Regularised patient-specific stopping power calibration for proton therapy planning based on proton radiographic images.

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 [Formula: see text]. 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 radiography with a commercial range telescope detector using dedicated post processing methods.

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.

A comprehensive theoretical comparison of proton imaging set-ups in terms of spatial resolution.

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 [Formula: see text] 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.

Study for online range monitoring with the interaction vertex imaging method.

Ion beam therapy enables a highly accurate dose conformation delivery to the tumor due to the finite range of charged ions in matter (i.e. Bragg peak (BP)). Consequently, the dose profile is very sensitive to patients anatomical changes as well as minor mispositioning, and so it requires improved dose control techniques. Proton interaction vertex imaging (IVI) could offer an online range control in carbon ion therapy. In this paper, a statistical method was used to study the sensitivity of the IVI technique on experimental data obtained from the Heidelberg Ion-Beam Therapy Center. The vertices of secondary protons were reconstructed with pixelized silicon detectors. The statistical study used the [Formula: see text] test of the reconstructed vertex distributions for a given displacement of the BP position as a function of the impinging carbon ions. Different phantom configurations were used with or without bone equivalent tissue and air inserts. The inflection points in the fall-off region of the longitudinal vertex distribution were computed using different methods, while the relation with the BP position was established. In the present setup, the resolution of the BP position was about 4-5 mm in the homogeneous phantom under clinical conditions (106 incident carbon ions). Our results show that the IVI method could therefore monitor the BP position with a promising resolution in clinical conditions.

First in situ TOF-PET study using digital photon counters for proton range verification.

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 (15)O 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 × 10(8) protons s(-1), and 10(10) 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 (10)C 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.

An advanced image processing method to improve the spatial resolution of ion radiographies.

We present an optimization method to improve the spatial resolution and the water equivalent thickness (WET) accuracy of ion radiographies. The method is designed for imaging systems measuring for each actively scanned beam spot the lateral position of the pencil beam and at the same time the Bragg curve (behind the target) in discrete steps without relying on tracker detectors to determine the ion trajectory before and after the irradiated volume. Specifically, the method was used for an imaging set-up consisting of a stack of 61 parallel-plate ionization chambers (PPIC) interleaved with absorber plates of polymethyl methacrylate (PMMA) working as a range telescope. The method uses not only the Bragg peak position, but approximates the entire measured Bragg curve as a superposition of differently shifted Bragg curves. Their relative weights allow to reconstruct the distribution of thickness around each scan spot of a heterogeneous phantom. The approach also allows merging the ion radiography with the geometric information of a co-registered x-ray radiography in order to increase its spatial resolution. The method was tested using Monte Carlo simulated and experimental proton radiographies of a PMMA step phantom and an anthropomorphic head phantom. For the step phantom, the effective spatial resolution was found to be 6 and 4 times higher than the nominal resolution for the simulated and experimental radiographies, respectively. For the head phantom, a gamma index was calculated to quantify the conformity of the simulated proton radiographies with a digitally reconstructed radiography (DRR) obtained from an x-ray CT and properly converted into WET. For a distance-to-agreement (DTA) of 2.5 mm and a relative WET difference (RWET) of 2.5%, the passing ratio was 100%/85% for the optimized/non-optimized case, respectively. When the optimized proton radiography was merged with the co-registered DRR, the passing ratio was 100% at DTA = 1.3 mm and RWET = 1.3%. A special interpolation method allows to strongly reduce the dose by using a coarser grid of the measured beam spot position with a 5 times larger grid distance. We show that despite a dose reduction of 25 times (leading to a dose of 0.016 mGy for the current imaging set-up), the image quality of the optimized radiographies remains fairly unaffected for both the simulated and experimental case.

Absolute prompt-gamma yield measurements for ion beam therapy monitoring.

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.

A method to increase the nominal range resolution of a stack of parallel-plate ionization chambers.

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.

Experimental investigations on carbon ion scanning radiography using a range telescope.

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.

Experimental characterization of a prototype detector system for carbon ion radiography and tomography.

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.

Crab spiders (Araneae: Thomisidae) in flowering plants in a Brazilian "Cerrado" ecosystem.

Although crab spiders are common in flowering plants, their relations with plant species and its floral traits have been poorly known in the Neotropics. Observations regarding plant habits, floral visitors and also floral characteristics such as anthesis, odour, shape, colour and floral resources were recorded in flowering plant species of an area of "Cerrado" on a 2 km long trail. Misumenops argenteus and Misumenops pallens accounted for 62.86% of the spiders captured on 22 flowering plant species. The plants Senna rugosa (Fabaceae), Styrax ferrugineus (Styracaceae) and Banisteriopsis campestris (Malpighiaceae), hosted, each one, about 10 to 17% of the total spiders collected and these plants had diurnal anthesis, bee-attractive flower colours such as yellow (S. rugosa), white (S. ferrugineus), and pink (B. campestris), poricidal anthers as well as being visited by bees which evidenced bee-pollination syndrome. This study is the first survey regarding crab spiders and their associations with plant species of the "Cerrado".

An integral test of FLUKA nuclear models with 160 MeV proton beams in multi-layer Faraday cups.

Monte Carlo (MC) codes are useful tools to simulate the complex processes of proton beam interactions with matter. In proton therapy, nuclear reactions influence the dose distribution. Therefore, the validation of nuclear models adopted in MC codes is a critical requisite for their use in this field. A simple integral test can be performed using a multi-layer Faraday cup (MLFC). This method allows separation of the nuclear and atomic interaction processes, which are responsible for secondary particle emission and the finite primary proton range, respectively. In this work, the propagation of 160 MeV protons stopping in two MLFCs made of polyethylene and copper has been simulated by the FLUKA MC code. The calculations have been performed with and without secondary electron emission and transport, as well as charge sharing in the dielectric layers. Previous results with other codes neglected those two effects. The impact of this approximation has been investigated and found to be relevant only in the proximity of the Bragg peak. Longitudinal charge distributions computed with FLUKA with both approaches have been compared with experimental data from the literature. Moreover, the contribution of different processes to the measurable signal has been addressed. A thorough analysis of the results has demonstrated that the nuclear and electromagnetic models of FLUKA reproduce the two sets of experimental data reasonably well.

Immunohistochemical study of 49 cutaneous melanomas: p53, PCNA, Bcl-2 expression and multidrug resistance.

AIMS AND BACKGROUND: Thickness and level of invasion are the main morphological elements for an approximate but not sufficiently sensitive prognostic evaluation of cutaneous melanomas. By using immunohistochemical methods it is possible to detect biological markers related to prognosis. We have studied p53, PCNA, Bcl-2 and P-gp expression in 49 primary cutaneous melanomas. MATERIALS: We used the immunophosphatase APAAP immunohistochemical method. The percentage of labeled cells (according to four classes of positivity: <5%; 5-25%; 25-50%; >50%) and the localization of immunoreactivity were expressed for each marker. Statistical analysis was performed to determine the correlations between markers and level or thickness of melanomas. RESULTS: We found a good correlation between p53 expression and melanoma thickness (P <0.005), PCNA and P-gp expression. No relationship was observed between Bcl-2 expression and the different variables considered or other markers. CONCLUSIONS: Our data seem to indicate an unfavorable prognostic role of higher nuclear p53 expression. However, we believe that our results need to be integrated with patients' clinical follow-up and with the study of the expression of these markers in benign melanocytic lesions to gain more accurate information about their prognostic significance.

Primary amebic meningoencephalitis with cerebral and cerebellar abscesses: case report.

A case of fatal primary amebic meningoencephalitis is reported. We need to remind ourselves that, if the usual laboratory tests fail to show any microbial or fungal agents either in the CSF or in fluids or tissues obtained at operation, it is imperative that a warm wet slide preparation be made. Primary amebic meningoencephalitis is a very rare disease, and it is only by prompt recognition of the amebae that we can make an early diagnosis and institute the appropriate therapy.

Contamination of Pantopaque by glass.

Investigation has shown that when ampules containing Pantopaque are opened, a variable amount of fragments of glass may fall into the Pantopaque. When the Pantopaque is injected into the spinal canal these fragments may also be injected. As yet the results of injecting fragments of glass into the spinal subarachnoid space are unknown. The glass can be removed by passing the Pantopaque through a 0.22 micron Millex Filter.

Computerized tomographic demonstration of rotational atlanto-axial fixation. Case report.

The authors report a case of rotational fixation of the atlanto-axial joint in which the diagnosis was not reached by conventional radiographic techniques. The clinical impression of rotational fixation was ultimately confirmed by computerized tomography. This new diagnostic modality can be very helpful in arriving at a very difficult diagnosis.

Case report. Computer assisted tomography in syringomyelia.

A case of cervicothoracic syringomyelia shown on computer assisted tomography is presented. Surgical verification was obtained, and the extent of the cord cavitation was also demonstrated.