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.

(in English): The subject of my dissertation is the decision of the subjects to participate in the early phase of clinical trial. The aim of this disseration is to detect and understand the ethical aspects of decision making of subjects with oncological diseases to participate in the early phase of clinical trial. In the theoretical part of my dissertation, I define the field of clinical research, describe the phases of clinical research and ethical codes important for clinical research. The current ethical dilemmas related to the participation of subjects in the early phase of clinical trial, which are being discussed by the professional public, are presented. The research part contains the results of interviews with seventeen respondents whose content correlates with the aim of the research part and it is to understand the decision- making of subjects to participate in the early phase of clinical trial in terms of subjectively constructed realities, which are different for individual respondents. The results of the research show that fourteen respondents identified one of the most important aspects of the decision-making to participate in the early phase of clinical trial of the recommendation of principal investigator and trust in a physician. Twelve respondents stated the most frequent reason...

(in English): The subject of my dissertation is the decision of the subjects to participate in the early phase of clinical trial. The aim of this disseration is to detect and understand the ethical aspects of decision making of subjects with oncological diseases to participate in the early phase of clinical trial. In the theoretical part of my dissertation, I define the field of clinical research, describe the phases of clinical research and ethical codes important for clinical research. The current ethical dilemmas related to the participation of subjects in the early phase of clinical trial, which are being discussed by the professional public, are presented. The research part contains the results of interviews with seventeen respondents whose content correlates with the aim of the research part and it is to understand the decision- making of subjects to participate in the early phase of clinical trial in terms of subjectively constructed realities, which are different for individual respondents. The results of the research show that fourteen respondents identified one of the most important aspects of the decision-making to participate in the early phase of clinical trial of the recommendation of principal investigator and trust in a physician. Twelve respondents stated the most frequent reason...

[pt] A probabilidade de alarme falso, alfa, dos gráficos de controle de processos depende dos seus limites de controle, que, por sua vez, dependem de estimativas dos parâmetros do processo. Esta tese apresenta inicialmente uma revisão dos principais trabalhos sobre o efeito dos erros de estimação dos parâmetros do processo sobre alfa quando se utiliza o gráfico de X e S individualmente e em conjunto. O desempenho dos gráficos é medido através de medidas de desempenho (número médio de amostras até o sinal, taxa de alarme falso, distribuição do número de amostras até o sinal, que, em geral, são variáveis aleatórias, função dos erros de estimação. Pesquisas recentes têm focado nas propriedades da distribuição condicional do número de amostras até o sinal, ou ainda, nas propriedades da distribuição da taxa de alarme-falso condicional. Esta tese adota esta abordagem condicional e analisa o efeito da estimação dos parâmetros do processo no desempenho conjunto dos gráficos de X e S em dois casos: Caso KU (Média conhecida – Variância desconhecida) e Caso UU (Média desconhecida – Variância desconhecida). A quase totalidade dos trabalhos anteriores considerou apenas um gráfico, isoladamente; sobre efeito da estimação dos parâmetros sobre o desempenho conjunto conhecemos apenas um trabalho, sobre gráficos de X e R, mas nenhum sobre gráficos de X e S. Os resultados da análise mostram que o desempenho dos gráficos pode ser muito afetado pela estimação de parâmetros e que o número de amostras iniciais requerido para garantir um desempenho desejado é muito maior que os números tradicionalmente recomendados na literatura normativa de controle estatístico de processo (livros texto e manuais). Esse número é, porém, menor que o máximo entre os números requeridos para os gráficos de X e de S individualmente. Questões a serem investigadas como desdobramento dessa pesquisa são também indicadas nas Considerações Finais e Recomendações. / [en] The false-alarm rate of control charts, alpha, depends on the control limits calculated, which depend, in turn, on the estimated process parameters. This dissertation initially presents a review of the main research articles about the effect of the estimation errors of the process parameters upon alpha when X and S charts are used separately and together. The charts performance is evaluated through performance measures (average run-length, false-alarm rate, run-length distribution, etc), which are, in general, random variables, function of the estimation errors. Recent researches focused on the properties of the conditional run-length, or still (in the case of Shewhart charts) on the properties of the conditional false-alarm rate distribution. This dissertation adopts this conditional approach and investigates the effect of parameter estimation on the joint behavior of X and S charts in two cases: KU Case (Known mean – Unknown variance) and UU Case (Unknown mean - Unknown variance). Almost all previous works considered just only one chart separately – just only one joint performance work is known by the author, one about the effect of the estimation errors of the process parameters upon X e R joint performance. The results show that the charts performance can be severely affected by the parameter estimation and the number of initial samples required to ensure the desirable performance is greater than the numbers of initial samples recommended by traditional statistical process control reference texts (books and manuals). This number is, however, smaller than the maximum between the numbers of samples required by the X and the S charts separately. Additional issues for follow-up research are recommended in the concluding section.

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