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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19567号 / 医博第4074号 / 新制||医||1013(附属図書館) / 32603 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武田 俊一, 教授 小川 誠司, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Chronic pancreatitis is considered a risk factor for pancreatic cancer. An exact mechanism how chronic inflammation of the pancreas leads to pancreatic cancer is not yet understood; the possibility of a shared genetic predisposition for both diseases is also assumed. A similar association in patients with AIP has not yet been demonstrated. The aim of our work was to expand the knowledge about relationship between chronic pancreatitis and pancreatic cancer. We studied the association of the diseases in two synchronous projects. In the first one, we examined the occurrence of pancreatic cancer in patients with autoimmune pancreatitis. In the second project, we investigated the presence of genetics variants associated with chronic pancreatitis in patients with pancreatic cancer. In the retrospective study of our cohort of patients, we were one of the very first in the world to show occurrence of pancreatic cancer in patients with autoimmune pancreatitis, and as the only one, we have defined the characteristics of such patients. To assess the association of the diseases, we performed a systematic review where we identified all reported cases of coincidence of pancreatic cancer and autoimmune pancreatitis; the incidence of cancer in patients with autoimmune pancreatitis was similar to that of patients...

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24136号 / 医博第4876号 / 新制||医||1060(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 藤田 恭之, 教授 波多野 悦朗, 教授 伊藤 貴浩 / 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24139号 / 医博第4879号 / 新制||医||1060(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 森信 暁雄, 教授 上野 英樹, 教授 金子 新 / 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24791号 / 医博第4983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 川口 義弥, 教授 小林 恭, 教授 小濱 和貴 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Le taux de mortalité dû au cancer est en hausse d’année en année. Le cancer du pancréas est l’un des plus mortels. Avec un taux de survie inférieur à 20% un an suivant le diagnostic, il y a une urgence pour développer de nouvelles molécules pour cibler cette maladie. La metformine, un biguanide utilisé cliniquement en tant qu’agent antidiabétique, s’est avérée à avoir des propriétés anticancéreuses. Les patients souffrant de diabète de type 2 prenant la metformine comme traitement sont moins à risque de développer plusieurs cancers dont celui du pancréas. Cependant, la metformine n’étant pas biodisponible, les doses à administrer seraient trop élevées pour la considérer comme thérapie anticancéreuse. Le groupe de recherche Schmitzer a synthétisé de nouveaux analogues de type biguanide plus lipophiles dans le but d’améliorer leur biodisponibilité. Le phényléthynylbenzyle biguanide (PEBB) est un des analogues présentant des propriétés antiprolifératives environ 800 fois plus puissantes que la metformine contre des cellules du cancer du pancréas. L’hexylbiguanide s’est aussi démarqué par sa spécificité pour les cellules cancéreuses et sa faible toxicité pour les cellules saines. Étant de bons candidats, des études in vivo ont été faites sur des souris en leur administrant le PEBB et l’hexylbiguanide afin d’obtenir des informations sur l’absorption et la distribution des composés. Pour ce faire, une méthode par LC-MS en mode multiple reaction monitoring (MRM) a été développée afin de quantifier différents analogues de biguanides dans le plasma de souris. De plus, une méthode par MALDI-TOF a été développée afin de localiser et quantifier les analogues dans les tissus par imagerie couplée à la spectrométrie de masse (IMS). Les expériences réalisées ont permis de suivre les composés dans le plasma et d’établir une cinétique d’absorption révélant que le PEBB atteint sa concentration plasmatique maximale environ à 1h après l’administration et que le composé est éliminé de la circulation sanguine à 80% au bout de 4h. Dans le cas de l’hexylbiguanide, la concentration plasmatique maximale est atteinte environ 30 minutes après l’administration pour être éliminé à plus de 90% après 4h. De plus, les études d’IMS ont révélé que le PEBB se distribue principalement dans le foie et légèrement dans les tumeurs. Aucune accumulation à long terme dans le foie n’a été observée, ce qui signifie que les risques de dommages hépatiques sont faibles. Les deux méthodes développées sont des méthodes puissantes IV et reproductibles afin de quantifier les différents types de biguanides dans les liquides biologiques ainsi que dans les tissus. / The death rate of cancer is increasing every year. Pancreatic cancer is one of the deadliest. With a survival rate of less than 20% one year post diagnosis, there is an emergency to develop new molecules to target this disease. Metformin, a biguanide clinically used as an antidiabetic agent, has been shown to have anticancer properties as well. Patients with type 2 diabetes taking metformin are less likely to develop several cancers including pancreatic cancer. However, due to the poor bioavailability of metformin, the doses would be too high to consider it as an anticancer treatment. The Schmitzer group has synthesized new biguanide analogues that are more lipophilic and thus more bioavailable. Phenylethynylbenzyl biguanide (PEBB) is one of the analogues with about 800 times more effective antiproliferative properties than metformin against pancreatic cancer cells. Hexylbiguanide also stood out for its specificity for cancer cells and its low toxicity for normal cells. In vivo studies were performed on mice by administering PEBB and hexylbiguanide to study the absorption and distribution of the compounds. For this aim, a LC-MS method was developed using Multiple Reaction Monitoring (MRM) mode to quantify different biguanide analogues in mice plasma. Complementarily, a MALDI-TOF method was developed to localize and quantify the analogues in tissues by imaging coupled to mass spectrometry (IMS). The experiments performed allowed to follow the compounds in plasma to establish absorption kinetics. These experiments revealed that PEBB reaches its maximum plasma concentration at 1h after administration and the compound is eliminated from the bloodstream at 80% after 6h. For hexylbiguanide, the maximum plasma concentration is reached about 30 minutes after administration and more than 90% is eliminated after 4 hours. In addition, IMS studies have shown that PEBB is distributed mainly in the liver and slightly in tumors. No accumulation in the liver was observed, which suggests that the risk of liver damage is low. These two methods are powerful and reproducible methods to quantify the different types of biguanides in biological fluids and tissues.

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Background Although pancreatic cancer incidence is low at 13.1 per 100,000 people, this cancer is difficult to treat and carries a poor 5-year survival rate. Additionally, pancreatic cancer survival rates vary disproportionately based on age and race. The objective of this study was to evaluate the association between 5-year survival of pancreatic cancer and the basic demographic factors age, race, and sex. Methods Data were retrieved from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 database, spanning from 2000-2017, using SEER*Stat. SPSS was used to calculate descriptive statistics for vital status, age, race, and sex. Odds ratios with confidence intervals were calculated using Epi Info. Case data were used to conduct survival analysis by age, race, and sex using OriginPro. Results Out of a total of 118,581 cases, 79.3% were White (n = 106,887), 12.5% were Black (n = 16,866), 7.4% were Asian or Pacific Islander (n = 9,960), 0.6% were American Indian/Alaskan Native (n = 792), and 0.2% were unknown race (n = 321). The odds ratio (OR) of dying before reaching 5+ survival was lowest for the Asian or Pacific Islander group (OR = 0.70, 95% CI: 0.66 - 0.74), followed by the group of Black patients (OR = 1.07, 95% CI: 1.02 - 1.13), the White patients group (OR = 1.12, 95% CI: 1.08 - 1.17), and the American Indian/Alaskan Native group (OR = 1.12, 95% CI: 0.89 - 1.40). The largest age group was 65-69 years old, comprising 14.7% (n = 19,866) of the dataset. Probability of 5+ year survival for pancreatic cancer patients was highest for the age group 15-19 years (n = 74). In general, 5+ year survival probability declined with age. Risk of death before reaching 5+ year pancreatic cancer survival was slightly higher in men (OR = 1.03, 95% CI: 1.00 - 1.07), who comprised 50.9% (n = 68,628) of the dataset. Discussion Findings from this study corroborate differences by age, race, and sex discussed in the literature. Differences in survival rates by race depart from some findings in literature documenting no significant differences in treatment outcome by race. Controlling for age in a future study in both race and sex survival probability analyses may be helpful. Further, stratifying by sex in survival probability analysis by race would be illuminating. In addition to survival analysis, regression modeling would be a useful next step.