京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20795号 / 医博第4295号 / 新制||医||1025(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 原田 浩, 教授 松原 和夫, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

In an optically random system, such as naturally occurring and man-made media, light undergoes pronounced multiple scattering. This phenomenon has shown a remarkable potential in characterizing complex materials. In this regime, scattering occurs from each individual center of the scattering and independent scattering events lead to multiple light scattering. This phenomenon is often described as a random walk of photons and can be modeled in terms of a diffusion equation based on the radiative transfer theory. In this thesis, we used optical path-length spectroscopy (OPS), which is an experimental method to obtain the path-length probability density of the propagating light in multiple scattering media, with a low-coherence optical field to investigate the distribution of photon path lengths in a skin cell model system. This method is capable of measuring the transport mean free path of light in a highly scattering medium and depth-resolved profiles of the backscattered light. Our OPS experimental configuration is based on a fiber-optic Michelson interferometer geometry using single mode optical fibers. We performed OPS based on low-coherence interferometry (LCI) on three-dimensional organotypic models of esophageal cell invasion by measuring the optical path-length distribution of backscattered light in normal and invasive conditions. The optical path-length distribution of light waves inside the cell samples provides information on how a change in the extracellular matrix affects invasiveness of the esophageal cells and induction of signaling pathways. Also, we demonstrated the compatibility to study the structural changes during a two-week period for in vitro cell samples.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25487号 / 医博第5087号 / 新制||医||1073(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 小濱 和貴, 教授 妹尾 浩, 教授 寺田 智祐 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

INTRODUÇÃO: A fistula esofagorrespiratória é complicação temida do câncer esofágico avançado. A paliação com prótese metálica autoexpansível é método amplamente empregado, porém com resultados conflitantes. OBJETIVO: Identificar fatores associados ao insucesso clínico do tratamento da fístula esofagorrespiratória maligna com prótese metálica autoexpansível. MÉTODOS: Estudo retrospectivo através da análise de banco de dados elaborado de forma prospectiva de pacientes submetidos ao tratamento da fístula esofagorrespiratória maligna com prótese metálica autoexpansível entre janeiro de 2009 e fevereiro de 2016 em hospital terciário dedicado ao tratamento do câncer. Foram coletados dados quanto à: características demográficas, nível de albumina sérica, capacidade funcional do paciente, doença pulmonar infecciosa em atividade no momento da passagem da prótese, tratamentos oncológicos prévios, momento do diagnóstico da fístula, tamanho e localização do trajeto fistuloso. RESULTADOS: Um total de 71 pacientes foram incluídos no estudo (55 homens, idade média de 59 anos). Insucesso clínico ocorreu em 44.3% dos pacientes. ECOG 3 ou 4, desenvolvimento da fístula durante o tratamento do câncer esofágico e diâmetro da fístula >= 1 cm foram fatores preditivos do insucesso clínico. ECOG 3 ou 4, doença pulmonar infecciosa em atividade no momento da passagem da prótese e tratamento oncológico prévio com radioterapia foram fatores preditivos de menor sobrevida. O grau de disfagia melhorou significativamente 15 dias após a passagem da prótese. A taxa total de eventos adversos foi de 30%. Migração da prótese e a oclusão da mesma por crescimento tumoral nas extremidades da prótese foram os eventos adversos mais comumente observados. CONCLUSÃO: A prótese metálica autoexpansível é um método terapêutico efetivo para o tratamento da fístula esofagorrespiratória maligna, no entanto, ECOG 3 ou 4, desenvolvimento da fístula durante o tratamento do câncer esofágico e diâmetro da fístula >= 1cm foram fatores preditivos do insucesso clínico após a passagem da prótese / INTRODUCTION: Malignant esophagorespiratory fistula is a serious and life-threatening complication of esophageal cancer. Self-expandable metal stents placement is a well accepted palliative treatment, however, with conflicting results. OBJECTIVE: To identify risk factors associated with clinical failure after self-expandable metal stents placement for the treatment of malignant esophagorespiratory fistula. METHODS: This was a retrospective analysis of a prospectively maintained database used at a tertiary cancer hospital, with patients treated with SEMS placement for MERF between January 2009 and February 2016. The following variables were collected: patient demographics, serum albumin level, Eastern Cooperative Oncology Group (ECOG) performance status, pulmonary infection, previous oncologic treatment, moment of diagnosis of the malignant esophagorespiratory fistula, size and classification of the fistulous tract. RESULTS: A total of 71 patients (55 males, mean age 59 years) were considered for the final analysis. Clinical failure occurred in 44.3% of the patients. ECOG 3 or 4, fistula development during esophageal cancer treatment and fistula diameter >= 1cm were factors associated with increased risk of clinical failure. ECOG 3 or 4, pulmonary infection at the time of SEMS placement and prior radiation therapy were predictive factors associated with lower overall survival. Dysphagia scores improved significantly 15 days after stent insertion. The overall stent-related adverse events rate was 30%. Stent migration and occlusion due to tumor overgrowth were the most commonly seen adverse events. CONCLUSION: SEMS placement is a reasonable treatment option for MERF, however, ECOG 3 or 4, fistula development during esophageal cancer treatment or large fistula diameter may be independent predictors of clinical failure after stenting

INTRODUÇÃO: A fistula esofagorrespiratória é complicação temida do câncer esofágico avançado. A paliação com prótese metálica autoexpansível é método amplamente empregado, porém com resultados conflitantes. OBJETIVO: Identificar fatores associados ao insucesso clínico do tratamento da fístula esofagorrespiratória maligna com prótese metálica autoexpansível. MÉTODOS: Estudo retrospectivo através da análise de banco de dados elaborado de forma prospectiva de pacientes submetidos ao tratamento da fístula esofagorrespiratória maligna com prótese metálica autoexpansível entre janeiro de 2009 e fevereiro de 2016 em hospital terciário dedicado ao tratamento do câncer. Foram coletados dados quanto à: características demográficas, nível de albumina sérica, capacidade funcional do paciente, doença pulmonar infecciosa em atividade no momento da passagem da prótese, tratamentos oncológicos prévios, momento do diagnóstico da fístula, tamanho e localização do trajeto fistuloso. RESULTADOS: Um total de 71 pacientes foram incluídos no estudo (55 homens, idade média de 59 anos). Insucesso clínico ocorreu em 44.3% dos pacientes. ECOG 3 ou 4, desenvolvimento da fístula durante o tratamento do câncer esofágico e diâmetro da fístula >= 1 cm foram fatores preditivos do insucesso clínico. ECOG 3 ou 4, doença pulmonar infecciosa em atividade no momento da passagem da prótese e tratamento oncológico prévio com radioterapia foram fatores preditivos de menor sobrevida. O grau de disfagia melhorou significativamente 15 dias após a passagem da prótese. A taxa total de eventos adversos foi de 30%. Migração da prótese e a oclusão da mesma por crescimento tumoral nas extremidades da prótese foram os eventos adversos mais comumente observados. CONCLUSÃO: A prótese metálica autoexpansível é um método terapêutico efetivo para o tratamento da fístula esofagorrespiratória maligna, no entanto, ECOG 3 ou 4, desenvolvimento da fístula durante o tratamento do câncer esofágico e diâmetro da fístula >= 1cm foram fatores preditivos do insucesso clínico após a passagem da prótese / INTRODUCTION: Malignant esophagorespiratory fistula is a serious and life-threatening complication of esophageal cancer. Self-expandable metal stents placement is a well accepted palliative treatment, however, with conflicting results. OBJECTIVE: To identify risk factors associated with clinical failure after self-expandable metal stents placement for the treatment of malignant esophagorespiratory fistula. METHODS: This was a retrospective analysis of a prospectively maintained database used at a tertiary cancer hospital, with patients treated with SEMS placement for MERF between January 2009 and February 2016. The following variables were collected: patient demographics, serum albumin level, Eastern Cooperative Oncology Group (ECOG) performance status, pulmonary infection, previous oncologic treatment, moment of diagnosis of the malignant esophagorespiratory fistula, size and classification of the fistulous tract. RESULTS: A total of 71 patients (55 males, mean age 59 years) were considered for the final analysis. Clinical failure occurred in 44.3% of the patients. ECOG 3 or 4, fistula development during esophageal cancer treatment and fistula diameter >= 1cm were factors associated with increased risk of clinical failure. ECOG 3 or 4, pulmonary infection at the time of SEMS placement and prior radiation therapy were predictive factors associated with lower overall survival. Dysphagia scores improved significantly 15 days after stent insertion. The overall stent-related adverse events rate was 30%. Stent migration and occlusion due to tumor overgrowth were the most commonly seen adverse events. CONCLUSION: SEMS placement is a reasonable treatment option for MERF, however, ECOG 3 or 4, fistula development during esophageal cancer treatment or large fistula diameter may be independent predictors of clinical failure after stenting

No description available.