Inactivation of V79 cells by low-energy protons, deuterons and helium-3 ions

Previous work by ourselves and by others has demonstrated that protons with a linear energy transfer (LET) about 30 V mu m(-1) are more effective at killing cells than doubly charged particles of the same LET. In this work we show that by using deuterons, which have about twice the range of protons with the same LET, it is possible to extend measurements of the RBE of singly charged particles to higher LET (up to 50 keV mu m(-1)). We report the design and use of a new arrangement for irradiating V79 mammalian cells. Cell survival. measurements have been made using protons in the energy range 1.0-3.7 MeV, deuterons in the energy range 0.9-3.4 MeV and He-3(2+) ions in the energy range 3.4-6.9 MeV;. This corresponds to volume-averaged LET (within the cell nucleus) between 10 and 28 keV mu m(-1) for protons, 18-50 keV mu m(-1) for deuterons, and 59-106 keV mu m(-1) for helium ions. Our results show no difference in the effectiveness of protons and deuterons matched for LET. However, for LET above about 30 keV mu m(-1) singly charged particles are more effective at inactivating cells than doubly-charged particles of the same LET and that this difference can be understood in terms of the radial dose distribution around the primary ion track.

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Oxidized and/or glycated low-density lipoprotein (LDL) may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 microg/ml native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor-kappaB (NF-kappaB) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO(-)) formation, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-kappaB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kappaB activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO(-) formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of superoxide dismutase 1 expression. Taken together, these results demonstrate pro-inflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.

Impact of geometric variations on delivered dose in highly focused single vocal cord IMRT

Purpose. To investigate the robustness of single vocal cord intensity modulated radiation therapy (IMRT) treatment plans for set-up errors, respiration, and deformation. Material and methods. Four-dimensional computed tomography (4D-CT) scans of 10 early glottic carcinoma patients, previously treated with conventional techniques, were used in this simulation study. For each patient a pre-treatment 4D-CT was used for IMRT planning, generating a reference dose distribution. Prescribed PTV dose was 66 Gy. The impact of systematic set-up errors was simulated by applying shifts of ± 2 mm to the planning CT scans, followed by dose re-calculation with original beam segments, MUs, etc. Effects of respiration and deformation were determined utilizing extreme inhale and exhale CT scans, and repeat scans acquired after 22 Gy, 44 Gy, and 66 Gy, respectively. All doses were calculated using Monte Carlo dose simulations. Results. Considering all investigated geometrical perturbations, reductions in the clinical target volume (CTV) V95%, D98%, D2%, and generalized equivalent uniform dose (gEUD) were limited to 1.2 ± 2.2%, 2.4 ± 2.9%, 0.2 ± 1.8%, and 0.6 ± 1.1 Gy, respectively. The near minimum dose, D98%, was always higher than 89%, and gEUD always remained higher than 66 Gy. Planned contra-lateral (CL) vocal cord DMean, gEUD, and V40 Gy were 38.2 ± 6.0 Gy, 43.4 ± 5.6 Gy, and 42.7 ± 14.9%. With perturbations these values changed by -0.1 ± 4.3 Gy, 0.1 ± 4.0 Gy, and -1.0 ± 9.6%, respectively. Conclusions. On average, CTV dose reductions due to geometrical perturbations were very low, and sparing of the CL vocal cord was maintained. In a few observations (6 of 103 simulated situations), the near-minimum CTV-dose was around 90%, requiring attention in deciding on a future clinical protocol. 

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)

Increasing Fruit and Vegetable Intake Has No Dose-Response Effect on Conventional Cardiovascular Risk Factors in Overweight Adults at High Risk of Developing Cardiovascular Disease

BACKGROUND: Improving diet and lifestyle is important for prevention of cardiovascular disease (CVD). Observational evidence suggests that increasing fruit and vegetable (FV) consumption may lower CVD risk, largely through modulation of established risk factors, but intervention data are required to fully elucidate the mechanisms by which FVs exert benefits on vascular health.

OBJECTIVE: The aim of this study was to examine the dose-response effect of FV intake on cardiovascular risk factors in adults at high CVD risk.

METHODS: This was a randomized controlled parallel group study involving overweight adults (BMI: >27 and ≤35 kg/m(2)) with a habitually low FV intake (≤160 g/d) and a high total risk of developing CVD (estimated ≥20% over 10 y). After a 4-wk run-in period where FV intake was limited to <2 portions/d (<160 g/d), 92 eligible participants were randomly assigned to 1 of 3 groups: to consume either 2, 4, or 7 portions (equivalent to 160 g, 320 g, or 560 g, respectively) of FVs daily for 12 consecutive weeks. Fasting venous blood samples were collected at baseline (week 4) and post-intervention (week 16) for analysis of lipid fractions and high-sensitivity C-reactive protein (hsCRP) concentrations. Compliance with the FV intervention was determined with use of self-reported FV intake and biomarkers of micronutrient status. Ambulatory blood pressure and body composition were also measured pre- and post-intervention.

RESULTS: A total of 89 participants completed the study and body composition remained stable throughout the intervention period. Despite good compliance with the intervention, no significant difference was found between the FV groups for change in measures of ambulatory blood pressure, plasma lipids, or hsCRP concentrations.

CONCLUSIONS: There was no evidence of a dose-response effect of FV intake on conventional CVD risk factors measured in overweight adults at high CVD risk. This trial was registered at clinicaltrials.gov as NCT00874341.

Investigating the Implications of a Variable RBE on Proton Dose Fractionation Across a Clinical Pencil Beam Scanned Spread-Out Bragg Peak

Purpose: To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited.

Methods and Materials: Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfraction period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism.

Results: Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens.

Conclusions: The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.

Modelação da qualidade do ar e da saúde humana: da mesoescala à dose

O actual, e crescente, padrão de consumo tem repercussões no ambiente que, inevitavelmente, se reflectem na saúde humana. A poluição atmosférica assume-se, na Europa, como um problema ambiental premente, por ter um elevado impacte na saúde dos cidadãos. Entre estes, há grupos particularmente vulneráveis, como os idosos, os doentes crónicos e as crianças. Vários estudos colocam em evidência a sensibilidade dos doentes asmáticos, em particular das crianças, à poluição atmosférica. No entanto, permanece por esclarecer o facto de a poluição atmosférica poder causar o aumento da prevalência desta doença, assim como a identificação dos principais poluentes atmosféricos responsáveis e os níveis de exposição seguros. O objectivo desta tese consiste no estudo da relação entre a poluição atmosférica e a saúde, contribuindo para o conhecimento nesta temática através do desenvolvimento de uma ferramenta e da sua aplicação a um caso de estudo concreto. Neste caso de estudo analisou-se a relação entre vários poluentes atmosféricos e o agravamento da sintomatologia em crianças asmáticas. Neste âmbito, foi desenvolvido o modelo doseAr, que possibilita o cálculo da exposição e da dose inalada, ao nível individual, de poluentes atmosféricos. Os resultados da aplicação do doseAr permitem a identificação dos microambientes onde a contribuição para a exposição e dose inalada de poluentes é mais relevante. Os microambientes interiores, em particular aqueles onde é desenvolvida actividade física exigente, são identificados como especialmente importantes. A relação entre a exposição e a dose inalada é claramente associada ao agravamento da asma nestas crianças, apesar dos níveis de poluição identificados serem baixos, face aos padrões de qualidade do ar existentes.

Estudo de otimização de imagem e dose em mamografia digital

O objetivo deste trabalho foi efetuar um estudo de otimização dos parâmetros de exposição do mamógrafo digital da marca GE, modelo Senographe DS instalado no Instituto Português de Oncologia de Coimbra (IPOC) baseado numa análise contraste detalhe e avaliar o impacto do resultado obtido na melhoria da capacidade de detecção clínica das estruturas da mama. O mamógrafo em estudo dispõe de um sistema de controle automático da exposição designado por sistema AOP (Automatic Optimization of Parameters) que foi otimizado pelo fabricante a partir da razão contraste ruído. O sistema AOP é usado na prática clínica na quase totalidade dos exames de mamografia realizados no IPOC. Tendo em conta o tipo de estrutura que se pretende visualizar na mamografia, nomeadamente estruturas de baixo contraste como as massas e estruturas de dimensão submilimétrica como as microcalcificações, a análise contraste detalhe poderia constituir uma abordagem mais adequada para o estudo de otimização dos parâmetros de exposição uma vez que permitiria uma avaliação conjunta do contraste, da resolução espacial e do ruído da imagem. Numa primeira fase do trabalho foi efetuada a caracterização da prática clínica realizada no mamógrafo em estudo em termos de espessura de mama comprimida “típica”, dos parâmetros técnicos de exposição e das opções de processamento das imagens aplicadas pelo sistema AOP (combinação alvo/filtro, tensão aplicada na ampola - kVp e produto corrente-tempo da ampola - mAs). Numa segunda fase foi realizado um estudo de otimização da qualidade da imagem versus dose na perspectiva dos parâmetros físicos. Para tal foi efetuada uma análise contrastedetalhe no objeto simulador de mama CDMAM e usada uma figura de mérito definida a partir do IQFinv (inverted image quality figure) e da dose glandular média. Os resultados apontaram para uma diferença entre o ponto ótimo resultante do estudo de otimização e o ponto associado aos parâmetros de exposição escolhidos pelo sistema AOP, designadamente no caso da mama pequena. Sendo a qualidade da imagem na perspectiva clínica um conceito mais complexo cujo resultado da apreciação de uma imagem de boa qualidade deve ter em conta as diferenças entre observadores, foi efetuado na última parte deste trabalho um estudo do impacto clínico da proposta de otimização da qualidade de imagem. A partir das imagens realizadas com o objeto simulador antropomórfico TOR MAM simulando uma mama pequena, seis médicos(as) radiologistas com mais de 5 anos de experiência em mamografia avaliaram as imagens “otimizadas” obtidas utilizando-se os parâmetros técnicos de exposição resultantes do estudo de otimização e a imagem resultante da escolha do sistema AOP. A análise estatística das avaliações feitas pelos médicos indica que a imagem “otimizada” da mama pequena apresenta uma melhor visualização das microcalcificações sem perda da qualidade da imagem na deteção de fibras e de massas em comparação com a imagem “standard”. Este trabalho permitiu introduzir uma nova definição da figura de mérito para o estudo de otimização da qualidade da imagem versus dose em mamografia. Permitiu também estabelecer uma metodologia consistente que pode facilmente ser aplicada a qualquer outro mamógrafo, contribuindo para a área da otimização em mamografia digital que é uma das áreas mais relevantes no que toca à proteção radiológica do paciente.

Habitual coffee and tea drinkers experienced increases in blood pressure after consuming low to moderate doses of caffeine; these increases were larger upright than in the supine posture

Caffeine users have been encouraged to consume caffeine regularly to maintain their caffeine tolerance and so avoid caffeine’s acute pressor effects. In controlled conditions complete caffeine tolerance to intervention doses of 250 mg develops rapidly following several days of caffeine ingestion, nevertheless, complete tolerance is not evident for lower intervention doses. Similarly complete caffeine tolerance to 250 mg intervention doses has been demonstrated in habitual coffee and tea drinkers’ but for lower intervention doses complete tolerance is not evident. This study investigated a group of habitual caffeine users following their self-determined consumption pattern involving two to six servings daily. Cardiovascular responses following the ingestion of low to moderate amounts caffeine (67, 133 and 200 mg) were compared with placebo in a double-blind, randomised design without caffeine abstinence. Pre-intervention and post-intervention (30 and 60 min) 90 s continuous cardiovascular recordings were obtained with the Finometer in both the supine and upright postures. Participants were 12 healthy habitual coffee and tea drinkers (10 female, mean age 36). Doses of 67 and 133 mg increased systolic pressure in both postures while in the upright posture diastolic pressure and aortic impedance increased while arterial compliance decreased. These vascular changes were larger upright than supine for 133 mg caffeine. Additionally 67 mg caffeine increased dp/dt and indexed peripheral resistance in the upright posture. For 200 mg caffeine there was complete caffeine tolerance. Cardiovascular responses to caffeine appear to be associated with the size of the intervention dose. Habitual tea and coffee drinking does not generate complete tolerance to caffeine as has been previously suggested. Both the type and the extent of caffeine induced cardiovascular changes were influenced by posture.

Simulações Monte Carlo da redução da dose no cristalino e na tiroide em exames de tomografia computorizada utilizando proteções de bismuto

A presente dissertação foi desenvolvida com colaboração do Campus Tecnológico e Nuclear e do Hospital de São José

Impact of using different radiation therapy techniques in breat cancer: contralateral breast dose

RESUMO: O cancro de mama e o mais frequente diagnoticado a indiv duos do sexo feminino. O conhecimento cientifico e a tecnologia tem permitido a cria ção de muitas e diferentes estrat egias para tratar esta patologia. A Radioterapia (RT) est a entre as diretrizes atuais para a maioria dos tratamentos de cancro de mama. No entanto, a radia ção e como uma arma de dois canos: apesar de tratar, pode ser indutora de neoplasias secund arias. A mama contralateral (CLB) e um orgão susceptivel de absorver doses com o tratamento da outra mama, potenciando o risco de desenvolver um tumor secund ario. Nos departamentos de radioterapia tem sido implementadas novas tecnicas relacionadas com a radia ção, com complexas estrat egias de administra ção da dose e resultados promissores. No entanto, algumas questões precisam de ser devidamente colocadas, tais como: E seguro avançar para tecnicas complexas para obter melhores indices de conformidade nos volumes alvo, em radioterapia de mama? O que acontece aos volumes alvo e aos tecidos saudaveis adjacentes? Quão exata e a administração de dose? Quais são as limitações e vantagens das técnicas e algoritmos atualmente usados? A resposta a estas questões e conseguida recorrendo a m etodos de Monte Carlo para modelar com precisão os diferentes componentes do equipamento produtor de radia ção(alvos, ltros, colimadores, etc), a m de obter uma descri cão apropriada dos campos de radia cão usados, bem como uma representa ção geometrica detalhada e a composição dos materiais que constituem os orgãos e os tecidos envolvidos. Este trabalho visa investigar o impacto de tratar cancro de mama esquerda usando diferentes tecnicas de radioterapia f-IMRT (intensidade modulada por planeamento direto), IMRT por planeamento inverso (IMRT2, usando 2 feixes; IMRT5, com 5 feixes) e DCART (arco conformacional dinamico) e os seus impactos em irradia ção da mama e na irradia ção indesejada dos tecidos saud aveis adjacentes. Dois algoritmos do sistema de planeamento iPlan da BrainLAB foram usados: Pencil Beam Convolution (PBC) e Monte Carlo comercial iMC. Foi ainda usado um modelo de Monte Carlo criado para o acelerador usado (Trilogy da VARIAN Medical Systems), no c odigo EGSnrc MC, para determinar as doses depositadas na mama contralateral. Para atingir este objetivo foi necess ario modelar o novo colimador multi-laminas High- De nition que nunca antes havia sido simulado. O modelo desenvolvido est a agora disponí vel no pacote do c odigo EGSnrc MC do National Research Council Canada (NRC). O acelerador simulado foi validado com medidas realizadas em agua e posteriormente com c alculos realizados no sistema de planeamento (TPS).As distribui ções de dose no volume alvo (PTV) e a dose nos orgãos de risco (OAR) foram comparadas atrav es da an alise de histogramas de dose-volume; an alise estati stica complementar foi realizadas usando o software IBM SPSS v20. Para o algoritmo PBC, todas as tecnicas proporcionaram uma cobertura adequada do PTV. No entanto, foram encontradas diferen cas estatisticamente significativas entre as t ecnicas, no PTV, nos OAR e ainda no padrão da distribui ção de dose pelos tecidos sãos. IMRT5 e DCART contribuem para maior dispersão de doses baixas pelos tecidos normais, mama direita, pulmão direito, cora cão e at e pelo pulmão esquerdo, quando comparados com as tecnicas tangenciais (f-IMRT e IMRT2). No entanto, os planos de IMRT5 melhoram a distribuição de dose no PTV apresentando melhor conformidade e homogeneidade no volume alvo e percentagens de dose mais baixas nos orgãos do mesmo lado. A t ecnica de DCART não apresenta vantagens comparativamente com as restantes t ecnicas investigadas. Foram tamb em identi cadas diferen cas entre os algoritmos de c alculos: em geral, o PBC estimou doses mais elevadas para o PTV, pulmão esquerdo e cora ção, do que os algoritmos de MC. Os algoritmos de MC, entre si, apresentaram resultados semelhantes (com dferen cas at e 2%). Considera-se que o PBC não e preciso na determina ção de dose em meios homog eneos e na região de build-up. Nesse sentido, atualmente na cl nica, a equipa da F sica realiza medi ções para adquirir dados para outro algoritmo de c alculo. Apesar de melhor homogeneidade e conformidade no PTV considera-se que h a um aumento de risco de cancro na mama contralateral quando se utilizam t ecnicas não-tangenciais. Os resultados globais dos estudos apresentados confirmam o excelente poder de previsão com precisão na determinação e c alculo das distribui ções de dose nos orgãos e tecidos das tecnicas de simulação de Monte Carlo usados.---------ABSTRACT:Breast cancer is the most frequent in women. Scienti c knowledge and technology have created many and di erent strategies to treat this pathology. Radiotherapy (RT) is in the actual standard guidelines for most of breast cancer treatments. However, radiation is a two-sword weapon: although it may heal cancer, it may also induce secondary cancer. The contralateral breast (CLB) is a susceptible organ to absorb doses with the treatment of the other breast, being at signi cant risk to develop a secondary tumor. New radiation related techniques, with more complex delivery strategies and promising results are being implemented and used in radiotherapy departments. However some questions have to be properly addressed, such as: Is it safe to move to complex techniques to achieve better conformation in the target volumes, in breast radiotherapy? What happens to the target volumes and surrounding healthy tissues? How accurate is dose delivery? What are the shortcomings and limitations of currently used treatment planning systems (TPS)? The answers to these questions largely rely in the use of Monte Carlo (MC) simulations using state-of-the-art computer programs to accurately model the di erent components of the equipment (target, lters, collimators, etc.) and obtain an adequate description of the radiation elds used, as well as the detailed geometric representation and material composition of organs and tissues. This work aims at investigating the impact of treating left breast cancer using di erent radiation therapy (RT) techniques f-IMRT (forwardly-planned intensity-modulated), inversely-planned IMRT (IMRT2, using 2 beams; IMRT5, using 5 beams) and dynamic conformal arc (DCART) RT and their e ects on the whole-breast irradiation and in the undesirable irradiation of the surrounding healthy tissues. Two algorithms of iPlan BrainLAB TPS were used: Pencil Beam Convolution (PBC)and commercial Monte Carlo (iMC). Furthermore, an accurate Monte Carlo (MC) model of the linear accelerator used (a Trilogy R VARIANR) was done with the EGSnrc MC code, to accurately determine the doses that reach the CLB. For this purpose it was necessary to model the new High De nition multileaf collimator that had never before been simulated. The model developed was then included on the EGSnrc MC package of National Research Council Canada (NRC). The linac was benchmarked with water measurements and later on validated against the TPS calculations. The dose distributions in the planning target volume (PTV) and the dose to the organs at risk (OAR) were compared analyzing dose-volume histograms; further statistical analysis was performed using IBM SPSS v20 software. For PBC, all the techniques provided adequate coverage of the PTV. However, statistically significant dose di erences were observed between the techniques, in the PTV, OAR and also in the pattern of dose distribution spreading into normal tissues. IMRT5 and DCART spread low doses into greater volumes of normal tissue, right breast, right lung, heart and even the left lung than tangential techniques (f-IMRT and IMRT2). However,IMRT5 plans improved distributions for the PTV, exhibiting better conformity and homogeneity in target and reduced high dose percentages in ipsilateral OAR. DCART did not present advantages over any of the techniques investigated. Di erences were also found comparing the calculation algorithms: PBC estimated higher doses for the PTV, ipsilateral lung and heart than the MC algorithms predicted. The MC algorithms presented similar results (within 2% di erences). The PBC algorithm was considered not accurate in determining the dose in heterogeneous media and in build-up regions. Therefore, a major e ort is being done at the clinic to acquire data to move from PBC to another calculation algorithm. Despite better PTV homogeneity and conformity there is an increased risk of CLB cancer development, when using non-tangential techniques. The overall results of the studies performed con rm the outstanding predictive power and accuracy in the assessment and calculation of dose distributions in organs and tissues rendered possible by the utilization and implementation of MC simulation techniques in RT TPS.

Evaluation of exposure biomarkers in offshore workers exposed to low benzene and toluene concentrations.

Characterize ethylbenzene and xylene air concentrations, and explore the biological exposure markers (urinary t,t-muconic acid (t,t-MA) and unmetabolized toluene) among petroleum workers offshore. Offshore workers have increased health risks due to simultaneous exposures to several hydrocarbons present in crude oil. We discuss the pooled benzene exposure results from our previous and current studies and possible co-exposure interactions. BTEX air concentrations were measured during three consecutive 12-h work shifts among 10 tank workers, 15 process operators, and 18 controls. Biological samples were collected pre-shift on the first day of study and post-shift on the third day of the study. The geometric mean exposure over the three work shifts were 0.02 ppm benzene, 0.05 ppm toluene, 0.03 ppm ethylbenzene, and 0.06 ppm xylene. Benzene in air was significantly correlated with unmetabolized benzene in blood (r = 0.69, p < 0.001) and urine (r = 0.64, p < 0.001), but not with urinary t,t-MA (r = 0.27, p = 0.20). Toluene in air was highly correlated with the internal dose of toluene in both blood (r = 0.70, p < 0.001) and urine (r = 0.73, p < 0.001). Co-exposures were present; however, an interaction of metabolism was not likely at these low benzene and toluene exposures. Urinary benzene, but not t,t-MA, was a reliable biomarker for benzene at low exposure levels. Urinary toluene was a useful biomarker for toluene exposure. Xylene and ethylbenzene air levels were low. Dermal exposure assessment needs to be performed in future studies among these workers.

Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection.

Cardiovascular effects of a medetomidine constant rate infusion at different dose levels in anaesthetized dogs

Les effets cardiovasculaires des alpha-2 agonistes, particulièrement importants chez les chiens, limitent leur utilisation en pratique vétérinaire. La perfusion à débit constant (PDC) de ces drogues, comme la médétomidine (MED) permettrait un contrôle plus précis de ces effets. Les effets hémodynamiques de plusieurs doses de MED en PDC ont été évalués chez le chien. Lors de cette étude prospective, réalisée en double aveugle, 24 chiens en santé, ont reçu de façon aléatoire une des 6 doses de MED PDC (4 chiens par groupe). Les chiens ont été ventilés mécaniquement pendant une anesthésie minimale standardisée avec de l’isoflurane dans de l’oxygène. Une dose de charge (DC) de médétomidine a été administrée aux doses de 0.2, 0.5, 1.0, 1.7, 4.0 ou 12.0 µg/kg pendant 10 minutes, après laquelle la MED PDC a été injectée à une dose identique à celle de la DC pendant 60 minutes. L’isoflurane a été administré seul pendant une heure après l’administration d’une combinaison d’ISO et de MED PDC pendant 70 minutes. La fréquence cardiaque (FC), la pression artérielle moyenne (PAM) et l’index du débit cardiaque (IC) ont été mesurés. Des prélèvements sanguins ont permis d’évaluer le profil pharmacocinétique. D’après ces études, les effets hémodynamiques de la MED PDC pendant une anesthésie à l’isoflurane ont été doses-dépendants. L’IC a diminué progressivement alors que la dose de MED augmentait avec: 14.9 (12.7), 21.7 (17.9), 27.1 (13.2), 44.2 (9.7), 47.9 (8.1), and 61.2 (14.1) % respectivement. Les quatre doses les plus basses n’ont provoqué que des changements minimes et transitoires de la FC, de la PAM et de l’IC. La pharmacocinétique apparaît clairement dose-dépendante. De nouvelles expériences seront nécessaires afin d’étudier l’utilisation clinique de la MED PDC.

A point-prevalence survey of antimicrobial utilisation within New Brunswick hospitals to focus antimicrobial stewardship efforts and decrease low-value care.

Introduction: Il est important de minimiser le gaspillage et les risques associés aux soins sans valeur. La gestion de l’utilisation des antimicrobiens vise à optimiser leur emploi et doit être adaptée au milieu et à sa population. Objectifs: Évaluer les profiles d’utilisation actuels des antimicrobiens et fixer des objectifs pour les interventions en matière de gestion des antimicrobiens. Méthode: Vingt-et-un hôpitaux du Nouveau-Brunswick offrant des soins de courte durée en médecine générale, en chirurgie et en pédiatrie ont pris part à une enquête sur la prévalence ponctuelle. Tous les patients admis aux hôpitaux participants et ayant reçu au moins un antimicrobien systémique ont été inscrits à l’étude. Les principaux critères d’évaluation étaient le profil d’utilisation, selon l’indication et l’antimicrobien prescrit, le bienfondé de l’utilisation et la durée de la prophylaxie chirurgicale. Des statistiques descriptives et un test d’indépendance 2 furent utilisés pour l’analyse de données. Résultats: L’enquête a été menée de juin à août 2012. Un total de 2244 patients ont été admis pendant la durée de l’étude et 529 (23,6%) ont reçu un antimicrobien. Au total, 691 antimicrobiens ont été prescrits, soit 587 (85%) pour le traitement et 104 (15%) pour la prophylaxie. Les antimicrobiens les plus souvent prescrits pour le traitement (n=587) étaient des classes suivantes : quinolones (25,6%), pénicillines à spectre étendu (10,2%) et métronidazole (8,5%). Les indications les plus courantes du traitement étaient la pneumonie (30%), les infections gastro-intestinales (16%) et les infections de la peau et des tissus mous (14%). Selon des critères définis au préalable, 23% (n=134) des ordonnances pour le traitement étaient inappropriées et 20% (n=120) n’avaient aucune indication de documentée. Les domaines où les ordonnances étaient inappropriées étaient les suivants : défaut de passage de la voie intraveineuse à la voie orale (n=34, 6%), mauvaise dose (n=30, 5%), traitement d’une bactériurie asymptomatique (n=24, 4%) et doublement inutile (n=22, 4%). Dans 33% (n=27) des cas, les ordonnances pour la prophylaxie chirurgicale étaient pour une période de plus de 24 heures. Conclusions: Les résultats démontrent que les efforts de gestion des antimicrobiens doivent se concentrer sur les interventions conventionnelles de gestion de l’utilisation des antimicrobiens, l’amélioration de la documentation, l’optimisation de l’utilisation des quinolones et la réduction au minimum de la durée de la prophylaxie chirurgicale.