Secondary neutron doses received by paediatric patients during intracranial proton therapy treatments.

This paper's goal is to assess secondary neutron doses received by paediatric patients treated for intracranial tumours using a 178 MeV proton beam. The MCNPX Monte Carlo model of the proton therapy facility, previously validated through experimental measurements for both proton and neutron dosimetry, was used. First, absorbed dose was calculated for organs located outside the clinical target volume using a series of hybrid computational phantoms for different ages and considering a realistic treatment plan. In general, secondary neutron dose was found to decrease as the distance to the treatment field increases and as the patient age increases. In addition, secondary neutron doses were studied as a function of the beam incidence. Next, neutron equivalent dose was assessed using organ-specific energy-dependent radiation weighting factors determined from Monte Carlo simulations of neutron spectra at each organ. The equivalent dose was found to reach a maximum value of ∼155 mSv at the level of the breasts for a delivery of 49 proton Gy to an intracranial tumour of a one-year-old female patient. Finally, a thorough comparison of the calculation results with published data demonstrated the dependence of neutron dose on the treatment configuration and proved the need for facility-specific and treatment-dependent neutron dose calculations.

Study of the secondary neutral radiation in proton therapy: toward an indirect in vivo dosimetry.

PURPOSE: Secondary particles produced in the collision of protons with beam modifiers are of concern in proton therapy. Nevertheless, secondary radiation can provide information on the dosimetric parameters through its dependency on the modulating accessories (range shifter and range modulating wheel). Relatively little data have been reported in the literature for low-energy proton beams. The present study aims at characterizing the neutron and photon secondary radiation at the low-energy proton therapy facility of the Centre Antoine Lacassagne (CAL), and studying their correlation to the dosimetric parameters to explore possible practical uses of secondary radiation in the treatment quality for proton therapy. METHODS: The Monte Carlo code MCNPX was used to simulate the proton therapy facility at CAL. Neutron and photon fluence, Φ, and ambient dose equivalent per proton dose, H∗(10)∕D, were determined across the horizontal main plane spanning the whole treatment room. H∗(10)∕D was also calculated at two positions of the treatment room where dosimetric measurements were performed for validation of the Monte Carlo calculations. Calculations and measurements were extended to 100 clinical spread-out Bragg Peaks (SOBPs) covering the whole range of therapeutic dose rates (D∕MU) employed at CAL. In addition, the values of D and MU were also calculated for each SOBP and the results analyzed to study the relationship between secondary radiation and dosimetric parameters. RESULTS: The largest production of the secondary particles takes place at the modulating devices and the brass collimators located along the optical bench. Along the beam line and off the beam axis to 2.5 m away, H∗(10)∕D values ranged from 5.4 µSv∕Gy to 5.3 mSv∕Gy for neutrons, and were 1 order of magnitude lower for photons. H∗(10)∕D varied greatly with the distance and angle to the beam axis. A variation of a factor of 5 was found for the different range of modulations (SOBPs). The ratios between calculations and measurements were 2.3 and 0.5 for neutrons and photons, respectively, and remained constant for all the range of SOBPs studied, which provided validation for the Monte Carlo calculations. H∗(10)∕D values were found to correlate to the proton dose rate D∕MU with a power fit, both for neutrons and photons. This result was exploited to implement a system to obtain D∕MU values from the measurement of the integrated photon ambient dose equivalent H∗(10) during treatment, which provides a method to control the dosimetric parameters D∕MU and D. CONCLUSIONS: The treatment room at CAL is moderately polluted by secondary particles. The constant ratio between measurements and calculations for all SOBPs showed that simulations correctly predict the dosimetric parameters and the dependence of the production of secondary particles on the modulation. The correlation between H∗(10)∕D and D∕MU is a useful tool for quality control and is currently used at CAL. This system works as an indirect in vivo dosimetry method, which is so far not feasible in proton therapy. This tool requires very simple instrumentation and can be implemented from the measurement of either photons or neutrons.

Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study.

PURPOSE: In radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnifeR  -based stereotactic irradiation (SBRT). MATERIAL AND METHODS: CT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy_RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level. RESULTS: Precision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%-20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT. CONCLUSIONS: ocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations.

A 60 MeV proton beam-line dedicated to research and development programs.

A new proton beam-line dedicated to R&D programs has been developed at CentreAntoine Lacassagne (CAL), in Nice (France), in collaboration with the Centrenational d'études spatiales (CNES). This is the second beam-line of the MEDICYC 65 MeV cyclotron that is currently in operation, the first being the clinical 'eye-line' used for ocular proton therapy. The R&D beam-line is proposed with two configurations, the first producing a Gaussian narrow beam of a few mm width, the second a 100 mm diameter flat beam with a homogeneity better than ±3%. The energy range is (20 - ∼60) MeV, where the exact upper limit depends on the beam configuration being used. The energy spread of the non-degraded beam is (0.3 ± 0.1) MeV. A beam current between 10 pA and 10 µA can be produced with a stability better than 0.2% above 100 pA, and 2% below. The beam can be monitored online at a precision better than 5% in the flux range 1E5 (1E6) - 1E9 (1E10) p/cm2/s for a flat (Gaussian) configuration, although work is in progress to extend this range. Targeted applications for the R&D beam-line are instrumentation research, radiation tolerance tests of components and radiobiology.

30 years of ocular proton therapy, the Nice view.

PURPOSE: Radiotherapy with protons (PT) is a standard treatment of ocular tumors. It achieves excellent tumor control, limited toxicities, and the preservation of important functional outcomes, such as vision. Although PT may appear as one homogenous technique, it can be performed using dedicated ocular passive scattering PT or, increasingly, Pencil Beam Scanning (PBS), both with various degrees of patient-oriented customization. MATERAIAL AND METHODS: MEDICYC PT facility of Nice are detailed with respect to their technical, dosimetric, microdosimetric and radiobiological, patient and tumor-customization process of PT planning and delivery that are key. 6684 patients have been treated for ocular tumors (1991-2020). Machine characteristics (accelerator, beam line, beam monitoring) allow efficient proton extraction, high dose rate, sharp lateral and distal penumbrae, and limited stray radiation in comparison to beam energy reduction and subsequent straggling with high-energy PBS PT. Patient preparation before PT includes customized setup and image-guidance, CT-based planning, and ocular PT software modelling of the patient eye with integration of beam modifiers. Clinical reports have shown excellent tumor control rates (∼95%), vision preservation and limited toxicity rates (papillopathy, retinopathy, neovascular glaucoma, dry eye, madarosis, cataract). RESULTS: Although demanding, dedicated ocular PT has proven its efficiency in achieving excellent tumor control, OAR sparing and patient radioprotection. It is therefore worth adaptations of the equipments and practice. CONCLUSIONS: Some of these adaptations can be transferred to other PT centers and should be acknowledeged when using non-PT options.

Radiochromic EBT2 film dosimetry for low-energy protontherapy.

PURPOSE: In protontherapy, accessories are used in order to adapt the beam to the surface and to the depth of the target. They are positioned close to the patient in order to avoid perturbation effects related to proton scattering. The level of contamination of the beam caused by these accessories may be assessed by examining the dose maps in parallel planes to the beam incidence. The EBT2 radiochromic film is a suitable tool for this task, as it can be cut into small pieces and immersed in water. Prior to use the EBT2 film for dose measurements, its response when exposed to a proton beam must be analysed. METHODS: The measurements were performed at the Centre Antoine Lacassagne, using the hospital-based MEDICYC isochronous cyclotron which provides 65 MeV protons. Monoenergetic as well as polyenergetic beams were used. Small pieces of EBT2 films were irradiated with proton beams in a small water phantom. Films were exposed at various angles close to the beam incidence and received doses ranging from 0.25 to 500 Gy. The optical density (OD) was studied as a function of angle, dose and linear energy transfer (LET). RESULTS: The effective atomic number of the active layer of the film is close to that of water which prevents disturbances of the measurement. However, the high density and the significant thickness of the Mylar substrate surrounding the active layer affect the use of the film in a parallel orientation to the beam. Therefore, the substrate layer may totally or partially slow down the protons. The measurement is then no longer representative to what happens in water. The measurement errors can be corrected by applying a tilt angle of at least 5° between the film and the beam. The dose analysis reveals that the green channel is the most sensitive in the dose range from 1 to 100 Gy. The OD is accurately described by a Weibull function of the dose with four free parameters. The Weibull function is valid for both monoenergetic and polyenergetic beams if the LET is limited to values below 15 MeV g(- 1) cm(2). When using a film orientation close to the beam incidence angle, increasing LET values are encountered throughout the film axis gradually with the protons slowing down in water. The EBT2 films show an underestimated response for higher LET values. The comparison of data from the present study to data obtained by other authors for EBT films allows modelling the underestimated response as a function of the LET. The definition improvement of the link between OD and LET requires to integrate more closely the beam energy characteristics. CONCLUSIONS: The EBT2 film is a suitable dosimeter for analysing dose plans in planes nearly parallel to the beam orientation by compensating the underestimated dose response due to LET.

Three-dimensional MRI-based treatment planning approach for non-invasive ocular proton therapy.

PURPOSE: To develop a high-resolution three-dimensional (3D) magnetic resonance imaging (MRI)-based treatment planning approach for uveal melanomas (UM) in proton therapy. MATERIALS/METHODS: For eight patients with UM, a segmentation of the gross tumor volume (GTV) and organs-at-risk (OARs) was performed on T1- and T2-weighted 7 Tesla MRI image data to reconstruct the patient MR-eye. An extended contour was defined with a 2.5-mm isotropic margin derived from the GTV. A broad beam algorithm, which we have called πDose, was implemented to calculate relative proton absorbed doses to the ipsilateral OARs. Clinically favorable gazing angles of the treated eye were assessed by calculating a global weighted-sum objective function, which set penalties for OARs and extreme gazing angles. An optimizer, which we have named OPT'im-Eye-Tool, was developed to tune the parameters of the functions for sparing critical-OARs. RESULTS: In total, 441 gazing angles were simulated for every patient. Target coverage including margins was achieved in all the cases (V95%  > 95%). Over the whole gazing angles solutions space, maximum dose (Dmax ) to the optic nerve and the macula, and mean doses (Dmean ) to the lens, the ciliary body and the sclera were calculated. A forward optimization was applied by OPT'im-Eye-Tool in three different prioritizations: iso-weighted, optic nerve prioritized, and macula prioritized. In each, the function values were depicted in a selection tool to select the optimal gazing angle(s). For example, patient 4 had a T2 equatorial tumor. The optimization applied for the straight gazing angle resulted in objective function values of 0.46 (iso-weighted situation), 0.90 (optic nerve prioritization) and 0.08 (macula prioritization) demonstrating the impact of that angle in different clinical approaches. CONCLUSIONS: The feasibility and suitability of a 3D MRI-based treatment planning approach have been successfully tested on a cohort of eight patients diagnosed with UM. Moreover, a gaze-angle trade-off dose optimization with respect to OARs sparing has been developed. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment.

Experimental demonstration of accurate Bragg peak localization with ionoacoustic tandem phase detection (iTPD).

Accurate knowledge of the exact stopping location of ions inside the patient would allow full exploitation of their ballistic properties for patient treatment. The localized energy deposition of a pulsed particle beam induces a rapid temperature increase of the irradiated volume and leads to the emission of ionoacoustic (IA) waves. Detecting the time-of-flight (ToF) of the IA wave allows inferring information on the Bragg peak location and can henceforth be used forin-vivorange verification. A challenge for IA is the poor signal-to-noise ratio at clinically relevant doses and viable machines. We present a frequency-based measurement technique, labeled as ionoacoustic tandem phase detection (iTPD) utilizing lock-in amplifiers. The phase shift of the IA signal to a reference signal is measured to derive theToF. Experimental IA measurements with a 3.5 MHz lead zirconate titanate (PZT) transducer and lock-in amplifiers were performed in water using 22 MeV proton bursts. A digital iTPD was performedin-silicoat clinical dose levels on experimental data obtained from a clinical facility and secondly, on simulations emulating a heterogeneous geometry. For the experimental setup using 22 MeV protons, a localization accuracy and precision obtained through iTPD deviates from a time-based reference analysis by less than 15µm. Several methodological aspects were investigated experimentally in systematic manner. Lastly, iTPD was evaluatedin-silicofor clinical beam energies indicating that iTPD is in reach of sub-mm accuracy for fractionated doses < 5 Gy. iTPD can be used to accurately measure theToFof IA signals online via its phase shift in frequency domain. An application of iTPD to the clinical scenario using a single pulsed beam is feasible but requires further development to reach <1 Gy detection capabilities.

Imaging issues specific to hadrontherapy (proton, carbon, helium therapy and other charged particles) for radiotherapy planning, setup, dose monitoring and tissue response assessment.

Imaging is critical to each step of precision radiation therapy, i.e. planning, setup, delivery and assessment of response. Hadrontherapy can be considered to deliver more precise dose distribution that may better spare normal tissues from intermediate low doses of radiation. In addition, hadrontherapy using high linear energy transfer ions may also be used for dose escalation on biological target volumes defined by functional imaging. However, the physical characteristics of hadrontherapy also make it more demanding in terms of imaging accuracy and image-based dose calculation. Some of the developments needed in imaging are specific to hadrontherapy. The current review addresses current status of imaging in proton therapy and the drawbacks of photon-based imaging for hadrons. It also addresses requirements in hadrontherapy planning with respect to multimodal imaging for proper target and organ at risk definition as well as to target putative radioresistant areas such as hypoxic ones, and with respect to dose calculation using dual energy CT, MR-proton therapy, proton radiography. Imaging modalities, such as those used in photon-based radiotherapy (intensity modulated and stereotactic radiotherapy), are somewhat already implemented or should be reaching "routine" hadrontherapy (at least proton therapy) practice in planning, repositioning and response evaluation optimizable within the next five years. Online monitoring imaging by PET, as currently developed for hadrontherapy, is already available. Its spatiotemporal limits restrict its use but similar to prompt gamma detection, represents an area of active research for the next 5 to 10 years. Because of the more demanding and specific dose deposit characteristics, developments image-guided hadrontherapy, such as specific proton imaging using tomography or ionoacoustics, as well as delivery with MR-proton therapy, may take another 10 years to reach the clinics in specific applications. Other aspects are briefly described such as range monitoring. Finally, the potential of imaging normal tissue changes and challenges to assess tumour response are discussed.

[Measurement of out-of-field dose to the uterus during proton therapy of the head and neck]. / Mesure de la dose délivrée hors champ à l'utérus lors d'un traitement ORL par protons.

The decision to irradiate during pregnancy is based on a risk benefit compromise of two kinds: maternal risk and fetal risk. The aim of this work is to determine the foetal risk, and uterine dose measurement in proton therapy. Foetal exposure during treatment is linked to two sources: the treatment phase, and the repositioning phase. An Alderson-Rando anthropomorphic ghost (170cm, 74kg) was positioned on the table in the treatment position. A tissue-equivalent proportional counter (TEPC), adapted to the analysis of complex radiation fields (neutron and photonics), was used to determine the irradiation related to the treatment phase. An AT1123 radiation survey meter was used to measure photons generated by X-ray radiation. I dosimetry was proposed using radio-photoluminescent dosimeters, allowing for a daily check of the dose received in the uterus. The treatment phase produces higher uterine doses than the positioning phase, but these remain very low. The equivalent dose received in the uterus for the entire treatment is estimated at 840 µSv. Using a methodology for measuring the out-of-field dose with pencil beam scanning proton therapy, the foetal dose in the first trimester was well below the acceptance dose of 100 mGy determined by the International Commission on Radiological Protection.

Beam characterization and feasibility study for a small animal irradiation platform at clinical proton therapy facilities.

A deeper understanding of biological mechanisms to promote more efficient treatment strategies in proton therapy demands advances in preclinical radiation research. However this is often limited by insufficient availability of adequate infrastructures for precision image guided small animal proton irradiation. The project SIRMIO aims at filling this gap by developing a portable image-guided research platform for small animal irradiation, to be used at clinical facilities and allowing for a precision similar to a clinical treatment, when scaled down to the small animal size. This work investigates the achievable dosimetric properties of different lowest energy clinical proton therapy beams, manipulated by a dedicated portable beamline including active focusing after initial beam energy degradation and collimation. By measuring the lateral beam size in air close to the beam nozzle exit and the laterally integrated depth dose in water, an analytical beam model based on the beam parameters of the clinical beam at the Rinecker Proton Therapy Center was created for the lowest available clinical beam energy. The same approach was then applied to estimate the lowest energy beam model of different proton therapy facilities, Paul Scherrer Institute, Centre Antoine Lacassagne, Trento Proton Therapy Centre and the Danish Centre for Particle Therapy, based on their available beam commissioning data. This comparison indicated similar beam properties for all investigated sites, with emittance values of a few tens of mm·mrad. Finally, starting from these beam models, we simulated propagation through a novel beamline designed to manipulate the beam energy and size for precise small animal irradiation, and evaluated the resulting dosimetric properties in water. For all investigated initial clinical beams, similar dosimetric results suitable for small animal irradiation were found. This work supports the feasibility of the proposed SIRMIO beamline, promising suitable beam characteristics to allow for precise preclinical irradiation at clinical treatment facilities.

Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes.

Adipose tissue is an active endocrine organ that produces a variety of secretory factors involved in the initiation of angiogenic processes. The bioactive peptide apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Here we investigated the potential role of apelin and its receptor, APJ, in the angiogenic responses of human endothelial cells and the development of a functional vascular network in a model of adipose tissue development in mice. Treatment of human umbilical vein endothelial cells with apelin dose-dependently increased angiogenic responses, including endothelial cell migration, proliferation, and Matrigel(R) capillary tubelike structure formation. These endothelial effects of apelin were due to activation of APJ, because siRNA directed against APJ, which led to long-lasting down-regulation of APJ mRNA, abolished cell migration induced by apelin in contrast to control nonsilencing siRNA. Hypoxia up-regulated the expression of apelin in 3T3F442A adipocytes, and we therefore determined whether apelin could play a role in adipose tissue angiogenesis in vivo. Epididymal white adipose tissue (EWAT) transplantation was performed as a model of adipose tissue angiogenesis. Transplantation led to increased apelin mRNA levels 2 and 5 days after transplantation associated with tissue hypoxia, as evidenced by hydroxyprobe staining on tissue sections. Graft revascularization evolved in parallel, as the first functional vessels in EWAT grafts were observed 2 days after transplantation and a strong angiogenic response was apparent on day 14. This was confirmed by determination of graft hemoglobin levels, which are indicative of functional vascularization and were strongly increased 5 and 14 days after transplantation. The role of apelin in the graft neovascularization was then assessed by local delivery of stable complex apelin-targeting siRNA leading to dramatically reduced apelin mRNA levels and vascularization (quantified by hemogloblin content) in grafted EWAT on day 5 when compared with control siRNA. Taken together, our data provide the first evidence that apelin/APJ signaling pathways play a critical role in the development of the functional vascular network in adipose tissue. In addition, we have shown that adipocyte-derived apelin can be up-regulated by hypoxia. These findings provide novel insights into the complex relationship between adipose tissue and endothelial vascular function and may lead to new therapeutic strategies to modulate angiogenesis.

Experimental characterisation of a proton kernel model for pencil beam scanning techniques.

The aim of this work is to perform Monte Carlo simulations of a proton pencil beam scanning machine, characterise the low-dose envelope of scanned proton beams and assess the differences between various approximations for nozzle geometry. Measurements and Monte Carlo simulations were carried out in order to describe the dose distribution of a proton pencil beam in water for energies between 100 and 220 MeV. Dose distributions were simulated by using a Geant4 Monte Carlo platform (TOPAS), and were measured in water using a two-dimensional ion chamber array detector. The beam source in air was adjusted for each configuration. Double Gaussian parameterisation was proposed for definition of the beam source model in order to improve simulations starting at the nozzle exit. Absolute dose distributions and field size factors were measured and compared with simulations. The influence of the high-density components present in the treatment nozzle was also investigated by analysis of proton phase spaces at the nozzle exit. An excellent agreement was observed between experimental dose distributions and simulations for energies higher than 160 MeV. However, minor differences were observed between 100 and 160 MeV, suggesting poorer modelling of the beam when the full treatment head was not taken into account. We found that the first ionisation chamber was the main cause of the tail component observed for low proton beam energies. In this work, various parameterisations of proton sources were proposed, thereby allowing reproduction of the low-dose envelope of proton beams and excellent agreement with measured data.

[Proton therapy for head and neck squamous cell carcinomas: From physics to clinic]. / Protonthérapie des carcinomes épidermoïdes des voies aérodigestives supérieures : de la physique à la clinique.

Intensity-modulated radiation therapy (IMRT) is presently the recommended technique for the treatment of locally advanced head and neck carcinomas. Proton therapy would allow to reduce the volume of irradiated normal tissue and, thus, to decrease the risk of late dysphagia, xerostomia, dysgeusia and hypothyroidism. An exhaustive research was performed with the search engine PubMed by focusing on the papers about the physical difficulties that slow down use of proton therapy for head and neck carcinomas. Range uncertainties in proton therapy (±3 %) paradoxically limit the use of the steep dose gradient in distality. Calibration uncertainties can be important in the treatment of head and neck cancer in the presence of materials of uncertain stoichiometric composition (such as with metal implants, dental filling, etc.) and complex heterogeneities. Dental management for example may be different with IMRT or proton therapy. Some uncertainties can be somewhat minimized at the time of optimization. Inter- and intrafractional variations and uncertainties in Hounsfield units/stopping power can be integrated in a robust optimization process. Additional changes in patient's anatomy (tumour shrinkage, changes in skin folds in the beam patch, large weight loss or gain) require rescanning. Dosimetric and small clinical studies comparing photon and proton therapy have well shown the interest of proton therapy for head and neck cancers. Intensity-modulated proton therapy is a promising treatment as it can reduce the substantial toxicity burden of patients with head and neck squamous cell carcinoma compared to IMRT. Robust optimization will allow to perform an optimal treatment and to use proton therapy in current clinical practice.

Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo.

The binding of 125I-factor Xa to human aortic smooth muscle cell (SMC) monolayers was studied. At 4 degreesC, 125I-factor Xa bound to a single class of binding sites with a dissociation constant value of 3.6+/-0.7 nM and a binding site density of 11,720+/-1,240 sites/cell (n = 9). 125I-factor Xa binding was not affected by factor X, thrombin, or by DX9065, a direct inhibitor of factor Xa, but was inhibited by factor Xa (IC50 = 5.4+/-0.2 nM; n = 9) and by antibodies specific for the effector cell protease receptor 1 (EPR-1), a well-known receptor of factor Xa on various cell types. A factor X peptide duplicating the inter-EGF sequence Leu83-Leu88-(Gly) blocked the binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 = 110+/-21 nM). Factor Xa increased phosphoinositide turnover in SMCs and when added to SMCs in culture was a potent mitogen. These effects were inhibited by DX9065 and by antibodies directed against EPR-1 and PDGF. Increased expression of EPR-1 was identified immunohistochemically on SMCs growing in culture and in SMCs from the rabbit carotid artery after vascular injury. When applied locally to air-injured rabbit carotid arteries, antibodies directed against EPR-1 (100 mug/ artery) strongly reduced myointimal proliferation 14 d after vascular injury (65-71% inhibition, P < 0.01). DX9065 (10 mg/kg, subcutaneous) inhibited myointimal proliferation significantly (43% inhibition, P < 0.05). These findings indicate that SMCs express functional high affinity receptors for factor Xa related to EPR-1, which may be of importance in the regulation of homeostasis of the vascular wall and after vascular injury.

Spread-out Bragg peak and monitor units calculation with the Monte Carlo code MCNPX.

The aim of this work was to study the dosimetric potential of the Monte Carlo code MCNPX applied to the protontherapy field. For series of clinical configurations a comparison between simulated and experimental data was carried out, using the proton beam line of the MEDICYC isochronous cyclotron installed in the Centre Antoine Lacassagne in Nice. The dosimetric quantities tested were depth-dose distributions, output factors, and monitor units. For each parameter, the simulation reproduced accurately the experiment, which attests the quality of the choices made both in the geometrical description and in the physics parameters for beam definition. These encouraging results enable us today to consider a simplification of quality control measurements in the future. Monitor Units calculation is planned to be carried out with preestablished Monte Carlo simulation data. The measurement, which was until now our main patient dose calibration system, will be progressively replaced by computation based on the MCNPX code. This determination of Monitor Units will be controlled by an independent semi-empirical calculation.

[CyberKnife robotic stereotactic radiotherapy: technical aspects and medical indications]. / Radiothérapie stéréotaxique robotisée par CyberKnife : aspects techniques et indications.

In 2006, 3 sites have been selected by the Institut national of cancer (Lille, Nancy et Nice) to evaluate a radiotherapy robot, the CyberKnife. This machine, able to track mobile tumours in real time, gives new possibilities in the field of extra cranial stereotactic radiotherapy. Functionalities and medico economical issues of the machine will be evaluated during 2 years on the 3 sites.

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma.

The proximity of organs at risk makes the treatment of head and neck squamous cell carcinoma (HNSCC) challenging by standard radiotherapy. The higher precision in tumor targeting of proton (P) therapy could promote it as the treatment of choice for HNSCC. Besides the physical advantage in dose deposition, few is known about the biological impact of P versus photons (X) in this setting. To investigate the comparative biological effects of P versus X radiation in HNSCC cells, we assessed the relative biological effectiveness (RBE), viability, proliferation and mRNA levels for genes involved in (lymph)angiogenesis, inflammation, proliferation and anti-tumor immunity. These parameters, particularly VEGF-C protein levels and regulations, were documented in freshly irradiated and/or long-term surviving cells receiving low/high-dose, single (SI)/multiple (MI) irradiations with P/X. The RBE was found to be 1.1 Key (lymph)angiogenesis and inflammation genes were downregulated (except for vegf-c) after P and upregulated after X irradiation in MI surviving cells, demonstrating a more favorable profile after P irradiation. Both irradiation types stimulated vegf-c promoter activity in a NF-κB-dependent transcriptional regulation manner, but at a lesser extent after P, as compared to X irradiation, which correlated with mRNA and protein levels. The cells surviving to MI by P or X generated tumors with higher volume, anarchic architecture and increased density of blood vessels. Increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in tumors generated with X-irradiated cells. Increased detection of lymphatic vessels in relapsed tumors from patients receiving X radiotherapy was consistent with these findings. This study provides new data about the biological advantage of P, as compared to X irradiation. In addition to its physical advantage in dose deposition, P irradiation may help to improve treatment approaches for HNSCC.

Thermoluminescence properties of CVD diamond for clinical dosimetry use.

The application of diamond to dosimetry is desirable because of its tissue equivalence, chemical inertness and small size, but this has not been commercially viable owing to the non-reproducible response of natural diamond. The chemical vapour deposition (CVD) of diamond permits controlled, reproducible and large-scale production of this material at potentially low cost. An investigation of some clinically relevant features like the depth-dose distribution as well as the absorbed dose profile, obtained using thermoluminescence (TL), is reported for several CVD diamond films. The TL characterisation presented here shows that CVD diamond films should be excellent TL-mode detectors in instances of radiotherapy and in vivo radiation dosimetry.

Monte Carlo simulation of a medical linear accelerator for radiotherapy use.

A Monte Carlo code MCNPX (Monte Carlo N-particle) was used to model a 25 MV photon beam from a PRIMUS (KD2-Siemens) medical linear electron accelerator at the Centre Antoine Lacassagne in Nice. The entire geometry including the accelerator head and the water phantom was simulated to calculate the dose profile and the relative depth-dose distribution. The measurements were done using an ionisation chamber in water for different square field ranges. The first results show that the mean electron beam energy is not 19 MeV as mentioned by Siemens. The adjustment between the Monte Carlo calculated and measured data is obtained when the mean electron beam energy is approximately 15 MeV. These encouraging results will permit to check calculation data given by the treatment planning system, especially for small fields in high gradient heterogeneous zones, typical for intensity modulated radiation therapy technique.