Risk scores' performance and their impact on operative decision-making in left-sided endocarditis: a cohort study.

The accuracy of contemporary risk scores in predicting perioperative mortality in infective endocarditis (IE) remains controversial. The aim is to evaluate the performance of existent mortality risk scores for cardiovascular surgery in IE and the impact on operability at high-risk thresholds. A single-center retrospective review of adult patients diagnosed with acute left-sided IE undergoing surgery from May 2014 to August 2019 (n = 142) was done. Individualized risk calculation was obtained according to the available mortality risk scores: EuroScore I and II, PALSUSE, Risk-E, Costa, De Feo-Cotrufo, AEPEI, STS-risk, STS-IE, APORTEI, and ICE-PCS scores. A cross-validation analysis was performed on the score with the best area under the curve (AUC). The 30-day survival was 96.5% (95%CI 91-98%). The score with worse area under the curve (AUC = 0.6) was the STS-IE score, while the higher was for the RISK-E score (AUC = 0.89). The AUC of the majority of risk scores suggested acceptable performance; however, statistically significant differences in expected versus observed mortalities were common. The cross-validation analysis showed that a large number of survivors (> 75%) would not have been operated if arbitrary high-risk threshold estimates had been used to deny surgery. The observed mortality in our cohort is significantly lower than is predicted by contemporary risk scores. Despite the reasonable numeric performance of the analyzed scores, their utility in judging the operability of a given patient remains questionable, as demonstrated in the cross-validation analysis. Future guidelines may advise that denial of surgery should only follow a highly experienced Endocarditis Team evaluation.

Study of the intracellular nanoparticle-based radiosensitization mechanisms in F98 glioma cells treated with charged particle therapy through synchrotron-based infrared microspectroscopy.

The use of nanoparticles (NP) as dose enhancers in radiotherapy (RT) is a growing research field. Recently, the use of NP has been extended to charged particle therapy in order to improve the performance in radioresistant tumors. However, the biological mechanisms underlying the synergistic effects involved in NP-RT approaches are not clearly understood. Here, we used the capabilities of synchrotron-based Fourier Transform Infrared Microspectroscopy (SR-FTIRM) as a bio-analytical tool to elucidate the NP-induced cellular damage at the molecular level and at a single-cell scale. F98 glioma cells doped with AuNP and GdNP were irradiated using several types of medical ion beams (proton, helium, carbon and oxygen). Differences in cell composition were analyzed in the nucleic acids, protein and lipid spectral regions using multivariate methods (Principal Component Analysis, PCA). Several NP-induced cellular modifications were detected, such as conformational changes in secondary protein structures, intensity variations in the lipid CHx stretching bands, as well as complex DNA rearrangements following charged particle therapy irradiations. These spectral features seem to be correlated with the already shown enhancement both in the DNA damage response and in the reactive oxygen species (ROS) production by the NP, which causes cell damage in the form of protein, lipid, and/or DNA oxidations. Vibrational features were NP-dependent due to the NP heterogeneous radiosensitization capability. Our results provided new insights into the molecular changes in response to NP-based RT treatments using ion beams, and highlighted the relevance of SR-FTIRM as a useful and precise technique for assessing cell response to innovative radiotherapy approaches.

A synchrotron-based infrared microspectroscopy study on the cellular response induced by gold nanoparticles combined with X-ray irradiations on F98 and U87-MG glioma cell lines.

The inclusion of nanoparticles (NP) in radiotherapy has been shown to increase the damaging effect on tumor cells. However, the mechanisms of action of NP combined with radiotherapy, and the influence of NP parameters and cell type on their radiosensitization capability at molecular and cellular levels still remain unclear. Gold NP (AuNP) have become particularly popular due to their multiple advantages. Within this context, our research work aimed to study the biochemical radiosensitization capacity of F98 and U87-MG glioma cell lines to 1.9 nm AuNP combined with X-ray irradiation. For this purpose, synchrotron-based infrared microspectroscopy (SR-FTIRM) was used as a powerful tool for biochemical composition and treatment response assessment of cells at a single-cell level. SR-FTIRM data, supported by multivariate analysis, revealed clear AuNP-induced changes in the DNA, protein and lipid spectral regions. The AuNP-related biochemical alterations appear prior to the irradiation, which gave us a first indication on the AuNP radiosensitization action. Biochemical modifications induced by the AuNP in the presence of radiotherapy irradiations include enhanced conformational changes in the protein secondary structures, variations in the intensity and position in the phosphodiester bands, and changes in the CH2 and CH3 stretching modes. These changes are better manifested at 24 hours post-irradiation time. SR-FTIRM results showed a clear heterogeneity in the biochemical cell response, probably due to the distinct cell-NP interactions and thus, to different DNA damage and cell death processes.

Development and commissioning of a Monte Carlo photon beam model for the forthcoming clinical trials in microbeam radiation therapy.

PURPOSE: A new radiotherapy technique, named microbeam radiation therapy (MRT), is under development at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). This innovative method is based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The promising results obtained in the preclinical studies have paved the way to forthcoming clinical trials, which are currently in preparation. Highly accurate dose calculations at the treatment planning stage are required in this context. The aims of this study are the development and experimental benchmarking of a photon beam source model, which will be the core of the future MRT treatment planning system (TPS). METHODS: The ID17 x-ray source was modeled by the synchrotron ray tracing code SHADOW. The Monte Carlo (MC) simulation code PENELOPE/PENEASY was employed to transport the photon beam from the source to the patient position through all the beamline components. The phase-space state variables of the particles reaching the patient position were used as an input to generate a photon beam model. Computed dose distributions in a homogeneous media were experimentally verified by using Gafchromic(®) films in a solid-water phantom. Benchmarking was split into two phases. First, the lateral dose profiles and the percentage depth-dose (PDD) curves in the broad beam configuration were considered. The acceptability criteria for radiotherapy dose computations recommended by international protocols such as the Technical Reports Series 430 (TRS 430) of the International Atomic Energy Agency (IAEA) were used. Second, the analogous dosimetric magnitudes in MRT irradiations, i.e., PDD of the central microbeam and the corresponding peak-to-valley dose ratios (PVDR) were evaluated and compared with MC calculations. RESULTS: A full characterization of the ID17 Biomedical Beamline (ESRF) synchrotron x-ray source and the development of an accurate photon beam model were achieved in this work. Calculated and experimental dose distributions agreed to within the recommended acceptability criteria described in international codes of practice (TRS 430) for broad beam irradiations. The overall deviation in low gradient areas amounted to 2%-3%. The maximum distance-to-agreement in high gradient regions was lower than 0.7 mm. MC calculations also reproduced MRT experimental results within uncertainty bars. These results validate the photon beam model for its use in MRT radiation therapy calculations. CONCLUSIONS: The first MC synchrotron photon beam model for MRT irradiations that reproduces experimental dose distributions in homogeneous media has been developed. This beam model will constitute an essential component of the TPS calculation engine for patient dose computation in forthcoming MRT clinical trials.

Scatter factors assessment in microbeam radiation therapy.

PURPOSE: The success of the preclinical studies in Microbeam Radiation Therapy (MRT) paved the way to the clinical trials under preparation at the Biomedical Beamline of the European Synchrotron Radiation Facility. Within this framework, an accurate determination of the deposited dose is crucial. With that aim, the scatter factors, which translate the absolute dose measured in reference conditions (2 × 2 cm(2) field size at 2 cm-depth in water) to peak doses, were assessed. METHODS: Monte Carlo (MC) simulations were performed with two different widely used codes, PENELOPE and GEANT4, for the sake of safety. The scatter factors were obtained as the ratio of the doses that are deposited by a microbeam and by a field of reference size, at the reference depth. The calculated values were compared with the experimental data obtained by radiochromic (ISP HD-810) films and a PTW 34070 large area chamber. RESULTS: The scatter factors for different microbeam field sizes assessed by the two MC codes were in agreement and reproduced the experimental data within uncertainty bars. Those correction factors were shown to be non-negligible for the future MRT clinical settings: an average 30% lower dose was deposited by a 50 µm microbeam with respect to the reference conditions. CONCLUSIONS: For the first time, the scatter factors in MRT were systematically studied. They constitute an essential key to deposit accurate doses in the forthcoming clinical trials in MRT. The good agreement between the different calculations and the experimental data confirms the reliability of this challenging micrometric dose estimation.

Monte Carlo-based treatment planning system calculation engine for microbeam radiation therapy.

PURPOSE: Microbeam radiation therapy (MRT) is a synchrotron radiotherapy technique that explores the limits of the dose-volume effect. Preclinical studies have shown that MRT irradiations (arrays of 25-75-µm-wide microbeams spaced by 200-400 µm) are able to eradicate highly aggressive animal tumor models while healthy tissue is preserved. These promising results have provided the basis for the forthcoming clinical trials at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). The first step includes irradiation of pets (cats and dogs) as a milestone before treatment of human patients. Within this context, accurate dose calculations are required. The distinct features of both beam generation and irradiation geometry in MRT with respect to conventional techniques require the development of a specific MRT treatment planning system (TPS). In particular, a Monte Carlo (MC)-based calculation engine for the MRT TPS has been developed in this work. Experimental verification in heterogeneous phantoms and optimization of the computation time have also been performed. METHODS: The penelope/penEasy MC code was used to compute dose distributions from a realistic beam source model. Experimental verification was carried out by means of radiochromic films placed within heterogeneous slab-phantoms. Once validation was completed, dose computations in a virtual model of a patient, reconstructed from computed tomography (CT) images, were performed. To this end, decoupling of the CT image voxel grid (a few cubic millimeter volume) to the dose bin grid, which has micrometer dimensions in the transversal direction of the microbeams, was performed. Optimization of the simulation parameters, the use of variance-reduction (VR) techniques, and other methods, such as the parallelization of the simulations, were applied in order to speed up the dose computation. RESULTS: Good agreement between MC simulations and experimental results was achieved, even at the interfaces between two different media. Optimization of the simulation parameters and the use of VR techniques saved a significant amount of computation time. Finally, parallelization of the simulations improved even further the calculation time, which reached 1 day for a typical irradiation case envisaged in the forthcoming clinical trials in MRT. An example of MRT treatment in a dog's head is presented, showing the performance of the calculation engine. CONCLUSIONS: The development of the first MC-based calculation engine for the future TPS devoted to MRT has been accomplished. This will constitute an essential tool for the future clinical trials on pets at the ESRF. The MC engine is able to calculate dose distributions in micrometer-sized bins in complex voxelized CT structures in a reasonable amount of time. Minimization of the computation time by using several approaches has led to timings that are adequate for pet radiotherapy at synchrotron facilities. The next step will consist in its integration into a user-friendly graphical front-end.

Unilateral pulmonary edema associated factors after minimally invasive mitral valve surgery.

BACKGROUND AND OBJECTIVES: In recent years, minimally invasive cardiac surgery (MICS) has been developed and applied to a greater number of pathologies, especially in mitral valve surgeries, as it obtains results comparable to those of conventional techniques while entailing lower surgical trauma and shorter recovery time. MICS requiring one-lung ventilation has been associated to the appearance of unilateral pulmonary edema (UPE), which is a potentially serious complication. The objective is determining the incidence of UPE after mitral MICS and its development associated factors. MATERIAL AND METHODS: Observational descriptive and single-center study analyzing data from patients undergoing mitral valve MICS (right mini-thoracotomy) consecutively collected between the years 2015 and 2017. RESULTS: A total of 93 patients were included and 26 presented UPE. The most common complications after mitral valve MICS were atrial fibrillation (38.7%), UPE (28%) and transient and/or definitive second- or third-degree auriculoventricular block (19.4%). The UPE group had longer ICU stay (3.3 ± 8.0 vs. 1.84 ± 2.23 days) and longer total hospitalization length-of-stay (15.5 ± 34.7 vs. 10.6 ± 7.5 days). The mortality in the UPE group was 3.9%. A significant association was found between the following collected variables and the development of postoperative UPE: preoperative baseline pulse oximetry, preoperative use of ACE inhibitors, postoperative atrial fibrillation and 24 first-hours cumulative chest tube drainage volume on the first 24 h. CONCLUSIONS: The incidence of UPE is high and its appearance is associated with a longer ICU and total length of stay. More studies are required to understand its pathophysiology and apply measures to help decreasing its appearance.

Monte Carlo dose enhancement studies in microbeam radiation therapy.

PURPOSE: A radical radiation therapy treatment for gliomas requires extremely high absorbed doses resulting in subsequent deleterious side effects in healthy tissue. Microbeam radiation therapy (MRT) is an innovative technique based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The synchrotron-generated x-ray beam is collimated and delivered to an array of narrow micrometer-sized planar rectangular fields. Several preclinical experiments performed at the Brookhaven National Laboratory (BNL) and at the European Synchrotron Radiation Facility (ESRF) confirmed that MRT yields a higher therapeutic index than nonsegmented beams of the same characteristics. This index can be greatly improved by loading the tumor with high atomic number (Z) contrast agents. The aim of this work is to find the high-Z element that provides optimum dose enhancement. METHODS: Monte Carlo simulations (PENELOPE/penEasy) were performed to assess the peak and valley doses as well as their ratio (PVDR) in healthy tissue and in the tumor, loaded with different contrast agents. The optimization criteria used were maximization of the ratio between the PVDR values in healthy tissue respect to the PVDR in the tumor and minimization of bone and brain valley doses. RESULTS: Dose enhancement factors, PVDR, and valley doses were calculated for different high-Z elements. A significant decrease of PVDR values in the tumor, accompanied by a gain in the valley doses, was found in the presence of high-Z elements. This enables the deposited dose in the healthy tissue to be reduced. The optimum high-Z element depends on the irradiation configuration. As a general trend, the best outcome is provided by the highest Z contrast agents considered, i.e., gold and thallium. However, lanthanides (especially Lu) and hafnium also offer a satisfactory performance. CONCLUSIONS: The remarkable therapeutic index in microbeam radiation therapy can be further improved by loading the tumor with a high-Z element. This study reports quantitative data on several dosimetric magnitudes in order to find the optimum contrast agent. Although the final choice of the element will also depend on possible cytotoxicity, three elements were found to be worthy of mention: gold, thallium, and lutetium.

Dosimetry protocol for the preclinical trials in white-beam minibeam radiation therapy.

PURPOSE: In the quest of a curative radiotherapy treatment for gliomas, new delivery modes are being explored. At the Biomedical Beamline of the European Synchrotron Radiation Facility, a new spatially fractionated technique, called minibeam radiation therapy (MBRT), is under development. The aims of this work were to assess different dosimetric aspects and to establish a dosimetry protocol to be applied in the forthcoming animal (rat) studies in order to evaluate the therapeutic index of this new radiotherapy approach. METHODS: Absolute dosimetry was performed with a thimble ionization chamber (PTW semiflex 31010) whose center was positioned at 2 g cm(-2) depth. To translate the dose measured in broad beam configuration to the dose deposited with a minibeam, the scatter factors were used. Those were assessed by using the Monte Carlo simulations and verified experimentally with Gafchromic films and a Bragg Peak chamber. The comparison of the theoretical and experimental data were used to benchmark the calculations. Finally, the dose distributions in a rat phantom were evaluated by using the validated Monte Carlo calculations. RESULTS: The absolute dosimetry in broad beam configuration was measured in reference conditions. The dose rate was in the range between 168 and 224 Gy∕min, depending on the storage ring current. A scatter factor of 0.80 ± 0.04 was obtained. Percentage depth dose and lateral profiles were evaluated both in homogenous and heterogeneous slab phantoms. The general good agreement between Monte Carlo simulations and experimental data permitted the benchmark of the calculations. Finally, the peak doses in the rat head phantom were assessed from the measurements in reference conditions. In addition, the peak-to-valley dose ratio values as a function of depth in the rat head were evaluated. CONCLUSIONS: A new promising radiotherapy approach is being explored at the ESRF: Minibeam Radiation Therapy. To assess the therapeutic index of this new modality, in vivo experiments are being planned, for which an accurate knowledge of the dosimetry is essential. For that purpose, a complete set of measurements and Monte Carlo simulations was performed. The first dosimetry protocol for preclinical trials in minibeam radiation therapy was established. This protocol allows to have reproducibility in terms of dose for the different biological studies.

Dosimetry protocol for the forthcoming clinical trials in synchrotron stereotactic radiation therapy (SSRT).

PURPOSE: An adequate dosimetry protocol for synchrotron radiation and the specific features of the ID17 Biomedical Beamline at the European Synchrotron Radiation Facility are essential for the preparation of the forthcoming clinical trials in the synchrotron stereotactic radiation therapy (SSRT). The main aim of this work is the definition of a suitable protocol based on standards of dose absorbed to water. It must allow measuring the absolute dose with an uncertainty within the recommended limits for patient treatment of 2%-5%. METHODS: Absolute dosimetry is performed with a thimble ionization chamber (PTW semiflex 31002) whose center is positioned at 2 g cm(-2) equivalent depth in water. Since the available synchrotron beam at the ESRF Biomedical Beamline has a maximum height of 3 mm, a scanning method was employed to mimic a uniform exposition of the ionization chamber. The scanning method has been shown to be equivalent to a broad beam irradiation. Different correction factors have been assessed by using Monte Carlo simulations. RESULTS: The absolute dose absorbed to water at 80 keV was measured in reference conditions with a 2% global uncertainty, within the recommended limits. The dose rate was determined to be in the range between 14 and 18 Gy/min, that is to say, a factor two to three times higher than the 6 Gy/min achievable in RapidArc or VMAT machines. The dose absorbed to water was also measured in a RW3 solid water phantom. This phantom is suitable for quality assurance purposes since less than 2% average difference with respect to the water phantom measurements was found. In addition, output factors were assessed for different field sizes. CONCLUSIONS: A dosimetry protocol adequate for the specific features of the SSRT technique has been developed. This protocol allows measuring the absolute dose absorbed to water with an accuracy of 2%. It is therefore satisfactory for patient treatment.

Out-of-field doses for scanning proton radiotherapy of shallowly located paediatric tumours-a comparison of range shifter and 3D printed compensator.

The lowest possible energy of proton scanning beam in cyclotron proton therapy facilities is typically between 60 and 100 MeV. Treatment of superficial lesions requires a pre-absorber to deliver doses to shallower volumes. In most of the cases a range shifter (RS) is used, but as an alternative solution, a patient-specific 3D printed proton beam compensator (BC) can be applied. A BC enables further reduction of the air gap and consequently reduction of beam scattering. Such pre-absorbers are additional sources of secondary radiation. The aim of this work was the comparison of RS and BC with respect to out-of-field doses for a simulated treatment of superficial paediatric brain tumours. EURADOS WG9 performed comparative measurements of scattered radiation in the Proteus C-235 IBA facility (Cyclotron Centre Bronowice at the Institute of Nuclear Physics, CCB IFJ PAN, Kraków, Poland) using two anthropomorphic phantoms-5 and 10 yr old-for a superficial target in the brain. Both active detectors located inside the therapy room, and passive detectors placed inside the phantoms were used. Measurements were supplemented by Monte Carlo simulation of the radiation transport. For the applied 3D printed pre-absorbers, out-of-field doses from both secondary photons and neutrons were lower than for RS. Measurements with active environmental dosimeters at five positions inside the therapy room indicated that the RS/BC ratio of the out-of-field dose was also higher than one, with a maximum of 1.7. Photon dose inside phantoms leads to higher out-of-field doses for RS than BC to almost all organs with the highest RS/BC ratio 12.5 and 13.2 for breasts for 5 and 10 yr old phantoms, respectively. For organs closest to the isocentre such as the thyroid, neutron doses were lower for BC than RS due to neutrons moderation in the target volume, but for more distant organs like bladder-conversely-lower doses for RS than BC were observed. The use of 3D printed BC as the pre-absorber placed in the near vicinity of patient in the treatment of superficial tumours does not result in the increase of secondary radiation compared to the treatment with RS, placed far from the patient.

Transoesophageal echocardiography accurately detects cardiac output variation: a prospective comparison with thermodilution in cardiac surgery.

BACKGROUND AND OBJECTIVE: Intraoperative Doppler ultrasound can be used to measure cardiac output by transoesophageal echocardiography. Recently, its reliability, when compared to the thermodilution technique, has been questioned. The purpose of this study was to compare intraoperative changes in cardiac output measured by echo-Doppler and by thermodilution in cardiac surgery. We also assessed the agreement between the techniques. METHODS: Fifty cardiac surgical patients (38 male, 12 female, mean age of 63.4 +/- 14.3 yr) were prospectively included after approval by the Ethics Committee of the Institution. Cardiac output was assessed by thermodilution, with 10 mL saline at 12 degrees C, and simultaneously and blindly by echo-Doppler in deep transgastric view with pulsed wave Doppler at the level of the left ventricular outflow tract. Matched thermodilution cardiac output and echo-Doppler cardiac output measurements were taken three times at the end of expiration, both pre- and post-cardiopulmonary bypass. RESULTS: Echo-Doppler measurements were obtained in 44 patients (88%). In three patients, Doppler recordings could not be obtained adequately, and three developed left ventricular outflow tract obstruction after bypass. Bland-Altman analysis revealed a bias of 0.015 L min(-1), with narrow limits of agreement (-1.21 to 1.22 L min(-1)) and 29.1% error. Echo-Doppler was accurate (92% sensitivity and 71% specificity, P = 0.008 by receiver operating characteristic curves) for detecting more than 10% of change in thermodilution cardiac output. There were no complications related to the study. CONCLUSIONS: The agreement between cardiac output by echo-Doppler and by thermodilution is clinically acceptable and transoesophageal echocardiography is a reliable tool to assess significant cardiac output changes in a population of selected patients.

[Serious mechanical complications associated with pulmonary artery catheters in cardiovascular and thoracic surgery]. / Complicaciones graves de tipo mecánico asociadas al catéter de arteria pulmonar en cirugía cardiovascular y torácica.

OBJECTIVE: Although the use of pulmonary artery catheters (PACs) in managing critical patients is a subject of debate, they continue to be inserted in many cases and possible complications should be taken into account. Our objective was to review the serious or potentially serious complications associated with PACs in our hospital in the past 15 years. PATIENTS AND METHODS: This was a retrospective study of seious mechanical complications of PAC use in patients who underwent vascular, cardiac, and thoracic surgery. RESULTS: The study included the records 7540 patients; 9 cases of serious complications were detected. These complications included 5 cases of pulmonary artery rupture (3 of which resulted in death), 1 perforated internal mammary vein, 1 knotted catheter, 1 bent one, and 1 case of a PAC becoming trapped in the surgical suture. CONCLUSIONS: The 0.12% incidence of complications is lower than rates found in the literature. Although these complications are rare, it is necessary to take precautions against their unexcepted appearance by carefully selecting the patients in whom PACs are placed and by paying special attention to the characteristic clinical and radiological signs of complications.

[Specialized training in anesthesiology: the opinions of supervising tutors]. / La formación especializada en Anestesiología desde la perspectiva de los tutores.

OBJECTIVE: To evaluate the common curriculum for teaching theoretical knowledge in anesthesiology in Catalonia, Spain; to assess differences between hospital teaching programs, evaluation systems, and the situation for tutors. MATERIAL AND METHODS: A 35-item questionnaire was sent to 49 accredited tutors during the 2005-2006 academic year. The questionnaire covered 1) the curriculum and training rotations, 2) teaching and research, and 3) assessment and tutorial interventions. An additional question asked the respondent's view on how to improve instruction. RESULTS: Eighty-five percent of the tutors responded. Seventy-eight percent of the residents (168/216) follow some form of external rotation, most often in pediatric anesthesia (79%). The common courses are considered useful by 96% of the tutors. Ninety-two percent are satisfied with the current annual examination and 79% would extend the residency training period to 5 years. Eighty-two percent of the teaching centers have weekly instructional sessions. Eighty-one percent of the tutors consider the resident's logbook, filled in by 77% of residents, to be useful for assessment. Eighty-five percent take teacher training courses, 65% feel that their work is being recognized, and 92% do not allot a specific period of time for teaching. CONCLUSIONS: The survey has helped shed light on the current training situation in Catalonia. The common courses are of great help. The number of external rotations is high, overloading certain areas. Improvements could be made by unifying external rotations, updating the curriculum and extending the training period to 5 years, recognizing the role of the tutor, and establishing a specific time for teaching activity.

COMPARISON OF RESPONSE OF PASSIVE DOSIMETRY SYSTEMS IN SCANNING PROTON RADIOTHERAPY-A STUDY USING PAEDIATRIC ANTHROPOMORPHIC PHANTOMS.

Proton beam therapy has advantages in comparison to conventional photon radiotherapy due to the physical properties of proton beams (e.g. sharp distal fall off, adjustable range and modulation). In proton therapy, there is the possibility of sparing healthy tissue close to the target volume. This is especially important when tumours are located next to critical organs and while treating cancer in paediatric patients. On the other hand, the interactions of protons with matter result in the production of secondary radiation, mostly neutrons and gamma radiation, which deposit their energy at a distance from the target. The aim of this study was to compare the response of different passive dosimetry systems in mixed radiation field induced by proton pencil beam inside anthropomorphic phantoms representing 5 and 10 years old children. Doses were measured in different organs with thermoluminescent (MTS-7, MTS-6 and MCP-N), radiophotoluminescent (GD-352 M and GD-302M), bubble and poly-allyl-diglycol carbonate (PADC) track detectors. Results show that RPL detectors are the less sensitive for neutrons than LiF TLDs and can be applied for in-phantom dosimetry of gamma component. Neutron doses determined using track detectors, bubble detectors and pairs of MTS-7/MTS-6 are consistent within the uncertainty range. This is the first study dealing with measurements on child anthropomorphic phantoms irradiated by a pencil scanning beam technique.

A requirement for the rac1 GTPase in the signal transduction pathway leading to cardiac myocyte hypertrophy.

We have used adenoviral-mediated gene transfer of a constitutively active (V12rac1) and dominant negative (N17rac1) isoform of rac1 to assess the role of this small GTPase in cardiac myocyte hypertrophy. Expression of V12rac1 in neonatal cardiac myocytes results in sarcomeric reorganization and an increase in cell size that is indistinguishable from ligand-stimulated hypertrophy. In addition, V12rac1 expression leads to an increase in atrial natriuretic peptide secretion. In contrast, expression of N17rac1, but not a truncated form of Raf-1, attenuated the morphological hypertrophy associated with phenylephrine stimulation. Consistent with the observed effects on morphology, expression of V12rac1 resulted in an increase in new protein synthesis, while N17rac1 expression inhibited phenylephrine-induced leucine incorporation. These results suggest rac1 is an essential element of the signaling pathway leading to cardiac myocyte hypertrophy.

Endothelial progenitor cells as putative targets for angiostatin.

Angiostatin, a product of the proteolytic cleavage of plasminogen, possesses potent antitumor and antiangiogenic properties in vivo. Studies with cultured endothelial cells suggest that under certain conditions, angiostatin inhibits the migration and proliferation of these cells or, alternatively, increases their rate of apoptosis. In general, the effects of angiostatin have been considerably less potent in vitro than in vivo. One potential explanation for this disparity is that the in vivo target of angiostatin is not the mature endothelial cell. Recently, evidence has accumulated to show that circulating endothelial progenitor cells (EPCs) contribute to neovascularization. In this study, we have isolated EPCs from human subjects and demonstrated that, in contrast to that of mature endothelial cells, the growth of EPCs is exquisitely sensitive to angiostatin. These results suggest that angiostatin and related compounds may exert their biological effects by inhibiting the contribution of EPCs to angiogenesis and not by altering the growth of mature endothelial cells.

Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles.

PURPOSE: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors' work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. METHODS: For this purpose, Monte Carlo calculations (gate/geant4 code) were performed. In particular, the geant4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes). RESULTS: This Monte Carlo study shows the influence of the simulations' parameters on the local dose enhancement and how more realistic configurations lead to a negligible increase of local energy deposition. The obtained dose enhancement factor was up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations). Additionally, no significant increase in the dissociative electron attachment processes was observed. CONCLUSIONS: The authors' results indicate that physical effects play a minor role in the amplification of damage, as a very low dose enhancement or increase of dissociative electron attachment processes is observed when the authors get closer to more realistic simulations. Thus, other effects, such as biological or chemical processes, may be mainly responsible for the enhanced radiosensibilization observed in biological studies. However, more biological studies are needed to verify this hypothesis.

Dosimetric evaluation of new approaches in GRID therapy using nonconventional radiation sources.

PURPOSE: Spatial fractionation of the dose has proven to be a promising approach to increase the tolerance of healthy tissue, which is the main limitation of radiotherapy. A good example of that is GRID therapy, which has been successfully used in the management of large tumors with low toxicity. The aim of this work is to explore new avenues using nonconventional sources: GRID therapy by using kilovoltage (synchrotron) x-rays, the use of very high-energy electrons, and proton GRID therapy. They share in common the use of the smallest possible grid sizes in order to exploit the dose-volume effects. METHODS: Monte Carlo simulations (penelope/peneasy and geant4/GATE codes) were used as a method to study dose distributions resulting from irradiations in different configurations of the three proposed techniques. As figure of merit, percentage (peak and valley) depth dose curves, penumbras, and central peak-to-valley dose ratios (PVDR) were evaluated. As shown in previous biological experiments, high PVDR values are requested for healthy tissue sparing. A superior tumor control may benefit from a lower PVDR. RESULTS: High PVDR values were obtained in the healthy tissue for the three cases studied. When low energy photons are used, the treatment of deep-seated tumors can still be performed with submillimetric grid sizes. Superior PVDR values were reached with the other two approaches in the first centimeters along the beam path. The use of protons has the advantage of delivering a uniform dose distribution in the tumor, while healthy tissue benefits from the spatial fractionation of the dose. In the three evaluated techniques, there is a net reduction in penumbra with respect to radiosurgery. CONCLUSIONS: The high PVDR values in the healthy tissue and the use of small grid sizes in the three presented approaches might constitute a promising alternative to treat tumors with such spatially fractionated radiotherapy techniques. The dosimetric results presented here support the interest of performing radiobiology experiments in order to evaluate these new avenues.