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Gastrointestinale Tumorpatienten leiden bei ihrer Akutaufnahme im Krankenhaus und in der sich anschließenden Chemotherapie unter somatischen, psychischen und sozialen Belastungen, die sie psychoonkologisch behandlungsbedürftig erscheinen lassen. Bei 60 % dieser Patienten wurde ein solcher Behandlungsbedarf festgestellt. Das Anliegen der Arbeit war es, neben der Ermittlung des psychoonkologischen Betreuungsbedarfs, die Teilnahmebereitschaft dieser Patienten an einer psychoonkologischen Intervention festzustellen und zwei unterschiedliche Therapieverfahren (kognitiv-verhaltenstherapeutisch ausgerichtete Gesprächstherapie und Entspannungstherapie in Form einer progressiven Muskelrelaxation) mit einer Kontrollgruppe (Darreichung von Informationsmaterial über das Krankheitsbild) zu vergleichen. Es konnte ein positiver Effekt der Intervention, besonders der Gesprächstherapie, auf die Reduktion der Angst und Depression bei hoch belasteten Tumorpatienten nachgewiesen werden. Der Betreuungsbedarf derjenigen Patienten, die nur Informationsmaterial über die bösartige Krankheit erhielten, veränderte sich dagegen in der Zeit ihrer Chemotherapie nicht. Verlaufsabhängig konnte gezeigt werden, dass die Veränderung des psychoonkologischen Betreuungsbedarfs bereits kurz nach der Intervention einsetzt. Es gab aber auch Patienten, die erst im Verlauf der Intervention während der Chemotherapie einen psychoonkologischen Betreuungsbedarf entwickelten, den sie zu Beginn der Untersuchung nicht hatten. Auch diese Patienten konnten durch die psychotherapeutischen Interventionsmaßnahmen erfolgreich behandelt werden. / Gastrointestinal cancer patients who are hospitalized and receiving chemotherapy suffer from somatic, psychological, and social stresses that can be counteracted with psycho-oncological treatment. In fact, 60% of this population has been found to be in need of such services. The aim of this study was to determine how many patients in need of these services would be willing to participate in a psychosocial intervention, and to compare the outcomes of groups receiving two different therapeutic approaches (cognitive behavioral talk therapy and relaxation therapy in the form of a progressive muscle relaxation) with those of a control group, who were simply given written materials about their illness that included information on relevant psychosocial issues. The interventions, especially the talk therapy, were observed to have a positive effect on alleviating depression and anxiety in highly burdened cancer patients. The patients who only received written information about their disease showed no changes in the degree to which they needed psycho-oncological support over the time they were receiving chemotherapy. While some patients experienced improvements soon after the interventions had begun, there were also cases of patients who hadn’t initially exhibited a need for psycho-oncological support but later came to develop this need over the course of undergoing chemotherapy. These patients were also successfully treated through the psychotherapeutic interventions.

AGUIA é uma aplicação web front-end, desenvolvida para gerenciar dados clínicos, demográficos e biomoleculares de pacientes coletados durante os ensaios clínicos gastrointestinais no MD Anderson Cancer Center. A diversidade de metodologias envolvidas na triagem de pacientes e no processamento da amostra traz uma heterogeneidade dos tipos de dados correspondentes. Sendo assim, estes devem ser baseados em uma arquitetura orientada a recurso que transforma dados heterogêneos em dados semânticos, mais especificamente em RDF (Resource Description Framework - Estrutura para a descrição de recursos). O banco de dados escolhido foi o S3DB, por este ter cumprido os requisitos necessários de transformação dos dados heterogêneos de diferentes fontes em RDF, distinguindo explicitamente a descrição do domínio e sua instanciação, permitindo simultaneamente a contínua edição de ambos. Além disso, ele usa um protocolo REST, e é de código aberto e domínio público o que facilita o desenvolvimento e divulgação. Contudo, por mais abrangente e flexível, um formato de web semântica pode por si só, não abordar a questão de representar o conteúdo de uma forma que faça sentido para especialistas do domínio. Assim, o objetivo do trabalho aqui descrito foi identificar um conjunto adicional de descritores que forneceu as especificações para a interface gráfica do usuário. Esse objetivo foi perseguido através da identificação de um formalismo que faz uso do esquema RDF para permitir a montagem automática de interfaces gráficas de uma forma significativa. Um modelo RDF generalizado foi, portanto, definido de tal forma que as mudanças nos descritores gráficos sejam automaticamente e imediatamente refletidas na configuração da aplicação web do cliente, que também está disponível neste trabalho. Embora os padrões de design identificados reflitam e beneficiem os requisitos específicos de interagir com os dados gerados pelos ensaios clínicos, a expectativa é que eles contenham pistas para uma solução de propósito geral. Em particular, sugere-se que os padrões mais úteis identificados pelos utilizadores deste sistema sejam suscetíveis de serem reutilizáveis para outras fontes de dados, ou pelo menos para outros bancos de dados semânticos de ensaios clínicos. / AGUIA is a web application front-end originally developed to manage clinical, demographic and biomolecular patient data collected during gastrointestinal clinical trials at MD Anderson Cancer Center. The diversity of methodologies involved in patient screening and sample processing, brings corresponding heterogeneity of data types. Thus, this data must be based on a Resource Oriented Architecture that transforms heterogeneous data in semantic data, most specifically in RDF (Resource Description Framework). The database chosen was a S3DB, because it met the necessary requirements of transforming heterogeneous data from different sources in RDF, explicitly distinguishing the description of the domain from its instantiation, while allowing for continuous editing of both. Furthermore, it uses a REST protocol, and is open source and in the public domain which facilitates development and dissemination. Nevertheless, comprehensive and flexible a semantic web format may be, it does not by itself address the issue of representing content in a form that makes sense for domain experts. Accordingly, the goal of the work described here was to identify an additional set of descriptors that provide specifications for the graphic user interface. That goal was pursued by identifying a formalism that makes use of the RDF schema to enable automatic assembly of graphic user interfaces in a meaningful manner. A generalized RDF model was therefore defined such that changes in the graphic descriptors are automatically and immediately reflected into the configuration of the client web browser interface application, which is also made available with this report. Although the design patterns identified reflect, and benefit, from the specific requirements of interacting with data generated by clinical trials, the expectation is that they contain clues for a general purpose solution. In particular, it is suggested that the most useful patterns identified by the users of this system are susceptible to being reusable for other data sources, or at least for other clinical trial semantic web data stores.

Background The detrimental impact of malnutrition and cachexia in cancer patients subjected to surgical resection is well established. However, how systemic and local metabolic alterations in cancer patients impact the serum metabolite signature, thereby leading to cancer-specific differences, is poorly defined. In order to implement metabolomics as a potential tool in clinical diagnostics and disease follow-up, targeted metabolite profiling based on quantitative measurements is essential. We hypothesized that the quantitative metabolic profile assessed by 1H nuclear magnetic resonance (NMR) spectroscopy can be used to identify cancer-induced catabolism and potentially distinguish between specific tumour entities. Importantly, to prove tumour dependency and assess metabolic normalization, we additionally analysed the metabolome of patients' sera longitudinally post-surgery in order to assess metabolic normalization. Methods Forty two metabolites in sera of patients with tumour entities known to cause malnutrition and cachexia, namely, upper gastrointestinal cancer and pancreatic cancer, as well as sera of healthy controls, were quantified by 1H NMR spectroscopy. Results Comparing serum metabolites of patients with gastrointestinal cancer with healthy controls and pancreatic cancer patients, we identified at least 15 significantly changed metabolites in each comparison. Principal component and pathway analysis tools showed a catabolic signature in preoperative upper gastrointestinal cancer patients. The most specifically upregulated metabolite group in gastrointestinal cancer patients was ketone bodies (3-hydroxybutyrate, P < 0.0001; acetoacetate, P < 0.0001; acetone, P < 0.0001; false discovery rate [FDR] adjusted). Increased glycerol levels (P < 0.0001), increased concentration of the ketogenic amino acid lysine (P = 0.03) and a significant correlation of 3-hydroxybutyrate levels with branched-chained amino acids (leucine, P = 0.02; isoleucine, P = 0.04 [FDR adjusted]) suggested that ketone body synthesis was driven by lipolysis and amino acid breakdown. Interestingly, the catabolic signature was independent of the body mass index, clinically assessed malnutrition using the nutritional risk screening score, and systemic inflammation assessed by CRP and leukocyte count. Longitudinal measurements and principal component analyses revealed a quick normalization of key metabolic alterations seven days post-surgery, including ketosis. Conclusions Together, the quantitative metabolic profile obtained by 1H NMR spectroscopy identified a tumour-induced catabolic signature specific to upper gastrointestinal cancer patients and enabled monitoring restoration of metabolic homeostasis after surgery. This approach was critical to identify the obtained metabolic profile as an upper gastrointestinal cancer-specific signature independent of malnutrition and inflammation.

Zytotoxische Chemotherapien, die zur Behandlung gastrointestinaler Karzinome eingesetzt werden, sind mit unerwünschten Wirkungen und insbesondere mit Hämatotoxizität verbunden. Diese können Behandlungsverzögerungen zur Folge haben, welche die Wirksamkeit der Tumortherapie und damit die Überlebenschancen verschlechtern. Chemotherapie-bedingte Nebenwirkungen sind variabel und das individuelle Risiko ist auf Grundlage klinischer Merkmale eines Patienten schwer vorherzusagen. Aus diesem Grund werden hierfür biomathematische Modelle der Hämatopoese unter Chemotherapie als modellbasierter Ansatz der Präzisionsmedizin vorgeschlagen. Bisher wurde die Leistung dieser Modelle nur in geringem Umfang für Therapien solider Tumore untersucht. In die vorliegende prospektive klinische multizentrische Beobachtungsstudie wurden 28 Patienten mit lokal fortgeschrittenem Adenokarzinom des Magens (n= 9, 32.1%), Ösophagus, ösophago-gastralen Übergangs (Typ I-III nach Siewert) (n=14, 50.0%) und Pankreaskarzinom (n=5, 17.9%) eingeschlossen, bei denen eine neoadjuvante oder adjuvante Chemotherapie mit dem FLO(T)- (5-Fluorouracil, Folinsäure, Oxaliplatin, Docetaxel) (n=23, 82.1%) oder FOLFIRINOX- (5-Fluorouracil, Folinsäure, Oxaliplatin und Irinotecan) Schema (n=5, 17.9%) geplant war. Während der Therapiezyklen wurden engmaschige Blutbildkontrollen durchgeführt. Darüber hinaus wurden die aufgetretenen Nebenwirkungen zu jedem Zyklus gemäß CTCAE v5.0 dokumentiert. Es wurde ein mechanistisches biomathematisches integriertes Modell der Hämatopoese, der Chemotherapie sowie der Wirkung hämatopoetischer Wachstumsfaktoren verwendet, um die individuelle, Chemotherapie-bedingte Hämatotoxizität eines Patienten vorherzusagen. Bei 21 Studienpatienten (75%) trat eine höhergradige hämatologische Toxizität (Grad 3 oder 4 nach CTCAE) auf, wobei es sich am häufigsten um eine Neutropenie handelte (n= 19, 67.9%). Für die Zyklen zwei, drei und sechs konnten die Neutropenie-Grade mit durchschnittlich weniger als einem Toxizitätsgrad Abweichung prognostiziert werden, die Leukopenie-Grade hingegen bis einschließlich Zyklus 6, die Thrombopenie-Grade sogar bis Zyklus 8. Somit unterschied sich die Vorhersagegenauigkeit für die verschiedenen hämatologischen Zelllinien. Die Übereinstimmung der Prognosen für die frühen Therapiezyklen (Zyklus 2 und 3) war für alle betrachteten Blutzelllinien und Therapie-Schemata ausgezeichnet. Bei den Prognosen für die späteren Therapiezyklen traten erwartungsgemäß größere Abweichungen zwischen den vorhergesagten und den klinisch beobachteten Toxizitätsgraden auf. Die Anwendung dieses biomathematischen Modells zur Vorhersage der individuellen hämatologischen Toxizität von Patienten mit gastrointestinalem Karzinom, die mit einem FLO(T)- oder FOLFIRINOX-Schema behandelt werden, führt selbst bei dieser heterogenen Population zu zuverlässigen Ergebnissen. Die Vorhersageleistung dieses Modells erwies sich für Kurzzeitprognosen als ausgezeichnet und für Langzeitprognosen als annehmbar. Der klinische Nutzen dieses präzisionsmedizinischen Ansatzes sollte in einer größeren prospektiven Kohorte weiter untersucht und validiert werden.

Made available in DSpace on 2015-03-04T18:50:20Z (GMT). No. of bitstreams: 1 Dissertacao_MiriaSCC.pdf: 3267159 bytes, checksum: f201a630eab8fd18b0da112537958c44 (MD5) Previous issue date: 2010-03-04 / Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior / AGUIA is a web application front-end originally developed to manage clinical, demographic and biomolecular patient data collected during gastrointestinal clinical trials at MD Anderson Cancer Center. The diversity of methodologies involved in patient screening and sample processing, brings corresponding heterogeneity of data types. Thus, this data must be based on a Resource Oriented Architecture that transforms heterogeneous data in semantic data, most specifically in RDF (Resource Description Framework). The database chosen was a S3DB, because it met the necessary requirements of transforming heterogeneous data from different sources in RDF, explicitly distinguishing the description of the domain from its instantiation, while allowing for continuous editing of both. Furthermore, it uses a REST protocol, and is open source and in the public domain which facilitates development and dissemination. Nevertheless, comprehensive and flexible a semantic web format may be, it does not by itself address the issue of representing content in a form that makes sense for domain experts. Accordingly, the goal of the work described here was to identify an additional set of descriptors that provide specifications for the graphic user interface. That goal was pursued by identifying a formalism that makes use of the RDF schema to enable automatic assembly of graphic user interfaces in a meaningful manner. A generalized RDF model was therefore defined such that changes in the graphic descriptors are automatically and immediately reflected into the configuration of the client web browser interface application, which is also made available with this report. Although the design patterns identified reflect, and benefit, from the specific requirements of interacting with data generated by clinical trials, the expectation is that they contain clues for a general purpose solution. In particular, it is suggested that the most useful patterns identified by the users of this system are susceptible to being reusable for other data sources, or at least for other clinical trial semantic web data stores. / AGUIA é uma aplicação web front-end, desenvolvida para gerenciar dados clínicos, demográficos e biomoleculares de pacientes coletados durante os ensaios clínicos gastrointestinais no MD Anderson Cancer Center. A diversidade de metodologias envolvidas na triagem de pacientes e no processamento da amostra traz uma heterogeneidade dos tipos de dados correspondentes. Sendo assim, estes devem ser baseados em uma arquitetura orientada a recurso que transforma dados heterogêneos em dados semânticos, mais especificamente em RDF (Resource Description Framework - Estrutura para a descrição de recursos). O banco de dados escolhido foi o S3DB, por este ter cumprido os requisitos necessários de transformação dos dados heterogêneos de diferentes fontes em RDF, distinguindo explicitamente a descrição do domínio e sua instanciação, permitindo simultaneamente a contínua edição de ambos. Além disso, ele usa um protocolo REST, e é de código aberto e domínio público o que facilita o desenvolvimento e divulgação. Contudo, por mais abrangente e flexível, um formato de web semântica pode por si só, não abordar a questão de representar o conteúdo de uma forma que faça sentido para especialistas do domínio. Assim, o objetivo do trabalho aqui descrito foi identificar um conjunto adicional de descritores que forneceu as especificações para a interface gráfica do usuário. Esse objetivo foi perseguido através da identificação de um formalismo que faz uso do esquema RDF para permitir a montagem automática de interfaces gráficas de uma forma significativa. Um modelo RDF generalizado foi, portanto, definido de tal forma que as mudanças nos descritores gráficos sejam automaticamente e imediatamente refletidas na configuração da aplicação web do cliente, que também está disponível neste trabalho. Embora os padrões de design identificados reflitam e beneficiem os requisitos específicos de interagir com os dados gerados pelos ensaios clínicos, a expectativa é que eles contenham pistas para uma solução de propósito geral. Em particular, sugere-se que os padrões mais úteis identificados pelos utilizadores deste sistema sejam suscetíveis de serem reutilizáveis para outras fontes de dados, ou pelo menos para outros bancos de dados semânticos de ensaios clínicos.