L’objectif du travail a été d’explorer la valeur pronostique pour les tumeurs de la vessie des polymorphismes de gènes associés à l’inflammation et du microenvironnement tumoral lymphocytaire CD8+. Pour les marqueurs constitutionnels, deux approches ont été conduites concomitamment, l’une explorant de façon globale les gènes associés à l’inflammation, l’autre ciblant un gène inflammatoire d’intérêt, PDL1, impliqué dans des points de contrôles immunologiques. A l’échelle du génome, en utilisant des méthodes statistiques soit classiques soit innovantes (dites multi marqueurs), nous avons démontré que les variants (SNP) dans les gènes TNIP1, CD5 et JAK3 étaient associés au risque de récidive des tumeurs de vessie non invasives du muscle alors que les variants dans les gènes MASP1, AIRE et CD3 étaient associés au risque de progression. Dans un deuxième temps, l’association entre variants dans le gène de PDL1 et pronostic des tumeurs de vessie a été explorée en appliquant une méthode classique « SNP par SNP » et une approche à l’échelle du gène. Nous avons identifié une forte association entre des variants de PDL1 et le pronostic de tumeurs de vessie envahissant le muscle dans une large cohorte prospective, mais sans pouvoir répliquer ce résultat dans une série issue du consortium TCGA.Dans les tumeurs n’envahissant pas le muscle, nous avons développé et évalué une méthode d’évaluation standardisée de l’infiltrat lymphocytaire CD8+, cellules T-cytotoxiques impliquées dans la mort des cellules tumorales. L’analyse morphométrique après double immuno-marquage des cellules tumorales et des lymphocytes CD8+ et numérisation a permis d’estimer de façon séparée le compte des cellules inflammatoires dans la tumeur et le stroma, et d’estimer l’hétérogénéité spatiale intra-tumorale. Nous avons montré que cette hétérogénéité limite les estimations de l’infiltrat CD8+ sur les puces tissulaires (Tissue Micro Array) qui échantillonnent les tumeurs de façon restrictive. Sous cette réserve, nous avons identifié dans les tumeurs n’envahissant pas le muscle une association entre l’infiltrat lymphocytaire CD8+ et le stade tumoral Ta/T1, ainsi qu’avec le risque de récidive des tumeurs T1. A l’avenir, variations génétiques constitutionnelles dans les gènes de l’inflammation et évaluation de l’infiltrat tumoral inflammatoire pourraient être intégrées en vue d’améliorer la prédiction du pronostic des tumeurs vésicales. / The aim of this study was to explore prognostic value for bladder cancer of germline polymorphisms in inflammatory genes and tumor CD8+ lymphocytic microenvironment. For constitutional markers, two approaches were conducted jointly: one genome-based using specific GWAS statistical methods, the other gene-based focusing on PDL1, an inflammatory gene implicated in immune checkpoints. At the genome level, using both standard and innovative statistical methods (multi marker methods Bayesian Lasso and Bayes A) we demonstrated that variants (SNPs) in TNIP1, CD5 and JAK3 were associated with the risk of recurrence of non-muscle invasive bladder cancer (NMIBC) while SNPs in MASP1, AIRE and CD3 were associated with risk of progression. Meanwhile, association between PDL1 and prognosis of NMIBC and muscle invasive BC (MIBC) was explored using classical SNPS by SNP investigations and a gene based approach. We identified a very strong association between PDL1 variants and MIBC prognosis in a large prospective cohort but failed replicating those results in the TCGA consortium series.In non-muscle invasive bladder cancer, we developed and evaluated a standardized counting approach of CD8+ cells, T-cytotoxic lymphocytes implicated in tumor cells death. Morphometric analysis after double immuno-staining of tumor cells and digitalization allowed separate estimation of CD8+ cells in the tumor and stroma compartment and estimation of spatial intra tumoral heterogeneity. We demonstrated that this heterogeneity compromised CD8+ estimation on Tissue Micro Arrays, which sample the tumors in a restrictive manner. Keeping those limitations in mind, we identified an association between CD8+ inflammatory infiltrate and both NMIBC stage and T1 tumours risk of recurrence. In the future, germline variation in inflammatory genes and evaluation of tumor inflammatory infiltrate could be integrated for better prediction of bladder cancer prognosis.

Most patients with bladder cancer are in the stage of non-muscle-invasive bladder cancer (NMIBC), while 30% of patients progress to the life-threatening muscle-invasive bladder cancer (MIBC) stage because of distant metastases. The selection of treatment options depends on the bladder cancer stage. We established a relationship network for the proteins from the mice urine samples collected during the progression of bladder cancer based on biological pathways and developed population pharmacodynamic models for the proteins in the light of their relationship network. Models that can quantitatively describe changes in the protein profiles of IL1a, IL1b, Csf2, and Casp3 in mice urine samples over time during bladder cancer progression were developed with the consideration of gender differences and progressing age. Our results assist the identification of the early protein diagnostic biomarkers in urine for detecting bladder cancer at its early stages and apply appropriate treatments on patients.

No description available.

OBJECTIVES: Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans. METHODS: A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels. RESULTS: Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure. CONCLUSIONS: Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.

OBJECTIVES: Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans. METHODS: A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels. RESULTS: Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure. CONCLUSIONS: Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.

No description available.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13466号 / 論医博第2253号 / 新制||医||1055(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 中島 貴子, 教授 藤田 恭之 / 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17946号 / 医博第3830号 / 新制||医||1000(附属図書館) / 30776 / 京都大学大学院医学研究科医学専攻 / (主査)教授 稲垣 暢也, 教授 小西 郁生, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Reprinted from Cancer Biomarkers, 15(4), Nakashima et al., Urine CXCL1 as a biomarker for tumor detection and outcome prediction in bladder cancer, 357-364, Copyright (2015), with permission from IOS Press. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19596号 / 医博第4103号 / 新制||医||1014(附属図書館) / 32632 / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 武田 俊一, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.