Brachytherapy is a form of radiotherapy in which radioactive sources are placed at short distances from, or even inside the target volume. The use of high dose rate brachytherapy is a widely accepted and clinically proven treatment for some stages of prostate cancer. The aim of this project was to investigate potential improvements on two of the most important aspects of high dose rate (HDR) and pulsed dose rate (PDR) prostate brachytherapy - prostate definition and treatment delivery verification. The use of magnetic resonance (MR) imaging in addition to the conventional computed tomography (CT) imaging methods currently used routinely for brachytherapy planning may provide some benefit in accurately defining the prostate and surrounding critical structures. The methods used in this project involved analysis of data sets provided by two Radiation Oncologists. The results presented showed inter-observer and intra-observer variations in the size and shape of the prostate, as well as analysis of the dosimetric differences that may be reported due to the differences in prostate size and shape. The results also included analysis of critical structure dosimetry - dose to the surrounding radio-sensitive rectum and urethra. In summary, the results showed that the prostate was defined to be smaller using MR imaging than CT, however the consistency between Oncologists was not significantly improved using MR imaging. MR imaging may be useful in reducing the dose to normal tissue surrounding the prostate and in obtaining better coverage of the smaller target volume, without compromising the critical structures. The use of LiF:Mg,Ti thermoluminescent dosimeters (TLDs) is a potential avenue for in vivo dose verification of an HDR or PDR prostate brachytherapy treatment plan. This project included a phantom study of these TLDs with the aim to determine their feasibility for clinical use. Cylindrical TLD rods (6 mm length x 1 mm diameter) were used, as these fit inside the brachytherapy needles implanted into the prostate, and therefore had potential to be used clinically to verify the dose delivered in the prostate. This study was extended to include determination of a correction factor to allow an independent radiation source (6 MV photon beam from a linear accelerator) to be used to obtain control readings for this relative dosimetric method. The results showed these TLDs to be a promising in vivo dosimeter for prostate brachytherapy with potential errors in the order of 4%. Their potential lies in the fact that they could detect and flag significant calculation errors in treatment plans, and they utilise equipment used routinely for external beam radiotherapy dosimetry in many treatment facilities, reducing the cost of implementing such a procedure.

Neste trabalho são apresentados os resultados obtidos com diodos resistentes a danos de radiação dos tipos fusão zonal padrão (FZ), fusão zonaI com difusão de oxigênio (DOFZ) e Czochralski magnético (MCz) em dosimetria de processamento por radiação gama. Estes dispositivos de junção p+-n-n+ foram manufaturados por Okmetic Oyj. (Vantaa, Finland) e processados no Centro de Microeletrônica da Universidade de Tecnologia de Helsinki no âmbito da colaboração RD50 do CERN. As sondas dosimétricas, baseadas nos dispositivos FZ, DOFZ and MCz, foram projetadas para operar sem tensão de polarização no modo de corrente direta como dosímetros on-line de radiação. As irradiações foram realizadas no Centro de Tecnologia das Radiações (CTR) no IPEN-CNEN/SP usando a fonte de 60Co (Gammacell 220 Nordion) com a taxa de dose de aproximadamente 2,4 kGy/h. A resposta em corrente de cada diodo foi medida em função do tempo de exposição em intervalos de dose desde 5 kGy até 50 kGy atingindo a dose total absorvida 275 kGy. Os resultados obtidos demonstraram um significante decréscimo da fotocorrente gerada em todos os dispositivos para doses totais absorvidas superiores a aproximadamente 25 kGy. Para reduzir este efeito, as amostras foram pré-irradiadas com raios gama do 60Co a uma dose de 700 kGy, para saturar a produção de armadilhas no volume sensível do diodo. Depois da pré-irradiação, apesar de serem menos sensíveis, todos os dispositivos apresentaram sinais de corrente estáveis mesmo para a dose total absorvida de 275 kGy. A fim de monitorar possíveis efeitos de danos de radiação VII produzidos nos diodos, as correntes de fuga e capacitância destes dispositivos foram medidas em função da dose total absorvida. As curvas de calibração dos dosímetros mostraram respostas quadráticas com coeficientes de correlação maiores do que 0,9999 para doses totais absorvidas de até 275 kGy. A comparação entre as respostas dosimétricas dos diodos estudados evidenciou que o melhor resultado foi obtido com o MCz que exibiu maiores sensibilidade e estabilidade do que os dispositivos FZ e DOFZ. No entanto, é importante notar que todos os diodos pré-irradiados podem ser utilizados como dosímetros em aplicações de processamento por radiação gama. / In this work we report on results obtained with rad-hard Standard Float Zone (FZ), Diffusion Oxygenated Float Zone (DOFZ) and Magnetic Czochralski (MCz) silicon diodes in gamma radiation processing dosimetry. These p+-n-n+ junction devices were manufactured by Okmetic Oyj. (Vantaa, Finland) and processed by the Microelectronics Center of Helsinki University of Technology in the framework of the CERN RD50 Collaboration. The dosimetric probes, based on FZ, DOFZ and MCz devices, were designed to operate without bias voltage in the direct current mode as on-line radiation dosimeter. The irradiations were performed in the Radiation Technology Center (CTR) at IPEN-CNEN/SP using a 60Co source (Gammacell 220 Nordion) with a dose rate around of 2.4 kGy/h. The current response of each diode was measured as a function of the exposure time in steps from 5 kGy up to 50 kGy to achieve a total absorbed dose of 275 kGy. The results obtained showed a significant decrease in the photocurrent generated in all devices for total absorbed doses higher than approximately 25 kGy. To reduce this effect, the samples were pre-irradiated with 60Co gamma rays at 700 kGy in order to saturate the trap production in the diodes sensitive volume. After pre-irradiation, despite of being less sensitive, all devices exhibited more stable photocurrent signals, even for total absorbed doses of 275 kGy. To monitor possible gamma radiation damage effects produced on the diodes, their dynamic leakage current and capacitance were measured as a function of the absorbed dose. IX The calibration curves of the dosimeters showed quadratic responses with correlation coefficient higher than 0.9999 for total absorbed dose up to 275 kGy. The comparison among the dosimetric response of the diodes studied evidenced that the best result was achieved with the MCz which exhibited higher sensitivity and stability than the FZ and DOFZ devices. However, it is important to note that all pre-irradiated diodes can be used as gamma dosimeters in radiation processing applications.

Les faisceaux de photons produits par les accélérateurs d'électrons linéaires médicaux sont plats, grâce à un cône égalisateur. Les technologies ont évolué et la présence d'un cône n'est plus indispensable. On parle alors de faisceaux FFF (flattening filter free). Les faisceaux FFF présentent des débits de dose plus élevés, des profils de dose hétérogènes, des spectres énergétiques différents et une diminution de la dose hors-champ. Cette thèse a eu pour but d'étudier les caractéristiques des faisceaux FFF, ainsi que l'impact de leur utilisation thérapeutique. Plusieurs thématiques ont été. Des expériences d'irradiation in vitro ont tout d'abord permis de s'assurer que les débits de dose FFF n'ont pas d'impact radiobiologique sur la réponse des cellules irradiées. Une large revue de la littérature a permis de corroborer ces résultats. Afin de maitriser les caractéristiques physiques des faisceaux FFF, des mesures ont été faites avec différents détecteurs. Les effets du spectre et du débit de dose sur la calibration en dose ont aussi été étudiés. Les faisceaux FFF ont été modélisés dans deux TPS. Les modèles ont été comparés entre les deux types de faisceaux et entre les deux TPS. La mise en place des traitements stéréotaxiques a aussi été l'occasion d'appréhender la dosimétrie des petits faisceaux. Nous avons étudié des cas VMAT de cancer de la prostate et des cas de stéréotaxies 3D de tumeurs pulmonaires. La comparaison donne un avantage aux faisceaux FFF. La maitrise de la physique et de la biologie des haut débits a permis de débuter les traitements FFF à l'IPC. Des études comparatives nous permettent aujourd'hui d'adapter leur utilisation au cas par cas. / In medical linear electron accelerators, photon beams profiles are homogenised using flattening filters. Technologies have evolved and the presence of this filter is no longer necessary. Flattening filter free (FFF) beams exhibit higher dose rates, heterogeneous dose profiles, modified energy spectra and lower out-of-field dose. This PhD aimed at studying the characteristics of unflattened beams, as well as their impact in clinical utilization. Several subjects were thoroughly investigated: radiobiology, dosimetry, quality controls, modelling and treatment planning. In vitro experiments ensured that the high dose-rate of FFF beams had not a radiobiological impact. A wide review of the literature was conducted to corroborate these results. In order to understand thoroughly the characteristics of FFF beams, measurements were conducted using several detectors. The effect of the spectra and dose rates of unflattened beams on dose calibration were also studied. FFF beams were modeled in two TPSs. The methods, results and model parameters have been compared between the available beam qualities as well as between both TPSs. Furthermore, the implementation of stereotactic treatments technique was the occasion to investigate small beam dosimetry. Prostate cancer cases treated with VMAT and pulmonary tumors treated with stereotactic 3D beams were also studied. The comparison of dose distributions and treatment metrics give advantage to FFF beams. Mastering physical and biological aspects of flattening filter free beams allowed the IPC to start FFF treatments. Comparative studies have since resulted in a deeper understanding on the pertinent use of these beams.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23408号 / 医博第4753号 / 新制||医||1052(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 古川 壽亮, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p> It has been suggested that combination treatment of high dose rate (HDR) intraluminal brachytherapy and PDT (Photodynamic therapy) in non-small cell lung cancer (NSCLC) may improve the efficacy of treatment, reduce the toxicity and improve quality of life for patients. To provide a cellular basis for this approach we have examined the in vitro sensitivity of normal lung fibroblasts (MRC5) and four NSCLC cell lines (SKMES-1, A549, NCIH460 and NCIH23) following, UVC treatment, HDR radiation, HDR radiation with Photofrin alone, PDT and combined HDR radiation and PDT. Cell sensitivity was measured using clonogenic survival. HDR radiation was cobalt-60 gamma rays (1.5-1.9 Gy/min). For PDT treatment, cells were exposed to 2.5 J.lg/ml Photofrin for 18-24 h followed by light exposure (20mW/cm2). D37 values calculated from the survival curves indicated a 2-fold difference in sensitivity to UVC, 6-fold difference in HDR radiation sensitivity and an 8-fold difference in PDT sensitivity. All cell lines showed a similar Photofrin uptake per cell when measured by flow cytometry using 488nm excitation and 620-675 nm emission wavelengths. Photofrin alone at concentrations up to 10 J.lg/ml had no significant effect on the survival of the NSCLC cell lines, whereas 10 J.lg/ml ofPhotofrin alone reduced survival significantly in MRC5 cells. A radiosensitizing effect of Photofrin was detected in MRC5 and NCIH460 cells, but not in A549, SKMES-1 and NCI-H23 cells. For combined treatment cells were exposed to Photofrin and then either exposed to light and 15-30 minutes later exposed to HDR radiation or exposed to HDR radiation and 15-30 minutes later exposed to light. Results showed that although light followed by gamma rays resulted in a somewhat greater tumor cell kill compared to gamma rays followed by light this difference was not significant for any of the cell lines tested. However, this difference was significant when data for all NSCLC cell lines were pooled. The combined treatment with high dose rate HDR radiation and PDT was not significantly different from an additive effect of the individual treatment modalities for in vitro survival of 4 NSCLC cells. In contrast the combined treatment was less than additive for the MRCS cells suggesting that the combined treatment would have the potential advantage of doing less damage to the normal lung cells and suggests that equivalent tumour cell kill in vivo may be possible at reduced systemic effects to patients. In preliminary experiments we have started to examine the effects of Photofrin-mediated PDT on the extra cellular signal-activated protein kinase (ERK) signaling pathway in NSCLC cells. The use of multiple NSCLC cell lines allows for the possible identification of cell line specific changes involved in resistance to PDT and HDR radiation and this will be explored in future work. </p> / Thesis / Master of Science (MSc)

Yes / We investigated whether companion drug resistance was associated with adverse outcome of the shorter MDR-TB regimen in Bangladesh, after adjusting for fluoroquinolone resistance. MDR/RR-TB patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB regimen were selected for the study. Drug resistance was determined using the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole genome sequencing. Low-level and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line injectable-susceptible TB, non-eligibility to the shorter MDR-TB regimen (initial resistance to either pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (aOR 1.01; 95%CI 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant TB. Our results suggest that resistance to companion drugs of the shorter MDR-TB regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone, and possibly kanamycin resistance. / Damien Foundation Belgium for its financial and logistic support to run the project including its research activities. European Research Council (Starting Grant INTERRUPTB 311725).

Irradiadores comerciais de grande porte são projetados para processarem grandes quantidades de produtos com altas doses, por exposição à radiação gama. A irradiação em escala industrial é efetuada de forma dinâmica, em que os produtos percorrem um caminho em torno de uma fonte de radiação, geralmente de 60Co, cuja atividade é da ordem de TBq a PBq (kCi a MCi). A dose será diretamente proporcional ao tempo transcorrido pelo material para percorrer este trajeto em torno da fonte. Entretanto, em algumas situações, principalmente para pesquisas ou processos de validação de clientes seguindo a norma ISO 11137, se faz necessário irradiar pequenas amostras com doses fracionadas na posição de irradiação estática. Nesta posição as amostras são colocadas dentro da sala de irradiação a uma distância fixa da fonte e as doses recebidas são determinadas utilizando-se dosímetros. Portanto, a dose somente será conhecida depois da irradiação, pela leitura dos mesmos. Entretanto, em irradiadores industriais, diferentes tipos de produtos com diferentes densidades atravessam o caminho entre a fonte e a posição de irradiação estática, onde estão as amostras. Conseqüentemente, a taxa de dose variará dependendo da densidade do produto, que está sendo irradiado dinamicamente. Uma metodologia adequada seria monitorar a dose recebida pelas amostras em tempo real, medindo a dose por meio de um detector de radiação, com uma melhor precisão e exatidão. Neste trabalho foi desenvolvida uma câmara de ionização cilíndrica de 0.9 cm3, para monitorar as altas doses recebidas por amostras em tempo real, na posição de irradiação estática de um irradiador gama de 60Co. Os gases de nitrogênio e de argônio a pressão de 10exp5 Pa (1 bar) foram utilizados para preencherem a câmara de ionização e determinar uma configuração de trabalho apropriada, para o detector ser utilizado em medidas de altas doses. Cabos de isolação mineral foram soldados diretamente ao corpo da câmara de ionização, para a transmissão do sinal gerado pelo detector até a eletrônica associada, distante cerca de 20 m. O sinal obtido foi cerca de 100 vezes maior do que o ruído de fundo. Este sistema dosimétrico foi testado em um irradiador gama de categoria I e na posição de irradiação estática de um irradiador de grande porte, em que diferentes taxas de dose foram obtidas utilizando materiais absorvedores. Foi encontrada uma boa linearidade do detector entre a dose e a carga, independentemente das diferentes taxas de dose. As incertezas de todas as curvas ficaram abaixo dos +/- 5 %, valor de incerteza máxima recomendada para um sistema dosimétrico de rotina. A câmara de ionização desenvolvida se mostrou adequada para ser utilizada como um dosímetro em tempo real, independente da degradação do espectro causada pela absorção dos fótons da fonte de 60Co, pelo material em irradiação dinâmica. / Industrial gamma irradiators facilities are designed for processing large amounts of products, which are exposed to large doses of gamma radiation. The irradiation, in industrial scale, is usually carried out in a dynamic form, where the products go through a 60Co gamma source with activity of TBq to PBq (kCi to MCi). The dose is estimated as being directly proportional to the time that the products spend to go through the source. However, in some situations, mainly for research purposes or for validation of customer process following the ISO 11137 requirements, it is required to irradiate small samples in a static position with fractional deliver doses. The samples are put inside the irradiation room at a fixed distance from the source and the dose is usually determined using dosimeters. The dose is only known after the irradiation, by reading the dosimeter. Nevertheless, in the industrial irradiators, usually different kinds of products with different densities go through between the source and the static position samples. So, the dose rate varies in function of the product density. A suitable methodology would be to monitor the samples dose in real time, measuring the dose on line with a radiation detector, which would improve the dose accuracy and avoid the overdose. A cylindrical ionization chamber of 0.9 cm3 has been developed for high-doses real-time monitoring, during the sample irradiation at a static position in a 60Co gamma industrial plant. Nitrogen and argon gas at pressure of 10exp5 Pa (1bar) was utilized to fill the ionization chamber, for which an appropriate configuration was determined to be used as a detector for high-dose measurements. To transmit the signal generated in the ionization chamber to the associated electronic and processing unit, a 20 m mineral insulated cable was welded to the ionization chamber. The signal to noise ratio produced by the detector was about 100. The dosimeter system was tested at a category I gamma irradiator and at an industrial irradiation plant in static position, using different absorbing materials. A good linearity of the detector was found between the dose and the accumulated charge, independently of the different dose rates caused by absorbing materials. The uncertainties for all curves were less than 5%, which is recommended for a dosimetric system routine. The developed ionization chamber showed to be suitable as a dosimeter on line, independently of the spectrum degradation caused by the absorption of the 60Co photons in the material under dynamic irradiation.

Irradiadores comerciais de grande porte são projetados para processarem grandes quantidades de produtos com altas doses, por exposição à radiação gama. A irradiação em escala industrial é efetuada de forma dinâmica, em que os produtos percorrem um caminho em torno de uma fonte de radiação, geralmente de 60Co, cuja atividade é da ordem de TBq a PBq (kCi a MCi). A dose será diretamente proporcional ao tempo transcorrido pelo material para percorrer este trajeto em torno da fonte. Entretanto, em algumas situações, principalmente para pesquisas ou processos de validação de clientes seguindo a norma ISO 11137, se faz necessário irradiar pequenas amostras com doses fracionadas na posição de irradiação estática. Nesta posição as amostras são colocadas dentro da sala de irradiação a uma distância fixa da fonte e as doses recebidas são determinadas utilizando-se dosímetros. Portanto, a dose somente será conhecida depois da irradiação, pela leitura dos mesmos. Entretanto, em irradiadores industriais, diferentes tipos de produtos com diferentes densidades atravessam o caminho entre a fonte e a posição de irradiação estática, onde estão as amostras. Conseqüentemente, a taxa de dose variará dependendo da densidade do produto, que está sendo irradiado dinamicamente. Uma metodologia adequada seria monitorar a dose recebida pelas amostras em tempo real, medindo a dose por meio de um detector de radiação, com uma melhor precisão e exatidão. Neste trabalho foi desenvolvida uma câmara de ionização cilíndrica de 0.9 cm3, para monitorar as altas doses recebidas por amostras em tempo real, na posição de irradiação estática de um irradiador gama de 60Co. Os gases de nitrogênio e de argônio a pressão de 10exp5 Pa (1 bar) foram utilizados para preencherem a câmara de ionização e determinar uma configuração de trabalho apropriada, para o detector ser utilizado em medidas de altas doses. Cabos de isolação mineral foram soldados diretamente ao corpo da câmara de ionização, para a transmissão do sinal gerado pelo detector até a eletrônica associada, distante cerca de 20 m. O sinal obtido foi cerca de 100 vezes maior do que o ruído de fundo. Este sistema dosimétrico foi testado em um irradiador gama de categoria I e na posição de irradiação estática de um irradiador de grande porte, em que diferentes taxas de dose foram obtidas utilizando materiais absorvedores. Foi encontrada uma boa linearidade do detector entre a dose e a carga, independentemente das diferentes taxas de dose. As incertezas de todas as curvas ficaram abaixo dos +/- 5 %, valor de incerteza máxima recomendada para um sistema dosimétrico de rotina. A câmara de ionização desenvolvida se mostrou adequada para ser utilizada como um dosímetro em tempo real, independente da degradação do espectro causada pela absorção dos fótons da fonte de 60Co, pelo material em irradiação dinâmica. / Industrial gamma irradiators facilities are designed for processing large amounts of products, which are exposed to large doses of gamma radiation. The irradiation, in industrial scale, is usually carried out in a dynamic form, where the products go through a 60Co gamma source with activity of TBq to PBq (kCi to MCi). The dose is estimated as being directly proportional to the time that the products spend to go through the source. However, in some situations, mainly for research purposes or for validation of customer process following the ISO 11137 requirements, it is required to irradiate small samples in a static position with fractional deliver doses. The samples are put inside the irradiation room at a fixed distance from the source and the dose is usually determined using dosimeters. The dose is only known after the irradiation, by reading the dosimeter. Nevertheless, in the industrial irradiators, usually different kinds of products with different densities go through between the source and the static position samples. So, the dose rate varies in function of the product density. A suitable methodology would be to monitor the samples dose in real time, measuring the dose on line with a radiation detector, which would improve the dose accuracy and avoid the overdose. A cylindrical ionization chamber of 0.9 cm3 has been developed for high-doses real-time monitoring, during the sample irradiation at a static position in a 60Co gamma industrial plant. Nitrogen and argon gas at pressure of 10exp5 Pa (1bar) was utilized to fill the ionization chamber, for which an appropriate configuration was determined to be used as a detector for high-dose measurements. To transmit the signal generated in the ionization chamber to the associated electronic and processing unit, a 20 m mineral insulated cable was welded to the ionization chamber. The signal to noise ratio produced by the detector was about 100. The dosimeter system was tested at a category I gamma irradiator and at an industrial irradiation plant in static position, using different absorbing materials. A good linearity of the detector was found between the dose and the accumulated charge, independently of the different dose rates caused by absorbing materials. The uncertainties for all curves were less than 5%, which is recommended for a dosimetric system routine. The developed ionization chamber showed to be suitable as a dosimeter on line, independently of the spectrum degradation caused by the absorption of the 60Co photons in the material under dynamic irradiation.

Base teórica: O surgimento de bactérias multirresistentes levou a uma renovação no interesse de antigos antimicrobianos, como a polimixina B, medicamento que foi descartado no passado devido sua toxicidade. Nas últimas duas décadas, esse antimicrobiano tornou-se um dos mais importantes agentes terapêuticos para o tratamento de infecções causadas por bactérias multirresistentes; porém, ainda faltam estudos clínicos que avaliem a segurança da polimixina B, especialmente em altas doses. Objetivo: Avaliar eventos adversos graves relacionados à infusão e a falência renal nos pacientes que receberam altas doses de polimixina B intravenosa. Métodos: Realizamos um estudo de coorte retrospectivo, multicêntrico. Incluímos pacientes que receberam > 3mg/kg/ dia ou uma dose total ≥250mg/dia de polimixina B, no período de janeiro de 2013 a dezembro de 2015. Para a avaliação dos eventos relacionados a infusão, foram incluídos pacientes que receberam ≥ 1 dose de polimixina B e para avaliação de falência renal incluiu apenas os pacientes que receberam ≥ 48 horas de polimixina B. Os desfechos principais avaliados foram os eventos adversos graves relacionados à infusão de acordo com os Critérios de Terminologia Comuns para Eventos Adversos (CTCAE v4.0) e a falência renal, utilizamos os critérios RIFLE (Risk, Injury, Failure, Loss and End stage), para categorizar os diferentes graus de lesão renal aguda. As variáveis incluídas no estudo foram as variáveis demográficas (idade, sexo), as variáveis individuais (peso, comorbidades, escore de Charlson), os fatores de gravidade (internação em UTI, uso de vasopressor, uso de bloqueador neuromuscular), outras fármacos nefrotóxicas, dose de polimixina utilizada (total, média diária e em mg/kg/dia), associação com outros medicamentos, e características da infecção (sítio, isolamento microbiológico) foram avaliadas em análise bivariada. Variáveis com P≤0.2 foram incluídas uma a uma, em ordem crescente, em modelo de regressão de COX. Variáveis com P< 0.1 permaneceram no modelo final. Resultados: Foram incluídos 222 pacientes para análise de eventos graves relacionados à infusão. A dose média de polimixina B foi de 3.61± 0.97 mg/kg /dia (dose total media = 268 mg/kg). Ocorreram eventos adversos graves relacionados à infusão em dois pacientes, determinando uma incidência bruta de 0.9% (intervalo de confiança de 95%, 0.2-3.2): um 7 evento classificado como um risco ameaçador a vida (efeito adverso classe IV) ocorreu em um paciente, homem, de 40 anos, internado no Centro de Terapia Intensiva, com fibrose cística, que recebeu 3,3 mg / kg / dia de PMB e desenvolveu dor torácica súbita, dispnéia e hipoxemia, no quarto dia de tratamento e o outro evento adverso grave (classe III), ocorreu em um paciente, homem, 23 anos, internado na enfermaria, com linfoma, que recebeu 3,6 mg / kg / dia de PMB , que apresentou parestesia perioral, tonturas e dispnéia no primeiro dia de tratamento. A falência renal foi analisada em 115 pacientes que receberam ≥ 48 horas de polimixina B e que não estavam em diálise no início do tratamento com Polimixina B; Falência renal foi encontrada em 25 de 115 (21,7%) pacientes expostos as PMB. Nosso estudo identificou que 54 [47,0%] pacientes desenvolveram algum grau de lesão renal aguda, pelos critérios de RIFLE: risco, 15 (27,8%), injúria, 14 (25,9%) e falência, 25 (46,3%) dentro das categorias do RIFLE. Além disso, droga vasoativa, outros fármacos nefrotóxicos e clearance de creatinina foram fatores de risco independentes para falência renal. Nem a dose diária de polimixina B ajustada para o peso corporal, nem a dose diária total foram associadas a falência renal. A mortalidade intra-hospitalar foi de 60% (134 pacientes): 26% (57 pacientes) morreram durante o tratamento e nenhum óbito foi durante a infusão. Conclusão: Altas doses de polimixina B no tratamento de infecções por bactérias gramnegativo apresentaram incidência baixa de eventos adversos agudos no nosso estudo e incidência de nefrotoxicidade elevadas, mas semelhantes a alguns estudos prévios com doses usuais”. Portanto, doses elevadas podem ser testadas em ensaios clínicos, objetivando melhorar os desfechos dos pacientes gravemente doentes com infecções por bactérias multirresistentes e minimizar o surgimento da resistência a polimixina B. / Background: The emergence of multiresistant bacteria has led to a renewal in the interest of old antimicrobials, such as polymyxin B, a drug that has been discarded in the past due to its toxicity. However, at this time, this antimicrobial has become one of the most important therapeutic agents for the treatment of infections caused by multiresistant bacteria but there is still a lack of clinical studies that evaluate the safety of polymyxin B, especially in relation to the use of high doses. This strategy, high doses, may be necessary in the fight against Gramnegative bacteria with a high minimum inhibitory concentration. Patients and methods: A retrospective, multicenter cohort study; the period evaluated was from January 2013 to December 2015, included patients who received > 3mg/kg/day or a total dose of ≥250mg/day of polymyxin B. The study included the evaluation of infusion-related events, patients who received ≥ 1 dose of polymyxin B and patients who received ≥ 48 hours of PMB were included for evaluation of renal failure. Major outcomes were serious adverse events related to infusion according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and categorized renal failure by the RIFLE criteria (Risk, Injury, Failure, Loss, End stage). Factors potentially related to nephrotoxicity or mortality in 30 days were: demographic variables (age, sex), individual variables (weight, comorbidities, Charlson score), severity factors (ICU admission, use of vasopressor, use of Neuromuscular blocker), nephrotoxicity (other nephrotoxic drugs), polymyxin dose (total, daily mean and mg / Kg / day), association of drugs and infection characteristics (site and microbiological isolate) were evaluated in bivariate analysis. Variables with P≤0.2 were included one by one, in ascending order, in a Cox regression model. Variables with P <0.1 remained in the final model. Results: Two of 222 patients presented a severe infusion-related adverse event during PMB infusion, resulting in a crude incidence of 0.9% (95% Confidence Interval [CI], 0.2-3.2); one was classified as life-threatening and one classified as severe (crude incidence of each adverse event, 0.45%; 95% CI, 0.08-2.5). The life-threatening adverse effect occurred in an ICU patient (crude incidence among ICU patients, 0.67%; 95% CI, 0.12-3.7), a 40-years old male with cystic fibrosis who used 3.3 mg/kg/day of PMB and developed sudden thoracic pain, dyspnea and hypoxemia, in the fourth day of treatment. The severe adverse effect occurred in a non-ICU patient (crude incidence among non-ICU patients, 1.3%; 95% CI, 0.2-7.2), a 23- years old male with lymphoma exposed to 3.6 mg/kg/day of PMB, who presented perioral 9 paresthesia, dizziness and dyspnea in the first day of treatment. Renal failure was analysed in 115 patients who received ≥48 hours of PMB and who were not previously in dialysis. A total of 54 [47.0%] patients developed any degree of AKI, categorised as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]) and 25 of 115 (21.7%) patients presented renal failure Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Conclusion: Results suggest that high dose regimens have similar safety profile of usual doses and could be further tested in clinical trials assessing strategies to improve patients’ outcomes and minimize the emergence of PMB resistance.

Introduction Treating localized prostate cancer with combination radiotherapy consisting ofexternal beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) has beenproven to result in better disease outcome than EBRT only. There is, however, a decreasingtrend in utilization of combination therapy, partially due to concerns for elevated toxicityrisks. Aim To determine which parameters correlate to acute and late (≤ 6 months) urinary toxicity(AUT and LUT) and acute and late rectal toxicity (ART and LRT), and thereafter createpredictive models for rectal toxicity. Methods Data on toxicity rates and 32 patient, tumor and treatment parameters were collectedfrom 359 patients treated between 2008 and 2018 with EBRT (42 Gy in 14 fractions) andHDR-BT (14.5 Gy in 1 fraction) for localized prostate cancer at Örebro University Hospital.Bivariate analyses were conducted on all parameters and the outcome variables AUT, LUT,ART and LRT grade ≥ 1, graded according to the RTOG-criteria. Parameters correlating toART and LRT in this and previous studies were included in multivariate logistic regressionanalyses for creation of predictive models. Results Most toxicities, 86%, were of grade 0 or 1, only 9% of patients had grade 2 – 3toxicity. Only 2 – 4 parameters correlated to the respective toxicities in bivariate analyses.Logistic regressions generated no significant predictors of ART or LRT. Therefore, nopredictive models were obtained. Conclusion None of the included parameters have enough discriminative abilities regardingrectal toxicity. Predictive models can most probably be obtained by including otherparameters and more patients.