京都大学 / 新制・論文博士 / 博士(医学) / 乙第13442号 / 論医博第2241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 羽賀 博典, 教授 藤田 恭之, 教授 伊藤 貴浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Gastric cancer is often diagnosed in the metastatic stage, and only 10% of patients survive for as long as 2 years. Current chemotherapy regimens show significant treatment-related toxicities. It is crucial to identify the patients that will benefit most from certain chemotherapy regimens in order to avoid unnecessary side effects. Patients and Methods: 2 patients with advanced gastric cancer repeatedly received 5-FU/cisplatin combination chemotherapy. Genomic DNA was extracted from tumor tissue and mononuclear blood cells. Genotype analysis of genes of metabolizing and DNA repair enzymes was carried out using a PCR-RFLP technique. Direct sequencing was used to identify mutations of the gene dihydropyrimidine dehydrogenase (DPD). Results: Prolonged survival of 51 and 29 months, respectively were observed in our 2 patients. Both patients were positive for genotypes of thymidylate synthase - the target enzyme of 5-FU - that are associated with improved drug response. DPD variants connected with increased toxicity were not observed. However, both patients also showed genotypes in cisplatin metabolizing enzymes which enhance the effect of the drug. Conclusion: Genotype analysis in drug metabolizing enzymes of 5-FU and cisplatin provide a possible explanation for extraordinary therapy effects observed in 2 patients with advanced gastric cancer. / Hintergrund: Das Magenkarzinom wird häufig im fortgeschrittenen Stadium diagnostiziert, und nur etwa 10% der Patienten überleben 2 Jahre. Aktuelle Chemotherapien zeigen eine hohe therapiebedingte Toxizität. Es ist daher von großer Bedeutung, diejenigen Patienten zu identifizieren, die von einer bestimmten Therapie profitieren, um anderen Patienten die Nebenwirkungen einer solchen Therapie zu ersparen. Patienten und Methoden: 2 Patienten mit fortgeschrittenem Magenkarzinom erhielten wiederholt eine Kombinationschemotherapie aus 5-FU/Cisplatin. Genomische DNS wurde aus Tumorgewebe und Leukozyten isoliert. Genotypanalysen von Genen, die am Metabolismus der Substanzen und am DNS-Reparaturprozess beteiligt sind, wurden mithilfe einer PCRRFLP-Methode durchgeführt. Das Gen der Dihydropyrimidindehydrogenase (DPD) wurde direkt sequenziert. Ergebnisse: Beide Patienten zeigten ein deutlich verlängertes Überleben von 51 bzw. 29 Monaten. Genotypen des 5-FU-Zielenzyms Thymidylatsynthase, die mit einem verbesserten Ansprechen assoziiert sind, konnten in beiden Patienten nachgewiesen werden. DPD-Varianten, die mit einer erhöhten Toxizität verbunden sind, wurden nicht beobachtet. Zusätzlich konnten bei beiden Patienten Genotypen in Cisplatin metabolisierenden Genen gefunden werden, die eine prolongierte Wirkung der Substanz bedingen. Schlussfolgerungen: Durch Genotypanalysen in Genen des 5-FU- und Cisplatin-Metabolismus konnte ein spezifisches pharmakogenetisches Profil identifiziert werden, das möglicherweise die Ursache eines außergewöhnlich guten Therapieeffektes in 2 Patienten mit fortgeschrittenem Magenkarzinom ist. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Recently, there has been an increase in the number of proton beam therapy (PBT) centers operating worldwide. For certain cases, proton beams have been shown to provide dosimetric and radiobiological advantages when used for cancer treatment, compared to the regular photon-beam based treatments. Under ideal circumstances, the dose given to the tissues surrounding a target can be reduced with PBT. The risk for side effects following treatment is then expected to decrease. Until present, mainly stationary targets, e.g. targets in the brain, have been treated with PBT. There is currently a growing interest to treat also target volumes in other parts of the body with PBT. However, there are sources of uncertainties, which must be more carefully considered when PBT is used, especially for PBT carried out with scanned proton beams. PBT is more sensitive to anatomical changes, e.g. organ motion or a variable gas content in the intestines, which requires that special precautions are taken prior to treating new tumour sites. In photon beam radiotherapy (RT) of moving targets, the main consequence of organ motion is the loss of sharpness of the dose gradients (dose smearing). When scanned proton beams are used, dose deformation caused by the fluctuations in the proton beam range, due to varying tissue heterogeneities (e.g., the ribs moving in and out of the beam path) and the so-called interplay effect, can be expected to impact the dose distributions in addition to the dose smearing. The dosimetric uncertainties, if not accounted for, may cause the planned and accurately calculated dose distribution to be distorted, compromising the main goal of RT of achieving the maximal local disease control while accepting certain risks for normal tissue complications. Currently there is a lack of clinical follow-up data regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumour sites in moving organs. On the other hand, the use of photon beams for this kind of cancer treatment is well-stablished. A treatment planning comparison between RT carried out with photons and with protons may provide guidelines for when PBT could be more suitable. New clinical applications of particle beams in cancer therapy can also be transferred from photon-beam treatments, for which there is a vast clinical experience. The evaluation of the different uncertainties influencing RT of different tumour sites carried out with photon- and with proton-beams, will hopefully create an understanding for the feasibility of treating cancers with scanned proton beams instead of photon beams. The comparison of two distinct RT modalities is normally performed by studying the dosimetric values obtained from the dose volume histograms (DVH). However, in dosimetric evaluations, the outcome of the treatments in terms of local disease control and healthy tissue toxicity are not estimated. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. In this thesis, different factors that should be taken into consideration in PBT, for treatments influenced by organ motion and density heterogeneities, were studied and their importance quantified. This thesis consists of three published articles (Articles I, II and III). In these reports, the dosimetric and biological evaluations of photon-beam and scanned proton-beam RT were performed and the results obtained were compared. The studies were made for two tumour sites influenced by organ motion and density changes, gastric cancer (GC) and liver metastases. For the GC cases, the impact of changes in tissue density, resulting from variable gas content (which can be observed inter-fractionally), was also studied. In this thesis, both conventional fractionations (implemented in the planning for GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. In this work, it was found that proton therapy provided the possibility to reduce the irradiations of the normal tissue located near the target volumes, compared to photon beam RT. However, the effects of density changes were found to be more pronounced in the plans for PBT. Furthermore, with proton beams, the reduction of the integral dose given to the OARs resulted in reduced risks of treatment-induced secondary malignancies.

Purpose: To understand the process of discovery and decision-making for adults with the CDH1 marker for hereditary diffuse gastric cancer (HDGC) and inherited breast cancer. Participants and Setting: Purposeful sampling included 20 participants; 17 adults (11 women and 6 men, ages 23–77) recruited through the No Stomach for Cancer organization; six participants were interviewed two times; with three healthcare providers also interviewed. Nineteen interviews were by telephone; one was in person. Methodological Approach: Grounded theory with constant comparison. Findings: The person diagnosed with the genetic marker CDH1 undergoes the decision-making process of Paving the way as they address this healthcare challenge. Paving the way explains the entry points for learning the risk, discerning testing for confirmation, choosing iterative individual cycles of surveillance, surgery, and ongoing adjustments postoperatively while normalizing to live longer. Implications for Nursing: Understanding the process of Paving the way explains and describes the nine key factors for decision-making and predicts the timing for nursing interventions for both post-genetic testing and pre- and postoperative assessment and planning. Knowledge Translation: Advocacy for the self and family is key to Paving the Way. Nursing has an opportunity to develop and expand the roles for navigator and counselor in the area of genetic testing. Patients undergoing PTG have chronic healthcare needs. Family implications for genetic testing require assessment beyond the individual.

This dissertation is author version of following the journal article. Takahiro Shimizu, Hiroyuki Marusawa, Yuko Matsumoto, Tadashi Inuzuka, Atsuyuki Ikeda, Yosuke Fujii, Sachiko Minamiguchi, Shin’ichi Miyamoto, Tadayuki Kou, Yoshiharu Sakai, Jean E. Crabtree, Tsutomu Chiba, Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection, Gastroenterology, Volume 147, Issue 2, August 2014, Pages 407-417.e3, ISSN 0016-5085, http://dx.doi.org/10.1053/j.gastro.2014.04.036. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18543号 / 医博第3936号 / 新制||医||1006(附属図書館) / 31443 / 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 武藤 学 / 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・課程博士 / 博士(医学) / 甲第21299号 / 医博第4388号 / 新制||医||1030(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 中川 一路, 教授 川上 浩司 / 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24138号 / 医博第4878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 村川 泰裕, 教授 波多野 悦朗, 教授 武藤 学 / 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24794号 / 医博第4986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 寺田 智祐, 教授 武藤 学, 教授 上杉 志成 / 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24799号 / 医博第4991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 武藤 学, 教授 石見 拓, 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

Predictive and prognostic factors in gastric cancer Šmíd D. Surgical clinic of University Hospital in Pilsen and Faculty of Medicine in Pilsen, Charles University in Prague. Introduction: Gastric cancer is one of malignant diseases which have the worst prognosis. Unfortunately, there are most patients with advanced-stage disease who have to be treated in a palliative way. Patients suffered from the same type of tumor, being at the same stage of disease and treated with the same chemotherapy have various rates of survival, which can be caused by diverse expression of selected genes impacting on the mechanism of cytostatic effects. The determination of these genes or microRNAs which regulate these genes could be used as a predictive factor for prediction of effects of administered chemotherapy. The determination of some microRNAs, or in the combination with suitable plasmatic factors, could be used as a prognostic factor for patients with gastric cancer. It is also possible to use this combination for early diagnosis of cancerogenesis Object: The aim is to verify the possibility to use expression of selected genes and some microRNAs in tumor tissue as a prognostic factor or a predictor for therapeutic effects of chemotherapy in patients with gastric cancer. Methodology: We retrospectively evaluated the group...