Lapatax: Safety profile of neoadjuvant lapatinib combined with docetaxel in Her 2/neu overexpressing breast cancer - EORTC protocol 10054

Objective: To assess the safety/tolerability of the combination lapatinib (L) and docetaxel (D) in patients with Her 2/neu overexpressing breast cancer (BC). This study is important as it will define how to deliver lapatinib with taxotere, a highly active drug in breast cancer. Patients and Methods: Female patients (pts) with locally advanced, inflammatory or large operable BC were treated with escalating doses of L from 1000 to 1250 mg/day, in combination with D given IV every 21 days at doses ranging from 75 to 100 mg/m2 for 4 cycles. At least 3 pts were treated at each dose level. The definition of dose limiting toxicity (DLT) is based on the toxicity assessed at cycle 1 as follows: any grade 3−4 non hematological toxicity, ANC < 0.5 G/L lasting for 7 days or more, febrile neutropenia or thrombocytopenia <25 G/L. GCSF was not permitted as primary prophylaxis. Core biopsies were mandatory at baseline and after cycle 4. Pharmcokinetic (PK) samples were collected on day 1 of cycles 1 and 2. Results: To date, 18 pts with a median age of 53 years (range 36−65) have been enrolled at 5 Dose Levels (DLs). The toxicity profile for 18 patients (68 documented cycles) is summarized below. At DL5 (1000/100), 2 pts had DLTs (neutropenia grade 4 _7 days and febrile neutropenia), and 3 additional pts were enrolled with primary prophylactic G-CSF. As expected, the safety profile improved and the dose escalation will continue with prophylactic G-CSF to investigate DL6 (1250/100). These findings are consistent with published Phase I data for this combination [1]. N= 18 patients n (%) Grade 1 Grade 2 Grade 3 Grade 4 neutropenia 1 (6) 3 (17) 13 (72) febrile neutropenia 2 (11) fatigue 8 (44) 7 (39) diarrhoea 9 (50) 3 (17) pain: joint/muscle/other 5 (28)/4 (22)/3 (17) 4 (22)/4 (22)/3 (17) 0/0/1 (6) constipation 2 (11) 3 (17) 1 (6) elevated transaminases SGPT/SGOT 7 (39)/5 (28) Conclusions: The main toxicity of the L + D combination is haematological and was reached at DL5 (1000/100), without primary GCSF. An additional DL6 with primary prophylactic GCSF is being investigated (1250/100). PK data will be presented at the meeting plus the recommended dose for phase II studies.

HBV or HCV coinfections and risk of myocardial infarction in HIV-infected individuals: the D:A:D Cohort Study.

BACKGROUND: Data on a link between HCV or HBV infection and the development of cardiovascular disease among HIV-negative and HIV-positive individuals are conflicting. We sought to investigate the association between HBV or HCV infection and myocardial infarction in HIV-infected individuals. METHODS: The prospective observational database of the D:A:D collaboration of 11 cohorts of HIV-infected individuals, including 212 clinics in Europe, the United States and Australia was used. Multivariate Poisson regression was used to assess the effect of HCV or HBV infection on the development of myocardial infarction after adjustment for potential confounders, including cardiovascular risk factors, diabetes mellitus and exposure to antiretroviral therapy. RESULTS: Of 33,347 individuals, 517 developed a myocardial infarction over 157,912 person-years, with an event rate of 3.3 events/1,000 person-years (95% confidence interval [CI] 3.0-3.6). Event rates (95% CIs) per 1,000 person-years in those who were HCV-seronegative and HCV-seropositive were 3.3 (3.0-3.7) and 2.7 (2.2-3.3), respectively, and for those who were HBV-seronegative, had inactive infection or had active infection were 3.2 (2.8-3.5), 4.2 (3.1-5.2) and 2.8 (1.8-3.9), respectively. After adjustment, there was no association between HCV seropositivity (rate ratio 0.86 [95% CI 0.62-1.19]), inactive HBV infection (rate ratio 1.07 [95% CI 0.79-1.43]) or active HBV infection (rate ratio 0.78 [95% CI 0.52-1.15]) and the development of myocardial infarction. CONCLUSIONS: We found no association between HBV or HCV coinfection and the development of myocardial infarction among HIV-infected individuals.

Comparison of 3D segmented gradient-echo and steady-state free precession coronary MRI sequences in patients with coronary artery disease.

OBJECTIVE: Our objective was to compare two state-of-the-art coronary MRI (CMRI) sequences with regard to image quality and diagnostic accuracy for the detection of coronary artery disease (CAD). SUBJECTS AND METHODS: Twenty patients with known CAD were examined with a navigator-gated and corrected free-breathing 3D segmented gradient-echo (turbo field-echo) CMRI sequence and a steady-state free precession sequence (balanced turbo field-echo). CMRI was performed in a transverse plane for the left coronary artery and a double-oblique plane for the right coronary artery system. Subjective image quality (1- to 4-point scale, with 1 indicating excellent quality) and objective image quality parameters were independently determined for both sequences. Sensitivity, specificity, and accuracy for the detection of significant (> or = 50% diameter) coronary artery stenoses were determined as defined in invasive catheter X-ray coronary angiography. RESULTS: Subjective image quality was superior for the balanced turbo field-echo approach (1.8 +/- 0.9 vs 2.3 +/- 1.0 for turbo field-echo; p < 0.001). Vessel sharpness, signal-to-noise ratio, and contrast-to-noise ratio were all superior for the balanced turbo field-echo approach (p < 0.01 for signal-to-noise ratio and contrast-to-noise ratio). Of the 103 segments, 18% of turbo field-echo segments and 9% of balanced turbo field-echo segments had to be excluded from disease evaluation because of insufficient image quality. Sensitivity, specificity, and accuracy for the detection of significant coronary artery stenoses in the evaluated segments were 92%, 67%, 85%, respectively, for turbo field-echo and 82%, 82%, 81%, respectively, for balanced turbo field-echo. CONCLUSION: Balanced turbo field-echo offers improved image quality with significantly fewer nondiagnostic segments when compared with turbo field-echo. For the detection of CAD, both sequences showed comparable accuracy for the visualized segments.

Granulocyte macrophage colony stimulating factor improves mucosal repair in a mouse model of acute colitis (P278)

Background and Aims: Granulocyte-macrophage colonystimulating factor (GM-CSF), a cytokine modulating the number and function of innate immune cells, has been shown to provide symptomatic benefit in some patients with Crohn's disease (CD). Since, it becomes widely appreciated that a timely and spatially regulated action of innate immune cells is critical for tissue regeneration, we tested whether GM-CSF therapy may favours intestinal mucosal repair in the acute mouse model of dextran sulfate sodium (DSS)-induced colitis. Methods: Mice treated with GM-CSF or saline were exposed for 7 days to DSS to induce colitis. On day 5, 7 and 10, mice were subjected to colonoscopy or sacrificed for evaluation of inflammatory reaction and mucosal healing. Results: GM-CSF therapy prevented body weight loss, diarrhea, dampened inflammatory reactions and ameliorated mucosal damages. Mucosal repair improvement in GM-CSF-treated mice was observed from day 7 on both by colonoscopy (ulceration score 1.2}0.3 (GM-CSF-treated) vs 3.1}0.5 (untreated), p = 0.01) and histological analysis (percentage of reepithelialized ulcers 55%}4% (GM-CSF-treated) vs 18%}13% (untreated), p = 0.01). GM-CSF therapy can still improve the colitis when hematopoietic, but not non-hematopoietic cells, are responsive to GM-CSF, as shown in WT→GM-CSFRKO chimeras. Lastly, we observed that GM-CSF-induced promotion of wound healing is associated with a modification of the cellular composition of DSS-induced colonic inflammatory infiltrate, characterized by the reduction of neutrophil numbers and early accumulation of CD11b+Gr1lo myeloid cells. Conclusion: Our study shows that GM-CSF therapy accelerates the complex program leading to tissue repair during acute colitis and suggests that GM-CSF promotion of mucosal repair might contribute to the symptomatic benefits of GM-CSF therapy observed in some CD patients.

Otimização da análise da atividade da redutase do nitrato e sua caracterização em folhas de cana-de-açúcar

O objetivo deste trabalho foi padronizar e caracterizar as condições para determinação da atividade da redutase do nitrato em tecido foliar de cana-de-açúcar, com uso do método in vivo. Amostras foliares foram coletadas de uma lavoura de primeira soqueira da cultivar IACSP 933046, com idade de seis meses. Foram estudadas diferentes condições de preparo das amostras foliares e do meio de incubação. O material que possibilitou a maior atividade da redutase do nitrato foi obtido pela amostragem de 25 discos de 1 cm de diâmetro, coletados às 13h, do centro da folha do tipo +1 sem nervura. O meio de incubação otimizado para a determinação da atividade dessa enzima em folhas de cana-de-açúcar deve ser composto por: 2,5 mL de KNO3 300 mmol L-1; 2,5 mL de tampão fosfato 285 mmol L-1 pH 7,3; 1,0 mL de Tween 20 a 0,6% (v/v); e 4,0 mL de água deionizada. A maior atividade da redutase do nitrato é obtida pela incubação das amostras por 90 min, a 32ºC, no escuro; é observada em plantas jovens formadas pela brotação da soqueira; e alcança o valor mínimo na fase de maturação das plantas.

Efeitos de modos de aplicação e concentrações de etefon na coloração da casa e outros atributos de qualidade do abacaxi 'Pérola'

As crescentes exigências do consumidor por uma aparência melhor do abacaxi 'Pérola' têm levado os produtores e intermediários a efetuarem aplicações do fitorregulador etefon sem o devido embasamento técnico-científico, com conseqüências negativas para os frutos e o material de plantio. Este trabalho visou a avaliar os efeitos de modos de aplicação e concentrações de etefon sobre a coloração da casca e outros aspectos externos e internos dos frutos de abacaxi 'Pérola', durante o armazenamento sob condições ambientais. Frutos verdosos foram colhidos e tratados em plantio comercial, em Itaberaba-BA, e, em seguida, armazenados e avaliados na Embrapa Mandioca e Fruticultura, Cruz das Almas-BA. Em delineamento inteiramente casualizado, com esquema fatorial 4 x 3 + 1 e número variável de repetições (cinco ou mais), foram estudadas quatro concentrações (500 mg L-1, 1.000 mg L-1, 2.000 mg L-1 e 4.000 mg L-1) de etefon, ácido 2-cloroetilfosfônico, diluído em água, além do tratamento-testemunha (0 mg L-1), e três formas de aplicação (pulverização com jato tipo 'filete' dirigido a um lado do fruto na pré-colheita, pulverização sobre os frutos colhidos e acondicionados aleatoriamente em balaios na pós-colheita, e imersão dos frutos, por dez segundos, depois de colhidos, sem atingir as coroas). Aos quatro, cinco, sete e onze dias após a colheita, foram avaliados a coloração e a firmeza da casca, bem como a coloração, firmeza, translucidez, teores de sólidos solúveis totais (SST), acidez (ATT) e a relação SST/ATT da polpa. O etefon acelerou o amarelecimento dos frutos, sem afetar a firmeza da casca e a qualidade interna dos frutos. A imersão determinou amarelecimento mais rápido e uniforme da casca dos frutos do que o observado para as demais formas de aplicação. Os resultados obtidos permitem recomendar a imersão rápida dos frutos de abacaxi 'Pérola', logo após a colheita, em soluções de etefon, nas concentrações de 500 a 2.000 mg L-1.

High hepatic and extrahepatic mortality and low treatment uptake in HCV-coinfected persons in the Swiss HIV cohort study between 2001 and 2013.

BACKGROUND & AIMS: The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS: We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS: Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS: Over the last 13years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

Avaliação morfométrica do tendão de Aquiles por ultra-sonografia

OBJETIVO: Determinar os valores normais dos diâmetros ântero-posterior e transversal do tendão de Aquiles na nossa população e correlacioná-los com sexo, faixa etária, cor da pele, grupo sanguíneo ABO e índice de massa corporal. MATERIAIS E MÉTODOS: Foi feita análise ultra-sonográfica de 100 tendões de Aquiles de 50 voluntários sadios, visando à mensuração dos diâmetros ântero-posterior e transversal desses tendões. Todos os exames foram realizados pelo mesmo examinador, em aparelho de ultra-sonografia com transdutor linear com freqüência de 10 MHz. RESULTADOS: Dos 50 voluntários estudados, 25 eram do sexo masculino e 25, do sexo feminino, com a faixa etária variando de 20 a 52 anos (média de 33,9 anos). O valor médio do diâmetro transversal do tendão de Aquiles foi de 13,3 ± 1,0 mm para o sexo feminino e 14,4 ± 1,4 mm para o sexo masculino; em relação ao diâmetro ântero-posterior, foi de 5,4 ± 0,5 mm para o sexo feminino e 5,6 ± 0,6 mm para o sexo masculino. Os diâmetros do tendão de Aquiles foram significativamente menores no sexo feminino (p < 0,05). Não houve diferença estatisticamente significativa entre os diâmetros ântero-posterior e transversal em relação a faixa etária, grupo sanguíneo e cor da pele. O grupo com índice de massa corporal de sobrepeso apresentou diâmetro transversal do tendão de Aquiles significativamente maior que do grupo com índice de massa corporal normal. CONCLUSÃO: Os valores médios encontrados na nossa casuística foram discordantes em relação à maioria dos estudos da literatura, demonstrando ser de grande importância a padronização e o emprego de tabelas próprias da nossa população na prática clínica diária.

A retrospective study of deep sternal wound infections: clinical and microbiological characteristics, treatment, and risk factors for complications.

Deep sternal wound infection (DSWI) is a feared complication following cardiac surgery. This study describes clinical, microbiological, and treatment outcomes of DSWI and determines risk factors for complications. Of 55 patients with DSWI, 66% were male and mean age was 68.2years. Initial sternotomy was for coronary artery bypass graft in 49% of patients. Sternal debridement at mean 25.4±18.3days showed monomicrobial (94%), mainly Gram-positive infection. Secondary sternal wound infection (SSWI) occurred in 31% of patients, was mostly polymicrobial (71%), and was predominantly due to Gram-negative bacilli. Risk factors for SSWI were at least 1 revision surgery (odds ratio [OR] 4.8 [95% confidence interval {CI} 1.0-22.4], P=0.047), sternal closure by muscle flap (OR 4.6 [1.3-16.8], P=0.02), delayed sternal closure (mean 27 versus 14days, P=0.03), and use of vacuum-assisted closure device (100% versus 58%, P=0.008). Hospital stay was significantly longer in patients with SSWI (69days versus 48days, P=0.04).

Same Performance Changes after Live High-Train Low in Normobaric vs. Hypobaric Hypoxia.

PURPOSE: We investigated the changes in physiological and performance parameters after a Live High-Train Low (LHTL) altitude camp in normobaric (NH) or hypobaric hypoxia (HH) to reproduce the actual training practices of endurance athletes using a crossover-designed study. METHODS: Well-trained triathletes (n = 16) were split into two groups and completed two 18-day LTHL camps during which they trained at 1100-1200 m and lived at 2250 m (P i O2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg) under NH (hypoxic chamber; FiO2 18.05 ± 0.03%) or HH (real altitude; barometric pressure 580.2 ± 2.9 mmHg) conditions. The subjects completed the NH and HH camps with a 1-year washout period. Measurements and protocol were identical for both phases of the crossover study. Oxygen saturation (S p O2) was constantly recorded nightly. P i O2 and training loads were matched daily. Blood samples and VO2max were measured before (Pre-) and 1 day after (Post-1) LHTL. A 3-km running-test was performed near sea level before and 1, 7, and 21 days after training camps. RESULTS: Total hypoxic exposure was lower for NH than for HH during LHTL (230 vs. 310 h; P < 0.001). Nocturnal S p O2 was higher in NH than in HH (92.4 ± 1.2 vs. 91.3 ± 1.0%, P < 0.001). VO2max increased to the same extent for NH and HH (4.9 ± 5.6 vs. 3.2 ± 5.1%). No difference was found in hematological parameters. The 3-km run time was significantly faster in both conditions 21 days after LHTL (4.5 ± 5.0 vs. 6.2 ± 6.4% for NH and HH), and no difference between conditions was found at any time. CONCLUSION: Increases in VO2max and performance enhancement were similar between NH and HH conditions.

Uptake and factors that influence the use of ‘sit less, move more’ occupational intervention strategies in Spanish office employees

Background Little is known about the types of ‘sit less, move more’ strategies that appeal to office employees, or what factors influence their use. This study assessed the uptake of strategies in Spanish university office employees engaged in an intervention, and those factors that enabled or limited strategy uptake. Methods The study used a mixed method design. Semi-structured interviews were conducted with academics and administrators (n = 12; 44 ± 12 mean SD age; 6 women) at three points across the five-month intervention, and data used to identify factors that influenced the uptake of strategies. Employees who finished the intervention then completed a survey rating (n = 88; 42 ± 8 mean SD age; 51 women) the extent to which strategies were used [never (1) to usually (4)]; additional survey items (generated from interviewee data) rated the impact of factors that enabled or limited strategy uptake [no influence (1) to very strong influence (4)]. Survey score distributions and averages were calculated and findings triangulated with interview data. Results Relative to baseline, 67% of the sample increased step counts post intervention (n = 59); 60% decreased occupational sitting (n = 53). ‘Active work tasks’ and ‘increases in walking intensity’ were the strategies most frequently used by employees (89% and 94% sometimes or usually utilised these strategies); ‘walk-talk meetings’ and ‘lunchtime walking groups’ were the least used (80% and 96% hardly ever or never utilised these strategies). ‘Sitting time and step count logging’ was the most important enabler of behaviour change (mean survey score of 3.1 ± 0.8); interviewees highlighted the motivational value of being able to view logged data through visual graphics in a dedicated website, and gain feedback on progress against set goals. ‘Screen based work’ (mean survey score of 3.2 ± 0.8) was the most significant barrier limiting the uptake of strategies. Inherent time pressures and cultural norms that dictated sedentary work practices limited the adoption of ‘walk-talk meetings’ and ‘lunch time walking groups’. Conclusions The findings provide practical insights into which strategies and influences practitioners need to target to maximise the impact of ‘sit less, move more’ occupational intervention strategies.

Elaboração e validação de escala diagramática para quantificação da severidade de entomosporiose em folhas de pereira

A entomosporiose, causada pelo fungo Entomosporium mespili, é uma das principais doenças da pereira (Pyrus sp.) no Brasil. Considerando-se a inexistência de métodos padronizados para quantificação dessa doença em folhas, o objetivo deste trabalho foi desenvolver uma escala diagramática para quantificação da severidade da entomosporiose da pereira. Para padronizar a avaliação, foi desenvolvida uma escala diagramática logarítmica com sete níveis (0,3; 1,0; 2,3; 5,1; 11,1; 22,4 e 40,0 % de área foliar lesionada). Para a validação da escala, nove avaliadores estimaram a severidade de 60 imagens digitalizadas de folhas, com diferentes níveis de severidade. As avaliações foram feitas em duas etapas: sem e com o auxílio da escala. A severidade real foi obtida através do programa Quant v.1.0. A acurácia e a precisão dos avaliadores foram determinadas por regressão linear simples entre a severidade real e a estimada. A escala proposta proporcionou bons níveis de acurácia e precisão, boa repetibilidade das estimativas, além de rapidez e facilidade na avaliação, constituindo-se em uma ferramenta útil em estudos epidemiológicos e no desenvolvimento de estratégias de controle da entomosporiose da pereira.

Prevalência e fatores associados à anemia em gestantes da região semi-árida do Estado de Alagoas

OBJETIVO: determinar a prevalência e fatores de risco associados à anemia em gestantes da região semi-árida de Alagoas. MÉTODOS: estudo de caráter transversal envolvendo amostra (n=150) obtida, considerando a prevalência estimada pela Organização Mundial da Saúde de 52%, com erro de 8% e intervalo de confiança de 95%. O processo de amostragem foi realizado em três estágios: 15 dentre os 38 municípios da região, quatro setores censitários por município e 24 domicílios por setor. Nestes, eram elegíveis todas as gestantes residentes, das quais se coletaram dados socioeconômicos, demográficos, antropométricos e de saúde. A anemia foi identificada por um nível de hemoglobina <11 g/dL e sua associação com os fatores de risco foi testada por meio de análise de regressão linear múltipla. RESULTADOS: a prevalência de anemia foi de 50%. Setenta e oito por cento das gestantes estavam sob acompanhamento pré-natal. Destas, 79,3% se encontravam no segundo ou terceiro trimestre de gestação. Contudo, apenas 21,2% faziam uso de suplemento de ferro. As variáveis associadas (p<0,05) de forma independente à anemia (gestantes anêmicas versus não anêmicas) foram: maior número de membros na família (4,5±2,3 versus 4,3±2,3; p=0,02), menor faixa etária da gestante (23,9±6,3 versus 24,7±6,7; p=0,04), bem como de seu companheiro (34,5±15,8 versus 36±17,5; p=0,03), não possuir vaso sanitário em casa (30,7 versus 24%; p<0,001), história de perda de filho por abortamento e/ou mortalidade (32,4 versus 16,4%; p<0,001), residência em zona rural (60 versus 46,7%; p=0,03), renda per capita

Volume de líquido amniótico e os desfechos maternos em gestantes com ruptura prematura das membranas pré-termo

OBJETIVO: Analisar entre pacientes com ruptura prematura de membranas pré-termo a associação do volume do líquido amniótico e os desfechos maternos.MÉTODOS: Estudo observacional do tipo coorte retrospectivo, realizado entre janeiro de 2008 e dezembro de 2012. Foram incluídas 86 gestantes com diagnóstico de ruptura prematura das membranas e idade gestacional entre a 24ªe a 35ª semanas, submetidas à mensuração do índice de líquido amniótico (ILA). Foram comparadas gestantes em dois pontos de cortes: com ILA <5,0 e ≥5,0 cm e ILA <3,0 e ≥3,0 cm. Foram excluídas mulheres com síndromes hipertensivas,diabetes mellitus, malformações fetais e com diagnóstico de infecção na admissão. Para análise estatística, foi utilizado o teste do χ2 ou exato de Fisher, quando pertinentes, e análise de regressão linear simples, adotando-se um nível de significância de 5%. Foi calculada a Razão de Risco (RR) e seu intervalo de confiança de 95% (IC95%).RESULTADOS: Quando avaliados os desfechos maternos em relação ao ILA ≥5,0 versus<5,0 cm, não foram encontradas diferenças estatisticamente significativas. Entretanto, em relação ao ILA <3,0 e ≥3,0 cm, foi verificado aumento do risco de corioamnionite (36,7 versus10,7%; RR: 3,4; IC95% 1,4 -8,3; p=0,004), não sendo observadas diferenças significativas para as outras variáveis estudadas. Houve ainda correlação positiva estatisticamente significativa entre o ILA e idade gestacional do parto (R2=0,78; p<0,0001).CONCLUSÕES: O ILA <3,0 cm aumenta em três vezes o risco para corioamnionite, e quanto maior o ILA, maior a idade gestacional do parto.