Unlike for Human Monocytes after LPS Activation, Release of TNF-α by THP-1 Cells Is Produced by a TACE Catalytically Different from Constitutive TACE

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-α, initially synthesized as a membrane-anchored precursor (pro-TNF-α), is processed by proteolytic cleavage to generate the secreted mature form. TNF-α converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-α.Here, we demonstrated the presence on THP-1 cells as on human monocytes of a constitutive proteolytical activity able to cleave pro-TNF-α. Revelation of the cell surface TACE protein expression confirmed that the observed catalytic activity is due to TACE. However, further studies using effective and innovative TNF-α inhibitors, as well as a highly selective TACE inhibitor, support the presence of a catalytically different sheddase activity on LPS activated THP-1 cells. It appears that this catalytically different TACE protease activity might have a significant contribution to TNF-α release in LPS activated THP-1 cells, by contrast to human monocytes where the TACE activity remains catalytically unchanged even after LPS activation.On the surface of LPS activated THP-1 cells we identified a releasing TNF-α activity, catalytically different from the sheddase activity observed on human monocytes from healthy donors. This catalytically-modified TACE activity is different from the constitutive shedding activity and appears only upon stimulation by LPS

Determination of MC-based predictive models for personalized and fast kV-CBCT organ dose estimation

International audiencePurpose or Objective: Monte Carlo (MC) simulations were shown to be a powerful tool to calculate accurately 3D dose distributions of kV-CBCT scans for a patient, based on planning CT images. However, this methodology is still heavy and time consuming, preventing its large use in clinical routine. This study hence explores a method to derive empirical functions relating organ doses to patient morphological parameters, in order to perform a fast and personalized estimation of doses delivered to critical organs by kV-CBCT scans used in IGRT protocols.Material and Methods: Doses to critical organs were first computed using a PENELOPE-based MC code previously validated [H. Chesneau et al., ESTRO 2016], for a set of fifty clinical cases (40 children and 10 adults) covering a broad range of anatomical localizations (head-and-neck, pelvis, thorax, abdomen) and scanning conditions for the Elekta XVI CBCT. Planning CT images were converted into voxellized patient geometries, using a dedicated tissue segmentation procedure: 5 to 7 biological tissues were assigned for soft tissues, whereas ten different bone tissues were required for accurate dosimetry in the kV energy range. Correlations between calculated mean organ doses and several morphological parameters (age, weight, height, BMI, thorax and hip circumference …) were then studied for each anatomical localization to derive appropriate empirical fitting functions.Results: As expected, results on the paediatric cohort show dose variations highly correlated with the patient morphology, varying in the range 3:1 between a 17-y old teenager and a 2-y old baby, for the same CBCT scan. Except for the head-and-neck localization, for which the mean organ doses show no significant variations with the morphology, doses to all major organs at risk can be predicted using linear or exponential functions for thorax, pelvis and abdomen scans. The use of morphological parameters directly measured on the planning CT allows to reach better correlations than global parameters such as BMI, because they represent most relevant indicators of the patient morphology at the scan time.Conclusion: This study demonstrates that it is possible to derive mathematical models predicting the doses delivered to major critical organs by kV-CBCT scans according to morphological parameters. This method allows a fast and personalized estimation of imaging doses usable in clinicalroutine

IGRT kV-CBCT dose calculations using Virtual Source Models and validated in phantoms using OSL

International audiencePurpose or Objective: With the growing use of X-ray imaging equipment in Image-Guided RadioTherapy (IGRT), the need to evaluate the dose-to-organs delivered by kV-CBCT imaging acquisition increases. This study aims to propose accurate Monte Carlo (MC) calculations of the patient dose-to-organs delivered by two commercially available kV-CBCT systems: the XVI from Elekta’s VERSA HD accelerator and the OBI from Varian’s TrueBeam system. Simulations are to be validated using in phantom OSL measurements.Material and Methods: For both kV-CBCT systems, the kV irradiation head geometry was implemented in the MC simulation code Penelope. As a first step, the resulting photon distributions were expressed as Virtual Source Models (VSM) for every standard irradiation condition (kVp,filtration, collimation); it was then validated and adjusted using in water-phantom measurements performed with a calibrated Farmer-type ionization chamber. In a second step, the validated VSMs were used to simulate the dose delivered by both the XVI and OBI systems in anthropomorphic phantoms, using standard clinical imaging protocols. Simulated dose-to-organs were then confronted to dose measurements performed using OSL inserted into the same phantoms, following a dosimetric protocol for OSLs previously established [1]. In addition, VSM results were confronted to their direct MC counterparts in order to evaluate the benefit of using such technique.Results: The current study highlights the possibility to reproduce OSL dose-to-organ measurements using VSM-driven Monte Carlo simulation with an overall agreement better than 20 %. In addition, the use of VSM in the MC simulation enables to speed-up the calculation time by a factor better than two (for the same statistical uncertainty) compared to direct MC simulation. Nevertheless, if direct and VSM calculations are in agreement inside the irradiation field, outside, VSM results tend to be significantly lower (10-30%).Conclusion: The use of a VSM was demonstrated to simplify and fasten MC simulations for personalized kV-CBCT MC dose estimation. In addition, OSLs enable to perform the low dose measurement in the kV range needed for in phantom X-ray imaging equipment dose QA. This study is to be completed in the near future by the addition of other standard X-ray imaging equipment dedicated to IGRT

Validation of histogram‐based virtual source models for different IGRT kV‐imaging systems

International audiencePurpose Image‐guided radiotherapy (IGRT) improves tumor control but its intensive use may entrain late side effects caused by the additional imaging doses. There is a need to better quantify the additional imaging doses, so they can be integrated in the therapeutic workflow. Currently, no dedicated software enables to compute patient‐specific imaging doses on a wide range of systems and protocols. As a first step toward this objective, we propose a common methodology to model four different kV‐imaging systems used in radiotherapy (Varian’s OBI, Elekta's XVI, Brainlab's ExacTrac, and Accuray's Cyberknife) using a new type of virtual source model based on Monte Carlo calculations. Methods We first describe our method to build a simplified description of the photon output, or virtual source models (VSMs), of each imaging system. Instead of being constructed using measurement data, as it is most commonly the case, our VSM is used as the summary of the phase‐space files (PSFs) resulting from a first Monte Carlo simulation of the considered x‐ray tube. Second, the VSM is used as a photon generator for a second MC simulation in which we compute the dose. Then, the proposed VSM is thoroughly validated against standard MC simulation using PSFs on the XVI system. Last, each modeled system is compared to profiles and depth‐dose‐curve measurements performed in homogeneous phantom. Results Comparisons between PSF‐based and VSM‐based calculations highlight that VSMs could provide equivalent dose results (within 1% of difference) than PSFs inside the imaging field‐of‐view (FOV). In contrast, VSMs tend to underestimate (for up to 20%) calculated doses outside of the imaging FOV due to the assumptions underlying the VSM construction. In addition, we showed that the use of VSMs allows reducing calculation time by at least a factor of 2.8. Indeed, for identical simulation times, statistical uncertainties on dose distributions computed using VSMs were much lower than those obtained from PSF‐based calculations. Conclusions For each of the four imaging systems, VSMs were successfully validated against measurements in homogeneous phantoms, and are therefore ready to be used for future preclinical studies in heterogeneous or anthropomorphic phantoms. The cross system modeling methodology developed here should enable, later on, to estimate precisely and accurately patient‐specific 3D dose maps delivered during a large range of kV‐imaging procedures

IGRT kV-imaging dose MC calculations validated in anthropomorphic phantoms using OSL

International audiencePurpose or Objective: While in-room Magnetic Resonance Imaging starts becoming part of radiotherapy (RT) treatments, the use of X-ray imaging equipment in Image-Guided RT (IGRT) is still growing and with it the need to evaluate the additional dose-to-organs it delivers. This study aims atverifying the accuracy of Monte Carlo (MC) calculation of the patient dose-to-organs delivered by four commercially available kV imaging systems: the XVI CBCT (Elekta), the OBI CBCT (Varian), the ExacTrac 2D-kV system (Brainlab) and the 2D-kV CyberKnife imaging system (Accuray). Simulations were validated against OSL measurements in the pediatric anthropomorphic phantom Grant (CIRS, ATOM) performed in three different clinical sites.Material and Methods: Each of the four kV-imaging systems was modeled as a Virtual Source Model (VSM) using the Penelope MC code. Such models were validated as part of a previous study using ionization chambers in water phantoms [G. Boissonnat et al., ESTRO 2017 Vienna]. In a second step, CT images of the phantom Grant were used to generate a voxelized phantom by converting the HU value of each voxel into the appropriate biological tissue (chemical composition and density). Then for each system, photons produced by the corresponding VSM were propagated in the voxelized phantom in order to obtain the 3D relative absorbed dose-to-medium map for three localizations (head, thorax and pelvis). MC-calculateddoses were calibrated in amplitude using the ratio between the air kerma measured with an ionization chamber at the isocenter and the corresponding simulated value. After calibrating OSLs in air kerma at every beam quality, OSL measurements were performed in the anthropomorphic phantom at three localizations (head and neck, thorax and pelvis). After verifying that beam quality inside the phantom was impacting OSL corrections factors of less than 5%, they were neglecting. Therefore measured air kerma values were converted into absorbed dose-in-medium values using the incoming beam quality before being compared to simulated dose values.Results: MC calculations were performed in 2 hours on a cluster of 40 CPUs with a MC uncertainty better than 5% in 1mm3 voxels. The current study highlights the possibility to reproduce absolute dose measurements using VSM-driven MC simulations with an overall agreement better than 20 % (inside the irradiation field) for all four kV imaging systems and for the three anatomical localizations as presented in Table 1.Conclusion: This study demonstrates that MC calculations based on VSMs allow obtaining reliable absolute doses for kV imaging protocols in a reasonable computing time. All these developments are currently integrated into a dedicated software for imaging dose prediction, which will also include the Tomotherapy MVCT imaging system [V. Passal et al., MCMA 2017 Napoli].This software will enable to study the magnitude of additional doses delivered by in-room X-Ray imaging positioning units during the course of a complete RT treatment

Additional file 1 of Health-related quality of life in children and adolescents with Marfan syndrome or related disorders: a controlled cross-sectional study

Supplementary Material 1