Prediction of image noise contributions in proton computed tomography and comparison to measurements.

We present a method to accurately predict image noise in proton computed tomography (pCT) using data generated from a Monte Carlo simulation and a patient or object model that may be generated from a prior x-ray CT image. This enables noise prediction for arbitrary beam fluence settings and, therefore, the application of fluence-modulated pCT (FMpCT), which can achieve prescribed noise targets and may significantly reduce the integral patient dose. We extended an existing Monte Carlo simulation of a prototype pCT scanner to include effects of quenching in the energy detector scintillators and constructed a beam model from experimental tracking data. Simulated noise predictions were compared to experimental data both in the projection domain and in the reconstructed image. Noise prediction agreement between simulated and experimental data in terms of the root-mean-square (RMS) error was better than 7% for a homogeneous water phantom and a sensitometry phantom with tubular inserts. For an anthropomorphic head phantom, modeling the anatomy of a five-year-old child, the RMS error was better than 9% in three evaluated slices. We were able to reproduce subtle noise features near heterogeneities. To demonstrate the feasibility of Monte Carlo simulated noise maps for fluence modulation, we calculated a fluence profile that yields a homogeneous noise level in the image. Unlike for bow-tie filters in x-ray CT this does not require constant fluence at the detector and the shape of the fluence profile is fundamentally different. Using an improved Monte Carlo simulation, we demonstrated the feasibility of using simulated data for accurate image noise prediction for pCT. We believe that the agreement with experimental data is sufficient to enable the future optimization of FMpCT fluence plans to achieve prescribed noise targets in a fluence-modulated acquisition.

Application of fluence field modulation to proton computed tomography for proton therapy imaging.

This simulation study presents the application of fluence field modulated computed tomography, initially developed for x-ray CT, to proton computed tomography (pCT). By using pencil beam (PB) scanning, fluence modulated pCT (FMpCT) may achieve variable image quality in a pCT image and imaging dose reduction. Three virtual phantoms, a uniform cylinder and two patients, were studied using Monte Carlo simulations of an ideal list-mode pCT scanner. Regions of interest (ROI) were selected for high image quality and only PBs intercepting them preserved full fluence (FF). Image quality was investigated in terms of accuracy (mean) and noise (standard deviation) of the reconstructed proton relative stopping power compared to reference values. Dose calculation accuracy on FMpCT images was evaluated in terms of dose volume histograms (DVH), range difference (RD) for beam-eye-view (BEV) dose profiles and gamma evaluation. Pseudo FMpCT scans were created from broad beam experimental data acquired with a list-mode pCT prototype. FMpCT noise in ROIs was equivalent to FF images and accuracy better than -1.3%(-0.7%) by using 1% of FF for the cylinder (patients). Integral imaging dose reduction of 37% and 56% was achieved for the two patients for that level of modulation. Corresponding DVHs from proton dose calculation on FMpCT images agreed to those from reference images and 96% of BEV profiles had RD below 2 mm, compared to only 1% for uniform 1% of FF. Gamma pass rates (2%, 2 mm) were 98% for FMpCT while for uniform 1% of FF they were as low as 59%. Applying FMpCT to preliminary experimental data showed that low noise levels and accuracy could be preserved in a ROI, down to 30% modulation. We have shown, using both virtual and experimental pCT scans, that FMpCT is potentially feasible and may allow a means of imaging dose reduction for a pCT scanner operating in PB scanning mode. This may be of particular importance to proton therapy given the low integral dose found outside the target.

The effect of beam purity and scanner complexity on proton CT accuracy.

PURPOSE: To determine the dependence of the accuracy in reconstruction of relative stopping power (RSP) with proton computerized tomography (pCT) scans on the purity of the proton beam and the technological complexity of the pCT scanner using standard phantoms and a digital representation of a pediatric patient. METHODS: The Monte Carlo method was applied to simulate the pCT scanner, using both a pure proton beam (uniform 200 MeV mono-energetic, parallel beam) and the Northwestern Medicine Chicago Proton Center (NMCPC) clinical beam in uniform scanning mode. The accuracy of the simulation was validated with measurements performed at NMCPC including reconstructed RSP images obtained with a preclinical prototype pCT scanner. The pCT scanner energy detector was then simulated in three configurations of increasing complexity: an ideal totally absorbing detector, a single stage detector and a multi-stage detector. A set of 15 cm diameter water cylinders containing either water alone or inserts of different material, size, and position were simulated at 90 projection angles (4° steps) for the pure and clinical proton beams and the three pCT configurations. A pCT image of the head of a detailed digital pediatric phantom was also reconstructed from the simulated pCT scan with the prototype detector. RESULTS: The RSP error increased for all configurations for insert sizes under 7.5 mm in radius, with a sharp increase below 5 mm in radius, attributed to a limit in spatial resolution. The highest accuracy achievable using the current pCT calibration step phantom and reconstruction algorithm, calculated for the ideal case of a pure beam with totally absorbing energy detector, was 1.3% error in RSP for inserts of 5 mm radius or more, 0.7 mm in range for the 2.5 mm radius inserts, or better. When the highest complexity of the scanner geometry was introduced, some artifacts arose in the reconstructed images, particularly in the center of the phantom. Replacing the step phantom used for calibration with a wedge phantom led to RSP accuracy close to the ideal case, with no significant dependence of RSP error on insert location or material. The accuracy with the multi-stage detector and NMCPC beam for the cylindrical phantoms was 2.2% in RSP error for inserts of 5 mm radius or more, 0.7 mm in range for the 2.5 mm radius inserts, or better. The pCT scan of the pediatric phantom resulted in mean RSP values within 1.3% of the reference RSP, with a range error under 1 mm, except in exceptional situations of parallel incidence on a boundary between low and high density. CONCLUSIONS: The pCT imaging technique proved to be a precise and accurate imaging tool, rivaling the current x-rays based techniques, with the advantage of being directly sensitive to proton stopping power rather than photon interaction coefficients. Measured and simulated pCT images were obtained from a wobbled proton beam for the first time. Since the in-silico results are expected to accurately represent the prototype pCT, upcoming measurements using the wedge phantom for calibration are expected to show similar accuracy in the reconstructed RSP.

An evaluation of spatial resolution of a prototype proton CT scanner.

PURPOSE: To evaluate the spatial resolution of proton CT using both a prototype proton CT scanner and Monte Carlo simulations. METHODS: A custom cylindrical edge phantom containing twelve tissue-equivalent inserts with four different compositions at varying radial displacements from the axis of rotation was developed for measuring the modulation transfer function (MTF) of a prototype proton CT scanner. Two scans of the phantom, centered on the axis of rotation, were obtained with a 200 MeV, low-intensity proton beam: one scan with steps of 4°, and one scan with the phantom continuously rotating. In addition, Monte Carlo simulations of the phantom scan were performed using scanners idealized to various degrees. The data were reconstructed using an iterative projection method with added total variation superiorization based on individual proton histories. Edge spread functions in the radial and azimuthal directions were obtained using the oversampling technique. These were then used to obtain the modulation transfer functions. The spatial resolution was defined by the 10% value of the modulation transfer function (MTF10%) in units of line pairs per centimeter (lp/cm). Data from the simulations were used to better understand the contributions of multiple Coulomb scattering in the phantom and the scanner hardware, as well as the effect of discretization of proton location. RESULTS: The radial spatial resolution of the prototype proton CT scanner depends on the total path length, W, of the proton in the phantom, whereas the azimuthal spatial resolution depends both on W and the position, u-, at which the most-likely path uncertainty is evaluated along the path. For protons contributing to radial spatial resolution, W varies with the radial position of the edge, whereas for protons contributing to azimuthal spatial resolution, W is approximately constant. For a pixel size of 0.625 mm, the radial spatial resolution of the image reconstructed from the fully idealized simulation data ranged between 6.31 ± 0.36 lp/cm for W = 197 mm i.e., close to the center of the phantom, and 13.79 ± 0.36 lp/cm for W = 97 mm, near the periphery of the phantom. The azimuthal spatial resolution ranged from 6.99 ± 0.23 lp/cm at u- = 75 mm (near the center) to 11.20 ± 0.26 lp/cm at u- = 20 mm (near the periphery). Multiple Coulomb scattering limits the radial spatial resolution for path lengths greater than approximately 130 mm, and the azimuthal spatial resolution for positions of evaluation greater than approximately 40 mm for W = 199 mm. The radial spatial resolution of the image reconstructed from data from the 4° stepped experimental scan ranged from 5.11 ± 0.61 lp/cm for W = 197 mm to 8.58 ± 0.50 lp/cm for W = 97 mm. In the azimuthal direction, the spatial resolution ranged from 5.37 ± 0.40 lp/cm at u- = 75 mm to 7.27 ± 0.39 lp/cm at u- = 20 mm. The continuous scan achieved the same spatial resolution as that of the stepped scan. CONCLUSIONS: Multiple Coulomb scattering in the phantom is the limiting physical factor of the achievable spatial resolution of proton CT; additional loss of spatial resolution in the prototype system is associated with scattering in the proton tracking system and inadequacies of the proton path estimate used in the iterative reconstruction algorithm. Improvement in spatial resolution may be achievable by improving the most likely path estimate by incorporating information about high and low density materials, and by minimizing multiple Coulomb scattering in the proton tracking system.

Operation of the Preclinical Head Scanner for Proton CT.

We report on the operation and performance tests of a preclinical head scanner developed for proton computed tomography (pCT). After extensive preclinical testing, pCT is intended to be employed in support of proton therapy treatment planning and pre-treatment verification in patients undergoing particle-beam therapy. In order to assess the performance of the scanner, we have performed CT scans with 200 MeV protons from both the synchrotron of the Loma Linda University Medical Center (LLUMC) and the cyclotron of the Northwestern Medicine Chicago Proton Center (NMCPC). The very high sustained rate of data acquisition, exceeding one million protons per second, allowed a full 360° scan to be completed in less than 7 minutes. The reconstruction of various phantoms verified accurate reconstruction of the proton relative stopping power (RSP) and the spatial resolution in a variety of materials. The dose for an image with better than 1% uncertainty in the RSP is found to be close to 1 mGy.

A scintillator-based approach to monitor secondary neutron production during proton therapy.

PURPOSE: The primary objective of this work is to measure the secondary neutron field produced by an uncollimated proton pencil beam impinging on different tissue-equivalent phantom materials using organic scintillation detectors. Additionally, the Monte Carlo code mcnpx-PoliMi was used to simulate the detector response for comparison to the measured data. Comparison of the measured and simulated data will validate this approach for monitoring secondary neutron dose during proton therapy. METHODS: Proton beams of 155- and 200-MeV were used to irradiate a variety of phantom materials and secondary particles were detected using organic liquid scintillators. These detectors are sensitive to fast neutrons and gamma rays: pulse shape discrimination was used to classify each detected pulse as either a neutron or a gamma ray. The mcnpx-PoliMi code was used to simulate the secondary neutron field produced during proton irradiation of the same tissue-equivalent phantom materials. RESULTS: An experiment was performed at the Loma Linda University Medical Center proton therapy research beam line and corresponding models were created using the mcnpx-PoliMi code. The authors' analysis showed agreement between the simulations and the measurements. The simulated detector response can be used to validate the simulations of neutron and gamma doses on a particular beam line with or without a phantom. CONCLUSIONS: The authors have demonstrated a method of monitoring the neutron component of the secondary radiation field produced by therapeutic protons. The method relies on direct detection of secondary neutrons and gamma rays using organic scintillation detectors. These detectors are sensitive over the full range of biologically relevant neutron energies above 0.5 MeV and allow effective discrimination between neutron and photon dose. Because the detector system is portable, the described system could be used in the future to evaluate secondary neutron and gamma doses on various clinical beam lines for commissioning and prospective data collection in pediatric patients treated with proton therapy.

Novel scintillation detector design and performance for proton radiography and computed tomography.

PURPOSE: Proton computed tomography (pCT) will enable accurate prediction of proton and ion range in a patient while providing the benefit of lower radiation exposure than in x-ray CT. The accuracy of the range prediction is essential for treatment planning in proton or ion therapy and depends upon the detector used to evaluate the water-equivalent path length (WEPL) of a proton passing through the object. A novel approach is presented for an inexpensive WEPL detector for pCT and proton radiography. METHODS: A novel multistage detector with an aperture of 10 × 37.5 cm was designed to optimize the accuracy of the WEPL measurements while simplifying detector construction and the performance requirements of its components. The design of the five-stage detector was optimized through simulations based on the geant4 detector simulation toolkit, and the fabricated prototype was calibrated in water-equivalent millimeters with 200 MeV protons in the research beam line of the clinical proton synchrotron at Loma Linda University Medical Center. A special polystyrene step phantom was designed and built to speed up and simplify the calibration procedure. The calibrated five-stage detector was tested in the 200 MeV proton beam as part of the pCT head scanner, using a water phantom and polystyrene slabs to verify the WEPL reconstruction accuracy. RESULTS: The beam-test results demonstrated excellent performance of the new detector, in good agreement with the simulation results. The WEPL measurement accuracy is about 3.0 mm per proton in the 0-260 mm WEPL range required for a pCT head scan with a 200 MeV proton beam. CONCLUSIONS: The new multistage design approach to WEPL measurements for proton CT and radiography has been prototyped and tested. The test results show that the design is competitive with much more expensive calorimeter and range-counter designs.

Characterisation of a track structure imaging detector.

The spatial distribution of radiation-induced ionisations in sub-cellular structures plays an important role in the initial formation of radiation damage to biological tissues. Using the nanodosimetry approach, physical characteristics of the track structure can be measured and correlated to DNA damage. In this work, a novel nanodosimeter is presented, which detects positive ions produced by radiation interacting with a gas-sensitive volume in order to obtain a high resolution image of the radiation track structure. The characterisation of the detector prototype was performed and different configurations of the device were tested by varying the detector cathode material and the working gas. Preliminary results show that the ionisation cluster size distribution can be obtained with this approach. Further work is planned to improve the detector efficiency in order to register the complete three-dimensional track structure of ionising radiation.

200 MeV proton radiography studies with a hand phantom using a prototype proton CT scanner.

Proton radiography has applications in patient alignment and verification procedures for proton beam radiation therapy. In this paper, we report an experiment which used 200 MeV protons to generate proton energy-loss and scattering radiographs of a hand phantom. The experiment used the first-generation proton computed tomography (CT) scanner prototype, which was installed on the research beam line of the clinical proton synchrotron at Loma Linda University Medical Center. It was found that while both radiographs displayed anatomical details of the hand phantom, the energy-loss radiograph had a noticeably higher resolution. Nonetheless, scattering radiography may yield more contrast between soft and bone tissue than energy-loss radiography, however, this requires further study. This study contributes to the optimization of the performance of the next-generation of clinical proton CT scanners. Furthermore, it demonstrates the potential of proton imaging (proton radiography and CT), which is now within reach of becoming available as a new, potentially low-dose medical imaging modality.

[Production of mycobacterial antigenes merged with cellulose binding protein domain in order to produce subunit vaccines against tuberculosis].

Protein genes Ag85A, Esat-6, and Cfp10 of Mycobacterium tuberculosis were sequenced using the database GenBank to implement selection and synthesis of primer pairs of given genes. PCR was used to obtain target amplicons of the genes. Chromosome DNA of M. tuberculosis H37Rv was used as the DNA amplification matrix. The PCR products were obtained using the plasmid pQE6, cloned, and amplified in the Escherichia coli M15 strain. Chimere products containing mycobacterial genes and cellulose binding protein domain (CBD), were obtained using the plasmid treated with restriction endonucleases. CBD fragment obtained using similar treatment of the ptt10 plasmid. The plasmids containing merged sequences of mycobacterial genes-antigenes and CBD were selected. The 3 mycobacterial genes were expressed in the E. coli M15 cells resulting in biosynthesis of corresponding recombinant proteins of expected molecular weight. Concentration of CBD, Cfp10-CBD, Ag85A-CBD, and ESAT6-CBD was 20%, 15%, and 15% total protein, respectively. The resulting chimere proteins provide high affinity for cellulose and high stability. Immobilization of CBD-containing recombinant proteins proceeds as one-stage process providing target protein purification and adsorption on cellulose. The vaccines produced using this technology are inexpensive because of low cost of cellulose sorbents as well as simultaneous use of cellulose for purification and immobilization of protein. Many cellulose preparations are not toxic, biocompatible, and widely used in medicine.

Water-equivalent path length calibration of a prototype proton CT scanner.

PURPOSE: The authors present a calibration method for a prototype proton computed tomography (pCT) scanner. The accuracy of these measurements depends upon careful calibration of the energy detector used to measure the residual energy of the protons that passed through the object. METHODS: A prototype pCT scanner with a cesium iodide (CsI(Tl)) crystal calorimeter was calibrated by measuring the calorimeter response for protons of 200 and 100 MeV initial energies undergoing degradation in polystyrene plates of known thickness and relative stopping power (RSP) with respect to water. Calibration curves for the two proton energies were obtained by fitting a second-degree polynomial to the water-equivalent path length versus calorimeter response data. Using the 100 MeV calibration curve, the RSP values for a variety of tissue-equivalent materials were measured and compared to values obtained from a standard depth-dose range shift measurement using a water-tank. A cylindrical water phantom was scanned with 200 MeV protons and its RSP distribution was reconstructed using the 200 MeV calibration. RESULTS: It is shown that this calibration method produces measured RSP values of various tissue-equivalent materials that agree to within 0.5% of values obtained using an established water-tank method. The mean RSP value of the water phantom reconstruction was found to be 0.995 ± 0.006. CONCLUSIONS: The method presented provides a simple and reliable procedure for calibration of a pCT scanner.

A nanodosimetric model of radiation-induced clustered DNA damage yields.

We present a nanodosimetric model for predicting the yield of double strand breaks (DSBs) and non-DSB clustered damages induced in irradiated DNA. The model uses experimental ionization cluster size distributions measured in a gas model by an ion counting nanodosimeter or, alternatively, distributions simulated by a Monte Carlo track structure code developed to simulate the nanodosimeter. The model is based on a straightforward combinatorial approach translating ionizations, as measured or simulated in a sensitive gas volume, to lesions in a DNA segment of one-two helical turns considered equivalent to the sensitive volume of the nanodosimeter. The two model parameters, corresponding to the probability that a single ion detected by the nanodosimeter corresponds to a single strand break or a single lesion (strand break or base damage) in the equivalent DNA segment, were tuned by fitting the model-predicted yields to previously measured double-strand break and double-strand lesion yields in plasmid DNA irradiated with protons and helium nuclei. Model predictions were also compared to both yield data simulated by the PARTRAC code for protons of a wide range of different energies and experimental DSB and non-DSB clustered DNA damage yield data from the literature. The applicability and limitations of this model in predicting the LET dependence of clustered DNA damage yields are discussed.

[Interaction of bacteria of the genus Bartonella with the host: inhibition of apoptosis, induction of proliferation, and formation of tumors].

The bacteria of the genus Bartonella are the causative agents for earlier not diagnosed or re-emergent diseases of the humans, danger of which increases in relation with increasing number of persons with the disturbed immune status. Bartonellae are intracellular parasites, the places of their habitation in the humans and animals are the endothelial cells of blood vessels and erythrocytes. The modern data concerning major factors of the Bartonellae virulence and host-bacteria interactions were considered and discussed in this article. The induction of the type IV secretion system, effector protein transmission, inhibition of the endothelial cells apoptosis, and induction of their proliferation lead to formation of new blood vessels and tumors.

[Dds20 operates in cds1-independent mechanism of tolerance to UV-induced DNA damage in Schizosaccharomyces pombe cells].

Repair of DNA double-stranded breaks caused by ionizing radiation or cellular metabolization, homologous recombination, is an evolutionary conserved process controlled by RAD52 group genes. Genes of recombinational repair also play a leading role in the response to DNA damage caused by UV light. Cells with deletion in gene dds20 of recombinational repair were shown to manifest hypersensitivity to the action of UV light at lowered incubation temperature. Epistatic analysis revealed that dds20+ is not a member of the NER and UVER gene groups responsible for the repair of DNA damage induced by UV light. The Dds protein has functions in the Cds1-independent mechanism of UV damage tolerance of DNA.

[Molecular genetic methods of typing of the Bartonellae].

The primer systems for the PCR detection of four house-keeping genes of bartonellae in clinical material were developed and tested. The tactics of the species RFLP typing was also developed and tested. The scheme of the species RFLP typing of bartonellae was tested using as an example two strains for the first time isolated in Russia from patients with endocarditis and fever of uncertain origin. The results of the typing were supported by sequencing of the amplicons obtained. According to the sequencing the isolates were attributed to the sub species Bartonella vinsonii, subsp. arupensis. The necessity of molecular epidemiological analysis of bartonelloses in Russia was substantiated.

[Cell phenotypes of a mutant in the gene encoding a Rad51 paralog in fission yeast].

The discovery of three Rad51 paralogs in Saccharomyces cerevisiae (Rad55, Rad57, and Dmc1), four in Schizosaccharomyces pombe (Rhp55, Rhp57, Rlp 1, and Dmc 1), and six in human (Rad51 B, Rad51 C, Rad51 D, Xrcc2, Xrcc3, and Dmcl) indicate the functional diversity and specialization of RecA-like proteins in the line from the lower to higher organisms. This paper reports characterization of a number of mitotic and meiotic phenotypes of the cells mutant in rlpl gene, encoding a paralog of Rad5 1, in fission yeasts. No evident role of Rlp I protein in the repair of spontaneous lesions emerging during mating type switching was found. Rlpl does not interact physically with Dmcl. An elevated expression of rhp51 has a dominant negative effect on the cell survivability of rlpl mutant exposed to a DNA-damaging agent. We assume that Rlp 1 acts at the stages of recombination connected with disassembling of the nucleoprotein filament formed by Rhp51 protein.

First attempts at prediction of DNA strand-break yields using nanodosimetric data.

We present the first results of our attempts to correlate yields of ionisation clusters in a gas model of DNA and corresponding double-strand break (DSB) yields in irradiated plasmids, using a simple statistical model of DNA lesion formation. Based on the same statistical model, we also provide a comparison of simulated nanodosimetric data for electrons and published DSB yields obtained with the PARTRAC code.