Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and ...the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.
We present a comprehensive analytical comparison of four types of proton imaging set-ups and, to this end, develop a mathematical framework to calculate the width of the uncertainty envelope around ...the most likely proton path depending on set-up geometry, detector properties, and proton beam parameters. As a figure of merit for the spatial resolution achievable with each set-up, we use the frequency at which the modular transfer function of a density step decreases below 10%. We verify the analytical results with Monte Carlo simulations. We find that set-ups which track the angle and position of individual protons in front of and behind the phantom would yield an average spatial resolution of 0.3-0.35 lp mm−1 assuming realistic geometric parameters (i.e. 30-40 cm distance between detector and phantom, 15-20 cm phantom thickness). For set-ups combining pencil beam scanning with either a position sensitive detector, e.g. an x-ray flat panel, or with a position insensitive detector, e.g. a range telescope, we find an average spatial resolution of about 0.1 lp mm−1 for an 8 mm FWHM beam spot size. The pixel information improves the spatial resolution by less than 10%. In both set-up types, performance can be significantly improved by reducing the pencil beam size down to 2 mm FWHM. In this case, the achievable spatial resolution reaches about 0.25 lp mm−1. Our results show that imaging set-ups combining double scattering with a pixel detector can provide sufficient spatial resolution only under very stringent conditions and are not ideally suited for computed tomography applications. We further propose a region-of-interest method for set-ups with a pixel detector to filter out protons which have undergone nuclear reactions and discuss the impact of tracker detector uncertainties on the most likely path.
Proton transmission imaging has been proposed and investigated as imaging modality complementary to x-ray based techniques in proton beam therapy. In particular, it addresses the issue of range ...uncertainties due to the conversion of an x-ray patient computed tomography (CT) image expressed in Hounsfield Units (HU) to relative stopping power (RSP) needed as input to the treatment planning system. One approach to exploit a single proton radiographic projection is to perform a patient-specific calibration of the CT to RSP conversion curve by optimising the match between a measured and a numerically integrated proton radiography. In this work, we develop the mathematical tools needed to perform such an optimisation in an efficient and robust way. Our main focus lies on set-ups which combine pencil beam scanning with a range telescope detector, although most of our methods can be employed in combination with other set-ups as well. Proton radiographies are simulated in Monte Carlo using an idealised detector and applying the same data processing chain used with experimental data. This approach allows us to have a ground truth CT-RSP curve to compare the optimisation results with. Our results show that the parameters of the CT-RSP curve are strongly correlated when using a pencil beam based set-up, which leads to unrealistic variation in the optimised CT-RSP curves. To address this issue, we introduce a regularisation procedure which guarantees a plausible degree of smoothness in the optimised CT-RSP curves. We investigate three different methods to perform the numerical projection operation needed to generate a proton digitally reconstructed radiography. We find that the approximate and computationally faster method performs as well as the more accurate but more demanding method. We perform a Monte Carlo experiment based on a head and neck patient to evaluate the range accuracy achievable with the optimised CT-RSP curves and find an agreement with the ground truth expectation of better than . Our results further indicate that the region in the patient in which the proton radiography is acquired does not necessarily have to correspond to the treatment volume to achieve this accuracy. This is important as the imaged region could be freely chosen, e.g. in order to spare organs at risk.
Proton transmission imaging uses protons with high enough energy to fully traverse the phantom/patient and to be captured in a suitable detector placed behind it. The measured residual energy or ...residual range provide a direct estimate of the water equivalent thickness (WET) of the image volume. Requirements for proton imaging to be exploitable in clinical practice include: sufficient WET accuracy and integrability into the treatment room and the clinical workflow, as well as an acceptably low dose to the patient and a sufficient spatial resolution. In this work, we report on experiments performed at the Institut Curie-Proton therapy center in Orsay (IC-CPO), France, using a commercial range telescope commonly employed for quality assurance measurements. The purpose was to keep the experimental set-up as simple as possible and to achieve nonetheless high WET accuracy radiographies by developing and applying dedicated post processing methods. We explain these methods in detail and discuss their performance. We assess the WET accuracy based on two different reference phantoms: a CIRS electron density phantom with tissue equivalent inserts and a homogeneous step phantom. We find an agreement between the measured and the reference WET values of 0.2-0.5 mm. The lowest investigated dose was 10 mGy per acquisition. It could be lowered by modifying the irradiation plan and lowering the beam current, though the latter would impose slight optimisations of the detector hardware. Our work suggests that proton radiographies with good WET accuracy can be obtained with a reasonable experimental effort that would facilitate integration into clinical routine.
Prompt-gamma emission detection is a promising technique for hadrontherapy monitoring purposes. In this regard, obtaining prompt-gamma yields that can be used to develop monitoring systems based on ...this principle is of utmost importance since any camera design must cope with the available signal. Herein, a comprehensive study of the data from ten single-slit experiments is presented, five consisting in the irradiation of either PMMA or water targets with lower and higher energy carbon ions, and another five experiments using PMMA targets and proton beams. Analysis techniques such as background subtraction methods, geometrical normalization, and systematic uncertainty estimation were applied to the data in order to obtain absolute prompt-gamma yields in units of prompt-gamma counts per incident ion, unit of field of view, and unit of solid angle. At the entrance of a PMMA target, where the contribution of secondary nuclear reactions is negligible, prompt-gamma counts per incident ion, per millimetre and per steradian equal to (124 ± 0.7stat ± 30sys) × 10−6 for 95 MeV u−1 carbon ions, (79 ± 2stat ± 23sys) × 10−6 for 310 MeV u−1 carbon ions, and (16 ± 0.07stat ± 1sys) × 10−6 for 160 MeV protons were found for prompt gammas with energies higher than 1 MeV. This shows a factor 5 between the yields of two different ions species with the same range in water (160 MeV protons and 310 MeV u−1 carbon ions). The target composition was also found to influence the prompt-gamma yield since, for 300/310 MeV u−1 carbon ions, a 42% greater yield ((112 ± 1stat ± 22sys) × 10−6 counts ion−1 mm−1 sr−1) was obtained with a water target compared to a PMMA one.
Ion beams exhibit a finite range and an inverted depth-dose profile, the Bragg peak. These favorable physical properties allow excellent tumor-dose conformality. However, they introduce sensitivity ...to range uncertainties. Although these uncertainties are typically taken into account in treatment planning, delivery of the intended dose to the patient has to be ensured daily to prevent underdosage of the tumor or overdosage of surrounding critical structures. Thus, imaging techniques play an increasingly important role for treatment planning and in situ monitoring in ion beam therapy. At the Heidelberg Ion Beam Therapy (HIT) center, a prototype detector system based on a stack of 61 ionization chambers has been assembled for the purpose of radiographic and tomographic imaging of transmitted energetic ions. Its applicability to ion-based transmission imaging was investigated experimentally. An extensive characterization of the set-up in terms of beam parameters and settings of the read-out electronics was performed. Overall, the findings of this work support the potential of an efficient experimental set-up as the range telescope equipped with high sensitivity and fast electronics to perform heavy ion radiography and tomography at HIT.
Objective: Endothelial dysfunction (ED) includes both microvascular and macrovascular complications and is considered a hallmark in the patho-physiology of metabolic syndrome (MetS). ED is ...characterized by impaired endothelium-dependent relaxation, excessive cytokines production, release of inflammatory factors and oxidative stress. The aim of this work is to setup experimental strategies to study in vitro macrovascular endothelial damages related to MerS: the same protocols will be used to test the role of natural compounds with nutraceutical interest (Berberine (BBR) and red yeast rice (RYR)). Methods: Endothelial complications associated to MetS were assessed treating human aortic endothelial cells (HAEC) with uric acids (UA). leptin and low density lipoproteins (LDL). We analyzed the modulation of some metabolic and biochemical markers (lipid peroxidation, cholesterol determination. ROS production) or 1CAM-I and Carnitine Palmitoyltransferase 2 (CPT2) production. The in vitro model was used to quantitatively characterize the modulation of these markers by natural compounds usually introduced with diet (BBR and RYR). Results: UA (6. 9 and 12mg/dl) treatment reduced HAEC viability, increased ROS production and modified ICAM-I expression. The incubation with Leptin (lOOng/ml) increased CPT2 expression (24 h). Moreover, LDL (200 ng/ml) promoted lipid peroxidation and altered cholesterol production. BBR and RYR differently affected the markers. Incubation of HAEC with BBR modified the response to both UA and Leptin, and counteracted ROS production, lipid peroxidation and ICAM-1 or CFT2 expression. RYR was less effective than BBR. Conclusions: In this work we developed a new simplified in vitro system suitable to evaluate ED associated to MetS. Moreover, the same system was used to test the role of natural compounds with nutraceutical applications to evaluate their possible preventive effect on ED development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Positron emission tomography (PET) is the imaging modality most extensively tested for treatment monitoring in particle therapy. Optimal use of PET in proton therapy requires in situ acquisition of ...the relatively strong 15O signal due to its relatively short half-life (~2 min) and high oxygen content in biological tissues, enabling shorter scans that are less sensitive to biological washout. This paper presents the first performance tests of a scaled-down in situ time-of-flight (TOF) PET system based on digital photon counters (DPCs) coupled to Cerium-doped Lutetium Yttrium Silicate (LYSO:Ce) crystals, providing quantitative results representative of a dual-head tomograph that complies with spatial constraints typically encountered in clinical practice (2 × 50°, of 360°, transaxial angular acceptance). The proton-induced activity inside polymethylmethacrylate (PMMA) and polyethylene (PE) phantoms was acquired within beam pauses (in-beam) and immediately after irradiation by an actively-delivered synchrotron pencil-beam, with clinically relevant 125.67 MeV/u, 4.6 × 108 protons s−1, and 1010 total protons. 3D activity maps reconstructed with and without TOF information are compared to FLUKA simulations, demonstrating the benefit of TOF-PET to reduce limited-angle artefacts using a 382 ps full width at half maximum coincidence resolving time. The time-dependent contributions from different radionuclides to the total count-rate are investigated. We furthermore study the impact of the acquisition time window on the laterally integrated activity depth-profiles, with emphasis on 2 min acquisitions starting at different time points. The results depend on phantom composition and reflect the differences in relative contributions from the radionuclides originating from carbon and oxygen. We observe very good agreement between the shapes of the simulated and measured activity depth-profiles for post-beam protocols. However, our results also suggest that available experimental cross sections underestimate the production of 10C for in-beam acquisitions, which in PE results in an overestimation of the predicted activity range by 1.4 mm. The uncertainty in the activity range measured in PMMA using the DPC-based TOF-PET prototype setup equals 0.2 mm-0.3 mm.
Ion beams offer an excellent tumor-dose conformality due to their inverted depth-dose profile and finite range in tissue, the Bragg peak (BP). However, they introduce sensitivity to range ...uncertainties. Imaging techniques play an increasingly important role in ion beam therapy to support precise diagnosis and identification of the target volume at the planning stage as well as to ensure the correspondence between the planning and treatment situation at the actual irradiation. For the purpose of improved treatment quality, ion-based radiographic images could be acquired at the treatment site before or during treatment and be employed to monitor the patient positioning and to check the patient-specific ion range. This work presents the initial experimental investigations carried out to address the feasibility of carbon ion radiography at the Heidelberg ion therapy center using a prototype range telescope set-up and an active raster scanning ion beam delivery system. Bragg curves are measured with a stack of ionization chambers (IC) synchronously to the beam delivery. The position of the BP is extracted from the data by locating the channel of maximum current signal for each delivered beam. Each BP is associated to the lateral and vertical positions of the scanned raster point extrapolated from the beam monitor system to build up a radiography. The radiographic images are converted into water equivalent thickness (WET) based on two calibrations of the detector. Radiographies of two phantoms of different complexities are reconstructed and their image quality is analyzed. A novel method proposed to increase the nominal range resolution of the IC stack is applied to the carbon ion radiography of an Alderson head phantom. Moreover, an x-ray digitally reconstructed radiography of the same anthropomorphic head phantom is converted in WET through the clinically used ion range calibration curve and compared with the carbon ion radiography based on a γ-index approach, yielding a good correspondence in terms of absolute WET within ±3%, 3 mm distance-to-agreement and, 87% passing ratio. Imaging artifacts at interfaces within the irradiated phantom due to the finite size of the beam, resulting in multiple maxima, are addressed. Overall, this work demonstrates the feasibility of the prototype range telescope to acquire ion-based transmission imaging with a resolution of up to 0.8 mm WET.
A detector prototype based on a stack of 61 parallel-plate ionisation chambers (PPIC) interleaved with absorber plates of polymethyl methacrylate (PMMA) was assembled for transmission imaging ...purposes in ion beam therapy. The thickness of the absorber sheets in the PPIC stack determines the nominal range resolution of the detector. In the current set-up, 3 mm PMMA slabs are used. The signal of the 61 active channels of the stack thereby provides a discrete approximation of the Bragg curve in the detector. In this work, a data processing method to increase the range resolution (MIRR) in a stack of ionization chambers is presented. In the MIRR the position of the maximum of the Bragg curve is deduced from the ratio of measured signals in adjacent PPIC channels. The method is developed based on Bragg curves obtained from Monte Carlo simulations and validated with experimental data of a wedge-shaped PMMA phantom acquired with the PPIC stack using carbon ion beams. The influence of the initial beam energy and of phantom inhomogeneities on the MIRR is quantitatively evaluated. Systematic errors as well as inaccuracies related to signal noise are discussed and quantified. It is shown that with the MIRR an increased range resolution of 0.7 mm PMMA equivalent or 0.8 mm water equivalent thickness is achieved for the considered experimental data.
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