Background: Palliative gemcitabine has been shown to prevent the deterioration of well-being and to prolong survival of patients with pancreatic cancer in phase III randomized controlled trials (RCTs). It is unknown whether the efficacy reported in RCTs has translated into effectiveness in routine clinical practice. Objectives: 1) To describe the characteristics of patients with pancreatic cancer treated with palliative gemcitabine at the regional cancer centres (RCCs) of Ontario, 2) To describe: clinical benefit at two months, defined as stable or improved well-being; time to treatment discontinuation; and overall survival, 3) To identify factors associated with clinical benefit, and 4) To compare the effectiveness of gemcitabine with its reported efficacy in RCTs. Methods: This was a retrospective analysis of prospectively collected data. The study included patients with pancreatic cancer treated with palliative gemcitabine at the RCCs of Ontario between 2008 and 2011. Information about well-being was patient self-reported as captured by the Edmonton Symptom Assessment System (ESAS) at the RCCs. The proportions of patients that achieved clinical benefit were reported. Time to treatment discontinuation and overall survival were calculated using Kaplan –Meier survival analysis. Logistic regression was used to identify factors associated with clinical benefit. iii Results: The study population included 423 patients. Only 168 (39.1%) patients completed a pre-treatment ESAS. Patients completing a pre-treatment ESAS were not different than those that did not. Patients treated at RCCs were not different than those in RCTs. The median age of the study population was 65 years, 50% were male, 57% had stage IV disease and 94% had adenocarcinoma morphology. Thirty-seven percent of patients achieved clinical benefit at two months. Median time to treatment discontinuation and overall survival was 2 and 5.7 months, respectively. Stage and pre-treatment wellbeing were associated with clinical benefit at two months. Similar proportions of patients at RCCs and RCTs experienced clinical benefit. Time to treatment discontinuation and survival were similar as well. Conclusions: Efficacy of gemcitabine in RCTs has translated into effectiveness for patients treated at the RCCs of Ontario. It is unknown if this is true for patients not treated at the RCCs. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-08-01 17:50:00.185

This study presents an integrated analysis of pancreatic ductal adenocarcinomas (PDACs) for identification of putative cancer driver genes in somatic copy number gains (SCNGs). SCNG data on 60 PDAC genomes was extracted to identify 756 genes, mapping to 20 genomic loci that are recurrently gained. Through copy number and gene expression analysis on a panel of 29 human pancreatic cancer cell lines, this gene catalogue was refined to 34 PDAC high-confidence candidate genes. The performance of these genes was assessed in pooled shRNA screens and only ECT2 showed significant essentiality to cell viability in specific PDAC cell lines with genomic gains at the 3q26.3 locus that harbor this gene. Targeted shRNA-mediated interference of ECT2, as well as pharmacological inhibition, are supportive of the pooled shRNA screen findings. These results favor ECT2 as a candidate target gene for further evaluation in the subset of PDACs presenting with 3q26 somatic copy number gains.

This study presents an integrated analysis of pancreatic ductal adenocarcinomas (PDACs) for identification of putative cancer driver genes in somatic copy number gains (SCNGs). SCNG data on 60 PDAC genomes was extracted to identify 756 genes, mapping to 20 genomic loci that are recurrently gained. Through copy number and gene expression analysis on a panel of 29 human pancreatic cancer cell lines, this gene catalogue was refined to 34 PDAC high-confidence candidate genes. The performance of these genes was assessed in pooled shRNA screens and only ECT2 showed significant essentiality to cell viability in specific PDAC cell lines with genomic gains at the 3q26.3 locus that harbor this gene. Targeted shRNA-mediated interference of ECT2, as well as pharmacological inhibition, are supportive of the pooled shRNA screen findings. These results favor ECT2 as a candidate target gene for further evaluation in the subset of PDACs presenting with 3q26 somatic copy number gains.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22746号 / 医博第4664号 / 新制||医||1047(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 小川 誠司, 教授 川口 義弥 / 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23376号 / 医博第4745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 中山 健夫, 教授 佐藤 俊哉, 教授 平井 豊博 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Evofosfamide, also formerly known as TH-302, is an investigational hypoxia-activated prodrug and is used to target cancerous cells under hypoxic conditions, which is a feature possessed by multiple solid tumors including pancreatic tumors. Gemcitabine, a cytotoxic agent, has for many years been the standard first-line treatment for metastatic pancreatic cancer in patients. In recent years, combination chemotherapeutic therapies have provided a new avenue for molecular targeting by increasing the probability of eliminating the cancer and minimizing the likelihood of resistance. We have evaluated multiple studies in an effort to shed light on an emerging prodrug, evofosfamide, which operates by selectively targeting the tumor hypoxic compartment. A web-based literature search was performed through PubMed and Google Scholar using the keywords 'evofosfamide', 'TH-302,' and 'pancreatic tumor.' Of the available results, 53 relevant studies were reviewed and summarized. Chemotherapeutic agents such as evofosfamide, which targets tumor hypoxia, are new agents against cancer cells. Current experience with these agents is limited as additional and longer prospective studies are needed to further evaluate the clinical efficacy and postmarketing safety profile.

Indianapolis / By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here we measure the longitudinal body composition changes in patients with advanced PDAC undergoing FOLFIRINOX therapy. We performed a retrospective review of 53 patients with advanced PDAC on FOLFIRINOX as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement, trend, univariate and multivariate analysis were performed. Three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle-and-Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (p=0.02). FW (HR=5.2; 95%CI=1.5-17.3) and MFW (HR=1.8; 95%CI=1.1-2.9) were associated with an increased risk of mortality compared to NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumors were also associated with decreased OMS. On multivariate analysis cachexia phenotype and chemotherapy response were independently associated with survival. Three phenotypes of cachexia were observed. Moreover, three phenotypes suggests molecular or genetic heterogeneity of host or tumor. Identifying these differences will be vital to defining optimal treatment for cachexia. Survival among FW was as poor as MFW suggesting adipose tissue plays a crucial role in cachexia. Blunting or possibly preventing cachexia may confer a significant survival advantage in patients with advanced PDAC.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20222号 / 医博第4181号 / 新制||医||1019(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 鈴木 実, 教授 高田 穣, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic cancer is the third leading cause of cancer-related deaths and is projected to rank second by 2030 in the United States. However, the etiology of this malignancy remains elusive, with family history, chronic pancreatitis, type 2 diabetes, and cigarette smoking as only established risk factors. Therefore, it is urgent and important to identify risk factors, especially modifiable ones (e.g. diet), for the primary prevention of this lethal disease. In this dissertation, we have investigated the associations of mineral intake, dietary quality, and body adiposity with the risk of pancreatic cancer among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Calcium, magnesium, and phosphorus are essential minerals that modulate energy metabolism and glucose homeostasis and may thus be involved in pancreatic carcinogenesis. In the first manuscript, we found that total calcium intake was associated with a reduced risk of pancreatic cancer. In addition, a significant linear inverse association was observed for total magnesium intake. The Healthy Eating Index, 2015 (HEI-2015) and the Dietary Quality Index- revised (DQI-R) have been developed to assess the overall quality or patterns of diet. In the second manuscript, we did not find significant associations between HEI-2015 or DQI-R scores and pancreatic cancer risk. However, a higher intake of some score components (i.e., calcium, vegetables, and whole grains) conferred a lower risk. Although mounting biological mechanisms have linked overweight and obesity to the development of pancreatic cancer, it is largely unclear whether prediagnostic body mass index (BMI) trajectory is associated with the risk of this disease. In the third manuscript, we revealed that prediagnostic adulthood BMI trajectory was not associated with pancreatic cancer risk, but a suggestively or significantly increased risk were identified for individuals who were overweight at age 20 or obese at age 50, compared with those who had a normal weight at the two respective time points. Taken together, the findings of research presented in this dissertation contribute to an improved understanding of the crucial roles of diet and adiposity in the etiology of pancreatic cancer, which may offer some new avenues for the prevention of this intractable malignancy.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13489号 / 論医博第2257号 / 新制||医||1059(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 松田 道行, 教授 波多野 悦朗, 教授 羽賀 博典 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM