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- Adipocyte secretome increases radioresistance of malignant melanocytes by improving cell survival and decreasing oxidative statusPublication . Coelho, Pedro; Silva, Liliana; Faria, Isabel; Vieira, Mónica; Monteiro, Armanda; Pinto, Gabriela; Prudêncio, Cristina; Fernandes, Rúben; Soares, RaquelRadiotherapy is a treatment option for the majority of malignancies. However, because melanoma is known to be radioresistant, the use of ionizing radiation as an adjuvant therapy in cutaneous melanoma patients is ineffective. Obesity has now been recognized as a risk factor for melanoma. High adiposity is generally associated with a more pro-oxidative status. Oxidative stress is a major player in radiation therapy and also a common link between obesity and cancer. Several adipocyte-released proteins are known to have a role in controlling cellular growth and pro-survival signaling. For that reason, we investigated the influence of 3T3-L1 mature adipocyte secretome in B16-F10 malignant melanocyte radiosensitivity. We evaluated B16-F10 cell survival and redox homeostasis when exposed to four daily doses of ionizing radiation (2 Gy per day) up to a total of 8 Gy in a medical linear accelerator. B16-F10 melanocytes exhibited slight alterations in survival, catalase activity, nitrative stress and total oxidant concentration after the first 2 Gy irradiation. The motility of the melanocytes was also delayed by ionizing radiation. Subsequent irradiations of the malignant melanocytes led to more prominent reductions in overall survival. Remarkably, 3T3-L1 adipocyte-secreted molecules were able to increase the viability and migration of melanocytes, as well as lessen the pro-oxidant burden induced by both the single and cumulative X-ray doses. In vitro adipocyte-released factors protected B16-F10 malignant melanocytes from both oxidative stress and loss of viability triggered by radiation, enhancing the radioresistant phenoyype of these cells with a concomitant activation of the AKT signaling pathway These results both help to elucidate how obesity influences melanoma radioresistance and support the usage of conventional medical linear accelerators as a valid model for the in vitro radiobiological study of tumor cell lines.
- Application of gold nanoparticles as radiosensitizer for metastatic prostate cancer cell linesPublication . Soares, Sílvia; Faria, Isabel; Aires, Fátima; Monteiro, Armanda; Pinto, Gabriela; Sales, Maria Goreti; Correa-Duarte, Miguel A.; Guerreiro, Susana G.; Fernandes, RúbenMore than 50% of all prostate cancer (PCa) patients are treated by radiotherapy (RT). Radioresistance and cancer recurrence are two consequences of the therapy and are related to dose heterogeneity and non-selectivity between normal and tumoral cells. Gold nanoparticles (AuNPs) could be used as potential radiosensitizers to overcome these therapeutic limitations of RT. This study assessed the biological interaction of different morphologies of AuNPs with ionizing radiation (IR) in PCa cells. To achieve that aim, three different amine-pegylated AuNPs were synthesized with distinct sizes and shapes (spherical, AuNPsp-PEG, star, AuNPst-PEG, and rods, AuNPr-PEG) and viability, injury and colony assays were used to analyze their biological effect on PCa cells (PC3, DU145, and LNCaP) when submitted to the accumulative fraction of RT. The combinatory effect of AuNPs with IR decreased cell viability and increased apoptosis compared to cells treated only with IR or untreated cells. Additionally, our results showed an increase in the sensitization enhancement ratio by cells treated with AuNPs and IR, and this effect is cell line dependent. Our findings support that the design of AuNPs modulated their cellular behavior and suggested that AuNPs could improve the RT efficacy in PCa cells.
- Automated fluence map optimization based on fuzzy inference systemsPublication . Dias, Joana; Rocha, Humberto; Ventura, Tiago; BC Ferreira; Lopes, Maria do CarmoThe planning of an intensity modulated radiation therapy treatment requires the optimization of the fluence intensities. The fluence map optimization (FMO) is many times based on a nonlinear continuous programming problem, being necessary for the planner to define a priori weights and/or lower bounds that are iteratively changed within a trial-and-error procedure until an acceptable plan is reached. In this work, the authors describe an alternative approach for FMO that releases the human planner from trial-and-error procedures, contributing for the automation of the planning process.
- Beam angle optimization in IMRT: are we really optimizing what matters?Publication . Rocha, Humberto; Dias, Joana Matos; Ventura, Tiago; BC Ferreira; Lopes, Maria do CarmoIntensity‐modulated radiation therapy (IMRT) is a modern radiotherapy modality that uses a multileaf collimator to enable the irradiation of the patient with nonuniform maps of radiation from a set of distinct beam irradiation directions. The aim of IMRT is to eradicate all cancerous cells by irradiating the tumor with a prescribed dose while simultaneously sparing, as much as possible, the neighboring tissues and organs. The optimal choice of beam irradiation directions—beam angle optimization (BAO)—can play an important role in IMRT treatment planning by improving organ sparing and tumor coverage, increasing the treatment plan quality. Typically, the BAO search is guided by the optimal value of the fluence map optimization (FMO)—the problem of obtaining the most appropriate radiation intensities for each beam direction. In this paper, a new score to guide the BAO search is introduced and embedded in a parallel multistart derivative‐free optimization framework that is detailed for the extremely challenging continuous BAO problem. For the set of 10 clinical nasopharyngeal tumor cases considered, treatment plans obtained for optimized beam directions clearly outperform the benchmark treatment plans obtained considering equidistant beam directions typically used in clinical practice. Furthermore, treatment plans obtained considering the proposed score clearly improve the quality of the plans resulting from the use of the optimal value of the FMO problem to guide the BAO search.
- Biological dose-escalated definitive radiation therapy in head and neck cancerPublication . Costa Ferreira, Brigida; Sá-Couto, Pedro; Khouri, Leila; Lopes, Maria do CarmoTo compare treatment outcome of patients with head and neck (HN) tumours treated with definitive radiation therapy that, mainly owing to differences in the fractionation scheme used with simultaneous integrated boost techniques, resulted in a different biological dose.
- Clinical and metabolic implications of obesity in prostate cancer: is testosterone a missing link?Publication . Duarte, Fernanda; Luís, C.; Baylina, Pilar; Faria, Isabel; Fernandes, Rúben; La Fuente, J. M.Objectives: To assess sex hormones in men with obesity and prostate cancer (PCa) and to study association between androgens and the pathogenesis biology of PCa in vitro. Subjects and methods: One hundred and eighty-one men older than 45 years selected from of a population attending to Urology departments screening for PCa, (78 participants without PCa and 103 patients with PCa). All participants were assessed for body mass index (BMI), age, Gleason score, and PSA. Endocrine profile was determined for LH, total testosterone (TT), 17β-estradiol (E2), prolactin and leptin. Biochemical profile (HbA1c, triacylglycerols and lipoproteins) was also determined. In vitro experiments were also performed, involving the study of 5α-dihydrotestosterone (DHT) and E2 in the presence of adipocyte-conditioned medium (aCM). Results: All variables were continuous and described a Gaussian distribution unless mentioned. To determine the relation of aggressiveness, variable were transformed into categories. Thus, PCa aggressiveness is associated with the increase of age and BMI (p < .0001) but with is decreased with TT and E2 (p < .05). Moreover, adipocyte-secreted molecules increase aggressiveness of PCa cells in vitro. Lastly, DTH but not E2 enables invasiveness in vitro. Conclusions: It was observed a coexistence of hormone axis profile alteration with sex hormones and BMI in PCa patients, in accordance with the new perspective of PCa pathogenesis.
- Clinical validation of a graphical method for radiation therapy plan quality assessmentPublication . Ventura, Tiago; Dias, Joana; Khouri, Leila; Netto, Eduardo; Soares, André; Costa Ferreira, Brigida; Rocha, Humberto; Lopes, Maria do CarmoBackground: This work aims at clinically validating a graphical tool developed for treatment plan assessment, named SPIDERplan, by comparing the plan choices based on its scoring with the radiation oncologists (RO) clinical preferences. Methods: SPIDERplan validation was performed for nasopharynx pathology in two steps. In the first step, three ROs from three Portuguese radiotherapy departments were asked to blindly evaluate and rank the dose distributions of twenty pairs of treatment plans. For plan ranking, the best plan from each pair was selected. For plan evaluation, the qualitative classification of ‘Good’, ‘Admissible with minor deviations’ and ‘Not Admissible’ were assigned to each plan. In the second step, SPIDERplan was applied to the same twenty patient cases. The tool was configured for two sets of structures groups: the local clinical set and the groups of structures suggested in international guidelines for nasopharynx cancer. Group weights, quantifying the importance of each group and incorporated in SPIDERplan, were defined according to RO clinical preferences and determined automatically by applying a mixed linear programming model for implicit elicitation of preferences. Intra- and inter-rater ROs plan selection and evaluation were assessed using Brennan-Prediger kappa coefficient. Results: Two-thirds of the plans were qualitatively evaluated by the ROs as ‘Good’. Concerning intra- and inter-rater variabilities of plan selection, fair agreements were obtained for most of the ROs. For plan evaluation, substantial agreements were verified in most cases. The choice of the best plan made by SPIDERplan was identical for all sets of groups and, in most cases, agreed with RO plan selection. Differences between RO choice and SPIDERplan analysis only occurred in cases for which the score differences between the plans was very low. A score difference threshold of 0.005 was defined as the value below which two plans are considered of equivalent quality. Conclusion: Generally, SPIDERplan response successfully reproduced the ROs plan selection. SPIDERplan assessment performance can represent clinical preferences based either on manual or automatic group weight assignment. For nasopharynx cases, SPIDERplan was robust in terms of the definitions of structure groups, being able to support different configurations without losing accuracy.
- Comparison of two beam angular optimization algorithms guided by automated multicriterial IMRTPublication . Ventura, Tiago; Rocha, Humberto; Costa Ferreira, Brigida; Dias, Joana; Lopes, Maria do CarmoTo compare two beam angle optimization (BAO) algorithms for coplanar and non-coplanar geometries in a multicriterial optimization framework.
- Compliance to radiation therapy of head and neck cancer patients and impact on treatment outcomePublication . Costa Ferreira, Brigida; Sá-Couto, P.; Lopes, M. C.; Khouri, L.The aims of the study were to evaluate head and neck cancer (HNC) patient's compliance to the planned radiation therapy (RT) using the department policy established in 2005 at IPOCFG and to estimate the impact on treatment outcome due to failure in receiving RT as prescribed.
- A derivative-free multistart framework for an automated noncoplanar beam angle optimization in IMRTPublication . Rocha, Humberto; Dias, Joana; Ventura, Tiago; BC Ferreira; Lopes, Maria do CarmoThe inverse planning of an intensity-modulated radiation therapy (IMRT) treatment requires decisions regarding the angles used for radiation incidence, even when arcs are used. The possibility of improving the quality of treatment plans by an optimized selection of the beam angle incidences-beam angle optimization (BAO)-is seldom done in clinical practice. The inclusion of noncoplanar beam incidences in an automated optimization routine is even more unusual. However, for some tumor sites, the advantage of considering noncoplanar beam incidences is well known. This paper presents the benefits of using a derivative-free multistart framework for the optimization of the noncoplanar BAO problem.
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