My MSc thesis is focused on parametric designs of Phase I clinical trials, using the continual reassessment method. A parametric model with unknown parameters is assumed. The observations are either toxic or nontoxic. Observations of toxicities are used to update the posterior distribution. Dose selection for the next patient is based on the estimated toxicity probability. The objective is to identify the maximum tolerated dose to be used in Phase II clinical trials. We introduce a new class of parametric functions for the continual reassessment method. This class is formed with the cumulative distribution function of the normal distribution. The major advantage is that we can choose different normal distributions to model different toxicity probability functions. We conduct simulation studies and compare our new design with the existing parametric designs, and have found that our design performs better by choosing the appropriate values of the mean and variance. / October 2016

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

No description available.

Escalonamento com controle de overdose (EWOC-PH, escalation with overdose control proporcional hazards) é um método bayesiano com controle de overdose que estima a dose máxima tolerada (MTD, maximum tolerated dose) assumindo que o tempo que um paciente leva para apresentar toxicidade segue o modelo de riscos proporcionais. Neste trabalho analisamos quais são as consequências em adotarmos um método que se baseia no modelo de riscos proporcionais quando o tempo até toxicidade segue o modelo de chances de sobrevivência proporcionais. A fim de buscar responder se teríamos uma superestimativa ou uma subestimativa da MTD foram feitas simulações em que consideramos dados de chances de sobrevivência proporcionais e aplicação do método EWOC-PH para analisarmos a MTD. Como uma extensão do método EWOC-PH, propomos o método EWOC-POS que assume que os tempos seguem o modelo de chances de sobrevivência proporcionais. / Escalation with overdose control proportional hazards is a Bayesian method with overdose control that estimates the maximum tolerated dose (MTD) assuming that the time a patient takes to show toxicity follows the proportional hazards model. In this work, we analyse the consequences of adopting a method based on the proportional hazard model when the time until toxicity follows the proportional survival model. In order to seek to answer if we would have an overestimate or an underestimate of MTD, simulations were performed in which we considered proportional odds survival data and application of the EWOC-PH method. As an extension of the EWOC-PH method, we propose the EWOC-POS method which assumes that time until toxicity follows the proportional odds survival model.

No description available.

The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.

SLÁMA, Michal. Total Socio-tolerant Drugs in the Youth - Social and Societal Implications. [Thesis] / Michal Sláma - Prague: Charles University, Hussite Theological Faculty, Department of Psychosocial science and Ethics. 2018. p. 129. Advisor of thesis: PhDr. Monika Nová, Ph.D. - Degree of professional qualification: Magister. - Praha: HTF, 2018. 128 p. The thesis is divided into a theoretical and a practical part. The topic of the diploma thesis is all-society tolerated drugs an their impact on youth - social and societal implications. In the theoretical basis of the thesis, we focus on the definition of the concepts of the all-society tolerated drugs and its division, the use of drugs, the emergence of addictionc and the treatment of an addiction. We identify the concept of the socio-economic and social impacts of drug use among youth, as a consequence of their consequences for the somatic health and the social environment of man. The implications and consequences of the use of all-human drugs in youth are also addressed in the empirical part of the thesis. In order to meet the objectives and tasks of the research, the quantitative research method is used in the practical part of the thesis, using the information obtained from anonymous respondents who were young people within a defined...

Introduction : La perfusion pulmonaire isolée (PPI) est une technique expérimentale dont l’objectif est d’administrer de fortes doses de chimiothérapie dans le poumon sans effets secondaires systémiques. Cette thèse s’est déroulée en trois étapes : première étape, déterminer in vitro la chimiothérapie la plus efficace en 30 minutes sur les cellules de cancers colo-rectaux (CCR). Deuxième étape, mettre au point la technique de PPI chez le porc. Troisième étape, mener une étude d’escalade de dose de chimiothérapie chez le porc en PPI.Méthodes : Première étape, des tests de cytotoxicité in vitro ont été menés sur un panel de cellules d’adénocarcinome colique humain avec les drogues de chimiothérapie les plus efficaces dans les essais cliniques. Deuxième étape, des porcs étaient traités par perfusion de chimiothérapie dans le poumon gauche isolé de la circulation générale pendant 30 minutes puis maintenus en vie pendant un mois. Troisième étape, les doses de chimiothérapie injectés étaient augmentées par palier jusqu’à obtenir une toxicité aigüe ou le décès des animaux.Résultats : La gemcitabine (GEM) fut la drogue ayant la plus grande efficacité anti-tumorale pour un traitement de 30 min. La PPI de GEM permit d’obtenir des concentrations élevées de GEM dans le parenchyme pulmonaire et la survie des animaux pendant un mois. Il n’existait pas de fuites systémiques de GEM. L’augmentation des doses de GEM permis de déterminer la dose maximale toxique à 320 mg et la toxicité limitant la dose à 640 mg. Conclusions : La technique de PPI avec la GEM est une technique sûre et reproductible permettant d’obtenir de fortes concentrations de GEM dans le parenchyme pulmonaire. / Introduction: The isolated lung perfusion (ILP) is an experimental technique which main objective is to deliver high dose of cytotoxic agent to the lung tissue without systemic exposure. The thesis took place in three stages: first stage, setting in vitro the chemotherapy the most efficient against colorectal cancer (CCR) cells in 30 min. Second stage, develop the ILP technique in a pig model. Third stage, lead a dose escalation study with chemotherapy by ILP.Methods: First stage, efficacy of various cytotoxic molecules against a panel of human CCR cell lines was tested in vitro after a 30-minute exposure. Second stage, pigs were treated with chemotherapy delivered by ILP during 30 minutes and kept alive during a month. Third stage, chemotherapy doses were increase in order to obtain acute toxicity or death of animals.Results: Gemcitabine (GEM) was the most efficient drug against CCR cells in 30 minutes. ILP with GEM permit to maintain high concentration in the lung parenchyma and pigs survival during one month. No systemic leaks were detected. Dose increase of GEM conduct to determine the maximal tolerated dose of GEM by ILP to 320 mg. Conclusions: ILP with GEM is a safety and reproducible technique allowing high GEM concentrations in the lung tissue.

Diese Arbeit, die auf persönlichen Erfahrungen als Asylbewerber in Deutschland basiert, fokussiert sich auf die sozioökonomische Integration von schwarzafrikanischen Asylbewerber:innen, d.h. mit einer Aufenthaltserlaubnis nach § 55 des deutschen Asylgesetzes, und von geduldeten Migrant:innen, d.h. mit einem Duldungsstatus nach § 60a des deutschen Aufenthaltsgesetzes. Die Arbeit untersucht ihre Teilnahme an deutschen Integrationskursen und ihren Zugang zu Arbeitserlaubnissen in den sechzehn Bundesländern, die von der Ausländerbehörde und der Bundesagentur für Arbeit streng kontrolliert werden. Die Ergebnisse zeigen, dass die Personen einer wirtschaftlichen Tätigkeit nachgehen, um ihren Lebensunterhalt in Deutschland zu bestreiten als auch um Familienangehörige in ihren Heimatländern zu unterstützen. Methodisch bedient sich die Arbeit eines Methodenmix, der ethno-soziogeographische Instrumente zur Datenerhebung, -verarbeitung und -analyse einsetzt. Zwischen 2016 und Juni 2021 wurden zwanzig Einzelfallstudien, dreihundert halbstrukturierte Fragebögen, sechs Fokusgruppendiskussionen mit der Zielgruppe und deutschen Beamten des Gerichts und der Ausländerbehörde sowie zwei Experteninterviews mit Abgeordneten deutscher Parlamente durchgeführt. Zu den aufgedeckten wirtschaftlichen Aktivitäten gehören der Drogenhandel, das Ausliefern von Zeitungen, informeller Streetfood-Verkauf, Friseurhandwerk, der Handel und das Testen auf Corona. Da informelle (illegale, halblegale und kriminelle) Wirtschaftspraktiken als Einstieg in den Arbeitsmarkt und als Reaktion auf die begrenzten Möglichkeiten der deutschen Behörden häufig genutzt werden, schließt die Arbeit mit der Aufforderung an die politischen Entscheidungsträger, den derzeitigen sozioökonomischen Integrationsrahmen für diese beiden Kategorien von Migrant:innen in Deutschland dringend zu überdenken. / This thesis, based on personal experience as an asylum seeker in Germany, focuses on the socio-economic integration of Black African asylum seekers, i.e. with a residence permission § 55 of the German Asylum Act, as well as tolerated migrants, i.e. with a toleration status § 60a German Residence Act. The thesis sheds light on their participation in German integration courses and their access to work permits across the sixteen German states, which are subject to strict regulations by the Foreigner Registration Office and the Federal Office of Work. The findings reveal that individuals engage in economic activities to financially sustain themselves within the territory and also to support family members in their home countries. Methodically, the thesis employs mixed methods, utilizing ethno-sociogeographical tools for data acquisition, processing, and analysis. Between 2016 and June 2021, the thesis conducted twenty individual case studies, three hundred semi-structured questionnaires, two expert interviews with members of German parliaments, six focus group discussions with the target group and German officials from the court, the Foreigner registration office. The economic activities uncovered include drug dealing, newspaper delivery, informal street food selling, hairdressing, trading, and COVID-19 testing. As there is a massive use of informal economic practices (illegal, semi-legal, and criminal) as entry point to the job market and as a response to limited opportunities provided by the German authorities, the thesis concludes with a call to policymakers to urgently reconsider the current socio-economic integration framework for this two categories of migrants in Germany.

No / PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.