Bei fortgeschrittenen rektosigmoidalen Karzinomen sollte grundsätzlich die chirurgische Resektion angestrebt werden. Es gibt allerdings zahlreiche der zumeist alten Patienten, die einer solchen Therapieform nicht zugeführt werden können (Inoperabilität, Ablehnung der Operation). Für diese Patienten stellt die palliative, endoskopische Lasertherapie nach wie vor eine effiziente Alternative dar. Im Rahmen einer prospektiven Untersuchung von 61 Patienten wurde über einen 3jährigen Beobachtungszeitraum der Einfluß der palliativen Therapie mit dem Neodym:YAG-Laser auf die Symptomatologie fortgeschrittener rektosigmoidaler Tumore analysiert. Die Ergebnisse bestätigten den auch in anderen Studiengruppen beschriebenen Kurzzeiteffekt (Behandlungsdauer bis zu 3 Monaten), wonach die tumorbedingte Darmokklusion durch den Laser beherrscht werden kann und damit die Anlage eines Anus praeter vermieden wird. Besonderes Augenmerk wurde auf 32 Patienten gelegt, die längerfristig behandelt wurden, da bezüglich eines Langzeiteffekts in der Literatur kaum Angaben zu finden sind. Behandlungs-dauer: min. 3,5, max. 16,8 Monate. Tumorlokalisation: Rektum und rektosigmoidaler Übergang. Die Ergebnisse der ersten 3 Behandlungsmonate (statistisch signifikanter Rückgang für abdominale Beschwerden und peranale Blutungen) lassen sich nicht fortsetzen, aber es wird eine Art "steady state" erreicht. Die wichtigste Zielgröße der Therapie, die Sicherung der Darmpassage, konnte bei dieser Patientengruppe in 87,5 % erreicht werden. Die methodenbedingte Komplikationsrate liegt bei 6,3 %; die therapiebedingte Letalität beträgt 0 %. Problematisch ist der Anteil von Patienten mit Stuhlinkontinenz, der im Verlauf der Therapie von 6,2 % auf 40,6 % drastisch anstieg. Dennoch sahen nahezu 90 % der Patienten ihre Lebensqualität erhalten, da es sich meist um Inkontinenz I. oder II. Grades handelt, was von der Mehrzahl der Patienten angesichts ihrer Lebenssituation toleriert wird. Somit stellt die endoskopische Lasertherapie auch unter dem Aspekt der Langzeitpalliation die Behandlung der Wahl dar. Im Vergleich mit der palliativen Anlage eines Anus praeter besitzt der Laser trotz Wieder-holungsbehandlungen deutliche Vorteile: die Therapie ist ambulant durchführbar, kostengünstiger, komplikationsärmer und führt zur besseren Symptombeeinflussung. / The symptomatology of advanced rectosigmoid carcinomas by palliative therapy with the Neodymium:YAG-laser. In principle surgical resection should be aspired to in advanced rectosigmoid carcinomas. Nevertheless, there are numerous, mostly older patients, who cannot receive such a therapy (inoperability, refusal of operation). For those patients palliative, endoscopical lasertherapy is still an efficient alternative. The influence of the palliative therapy with the Nd:YAG-laser on the symptomatology of advanced rectosigmoid tumours was investigated in a prospective study of 61 patients over a 3-year period. The results also confirm the short-term effect reported by other study groups (duration of treatment up to 3 months) that occlusion of the colon can be controlled by laser-therapy and thereby the application of a colostomy may be avoided. Special attention was given to 32 patients treated for a longer duration, since reference in the medical literature relating to long-term effects of lasertherapy are rarely to be found. Duration of treatment: 3,5 to 16,8 months. Tumour location: rectum and rectosigmoid. The results of lasertherapy during the first 3 months (statistically significant reduction of abdominal symptoms and bleeding) cannot continue but it can be achieve a steady state. The maintenance of luminal patency as the most important aim of therapy in these group of patients was achieved in 87,5 %. The rate of method-related complication was 6,3 %; the treatment-related mortality was 0 %. Problematic is the increase in fecal incontinence from 6,2 % to 40,6 % seen in the patient group during the therapy. However nearly 90 % of the patients did not report significant reduction in life quality, since most fecal incontinence can be classified as first or second degree, which is tolerated by the patients in their current life situation. Consequently, the endoscopical laser-therapy is the treatment of choice also under the aspect of long-term palliation. The laser has clear advantages in comparison with the palliative colostomy in spite of the need for repeated applications: possibility of outpatient treatment, cost-effectiveness, low complication rate and better influence on symptomatology.

Submitted by Claudio Meilman Ferreira (claudio.meilman@gmail.com) on 2017-01-05T15:53:53Z No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) / Approved for entry into archive by ÁUREA CORRÊA DA FONSECA CORRÊA DA FONSECA (aurea.fonseca@fgv.br) on 2017-01-06T13:51:55Z (GMT) No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) / Made available in DSpace on 2017-01-17T12:18:01Z (GMT). No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) Previous issue date: 2016-12-06 / The impact of economic incentives on healthier eating is unclear, particularly in the long-term (i.e., after the intervention period). This research assessed the short- and long-term effectiveness of a private nutrition company’s promotion initiative in school cafeterias in Belo Horizonte, Brazil. Two hundred and eight children and adolescents from 3 schools participated in a short-lived, lottery-based incentives program contingent on the purchase of locally promoted healthy products. One hundred and forty-four children and adolescents from a fourth comparable school served as controls. A multilevel model compared the average number of promoted healthy products purchased daily per participant before (26 weekdays), during (9 weekdays), and after (28 weekdays) the intervention period. The results indicate a clear short-term effect. The incentives program significantly increased the purchase of promoted healthy products during (vs. before) the intervention period in the treated schools, specially among girls and younger children. On average, no long-term effect was observed. The purchase of the promoted healthy products returned to pre-intervention levels immediately after the removal of the incentives program. Interestingly, a detailed analysis revealed a rather heterogeneous long-term effect based on past consumption behavior. The incentive promoted a positive long-term effect on the children who had never consumed the incentivized healthier products prior to the intervention, whereas a negative long-term effect was noted for the already habitual consumers of the targeted healthier products. Past consumption behavior must be taken into consideration for a complete understanding of the long-term effects of incentives on healthier eating. / O impacto de incentivos econômicos sobre a alimentação saudável não é claro, particularmente no longo prazo (ou seja, após o período da intervenção). Esta pesquisa avaliou a eficácia de curto e longo prazo de uma iniciativa de promoção de uma empresa de nutrição privada em cantinas escolares em Belo Horizonte, Brasil. Duzentas e oito crianças e adolescentes de três escolas participaram de um programa de incentivos de curta duração baseado em um sorteio, condicionado à compra de produtos saudáveis promovidos localmente. Cento e quarenta e quatro crianças e adolescentes de uma quarta escola comparável serviram como controles. Um modelo multinível comparou o número médio de produtos saudáveis promovidos adquiridos diariamente por participante antes (26 dias úteis), durante (9 dias úteis) e após (28 dias úteis) o período da intervenção. Os resultados indicam um efeito claro de curto prazo. O programa de incentivos aumentou significativamente a compra de produtos saudáveis promovidos durante o período da intervenção (vs. antes) nas escolas tratadas, especialmente entre as meninas e crianças mais novas. Em média, nenhum efeito de longo prazo foi observado. A compra dos produtos saudáveis promovidos retornou aos níveis pré-intervenção imediatamente após a remoção do programa de incentivos. Curiosamente, uma análise detalhada revelou um efeito bastante heterogêneo de longo prazo baseado no comportamento prévio de consumo dos indivíduos. O incentivo promoveu um efeito positivo de longo prazo sobre as crianças que nunca haviam consumido os produtos promovidos e saudáveis antes da intervenção, ao passo que um efeito negativo de longo prazo foi observado para os consumidores já habituais dos produtos mais saudáveis visados. O comportamento do consumo passado deve ser levado em consideração para uma melhor compreensão dos efeitos de longo prazo de incentivos sobre uma alimentação mais saudável.

Les données de la littérature concernant la tolérance à long terme du traitement par hormone de croissance (GH) recombinante sont très réduites. L’objectif du travail rapporté dans cette thèse porte sur l’analyse de la morbidité chez 6874 patients de l’étude SAGhE traités en France dans le cadre d’un déficit idiopathique en GH ou d’une petite taille constitutionnelle, avec les 3 axes de travail suivants : Risque neurovasculaire : Utilisant des données de référence issues de 2 registres de population, nous avons montré une augmentation du risque d’accident vasculaire cérébral (SIR à 3.5 ou 4.4 selon le registre considéré), et plus particulièrement d’hémorragies sous-arachnoïdiennes (SIR 5.7 ou 6.3). Risque de diabète : Utilisant les prescriptions d’antidiabétiques fournies par le SNIIRAM au sein de notre cohorte, nous n’avons pas mis en évidence d’augmentation de la prévalence du diabète traité (SPR 1.0). Risque de cancer : En comparaison au registre de référence du réseau FRANCIM, il n’y a pas de différence significative dans le risque de survenue d’un cancer (SIR 0.7). En revanche, le risque de développer une tumeur osseuse est 3.5 fois plus élevé chez les sujets exposés à l’hormone de croissance dans l’enfance. Les évènements ont été identifiés à partir de trois sources : a) RNIPP et CépiDC pour la connaissance du statut vital et les causes de décès si le sujet est décédé, b) Questionnaire de santé envoyé aux sujets non décédés, c) Données SNIIRAM à partir d’une extraction spécifique basée sur les identifiants des sujets de notre cohorte, permettant d’obtenir les codes CIM-10 des déclarations d’Affection Longue Durée, les codages PMSI entre 2008 et 2010 correspondant aux hospitalisations, et les prescriptions d’antidiabétiques. / The literature is scarce regarding the long term effect of synthetic growth hormone (GH) treatment. The objective of this thesis was to analyse the morbidity of 6874 patients from the French SAGhE study treated by GH for short stature, focusing on three themes: Neurovascular risk: Using two population-based registries, we showed an increase in the risk of stroke (SIR 3.5 to 4.4 according the registry used), more specifically for the subarachnoid hemorrhage (SIR 5.7 or 6.3). Risk of diabetes : Using the antidiabetic drugs deliveries obtained from the French national health insurance database, no difference in the risk of treated diabetes was found (SPR 1.0). Risk of cancer : Compared with the French population-based registries of cancer, no significant difference in the risk of cancer was found (SIR 0.7), but the excess risk for bone tumor is 3.5 . Events were identified from three sources : a) Information on vital status collected from the Répertoire National d’Identification des Personnes Physiques and cause of death as indicated on death certificate, b) Health questionnaire sent to all living patients, c) Data extracted from the French national health insurance information, including the French hospital discharge database, also called Programme de Médicalisation des Systèmes d’Information from 2008 to December 2010, long-lasting affection statements, and antidiabetics drugs deliveries.

Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM. The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling. The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes. This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.