Bortezomib(Velcade (R))-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation.

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35.

How to screen for problematic cannabis use in population surveys: an evaluation of the Cannabis Use Disorders Identification Test (CUDIT) in a Swiss sample of adolescents and young adults.

BACKGROUND/AIMS: Cannabis use is a growing challenge for public health, calling for adequate instruments to identify problematic consumption patterns. The Cannabis Use Disorders Identification Test (CUDIT) is a 10-item questionnaire used for screening cannabis abuse and dependency. The present study evaluated that screening instrument. METHODS: In a representative population sample of 5,025 Swiss adolescents and young adults, 593 current cannabis users replied to the CUDIT. Internal consistency was examined by means of Cronbach's alpha and confirmatory factor analysis. In addition, the CUDIT was compared to accepted concepts of problematic cannabis use (e.g. using cannabis and driving). ROC analyses were used to test the CUDIT's discriminative ability and to determine an appropriate cut-off. RESULTS: Two items ('injuries' and 'hours being stoned') had loadings below 0.5 on the unidimensional construct and correlated lower than 0.4 with the total CUDIT score. All concepts of problematic cannabis use were related to CUDIT scores. An ideal cut-off between six and eight points was found. CONCLUSIONS: Although the CUDIT seems to be a promising instrument to identify problematic cannabis use, there is a need to revise some of its items.

Strategies for improving outcomes in NSCLC: a look to the future.

Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to recruit patients on the basis of tumour biology rather than clinical characteristics. However, identification of predictive biomarkers is required to maximise the benefits of new approaches and expedite the drug development process. Nevertheless, the NSCLC landscape is changing rapidly, and recent improvements in our understanding of the molecular biology of the disease will help in the identification of novel targeted agents as well as assisting in the development of personalised strategies for the numerous small subsets of defined NSCLC. Progress in imaging and treatment delivery is also likely to improve outcomes for patients with the disease. This article outlines recent progress in the treatment of NSCLC, identifies current challenges and describes proposals for improving the future management of the disease. It is hoped that implementation of some of these strategies will go some way to improving the outlook for patients with NSCLC.

L'agression de la victime, une modalité de gestion de la conflictualité psychique et de restauration d'une continuité interne

Cet article interroge les fonctions psychologiques que peuvent occuper les victimes dans l'économie psychique de l'auteur d'une agression, dans le cadre de la commission de certaines infractions à caractère sexuel et violent. Nous montrerons que chez des sujets pour lesquels la dynamique psychique de l'acte renvoie à un mouvement défensif contre des angoisses majeures sur le plan identitaire et objectal, le recours à la victime dans l'acte d'agression assurerait une fonction de continuité interne face à la discontinuité identitaire.

Erosão hídrica em um Nitossolo Háplico submetido a diferentes sistemas de manejo sob chuva simulada. II - Perdas de nutrientes e carbono orgânico

Com a erosão hídrica, há o transporte de nutrientes para fora das lavouras e, com isso, pode ocorrer o empobrecimento dos solos e a contaminação do ambiente fora do local da erosão. Utilizando um simulador de chuvas de braços rotativos, foram aplicadas, no campo, três chuvas simuladas no cultivo do milho e três no de feijão, com intensidade constante de 64 mm h-1 e energia cinética de 0,2083 MJ ha-1 mm-1 , no Planalto Sul Catarinense, entre março de 2001 e abril de 2003, para avaliar as perdas de nutrientes e carbono orgânico (CO) pela erosão hídrica sobre os seguintes tratamentos de manejo do solo, em duas repetições: solo sem cultivo com uma aração + duas gradagens (SSC); cultivos de milho e feijão com uma aração + duas gradagens sobre resíduos dessecados (PCO); cultivos de milho e feijão em semeadura direta sobre resíduos dessecados em solo previamente preparado (SDI); cultivos de milho e feijão em semeadura direta sobre resíduos dessecados em solo nunca preparado (SDD), cultivos de milho e feijão em semeadura direta sobre resíduos queimados em solo nunca preparado (SDQ); e solo sem cultivo com campo nativo melhorado (CNM). Utilizou-se um Nitossolo Háplico alumínico argiloso, com inclinação média do terreno de 0,165 m m-1. As concentrações dos nutrientes e do CO nos sedimentos transportados por erosão foram maiores nos preparos conservacionistas do que nos convencionais, enquanto as perdas totais comportaram-se de maneira inversa. Na água da enxurrada, as concentrações e as perdas de NH4+ e NO3- diminuíram do cultivo do milho para o do feijão, enquanto as de P aumentaram. No caso do K, ocorreu redução da concentração e aumento das perdas. As taxas de empobrecimento do solo situaram-se, em geral, próximas de um para os nutrientes e para o CO. As concentrações dos nutrientes e do CO nos sedimentos transportados correlacionaram-se, linear e positivamente, com a composição química da camada de 0-0,025 m de profundidade do solo de onde o sedimento foi removido.

Link between genotype and antimicrobial resistance in bovine mastitis-related Staphylococcus aureus strains, determined by comparing Swiss and French isolates from the Rhône Valley.

Staphylococcus aureus is a major bovine mastitis pathogen. Although the reported antimicrobial resistance was generally low, the emergence of new genetic clusters in bovine mastitis requires examination of the link between antimicrobial resistance and genotypes. Here, amplified fragment length polymorphism (AFLP) profiles and standard antimicrobial resistance profiles were determined in order to characterize a total of 343 S. aureus cow mastitis isolates from two geographically close regions of Switzerland and France. AFLP profiles revealed similar population compositions in the two regions, with 4 major clusters (C8, C20, C97, and C151), but the proportions of isolates in each cluster significantly diverged between the two countries (P = 9.2 × 10⁻⁹). Antimicrobial resistance was overall low (< 5% resistance to all therapeutically relevant molecules), with the exception of penicillin resistance, which was detected in 26% of the isolates. Penicillin resistance proportions differed between clusters, with only 1 to 2% of resistance associated with C20 and C151 and up to 70% associated with bovine C97. The prevalence of C20 and C8 was unexpectedly high and requires further investigation into the mechanism of adaptation to the bovine host. The strong association of penicillin resistance with few clusters highlights the fact that the knowledge of local epidemiology is essential for rational choices of antimicrobial treatment in the absence of susceptibility testing. Taken together, these observations argue in favor of more routine scrutiny of antimicrobial resistance and antibiotic-resistant clones in cattle and the farm environment.

Variação na temperatura do solo em três sistemas de manejo na cultura do feijão

A temperatura do solo é uma propriedade que afeta diretamente o crescimento das plantas e é influenciada pelo balanço de energia na superfície do solo. Dessa maneira, os sistemas de manejo do solo têm efeito na temperatura, visto que alteram as condições da superfície do solo. O objetivo deste estudo foi determinar o efeito de três sistemas de manejo na temperatura do solo durante todo o ciclo do feijoeiro. O delineamento experimental foi de blocos ao acaso, com os seguintes preparos do solo: plantio direto há sete anos (PD); plantio direto revolvido por uma aração e uma gradagem (PDar) e plantio direto revolvido por escarificador (PDesc), distribuídos em quatro blocos. O solo do experimento é classificado como Argissolo Vermelho-Amarelo distrófico arênico. A temperatura do solo foi determinada durante todo o ciclo do feijoeiro, realizando-se leituras a cada 10 min, em um sistema automatizado de coleta de dados, com sensores do tipo termopar (cobre-constantan), instalados na profundidade de 0,025 m e a 0,10 m. Foram determinadas a densidade do solo e a produtividade do feijoeiro. Durante todo o ciclo do feijoeiro, o PD apresentou a menor temperatura máxima e a menor amplitude diária entre os sistemas de manejo. Na profundidade de 0,025 m, o PDar apresentou temperatura máxima de 42,2 °C, o PDesc de 43,7 °C e o PD de 36,1 °C. A variação diária da temperatura do solo num dia com 12 h de sol, no início do desenvolvimento das plantas (02/12/2002), indicou que a maior temperatura ocorreu próximo às 15 h, com valores de 40 ºC, no PDar, e 30 ºC, no PD, na profundidade de 0,025 m. Quando as plantas sombreavam o solo, não houve diferenças na temperatura do solo entre os sistemas de manejo. As diferenças na temperatura do solo não provocaram diferenças na produtividade de grãos do feijoeiro, haja vista que os maiores efeitos da temperatura do solo ocorrem na germinação e emergência das plântulas.

Carga máxima de fósforo admissível ao reservatório Piraquara II, uma aplicação do processo TMDL

Para implementação e operacionalização da política brasileira de recursos hídricos, é imprescindível o uso de ferramentas de planejamento que considerem o efeito de todas as atividades ou processos que causam ou contribuem para a degradação da qualidade de um corpo d'água. Neste sentido, aplicou-se o processo TMDL (total maximum daily load), desenvolvido pela Agência de Proteção Ambiental dos Estados Unidos (EPA), para o P, na área de drenagem de contribuição ao futuro reservatório Piraquara II, bacia hidrográfica do rio Piraquara, Paraná. O processo TMDL determina a quantidade máxima de cargas de um poluente que um corpo d'água pode receber sem violar os padrões estabelecidos de qualidade da água e aloca cargas deste poluente entre fontes de poluição pontuais e difusas. No presente estudo, utilizou-se o método TMDL, com o objetivo de demonstrar ser ele uma ferramenta útil no processo de gestão dos recursos hídricos. Simularam-se cenários de uso do solo, por meio de modelagem matemática, até obter-se uma concentração de P total no reservatório abaixo da faixa limite para ocorrência de eutrofização, de 0,025 a 0,10 mg L-1, estabelecida no estudo. Realizou-se uma simulação de uso atual do solo, visando prever a condição inicial de qualidade da água no corpo d'água, na qual a concentração de P total no reservatório resultante não atendeu ao padrão estabelecido. Procedeu-se a uma segunda simulação com adoção das medidas de controle, recomposição de mata ciliar e plantio direto, para reduzir a exportação de carga de P total da bacia. Obteve-se uma melhoria na qualidade da água do reservatório, indicando que as medidas adotadas foram suficientes para atingir o padrão estabelecido, o que demonstra a aplicabilidade do método.

Cristallochemical characterization of synthetic Zn-substituted maghemites (g-Fe2-xZn xO3)

Maghemite (g-Fe2O3) is the most usually found ferrimagnetic oxide in red basalt-derived soils. The variable degrees of ionic substitution of Fe3+ for different metals (e.g. Ti4+, Al3+, Mg2+, Zn2+, and Mn2+) and non-metals in the maghemite structure influence some cristallochemical features of this iron oxide. In this study, synthetic Zn-substituted maghemites were prepared by co-precipitation in alkaline aqueous media of FeSO4.7H2O with increasing amounts of ZnSO4.7H2O to obtain the following sequence of Fe3+ for Zn2+ substitutions: 0.0, 0.025, 0.05, 0.10, 0.15, 0.20, and 0.30 mol mol-1. The objective of this work was to evaluate the cristallochemical alterations of synthetic Zn-substituted maghemites. The dark black synthetic precipitated material was heated to 250 °C during 4 h forming a brownish maghemite that was characterized by chemical analysis as well as X ray diffraction (XRD), specific surface area and mass-specific magnetic susceptibility. The isomorphic substitution levels observed were of 0.0013, 0.0297, 0.0590, 0.1145, 0.1764, 0.2292 and 0.3404 mol mol-1, with the formation of a series of maghemites from Fe2Zn0O3 to Fe(1.49)Zn(0.770)O3 . The increase in Fe3+ for Zn2+ substitution, [Zn mol mol-1] increased the dimension a0 of the cubic unit cells of the studied maghemites according to the regression equation: a0 = 0.8343 + 0.02591Zn (R² = 0.98). On the other hand, the mean crystallite dimension and mass-specific magnetic susceptibility of the studied maghemites decreased with increasing isomorphic substitution.