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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23375号 / 医博第4744号 / 新制||医||1051(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 中本 裕士, 教授 松田 秀一, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No / Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.

Orientador: Luis Otavio Zanatta Sarian / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-11-07T13:22:12Z (GMT). No. of bitstreams: 1 Oliveira_AntonioCarlosZulianide_D.pdf: 2312185 bytes, checksum: 6a45c1be8238c13c3a584fdc2ef426e4 (MD5) Previous issue date: 2013 / Resumo: Introdução: Ensaios clínicos das últimas duas décadas do século XX demonstraram a superioridade da radioterapia associada à quimioterapia na abordagem do carcinoma espinocelular do colo do útero (CEC). Contudo, tais estudos abordaram todos os estádios clínicos e para o subgrupo de mulheres com CEC estádio IIIB e os benefícios da quimioterapia não foram totalmente comprovados. Objetivos: Esta tese divide-se em dois estudos: 1) uma comparação histórica de sobrevida livre de doença (SLD), sobrevida total (ST) e toxicidade de tratamento em mulheres com CEC IIIB submetidas à braquiterapia de baixa taxa de dose (BBTD) versus braquiterapia de alta taxa de dose exclusiva (BATD) versus braquiterapia de alta taxa de dose associada à quimioterapia (BATD-QT) e 2) um ensaio clínico aleatorizado comparando esses mesmos parâmetros em mulheres submetidas à BATD versus BATD-QT. Métodos: Na comparação histórica de tratamentos, foram levantados os dados de evolução de pacientes admitidas entre 1985 e 2005 no CAISM-UNICAMP e seguidas até 2007, totalizando 230 pacientes com CEC IIIB que receberam BBTD (42 pacientes), BATD (155 pacientes) ou BATD-QT (33 pacientes). As SLD e ST das mulheres nos três grupos foram comparadas usando curvas de sobrevida tipo Kaplan-Meyer e testes de log-rank. Já o ensaio clínico aleatorizado foi realizado entre setembro de 2003 e julho de 2010. Foram incluídas no estudo 147 mulheres com CEC IIIB. Após aceitarem participar e assinarem o termo de consentimento, as mulheres foram randomizadas para BATD ou BATD-QT através de planilha de aleatorização criada pelo programa SAS e trazida ao conhecimento de pacientes e médicos através de envelopes opacos. Todas as mulheres receberam teleterapia com dose de 45Gy para a região pélvica em 25 frações, 14,4Gy de reforço no(s) paramétrio(s) comprometido(s) e BATD em quatro frações semanais de 7Gy, prescritos no ponto A. O grupo BATD-QT recebeu cisplatina concomitante semanal (40mg/m2) durante a teleterapia pélvica. O follow-up durou até janeiro de 2013, (72 pacientes do grupo com cisplatina e 75 no grupo-controle), com o seguimento médio de 54,9 meses (intervalo interquartil = 55,4 meses). Comparações de SLD e ST foram realizadas usando curvas de Kaplan-Meyer, testes de log-rank e modelos multivariados de Riscos Proporcionais de Cox, os quais englobaram características clínicas das mulheres como variáveis de controle. Resultados: Na comparação histórica, a SLD média para o grupo BATD foi de 60%, para BBTD 45% e para BATD-QT foi de 65% (p = 0,02). Já a ST foi de 65% para o grupo BATD, 49% para BBTD e a ST em dois anos para o grupo BATD-QT foi de 86% (p = 0,02). A toxicidade retal de grau II foi de 7% para o grupo que recebeu BBTD, de 4% para BATD e 7% para o grupo BATD-QT, que teve um caso de toxicidade retal grau IV. No ensaio clínico aleatorizado, mulheres alocadas no grupo BATD-QT tiveram SLD significativamente melhor (RR = 0,52, 95% CI 0,28-0,98, p = 0,04), porém não houve diferença em relação a ST (RR = 0,67, 95% CI 0,37-1,183, p = 0,16). Mulheres com Karnofsky <90 tiveram uma SLD significativamente pior (RR = 2,52, 95% CI 1,23-4,78, p = 0,01). O mesmo ocorreu para as mulheres com invasão parametrial bilateral até a parede óssea (RR = 2,93, 95% CI 1,21-7,13, p = 0,02), e a hemoglobina média durante o tratamento <10mg/dL (RR = 2,22, 95% CI 1,01-4,93, p = 0,04). A ST também foi menor em mulheres com Karnofsky <90 (RR = 2,75, 95% CI 1,29-5,87, p <0,01), e hemoglobina média durante o tratamento <10mg/dL (RR = 2,82, 95% CI 1,27-6,29, p = 0,01). Conclusões: Na revisão da série histórica, as pacientes que receberam braquiterapia de alta taxa de dose tiveram melhores SLD e ST, e as taxas de toxicidade não foram diferentes entre os três grupos. O ensaio clínico, que é o único estudo controlado randomizado comparando a BATD-QT e BATD para CEC IIIB, sugere que há um pequeno, mas significativo, benefício na SLD com a adição de cisplatina à BATD, com uma toxicidade aceitável / Abstract: Introduction: Clinical trials of the last two decades of the twentieth century demonstrated the superiority of radiotherapy combined with chemotherapy in the management of squamous cell carcinoma of the cervix (SCC). However, such studies have addressed all clinical stages and for the subgroup of women with stage IIIB SCC the benefits of chemotherapy have not been fully proven. Objectives: This thesis is divided into two studies: 1) a historical comparison of disease-free survival (DFS), overall survival (OS) and toxicity of treatment in women with SCC IIIB undergoing low-dose rate brachytherapy (LDR) brachytherapy versus high dose rate exclusive (HDR) brachytherapy versus high dose rate associated with chemotherapy (CHT) and 2) a randomized clinical trial comparing these parameters in women undergoing HDR versus CHT. Methods: In the historical comparison of treatments, data on the outcomes of patients admitted between 1985 and 2005 in CAISM-Unicamp and followed until 2007 were collected, totaling 230 patients with SCC stage IIIB who received either LDR (42 patients), HDR (155 patients) or CHT (33 patients). The DFS and OS of women in the three groups were compared using Kaplan-Meyer survival curves and the "log-rank" test. The randomized clinical trial was conducted between September 2003 and July 2010. A total of 147 with SCC stage IIIB were included. After accepting to participate and signing the consent form, women were randomized to HDR or CHT through a randomization spreadsheet created by SAS program and concealment allocation of patients through opaque envelopes. Patients of either the CHT or HDR groups received external-beam radiation (45 Gy) to the entire pelvic region in 25 fractions over a 5-week period. Compromised parametria were treated with 14.4 Gy boost. High-dose rate brachytherapy consisted of four weekly fractions of 7 Gy prescribed to point A. Patients in the CHT group also received concomitant weekly cisplatin (40mg/m2) during the pelvic external beam radiotherapy. The follow-up lasted until January 2013 (72 patients in the cisplatin group and 75 in the control group), with a mean follow-up of 54.9 months (interquartile range = 55.4 months). Comparisons of DFS and OS were performed using Kaplan-Meyer log-rank tests and multivariate models of Cox proportional hazards model, which encompassed the clinical characteristics of women as control variables. Results: In the historical comparison, the DFS for the group HDR was 60% , 45% for LDR and 65% for CHT (p = 0.02). The OS was 65% for the HDR group, 49% for LDR and 86% for CHT (p = 0.02). The Grade II rectal toxicity was 7% for LDR, 4% in HDR patients and 7% in CHT group, which had a case of rectal toxicity grade IV. In the randomized clinical trial, women in the CHT group had significantly better DFS (RR = 0.52, 95% CI from 0.28 to 0.98, p = 0.04), but there was no difference in OS (RR = 0.67, 95% CI 0.37 to 1.183, p = 0.16). Women with Karnofsky <90 had a significantly worse DFS (RR = 2.52, 95% CI 1.23 to 4.78, p = 0.01). The same was true for women with bilateral parametrial invasion to the bone wall (RR = 2.93, 95% CI 1.21 to 7.13, p = 0.02), and mean hemoglobin during treatment <10mg/dL (RR = 2.22, 95% CI 1.01 to 4.93, p = 0.04). The OS was also lower in women with Karnofsky <90 (RR = 2.75, 95% CI 1.29 to 5.87, p <0.01), and mean hemoglobin during treatment <10mg/dL (RR = 2, 82, 95% CI 1.27 to 6.29, p = 0.01). Conclusions: Patients who received HDR had better DFS and OS, and toxicity rates were not different among the three groups. The randomized trial, which is the only randomized controlled study comparing HDR and CHT for CEC IIIB, suggests that there is a small but significant DFS benefit with the addition of cisplatin to HDR, with acceptable toxicity / Doutorado / Oncologia Ginecológica e Mamária / Doutor em Ciências da Saúde

No description available.

Introduction The prognosis in oesophago-gastric cancer is poor with less than 15% patients surviving beyond 5 years after diagnosis. The addition of neoadjuvant therapy has been shown to increase survival in patients suitable for curative surgery. However, the additional gains are modest and the majority of patients do not respond sufficiently from therapy to gain any benefit. There is an urgent need to identify markers that can predict response to neoadjuvant therapy in order provide safer, more effective, individualised treatment regimes. Methods A prospective, multi-centre, collaborative study was undertaken in patients with oesophago-gastric cancer undergoing neoadjuvant therapy and potentially curative surgery. Levels of circulating biomarkers M2-Pyruvate kinase, alkaline phosphatase, CA19-9, CEA and CA 72-4 were measured in patients before and after administering the first cycle of chemotherapy. Binary logistic regression analysis was performed to assess the ability of biomarkers to predict histological response to therapy. Results 165 patients were recruited to the main study. 105 patients had complete histopathological data for analysis. There were 27 responders and 78 non-responders to neoadjuvant therapy. There were no differences in pre-therapy demographic, pathological or treatment factors between the two groups. Responders had less post-operative lymphovascular invasion (P= 0.004) and higher R0 resection rates (P=0.03). Pre-therapy M2-Pyruvate kinase levels were lower in responders compared to non-responders (P=0.037) and levels were able to predict response with each unit increase in the biomarker level being associated with a 4.1% decrease in the likelihood of response (P=0.027). M2-PK levels were not associated with any pre-operative demographic, clinical or pathological factors. Conclusions Pre-therapy dimeric M2-PK levels can predict response to neoadjuvant therapy in patients with oesophago-gastric cancer. The test could be of clinical value for 1 in every 8 patients undergoing the test.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13132号 / 論医博第2136号 / 新制||医||1024(附属図書館) / (主査)教授 溝脇 尚志, 教授 坂井 義治, 教授 山田 泰広 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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・論文博士 / 博士(医学) / 乙第13219号 / 論医博第2166号 / 新制||医||1033(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 修, 教授 戸口田 淳也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Treatment of pancreatic cancer is an important medical problem. Most pancreatic cancer patients are diagnosed with advanced disease and their prognosis is poor. In Lithuania there were 440 new cases in year 2004. More than fifty percent of patients are diagnosed with stage IV disease [Kurtinaitis J et al., 2005]. Median survival of patients diagnosed with pancreatic cancer, depending on a stage of a disease, spread of the tumor, treatment method, functional status of a patient is from 6 to 20 months. Five-year survival is only 0–5 percent [Bramhall S et al., 1998; Oya N, 2004]. Today, pancreatic cancer is treated by combined methods: surgery combined with RT and/or chemotherapy. It is questionable if a patient diagnosed with pancreatic cancer in early stages must be treated by adjuvant treatment methods, or should patients diagnosed with unresectable cancer be treated with chemotherapy or ChRT; and what is more important for the patient: increased survival or better quality of life. Kaunas University of Medicine Clinic (KMUC) is a suitable hospital to treat patients diagnosed with pancreatic cancer. At the Clinic of Surgery pancreatic cancer patients are treated by radical and palliative surgery; and at the Clinic of Oncology patients with pancreatic cancer are treated applying contemporary methods of RT, chemotherapy and combined treatment methods. In this thesis treatment results of patients treated for resectable and unresectable pancreatic cancer from year 1987 to year... [to full text]