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T14:37:04Z (GMT). No. of bitstreams: 1 Campos_CamiladeMelo_M.pdf: 1462137 bytes, checksum: faa2f41f3fb8975de5506f358d8e374d (MD5) Previous issue date: 2014 / Resumo: A discriminação de tumores malignos entre mulheres com diagnóstico de massas anexiais pode ser difícil devido a limitações na acurácia do exame ultrassonográfico e à disponibilidade de pessoal especializado para realizá-lo. O índice de risco de malignidade visa a simplificar e padronizar a rotina ultrassonográfica para fornecer uma avaliação rápida e direta da massa anexial. Neste estudo foi examinado o desempenho de quatro variações deste índice (IRM 1 a 4) em um centro terciário de assistência e pesquisa em câncer ginecológico com a realização de exame ultrassonográfico por pessoal inserido em programa de treinamento supervisionado. Método: 158 mulheres com diagnóstico de massa anexial foram avaliadas antes da cirurgia utilizando-se as quatro variações do IRM. O exame foi realizado por ultrassonografistas com níveis variados de experiência e incluídos em programa de treinamento. Indicadores de desempenho para os diferentes tipos de IRM foram calculados utilizando-se de metodologia conhecida e o padrão-ouro para diagnóstico foi a análise anatomopatológica. Resultados: A prevalência de tumores malignos foi de 32%. Pacientes com tumores malignos eram mais idosas quando comparadas às pacientes com diagnóstico de tumores benignos (idade média 45,9+15,0 anos versus 55,7+16,2; p<0,001). A maioria (77%) dos tumores malignos era epitelial, embora 7/51 (13%) eram originados do estroma. Aproximadamente metade dos tumores primários ovarianos era estágio I. Endometriomas foram as mais frequentes (11%) massas vii anexiais não neoplásicas. Mulheres com tumores malignos apresentaram níveis de CA125, escores de ultrassom e número de tumores com diâmetro >7 cm significativamente maiores que mulheres com tumores benignos. Quando se comparou o desempenho das variantes do IRM no melhor ponto de corte determinado pela análise da curva ROC (receiver operator characteristic), percebeu-se que as variantes do IRM apresentam desempenho semelhante na população geral (pré e pós-menopausa). Entre as mulheres na pré-menopausa, a melhor sensibilidade é obtida com o IRM2 (90%; 95% IC 83-97%) e com o IRM4 (89%; 95% IC 81-97%). A especificidade entre as diferentes variantes do IRM não apresentou diferença significativa. O mesmo desempenho foi obtido entre as variantes do IRM nas mulheres na pré e pós-menopausa. Foram também analisados os indicadores de desempenho nas diferentes variantes do IRM nos pontos de corte progressivos na população geral (pré e pós-menopausa). Os pontos de corte recomendados pela literatura para os IRM1 a 3 é 200 e para o IRM4 é 450. Nesses pontos de corte recomendados, a sensibilidade entre os diferentes IRM variou entre 68% e 78% e a especificidade variou entre 82% e 87%. A pior correspondência entre valores do IRM e o resultado final anatomopatologico foi obtido entre os tumores borderline, em que os tumores foram classificados incorretamente em 50% dos casos utilizando o IRM1 e 3 e em 37% dos casos utilizando o IRM2 e 4. Proporções similares de tumores classificados corretamente e incorretamente foram obtidos com as quatro variantes do IRM. Os tumores epiteliais são mais bem classificados pelo IRM que os não epiteliais. A taxa de falso negativo é maior entre os tumores do estroma: 5/7 tumores de células da granulosa foram incorretamente classificados como viii benignos entre as quatro variantes do IRM. Tumores borderlines foram incorretamente classificados como benignos em 37% a 50% dos casos, dependendo do IRM utilizado. Falsos negativos entre as quatro variantes do IRM são maiores em mulheres com tumores de estágio 1 quando comparados com mulheres em estágio mais avançado (p com valor significativo entre as quatro variantes). Os IRM 1 e 3 classificaram incorretamente a maioria dos tumores estágio 1 como benigno; IRM 2 classifica melhor tumores de estágio 1. É importante ressaltar que 7 tumores de células da granulosa eram estágio 1. Analisou-se a curva ROC para os diferentes IRM na discriminação das mulheres entre tumores malignos e benignos. Os testes que compararam a área sobre a curva de todas as curvas revelaram superioridade discreta do IRM4 sobre o IRM2 (p=0.06). Todos os outros testes realizados entre as curvas não obtiveram resultado significativo. Conclusão: o IRM apresentou desempenho aceitável em um centro terciário de assistência e pesquisa em câncer ginecológico, com ultrassonografistas de conhecimento moderado e em treinamento. O equilíbrio entre o desempenho e a viabilidade, devido à baixa complexidade da realização do exame ultrassonográfico, favorece o IRM quando comparado a outros modelos de triagem para avaliação de massas anexiais / Abstract: Discriminating women with ovarian malignancies among those with adnexal masses may be difficult in medium resource settings due to limitations in ultrasound accuracy and availability of specialized personnel. The Risk of Malignancy Index (RMI) aims at simplifying and standardizing the ultrasound routine in order to provide a fast and straightforward evaluation of the adnexal mass. We examined the performance of four RMI variants (RMI 1 to 4) in a middle-resources gynecologic cancer center, with ultrasound performed by personnel under a training program. Methods: 158 referred due to an adnexal mass were evaluated before surgery using the four RMI variants. Ultrasound was performed by sonographers with variable expertise levels and enduring a training program. Performance indicators for the RMI variants were calculated using standard methodology and the gold standard was pathology of the adnexal mass. Results: The prevalence of malignant tumor was 32%. Patients with malignant tumors were significantly more aged than their counterparts with benign adnexal masses (mean age 45.9+15.0 years versus 55.7+16.2; p<0.001). Most (77%) malignant tumors were epithelial, although 7/51 (13%) were originated in the stroma. Approximately half of the malignant primary ovarian tumors were stage I. Endometriomas were the most frequent (11%) non-neoplasic adnexal masses. Women with malignant tumors had significantly higher CA125 levels, US Scores and tumors of >7cm in diameter than women with benign masses. When comparing the performance of x the RMI variants using the optimal cutoff points as determined with ROC analyses, we notivce than in the general population (pre and postmenopausal women), RMI variants yielded similar performance indicators. In the subset of premenopausal women, the best sensitivity was obtained with RMI 2 (90%; 95%CI 83-97%) and RMI4 (89%; 95%CI 81-97%). Specificity for the RMI variants did not differ significantly. Similar performance was obtained for the RMI variants in pre and post-menopausal women. We then analysed the performance indicators of RMI variants at progressive cutoff points in the general (pre- and postmenopausal) population. The standard (literature recommended) cutoff points for RMI 1 to 3 is 200 and for RMI 4 is 450. At these recommend cutoff points, the sensitivity of the different RMI1 vary from 68% to 78% and specificity vary from 82% to 87%. The worst correspondence between RMI values and final pathology was obtained for borderline tumors, which were incorrectly classified in 50% of the cases using RMI 1 and 3 and 37% of the cases using RMI 2 and 4. Similar proportions of correctly and incorrectly classified benign and malignant tumors were obtained with the four RMI variants. Clearly, RMI classified epithelial tumors much better than it did with non-epithelial tumors. The false negative rate was higher for stromal tumors: 5/7 granulosa cell tumors were incorrectly classified as benign by the four RMI variants. Borderline tumors were also incorrectly classified as benign in 37-50% of the cases depending on the RMI variant used. False negatives of for the RMI variants are higher in women with stage 1 tumors compared to women with more advanced stages (significant p values for all variants). RMI 1 and 3 incorrectly classified the majority of stage 1 tumors as benign; RMI 2 was the variant that best classified stage 1 tumors. It is worth noting that all 7 granulosa cell tumors were xi stage 1. We analysed the receiver¿operating characteristics curve analysis of RMI variants for the discrimination of women with malignant tumors from those with benign tumors. The pairwise permutation tests comparing the AUC for the curves revealed marginally significant superiority of RMI4 over RMI2 (p=0.06). All other pairwise comparisons between the curves returned nonsignificant results. Conclusions: RMI performed acceptably in a medium-resource setting where sonographers had moderate expertise and/or were under training. The tradeoff between performance and feasibility, due to lower ultrasound complexity, favors RMI over other adnexal mass ultrasound-based triaging models / Mestrado / Oncologia Ginecológica e Mamária / Mestra em Ciências da Saúde

INTRODUÇÃO: O diagnóstico do câncer de próstata em pacientes com níveis séricos do antígeno prostático específico persistentemente elevados após biópsia prostática negativa representa um grande desafio para urologistas e patologistas. A baixa especificidade do antígeno prostático específico e a baixa sensibilidade da biópsia prostática guiada por ultra-som são os maiores obstáculos observados na prática clínica. Apesar do uso de diversos métodos para prever a presença de câncer na glândula, nenhum deles tem precisão absoluta, obrigando os pacientes a realizar novas biópsias. Neste contexto, a descoberta de novos marcadores diagnósticos para o câncer da próstata tornase necessária. OBJETIVO: Avaliar o valor diagnóstico da expressão de seis genes no tecido prostático de pacientes com câncer de próstata clinicamente localizado. MÉTODOS: O estudo consistiu na análise de 50 pacientes com diagnóstico de câncer da próstata, submetidos à prostatectomia radical por doença localizada. A seleção dos genes foi baseada em um estudo prévio que utilizou a tecnologia de microarray (Agilent Technologies 44k whole human genome, two-color) em pacientes com câncer de próstata, divididos de acordo com as características clínico-patológicas. Entre os 4.147 genes com expressão diferenciada entre os casos de câncer de próstata, seis genes (PSMA, TMEFF2, GREB1, TH1L, IgH3 e PGC) foram selecionados. Estes genes foram então testados quanto a seu valor diagnóstico no câncer da próstata através da técnica de reação em cadeia da polimerase quantitativa com transcriptase reversa. Na primeira etapa do estudo, amostras de tecido maligno de 33 pacientes com câncer de próstata foram avaliadas. O grupo controle foi composto de nove pacientes com hiperplasia benigna da próstata. Na segunda etapa do estudo foram analisadas amostras de tecido benigno dos demais 17 pacientes com câncer da próstata. O mesmo grupo controle foi utilizado para comparação. RESULTADOS: A análise demonstrou que o PSMA estava super-expresso (em média nove vezes) e o PGC sub-expresso (em média de 1,3 x 10-4 vezes) no tecido neoplásico de todos os casos de câncer quando comparados com os casos de hiperplasia benigna. Os demais genes demonstraram um padrão de expressão variado, não permitindo a diferenciação entre os tecidos malignos e benignos. Quando estes resultados foram testados no tecido prostático benigno dos pacientes com câncer, o PGC manteve o mesmo padrão de expressão em todos os casos e o PSMA, apresentou-se super-expresso em 88% dos pacientes (média de 12 vezes), em relação aos casos de hiperplasia benigna. CONCLUSÃO: A combinação da super-expressão do PSMA e sub-expressão do PGC no tecido prostático pode representar uma evidência objetiva de presença de Cap. Análises clínicas prospectivas adicionais são necessárias para confirmar estes resultados / Introduction and objective: Prostate cancer (PCa) diagnosis in men with persistently increased PSA after a negative initial prostate biopsy has become a great challenge for urologists and pathologists. Despite the use of several methods to increase the sensitivity of prostate biopsy, the false-negative rates remain substantial, leading many patients to undergo repeated procedures. We analyzed the diagnostic value of six genes in the prostatic tissue of patients with clinically localized PCa, in order to predict the presence of cancer. Methods: The study was comprised by 50 patients with clinically localized PCa who underwent radical prostatectomy. Gene selection was based on a microarray analysis of patients with PCa. Among the 4,147 genes with different expressions between two groups, six genes (PSMA, TMEFF2, GREB1, TH1L, IgH3 and PGC) were selected. These genes were tested for its cancer diagnostic role using the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method. In the first part of the study, malignant tissue samples from 33 patients were analyzed, and in the second part we analyzed benign tissue samples of the other 17 patients with PCa. The control group was comprised of prostatic tissue samples of patients with benign prostatic hyperplasia (BPH). Results: The analysis of malignant prostatic tissue by qRTPCR showed that PSMA was over-expressed (mean nine times) and PGC was under-expressed (mean 1.3 x 10-4 times) in all cases when compared to BPH. The other four tested genes showed a variable expression pattern not allowing a differentiation between benign and malignant cases. When we tested these results in the benign prostate tissues from patients with PCa, PGC maintained the expression pattern, and PSMA, despite over-expression in most cases (mean 12 times), two cases (12%) presented under-expression. Conclusions: PGC under-expression and PSMA over-expression in the tissue may represent an objective evidence of prostate cancer and constitute a powerful adjunctive method in patients with negative prostate biopsy. Further prospective clinical analyses are necessary to confirm theses results

Focal liver lesions are commonly encountered in clinical practice. To be able to differentiate potentially life-threatening lesions from clinically insignificant lesions, and to be able to treat them effectively are the two basic problems of a clinician who comes across such lesions. Percutaneous intervention of the liver with a needle enables a clinician to solve the above two problems in a minimally invasive manner. To date, there is a diversity of needle-related percutaneous interventional procedures that are applicable to the clinical management of patients with liver lesions, such as biopsy of focal lesions, drainage of abscesses, and ablation of tumors. Despite a reasonable safety and efficacy associated with these procedures, there are always grounds of further improvement in techniques and technology of needle-related percutaneous procedures to achieve an even better outcome. It was hypothesized that the application of needle-related interventional radiology to clinical management of focal liver lesions could be facilitated and extended with advancement and refinement in needle-related techniques and technology. This thesis was based on a series of nine studies that aimed to explore the potential of needle-related percutaneous interventions in the clinical management of focal liver lesions and to study the effect of the introduction of innovations in needle-related techniques and technology on such clinical applications. It was concluded that the hypothesis was confirmed. / Yu Chun Ho. / "April 2006." / Adviser: Anil Ahuja. / Source: Dissertation Abstracts International, Volume: 68-08, Section: B, page: 5176. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 219-235). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Fan, Dahua. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 117-155). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.