京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21686号 / 医博第4492号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 小川 誠司, 教授 武田 俊一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: Colorectal cancer (CRC) is the most common malignant tumor in both sexes in the Czech Republic. Prognostic factors in CRC can be classified as clinical (stage at the time of diagnosis, histological type of tumor), genetic (RAS, BRAF), immunological (Immunoscore)and biochemical (CEA, CA 19-9, miRNA). MicroRNAs (miRNAs) regulate the expression of oncogenes and tumor suppressors. The regulatory function of miRNAs is influenced by single nucleotide polymorphisms (SNPs) of target miRNA binding sites (miRSNPs). Aims: To evaluate the currently available prognostic factors for CRC patients treated using targeted therapies and assess the role of novel ones, including miRNA. Methods: The thesis includes clinical works focused on targeted treatment of colorectal cancer, original work focused on the role of miRNA in colorectal cancer pathogenesis and especially as a prognostic and predictive marker, work focused on functional polymorphisms of DNA repair genes and a review article summarizing biochemical factors influencing the effect of fluoropyrimidine cytostatics in the treatment of colorectal cancer. Results: We have identified miR-17/92 as a non-invasive biomarker for predicting post-treatment prognosis in patients with a higher risk of relapse, as well as miRSNPs rs8679 polymorphisms as a...

No description available.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Genetic Counselling Johannesburg, 2013 / Five to ten percent of both breast and ovarian cancer cases are attributable to dominantly inherited mutations in genes that predispose to cancer, with a large proportion caused by mutations in the breast and ovarian cancer predisposing genes BRCA1 and BRCA2. Testing for these inherited cancers is indicated for individuals identified as being at high risk, or moderate to high risk, of having a cancer syndrome based on their family history of breast and/or ovarian cancer. Screening for high-risk individuals through services such as genetic counselling, has the potential to improve outcomes for these individuals and lower mortality rates. This study focused on individuals who attended genetic counselling for breast and/or ovarian cancer at the Genetic Counselling Clinics of the Division of Human Genetics, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg from 2001 to 2010. The study was divided into a file review on 218 counsellees and a telephonic interview of 50 counsellees. Focusing on breast and/or ovarian cancer, the study aimed to review who attends genetic counselling and why; who is offered genetic testing; what testing is offered and performed and; who pays for the testing, as well as gain a better understanding of how the service is received by counsellees. The study found that the majority of counsellees are white females, at a high risk of inherited breast and/or ovarian cancer, attend the genetic counselling session alone and are self-referred. There is an under representation of the black and coloured populations and an over representation of the Ashkenazi Jewish population in the cohort. The study‟s findings showed that a main motivator for individuals attending genetic counselling was for BRCA mutation testing, with the majority of testing offered being nationally based testing. The study also demonstrated that the service is generally well received and counsellees reported having a positive experience. Overall, the study pointed to the general lack of understanding and public awareness of genetic counselling, with suggestions to market to both the general population and to other medical professionals in order to reach more high risk individuals. On a practical level, a follow up service was suggested to ensure counsellees adhered to screening measures, informing counsellees on changes to testing protocols and identifying family members who may be at an increased risk of inherited breast and/or ovarian cancer.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Introduction: Referral for CS/HIPEC is variable, and barriers encountered by referring physicians are unknown. Identification of such barriers is useful for the creation of tailored knowledge translation (KT) strategies. Methods: Interviews of 20 medical oncologists and surgeons in the New York (NY) area were completed to identify barrier topics, using the Pathman framework of uptake of innovations (awareness, agreement, adoption, adherence) at the various levels of the individual, practice group, and organization. Barriers were used to structure a survey for evaluation of prevalence at the population level of medical oncologists and surgeons in NY State. Results: Barrier topics of awareness included training at a CS/HIPEC center, and availability of multidisciplinary cancer conferences. Agreement barriers centered mainly on quality of published literature, and the paradigm shift of carcinomatosis as a systemic to locoregional disease process. Adoption barriers included knowledge of outcomes of a CS/HIPEC surgeon, and concerns with morbidity/mortality rates. Adherence barriers included the lack of reflection of CS/HIPEC in current CPGs, financial/resource and logistic concerns of referrals, and lack of quality measures for the procedure. For the survey, 119 responded (12% response rate), including 42 medical oncologist and 77 surgeons. The majority were aware of CS/HIPEC (n=113, 95%). Medical oncologists were less likely than surgeons to agree with CS/HIPEC related to published evidence (76% vs 92 %, p = 0.02). Surgeons were more likely to be aware of where to refer patients for the procedure, and were less likely to have concerns regarding morbidity/mortality, compared with medical oncologists (p = 0.05, p = 0.04). Representation of CS/HIPEC in CPGs and quality measures/outcomes data was felt to result in adherence to a regular referral practice. Discussion: This prospective study of stakeholders for CS/HIPEC is the first to evaluate and characterize barriers to referral for this complex and controversial surgical innovation, with prevalence at the population level. / Thesis / Master of Health Sciences (MSc) / This thesis identifies problems encountered with referring patients to a specialist surgeon for a procedure that involves both surgical removal of tumors and treatment of the abdominal cavity with chemotherapy. These problems are evaluated from interviews with specialists in the field, and then evaluated at a higher level of all practicing referring specialists through a survey. The results will be used to improve patient outcomes in the future.

Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of a cancer stem-like phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in developing and maintaining cancer stem cells by establishing embryonic stem-like transcriptional programs, thus altering the balance between self-renewal and differentiation. Through my work, I have identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, I demonstrate that G9a activity is essential for the maintenance of an embryonic stem-like transcriptional signature that is required to promote self-renewal, tumorigenicity and an undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. By integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, the canonical Wnt pathway, epithelial-to-mesenchyme transition and extracellular matrix organization were identified as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Considering such novel insights on the role of G9a as a driver of the cancer stem cell phenotype, as well as a promoter of self-renewal, tumorigenicity and an undifferentiated state, I established and executed a multi-step drug screening pipeline to identify new repurposed drugs that selectively alter G9a functions in human CSCs. This pipeline revealed 3 new drug candidates that inhibit H3K9me2 deposition and impair human CSCs in culture. Future in-depth characterization of those candidates will represent an important step toward the development of novel CSC-targeting therapeutics.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13561号 / 論医博第2290号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 今中 雄一, 教授 村川 泰裕 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24798号 / 医博第4990号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 萩原 正敏, 教授 妹尾 浩, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23572号 / 医博第4786号 / 新制||医||1054(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 武藤 学, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM