Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

BACKGROUND: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. METHODS: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. FINDINGS: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. INTERPRETATION: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. FUNDING: Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

Rugosidade da superfície de um Cambissolo Húmico relacionada com o preparo e compactação do solo sob chuva natural

A rugosidade superficial do solo é uma característica importante, pois influencia a infiltração e a armazenagem de água no solo, a retenção de sedimentos na superfície e a erosão hídrica. Por sua vez, a rugosidade é influenciada pelo preparo, umidade e compactação do solo, pelos resíduos culturais, pelo efeito residual do uso do solo e pela erosividade da chuva. Este trabalho teve o objetivo de quantificar o efeito do tipo de preparo, da compactação do solo e da erosividade da chuva sobre o índice de rugosidade superficial ao acaso modificado (RRM), em um experimento conduzido sob chuva natural em um Cambissolo Húmico Alumínico léptico, com declividade média de 0,03 m m-1, entre setembro e novembro de 2008, em Lages, SC, com os seguintes tratamentos: (1) superfície quase lisa em solo compactado (LIC); (2) superfície quase lisa em solo não compactado (LINC); (3) uma aração e duas gradagens em solo compactado (PCC); (4) uma aração e duas gradagens em solo não compactado (PCNC); (5) uma escarificação em solo compactado (ESC); e (6) uma escarificação em solo não compactado (ESNC). O microrrelevo do solo foi medido com rugosímetro mecânico de varetas, em seis oportunidades: imediatamente antes e imediatamente após instalar os tratamentos; e após a ocorrência de cada um dos valores de erosividade (EI30) da chuva: 136, 190, 630 e 265 MJ mm ha-1 h-1. O preparo do solo com aração e gradagens e com escarificação aumentou o índice RRM em relação a antes do preparo, tanto em solo não compactado quanto em solo compactado. O aumento desse índice foi de 3,72 vezes em aração e gradagens e de 3,88 vezes na escarificação, na média do solo compactado e não compactado. A compactação do solo aumentou o índice RRM, independentemente do tipo de preparo. No caso da aração e gradagens, o aumento nesse índice foi de 4,58 vezes no solo compactado e de 3,04 vezes no não compactado, logo após o preparo; em se tratando da escarificação, em solo compactado o aumento pelo preparo foi de 5,49 vezes e de 2,61 vezes no solo não compactado, também logo após o preparo. A erosividade da chuva diminuiu o índice RRM, independentemente do tipo de preparo e da compactação do solo, cuja relação foi descrita pelo modelo y = ae-bx.

Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study.

OBJECTIVE: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX. METHODS: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX). RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points. CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort.

Poison without antidote for the historical Socrates and french classical tragedy in El verí del teatre (The Poison of the Theatre) by Rodolf Sirera. (An extreme dose of sadism to put a stop to the excesses of theatrical fiction).

Socrates' serene attitude before his death -although this is questioned-, as described by Xenophon in his Apologia Socratis becomes for the playwright Rodolf Sirera a useful reference in an effort to reflect boldly on the limits of theatrical fiction in another clear example of the Classical Tradition, including that derived from Baroque Tragedy. However, in this case, it is judged severely to make us more conscious of the risk of turning life into a mere theatrical performance and human beings into actors and actresses in a play they did not write.

Verí sense antídot per al Sòcrates històric i la tragèdia barroca al Verí del teatre de Rodolf Sirera. (Una dosi extrema de sadisme per aturar els excessos de la ficció teatral).

Socrates' serene attitude before his death -although this is questioned-, as described by Xenophon in his Apologia Socratis becomes for the playwright Rodolf Sirera a useful reference in an effort to reflect boldly on the limits of theatrical fiction in another clear example of the Classical Tradition, including that derived from Baroque Tragedy. However, in this case, it is judged severely to make us more conscious of the risk of turning life into a mere theatrical performance and human beings into actors and actresses in a play they did not write.

Nuclear and cytoplasmic triiodothyronine-binding sites in primary sensory neurons and Schwann cells: radioautographic study during development.

The effects of the thyroid hormones on target cells are mediated through nuclear T3 receptors. In the peripheral nervous system, nuclear T3 receptors were previously detected with the monoclonal antibody 2B3 mAb in all the primary sensory neurons throughout neuronal life and in peripheral glia at the perinatal period only (Eur. J. Neurosci. 5, 319, 1993). To determine whether these nuclear T3 receptors correspond to functional ones able to bind T3, cryostat sections and in vitro cell cultures of dorsal root ganglion (DRG) or sciatic nerve were incubated with 0.1 nM [125I]-labeled T3, either alone to visualize the total T3-binding sites or added with a 10(3) fold excess of unlabeled T3 to estimate the part due to the non-specific T3-binding. After glutaraldehyde fixation, radioautography showed that the specific T3-binding sites were largely prevalent. The T3-binding capacity of peripheral glia in DRG and sciatic nerve was restricted to the perinatal period in vivo and to Schwann cells cultured in vitro. In all the primary sensory neurons, specific T3-binding sites were disclosed in foetal as well as adult rats. The detection of the T3-binding sites in the nucleus indicated that the nuclear T3 receptors are functional. Moreover the concomitant presence of both T3-binding sites and T3 receptors alpha isoforms in the perikaryon of DRG neurons infers that: 1) [125I]-labeled T3 can be retained on the T3-binding 'E' domain of nascent alpha 1 isoform molecules newly-synthesized on the perikaryal ribosomes; 2) the alpha isoforms translocated to the nucleus are modified by posttranslational changes and finally recognized by 2B3 mAb as nuclear T3 receptor. In conclusion, the radioautographic visualization of the T3-binding sites in peripheral neurons and glia confirms that the nuclear T3 receptors are functional and contributes to clarify the discordant intracellular localization provided by the immunocytochemical detection of nuclear T3 receptors and T3 receptor alpha isoforms.

Evaluating appropriateness of treatment for Crohn's disease : feasibility of an explicit approach

Résumé Dans la maladie de Crohn, le clinicien ne dispose pas toujours d'études prospectives randomisées ou autres preuves solides sur lesquelles appuyer sa décision thérapeutique. Pour pallier ce manque, la méthode RAND, qui combine une revue détaillée de la littérature et une synthèse méthodique de l'opinion d'experts, a été utilisée pour développer des critères détaillés d'adéquation de traitements pour les différentes présentations cliniques de la maladie de Crohn. La présente étude a eu pour but d'examiner la faisabilité d'une utilisation rétrospective de ces critères dans une cohorte de patients souffrant de maladie de Crohn. Les dossiers médicaux des patients ayant consulté leur spécialiste au moins une fois dans les 6 mois précédents ont été revus à la recherche des éléments établis par les experts. Pour les dossiers contenant tous les éléments nécessaires, l'adéquation des divers traitements a été évaluée. Les dossiers médicaux de 260 patients suivis par 22 gastro-entérologues ont été examinés. 116 patients ont été exclus pour absence de consultation dans les 6 mois précédents. 136 patients (53%) représentant 148 consultations ont été retenus. Dans plus de 90% des cas, les éléments nécessaires à l'évaluation de l'adéquation du traitement étaient disponibles, cette proportion variant quelque peu selon la catégorie de la maladie. En appliquant les critères lorsque les éléments nécessaires étaient présents dans le dossier médical, 18% des indications aux traitements étaient appropriées, 29% inappropriées et pour 38% l'indication était incertaine. Pour 15% des cas, la situation clinique rencontrée n'avait pas été explicitement évaluée par les experts. Les informations nécessaires à l'évaluation des indications aux divers traitements de la maladie de Crohn sont disponibles dans la très grande majorité des dossiers médicaux, permettant ainsi l'évaluation de l'adéquation des traitements. Cette étude ouvre la voie à l'utilisation prospective de ces critères.

Le dictionnaire bilingue peut-il s'intégrer profitablement dans une stratégie d'apprentissage d'une langue étrangère ?

Lors de l'apprentissage d'une langue étrangère, l'apprenant ne s'interroge guère sur la légitimité d'appréhender la langue cible via sa langue maternelle. En témoignent l'achat et l'utilisation rarement questionnés du dictionnaire bilingue. Pourtant, sur le long terme, ces pratiques sont loin d'être exemptes d'écueils. Cet article examinera quelques-uns des inconvénients d'une telle stratégie d'apprentissage.

Dynamic, auxin-responsive plasma membrane-to-nucleus movement of Arabidopsis BRX.

In Arabidopsis, interplay between nuclear auxin perception and trans-cellular polar auxin transport determines the transcriptional auxin response. In brevis radix (brx) mutants, this response is impaired, probably indirectly because of disturbed crosstalk between the auxin and brassinosteroid pathways. Here we provide evidence that BRX protein is plasma membrane-associated, but translocates to the nucleus upon auxin treatment to modulate cellular growth, possibly in conjunction with NGATHA class B3 domain-type transcription factors. Application of the polar auxin transport inhibitor naphthalene phthalamic acid (NPA) resulted in increased BRX abundance at the plasma membrane. Thus, nuclear translocation of BRX could depend on cellular auxin concentration or on auxin flux. Supporting this idea, NPA treatment of wild-type roots phenocopied the brx root meristem phenotype. Moreover, BRX is constitutively turned over by the proteasome pathway in the nucleus. However, a stabilized C-terminal BRX fragment significantly rescued the brx root growth phenotype and triggered a hypocotyl gain-of-function phenotype, similar to strong overexpressors of full length BRX. Therefore, although BRX activity is required in the nucleus, excess activity interferes with normal development. Finally, similar to the PIN-FORMED 1 (PIN1) auxin efflux carrier, BRX is polarly localized in vascular cells and subject to endocytic recycling. Expression of BRX under control of the PIN1 promoter fully rescued the brx short root phenotype, suggesting that the two genes act in the same tissues. Collectively, our results suggest that BRX might provide a contextual readout to synchronize cellular growth with the auxin concentration gradient across the root tip.

ESTIMATIVA DA EROSIVIDADE DE CHUVAS NO ESTADO DO PARANÁ PELO MÉTODO DA PLUVIOMETRIA: ATUALIZAÇÃO COM DADOS DE 1986 A 2008

Três estimativas de erosividade de chuvas no Estado do Paraná foram feitas nas décadas de 1980-90, mas nenhuma outra depois. Os objetivos deste trabalho foram atualizar, numa quarta estimativa, as informações de erosividade anual das chuvas para o Paraná, com dados pluviométricos de 1986 a 2008; e gerar informações de erosividade mensal para identificar a distribuição temporal da erosividade. Foram utilizados os métodos pluviográfico e pluviométrico de determinação de erosividade. O primeiro serviu para revalidar equações prévias de correlação entre erosividade por pluviografia e por pluviometria, isso feito em três localidades; já o segundo, para calcular o coeficiente de chuva em 114 localidades, utilizando-se dados de precipitação média mensal e anual, e então a erosividade, com as equações de correlação revalidadas. Mapas de erosividade anual e mensal foram gerados por interpolações geoestatísticas. A erosividade variou entre 5.449 e 12.581 MJ mm ha-1 h-1 ano-1 e aumentou no sentido oeste, a partir da região metropolitana de Curitiba; e no sentido sul, a partir do noroeste paranaense. Isso resultou em maiores erosividades nas regiões centro-sul (Guarapuava), centro-ocidental (Campo Mourão), oeste (Cascavel) e, principalmente, sudoeste (Pato Branco). Também houve incremento de erosividade a partir da região metropolitana de Curitiba, no sentido leste, indicando o litoral como outra região crítica em termos de erosividade. A maior erosividade mensal ocorreu em janeiro (média estadual de 1394 MJ mm ha-1 h-1 mês-1), seguida por tendência de diminuição até agosto (331 MJ mm ha-1 h-1 mês-1), quando então tornou a aumentar. Porém, ocorrem dois importantes repiques de erosividade: um em maio e outro em outubro (843 e 1.173 MJ mm ha-1 h-1 mês-1, respectivamente), principalmente nas regiões sudoeste e oeste. Esses repiques coincidem com períodos de implantação de culturas de inverno ou de verão nessas regiões. Em relação à última estimativa de erosividade anual, feita em 1993, houve aumento da área delimitada pela linha isoerodente de 11.000 MJ mm ha-1 h-1 ano-1 nas regiões sudoeste e oeste e um deslocamento das linhas isoerodentes de 7.000 e 8.000 MJ mm ha-1 h-1 ano-1 para o sentido leste nas regiões norte pioneiro, centro-oriental e sudeste, sugerindo elevação da erosividade nessas regiões. Tais alterações de erosividade podem estar associadas às eventuais mudanças no clima da região, mas também ao simples fato de este estudo estar considerando maior quantidade de dados em relação aos estudos anteriores. Concluiu-se que as equações de correlação determinadas entre os métodos pluviográfico e pluviométrico, obtidas para o Paraná em trabalhos anteriores, continuam válidas; os meses críticos quanto à erosividade são janeiro, maio e outubro; e as menores erosividades ocorrem nas regiões noroeste e metropolitana do Estado.