Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era:an analysis based on data from the European Blood and Marrow Transplantation Registry

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

YSOVAR: Mid-infrared Variability in the Star-forming Region Lynds 1688

The emission from young stellar objects (YSOs) in the mid-infrared (mid-IR) is dominated by the inner rim of their circumstellar disks. We present IR data from the Young Stellar Object VARiability (YSOVAR) survey of ~800 objects in the direction of the Lynds 1688 (L1688) star-forming region over four visibility windows spanning 1.6 yr using the Spitzer Space Telescope in its warm mission phase. Among all light curves, 57 sources are cluster members identified based on their spectral energy distribution and X-ray emission. Almost all cluster members show significant variability. The amplitude of the variability is larger in more embedded YSOs. Ten out of 57 cluster members have periodic variations in the light curves with periods typically between three and seven days, but even for those sources, significant variability in addition to the periodic signal can be seen. No period is stable over 1.6 yr. Nonperiodic light curves often still show a preferred timescale of variability that is longer for more embedded sources. About half of all sources exhibit redder colors in a fainter state. This is compatible with time-variable absorption toward the YSO. The other half becomes bluer when fainter. These colors can only be explained with significant changes in the structure of the inner disk. No relation between mid-IR variability and stellar effective temperature or X-ray spectrum is found.

A matemática e o comércio em Portugal através das obras de aritméticos do século XVI: Gaspar Nicolas, Ruy Mendes e Bento Fernandes

Esta dissertação tem como objetivo a divulgação de temas e de algoritmos presentes nos tratados de aritmética prática do século XVI. Pretendemos delinear a atuação dos seus autores face aos desafios do mundo mercantil envolvente. Sendo o nosso «ator principal» Ruy Mendes, esta escolha deve-se a dois motivos: entre os três autores é aquele que tem sido menos mencionado e estudado; os interesses de Mendes parecem-nos mais distantes do mundo mercantil. Assim, no desenrolar deste estudo apresentaremos a Prática do ponto de vista da estrutura e organização, contemplando os seguintes pontos: uma Matemática básica; a Matemática pour elle Même; uma Matemática para o comércio. Neste último ponto incluiremos as regras locais do comércio português: a regra de quarto e vintena e a regra da conta de Flandres. Para cada assunto é realizado um estudo comparativo com os dois tratados da mesma época: o Tratado da Pratica d'Arismetica de Gaspar Nicolas e o Tratado da Arte d'Arismetica de Bento Fernandes. Apesar de se tratar de autores já referidos por alguns historiadores, consideramos que não foram ainda estudados do ponto de vista do interesse intrínseco presente no conhecimento histórico da Matemática, bem como na sua atuação relativamente à divulgação do cálculo aritmético e do seu contributo para o desenvolvimento da Matemática através de problemas práticos.

Charles e Ray Eames, o casamento entre razão e emoção no design

O racionalismo surge como uma corrente filosófica, cuja operação mental e lógica é evidenciada. Sendo a principal característica do pensamento moderno o método, a bauhaus representa para o design a forma como a indústria se despiu dos ornamentos, buscando o ideal de forma e função. Numa corrente contemporânea, o design emocional retoma, além das funções que um objeto pode ter, estéticas, práticas e simbólicas, também as emocionais de identificação, fazendo rever os métodos. Este artigo faz uma relação deste contexto com a forma brilhante com que o casal Charles e Ray Eames, criou um método absolutamente emocional para a criação do design, iniciando, com a invenção do contraplacado, e depois com acesso a diversas tecnologias advindas do pós-guerra, um processo muito interessante de construção de design, aliando arte e técnica, produzindo assentos atemporais, encontrados facilmente no mundo contemporâneo.

La Réforme industrielle ou le Phalanstère : journal proposant la fondation d'une phalange, réunion de 1100 personnes associées en travaux de culture, fabrique et ménage / [dir. Charles Fourier]

1832/06/01 (T1,N1)-1834/02/28 (T2,N39).

La Réforme industrielle ou le Phalanstère : journal proposant la fondation d'une phalange, réunion de 1100 personnes associées en travaux de culture, fabrique et ménage / [dir. Charles Fourier]

Périodicité : Hebdomadaire (1832-16 août 1833) ; mensuel (sept. 1833-1834)

Revue historique de la Révolution française / dir. Charles Vellay

1913 (A4,T4,N13)- (A4,T4,N16).

Revue historique de la Révolution française / dir. Charles Vellay

1914/01 (A5,T5,N17)-1914/06 (A5,T5,N18).

Revue historique de la Révolution française / dir. Charles Vellay

1915/07 (A6,T8,N23)-1915/12 (A6,T8,N24).

Revue historique de la Révolution française / dir. Charles Vellay

1917/01 (A8,T11,N29)-1917/06 (A8,T11,N30).

Revue historique de la Révolution française / dir. Charles Vellay

1918 (A9,T13,N33)- (A9,T13,N36).