A comparative study of sensitizers and liposome composition in radiation-induced controlled drug release for cancer therapy.

This study investigates drug-loaded liposomes designed for controlled release under ionizing radiation to refine cancer treatment precision. Liposomes as carriers enable targeted chemotherapy delivery, reducing healthy tissue damage risk. Liposomes containing poly- or mono-unsaturated fatty acids and various sensitizing agents were assessed for responsiveness to UV light and γ photon irradiation including rose bengal (RB), protoporphyrin IX (PPIX), verteporfin (VP), cercosporin (CERC) and hypericin (HYP). Carboxyfluorescein (CF) was used as a surrogate for drug release measurements. VP and PPIX induced rapid drug release and lipid peroxidation under UV light, while RB prompted quick drug release under UV light and a modest immediate release under γ irradiation, eventually reaching full release a few hours after irradiation, demonstrating dose-dependent effects. Smaller liposomes displayed accelerated release, emphasizing size-dependent kinetics. In vitro analyses evaluated radiosensitizing effects of RB-loaded liposomes. Clonogenic assays indicated that RB-filled liposomes had minimal direct radiobiological effects but increased indirect radiation damage, as shown by the curvature of the cell survival curve. Our study sheds light on factors influencing liposomal drug release under ionizing radiation, spotlighting RB as a promising radiosensitizer requiring further investigation for cancer therapy potential.

Dictionary-based software for proton dose reconstruction and submilimetric range verification.

Objective.This paper presents a new method for fast reconstruction (compatible with in-beam use) of deposited dose during proton therapy using data acquired from a PET scanner. The most innovative feature of this novel method is the production of noiseless reconstructed dose distributions from which proton range can be derived with high precision.Approach.A new MLEM & simulated annealing (MSA) algorithm, developed especially in this work, reconstructs the deposited dose distribution from a realistic pre-calculated activity-dose dictionary. This dictionary contains the contribution of each beam in the plan to the 3D activity and dose maps, as calculated by a Monte Carlo simulation. The MSA algorithm, usinga prioriinformation of the treatment plan, seeks for the linear combination of activities of the precomputed beams that best fits the observed PET data, obtaining at the same time the deposited dose.Main results.the method has been tested using simulated data to determine its performance under 4 different test cases: (1) dependency of range detection accuracy with delivered dose, (2) in-beam versus offline verification, (3) ability to detect anatomical changes and (4) reconstruction of a realistic spread-out Bragg peak. The results show the ability of the method to accurately reconstruct doses from PET data corresponding to 1 Gy irradiations, both in intra-fraction and inter-fraction verification scenarios. For this dose level (1 Gy) the method was able to spot range variations as small as 0.6 mm.Significance.out method is able to reconstruct dose maps with remarkable accuracy from clinically relevant dose levels down to 1 Gy. Furthermore, due to the noiseless nature of reconstructed dose maps, an accuracy better than one millimeter was obtained in proton range estimates. These features make of this method a realistic option for range verification in proton therapy.

PeneloPET, a Monte Carlo PET simulation tool based on PENELOPE: features and validation.

Monte Carlo simulations play an important role in positron emission tomography (PET) imaging, as an essential tool for the research and development of new scanners and for advanced image reconstruction. PeneloPET, a PET-dedicated Monte Carlo tool, is presented and validated in this work. PeneloPET is based on PENELOPE, a Monte Carlo code for the simulation of the transport in matter of electrons, positrons and photons, with energies from a few hundred eV to 1 GeV. PENELOPE is robust, fast and very accurate, but it may be unfriendly to people not acquainted with the FORTRAN programming language. PeneloPET is an easy-to-use application which allows comprehensive simulations of PET systems within PENELOPE. Complex and realistic simulations can be set by modifying a few simple input text files. Different levels of output data are available for analysis, from sinogram and lines-of-response (LORs) histogramming to fully detailed list mode. These data can be further exploited with the preferred programming language, including ROOT. PeneloPET simulates PET systems based on crystal array blocks coupled to photodetectors and allows the user to define radioactive sources, detectors, shielding and other parts of the scanner. The acquisition chain is simulated in high level detail; for instance, the electronic processing can include pile-up rejection mechanisms and time stamping of events, if desired. This paper describes PeneloPET and shows the results of extensive validations and comparisons of simulations against real measurements from commercial acquisition systems. PeneloPET is being extensively employed to improve the image quality of commercial PET systems and for the development of new ones.

Design and performance evaluation of a coplanar multimodality scanner for rodent imaging.

This work reports on the development and performance evaluation of the VrPET/CT, a new multimodality scanner with coplanar geometry for in vivo rodent imaging. The scanner design is based on a partial-ring PET system and a small-animal CT assembled on a rotatory gantry without axial displacement between the geometric centers of both fields of view (FOV). We report on the PET system performance based on the NEMA NU-4 protocol; the performance characteristics of the CT component are not included herein. The accuracy of inter-modality alignment and the imaging capability of the whole system are also evaluated on phantom and animal studies. Tangential spatial resolution of PET images ranged between 1.56 mm at the center of the FOV and 2.46 at a radial offset of 3.5 cm. The radial resolution varies from 1.48 mm to 1.88 mm, and the axial resolution from 2.34 mm to 3.38 mm for the same positions. The energy resolution was 16.5% on average for the entire system. The absolute coincidence sensitivity is 2.2% for a 100-700 keV energy window with a 3.8 ns coincident window. The scatter fraction values for the same settings were 11.45% for a mouse-sized phantom and 23.26% for a rat-sized phantom. The peak noise equivalent count rates were also evaluated for those phantoms obtaining 70.8 kcps at 0.66 MBq/cc and 31.5 kcps at 0.11 MBq/cc, respectively. The accuracy of inter-modality alignment is below half the PET resolution, and the image quality of biological specimens agrees with measured performance parameters. The assessment presented in this study shows that the VrPET/CT system is a good performance small-animal imager, while the cost derived from a partial ring detection system is substantially reduced as compared with a full-ring PET tomograph.

The effect of tissue-segmented attenuation maps on PET quantification with a special focus on large arteries. / Efecto de la segmentación por tejidos en los mapas de atenuación sobre la cuantificación PET con especial hincapié en grandes arterias.

OBJECTIVES: Accuracy on quantitative PET image analysis relies on the correct application of attenuation correction which is one of the major challenges for PET/MRI that remains to be solved. The purpose of this study is to evaluate the effect of MRI-based attenuation maps and the use of flexible coils on the quantitative accuracy of PET images with a special focus on large arteries. MATERIALS AND METHODS: PET/CT data from eight oncologic patients was used. PET data was reconstructed using attenuation maps with different level of detail emulating several approaches available on current PET/MRI scanners. PET images obtained with CT-based and MRI-based attenuation maps were compared to evaluate the quantitative biases obtained. The quantitative effect produced by flexible MRI receiver coils on the attenuation maps was also studied. RESULTS: The use of simpler attenuation maps produced increased biases between PET data reconstructed with CT-based and MRI-based attenuation maps for fat, non-fat soft-tissues and bone. Biases in lung were very high due to the large heterogeneity and inter-patient variability of the lung. The quantification on large arteries had small deviations except for the case when flexible coils were used. The TBR provided smaller biases in all cases as it cancelled out the similar deviations obtained for arteries and reference veins. CONCLUSIONS: Simplified attenuation maps used on PET/MRI significantly increase the quantitative variability of PET images especially on lungs and bones. The quantification of PET images acquired with PET/MRI scanners applied to studies of atherosclerosis has small deviations, especially when the TBR is considered.

FIRST: Fast Iterative Reconstruction Software for (PET) tomography.

Small animal PET scanners require high spatial resolution and good sensitivity. To reconstruct high-resolution images in 3D-PET, iterative methods, such as OSEM, are superior to analytical reconstruction algorithms, although their high computational cost is still a serious drawback. The higher performance of modern computers could make iterative image reconstruction fast enough to be viable, provided we are able to deal with the large number of probability coefficients for the system response matrix in high-resolution PET scanners, which is a difficult task that prevents the algorithms from reaching peak computing performance. Considering all possible axial and in-plane symmetries, as well as certain quasi-symmetries, we have been able to reduce the memory requirements to store the system response matrix (SRM) well below 1 GB, which allows us to keep the whole response matrix of the system inside RAM of ordinary industry-standard computers, so that the reconstruction algorithm can achieve near peak performance. The elements of the SRM are stored as cubic spline profiles and matched to voxel size during reconstruction. In this way, the advantages of 'on-the-fly' calculation and of fully stored SRM are combined. The on-the-fly part of the calculation (matching the profile functions to voxel size) of the SRM accounts for 10-30% of the reconstruction time, depending on the number of voxels chosen. We tested our approach with real data from a commercial small animal PET scanner. The results (image quality and reconstruction time) show that the proposed technique is a feasible solution.

Monte Carlo simulations versus experimental measurements in a small animal PET system. A comparison in the NEMA NU 4-2008 framework.

In this work a comparison between experimental and simulated data using GATE and PeneloPET Monte Carlo simulation packages is presented. All simulated setups, as well as the experimental measurements, followed exactly the guidelines of the NEMA NU 4-2008 standards using the microPET R4 scanner. The comparison was focused on spatial resolution, sensitivity, scatter fraction and counting rates performance. Both GATE and PeneloPET showed reasonable agreement for the spatial resolution when compared to experimental measurements, although they lead to slight underestimations for the points close to the edge. High accuracy was obtained between experiments and simulations of the system's sensitivity and scatter fraction for an energy window of 350-650 keV, as well as for the counting rate simulations. The latter was the most complicated test to perform since each code demands different specifications for the characterization of the system's dead time. Although simulated and experimental results were in excellent agreement for both simulation codes, PeneloPET demanded more information about the behavior of the real data acquisition system. To our knowledge, this constitutes the first validation of these Monte Carlo codes for the full NEMA NU 4-2008 standards for small animal PET imaging systems.

Evaluation of resistive-plate-chamber-based TOF-PET applied to in-beam particle therapy monitoring.

Particle therapy is a highly conformal radiotherapy technique which reduces the dose deposited to the surrounding normal tissues. In order to fully exploit its advantages, treatment monitoring is necessary to minimize uncertainties related to the dose delivery. Up to now, the only clinically feasible technique for the monitoring of therapeutic irradiation with particle beams is Positron Emission Tomography (PET). In this work we have compared a Resistive Plate Chamber (RPC)-based PET scanner with a scintillation-crystal-based PET scanner for this application. In general, the main advantages of the RPC-PET system are its excellent timing resolution, low cost, and the possibility of building large area systems. We simulated a partial-ring scanner based on an RPC prototype under construction within the Fondazione per Adroterapia Oncologica (TERA). For comparison with the crystal-based PET scanner we have chosen the geometry of a commercially available PET scanner, the Philips Gemini TF. The coincidence time resolution used in the simulations takes into account the current achievable values as well as expected improvements of both technologies. Several scenarios (including patient data) have been simulated to evaluate the performance of different scanners. Initial results have shown that the low sensitivity of the RPC hampers its application to hadron-beam monitoring, which has an intrinsically low positron yield compared to diagnostic PET. In addition, for in-beam PET there is a further data loss due to the partial ring configuration. In order to improve the performance of the RPC-based scanner, an improved version of the RPC detector (modifying the thickness of the gas and glass layers), providing a larger sensitivity, has been simulated and compared with an axially extended version of the crystal-based device. The improved version of the RPC shows better performance than the prototype, but the extended version of the crystal-based PET outperforms all other options.

Optimized light sharing for high-resolution TOF PET detector based on digital silicon photomultipliers.

The majority of current whole-body PET scanners are based on pixelated scintillator arrays with a transverse pixel size of 4 mm. However, recent studies have shown that decreasing the pixel size to 2 mm can significantly improve image spatial resolution. In this study, the performance of Digital Photon Counter (DPC) from Philips Digital Photon Counting (PDPC) was evaluated to determine their potential for high-resolution whole-body time of flight (TOF) PET scanners. Two detector configurations were evaluated. First, the DPC3200-44-22 DPC array was coupled to a LYSO block of 15 × 15 2 × 2 × 22 mm(3) pixels through a 1 mm thick light guide. Due to light sharing among the dies neighbour logic of the DPC was used. In a second setup the same DPC was coupled directly to a scalable 4 × 4 LYSO matrix of 1.9 × 1.9 × 22 mm(3) crystals with a dedicated reflector arrangement allowing for controlled light sharing patterns inside the matrix. With the first approach an average energy resolution of 14.5% and an average CRT of 376 ps were achieved. For the second configuration an average energy resolution of 11% and an average CRT of 295 ps were achieved. Our studies show that the DPC is a suitable photosensor for a high-resolution TOF-PET detector. The dedicated reflector arrangement allows one to achieve better performances than the light guide approach. The count loss, caused by dark counts, is overcome by fitting the matrix size to the size of DPC single die.

Improved dead-time correction for PET scanners: application to small-animal PET.

Pile-up and dead-time are two main causes of nonlinearity in the response of a PET scanner as a function of activity in the field of view (FOV). For a given scanner and acquisition system, pile-up effects depend on the material and size of the object being imaged and on the distribution of activity inside and outside the FOV, because these factors change the singles-to-coincidences ratio (SCR). Thus, it is difficult to devise an accurate correction that would be valid for any acquisition. In this work, we demonstrate a linear relationship between SCR and effective dead-time, which measures the effects of both dead-time (losses) and pile-up (gains and losses). This relationship allows us to propose a simple method to accurately estimate dead-time and pile-up corrections using only two calibration acquisitions with, respectively, a high and low SCR. The method has been tested with simulations and experimental data for two different scanner geometries: a scanner with large area detectors and no pile-up rejection, and a scanner composed of two full rings of smaller detectors. Our results show that the SCR correction method is accurate within 7%, even for high activities in the FOV, and avoids the bias of the standard single-parameter method.

Positron range estimations with PeneloPET.

Technical advances towards high resolution PET imaging try to overcome the inherent physical limitations to spatial resolution. Positrons travel in tissue until they annihilate into the two gamma photons detected. This range is the main detector-independent contribution to PET imaging blurring. To a large extent, it can be remedied during image reconstruction if accurate estimates of positron range are available. However, the existing estimates differ, and the comparison with the scarce experimental data available is not conclusive. In this work we present positron annihilation distributions obtained from Monte Carlo simulations with the PeneloPET simulation toolkit, for several common PET isotopes ((18)F, (11)C, (13)N, (15)O, (68)Ga and (82)Rb) in different biological media (cortical bone, soft bone, skin, muscle striated, brain, water, adipose tissue and lung). We compare PeneloPET simulations against experimental data and other simulation results available in the literature. To this end the different positron range representations employed in the literature are related to each other by means of a new parameterization for positron range profiles. Our results are generally consistent with experiments and with most simulations previously reported with differences of less than 20% in the mean and maximum range values. From these results, we conclude that better experimental measurements are needed, especially to disentangle the effect of positronium formation in positron range. Finally, with the aid of PeneloPET, we confirm that scaling approaches can be used to obtain universal, material and isotope independent, positron range profiles, which would considerably simplify range correction.

Misalignments calibration in small-animal PET scanners based on rotating planar detectors and parallel-beam geometry.

Technological advances have improved the assembly process of PET detectors, resulting in quite small mechanical tolerances. However, in high-spatial-resolution systems, even submillimetric misalignments of the detectors may lead to a notable degradation of image resolution and artifacts. Therefore, the exact characterization of misalignments is critical for optimum reconstruction quality in such systems. This subject has been widely studied for CT and SPECT scanners based on cone beam geometry, but this is not the case for PET tomographs based on rotating planar detectors. The purpose of this work is to analyze misalignment effects in these systems and to propose a robust and easy-to-implement protocol for geometric characterization. The result of the proposed calibration method, which requires no more than a simple calibration phantom, can then be used to generate a correct 3D-sinogram from the acquired list mode data.

Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy.

The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non-invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as (11)C, (15)O, (13)N, (30)P and (38)K were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity.

The reliability of proton-nuclear interaction cross-section data to predict proton-induced PET images in proton therapy.

In vivo PET range verification relies on the comparison of measured and simulated activity distributions. The accuracy of the simulated distribution depends on the accuracy of the Monte Carlo code, which is in turn dependent on the accuracy of the available cross-section data for ß(+) isotope production. We have explored different cross-section data available in the literature for the main reaction channels ((16)O(p,pn)(15)O, (12)C(p,pn)(11)C and (16)O(p,3p3n)(11)C) contributing to the production of ß(+) isotopes by proton beams in patients. Available experimental and theoretical values were implemented in the simulation and compared with measured PET images obtained with a high-resolution PET scanner. Each reaction channel was studied independently. A phantom with three different materials was built, two of them with high carbon or oxygen concentration and a third one with average soft tissue composition. Monoenergetic and SOBP field irradiations of the phantom were accomplished and measured PET images were compared with simulation results. Different cross-section values for the tissue-equivalent material lead to range differences below 1 mm when a 5 min scan time was employed and close to 5 mm differences for a 30 min scan time with 15 min delay between irradiation and scan (a typical off-line protocol). The results presented here emphasize the need of more accurate measurement of the cross-section values of the reaction channels contributing to the production of PET isotopes by proton beams before this in vivo range verification method can achieve mm accuracy.

[Scurvy and acquired ichthyosis associated to Whipple's disease]. / Escorbuto e ictiosis adquirida asociadas a enfermedad de Whipple.

The skin manifestations, except for hyperpigmentation, are uncommon in Whipple's disease (WD). We present the case of a 48-year-old male with chronic diarrhea and long course general syndrome associated to neurological manifestations. Skin examination revealed lesions in the lower limbs and gums that were clinically consistent with scurvy and were confirmed by histological study and measurement of blood vitamin C levels. Furthermore, he had lesions that were clinically and histologically consistent with acquired ichthyosis. The digestive tract biopsy study showed non-necrotizing epithelioid granulomas without the presence of PAS positive macrophages. The patient was diagnosed of Whipple's disease through the identification of genomic fragments of Tropheryma Whippelii by PCR in duodenal samples. He was treated with antibiotics for two years with resolution of the cutaneous and digestive picture but with partial improvement of the neurological symptoms. In the literature reviewed, we did not find any case of acquired ichthyosis associated to WD and only one of scurvy secondary to this rare disease.

[Necrobiotic xanthogranuloma with scleroatrophic lichen associated with paraproteinemia]. / Xantogranuloma necrobiótico con paraproteinemia asociado a liquen escleroatrófico.

Necrobiotic xanthogranuloma (Xn) with paraproteinemia is a histiocytoxanthomatosis (non-X histiocytosis) that affects the dermis and subcutaneous tissue of the face and less frequently the trunk and limbs. We present the case of a 58-year-old woman with a previous background of IgG (lambda) paraproteinemia and multiple autoimmune diseases, that associate clinically and histologically typical lesions of Xn on face, neck and limbs and of lichen sclerosus et atrophius (LEA) on skin and mucosae. The treatments performed were ineffective, the Xn lesions followed a chronic and progressive course with increased number, size and ulceration of them. The paraproteinemia has remained stable since it was diagnosed eight years ago. We have not found the association of Xn with paraproteinemia and SAL described in the literature. We review the characteristics of this rare disease and its possible pathogenic mechanisms.