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Aims Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. Methods and results Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8–53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3–L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis—characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts—and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). Conclusion In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development. [Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

BACKGROUND: Simultaneous reconstruction of emission and attenuation images in time-of-flight (TOF) positron emission tomography (PET) does not provide a unique solution. In this study, we propose to solve this limitation by including additional information given by a reference object with known attenuation placed outside the patient. Different configurations of the reference object were studied including geometry, material composition, and activity, and an optimal configuration was defined. In addition, this configuration was tested for different timing resolutions and noise levels. RESULTS: The proposed strategy was tested in 2D simulations obtained by forward projection of available PET/CT data and noise was included using Monte Carlo techniques. Obtained results suggest that the optimal configuration corresponds to a water cylinder inserted in the patient table and filled with activity. In that case, mean differences between reconstructed and true images were below 10%. However, better results can be obtained by increasing the activity of the reference object. CONCLUSION: This study shows promising results that might allow to obtain an accurate attenuation map from pure TOF-PET data without prior knowledge obtained from CT, MRI, or transmission scans. This work was supported by a grant from the Comunidad de Madrid (2016-T1/TIC-1099). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII); the Ministerio de Ciencia, Innovación y Universidades (MCNU); and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

A dynamic light scattering (DLS) instrument has been assembled using low-cost components. This setup includes an inexpensive laser diode, a silicon photomultiplier (SiPM) including amplifier electronics, a digital oscilloscope, and a regular PC. A set of latex nanoparticles with different sizes has been used to fully characterize the instrument for multiple acquisition configurations. In addition, results were compared to those obtained by transmission electron microscopy (TEM) and a commercial DLS equipment including gold and iron oxide nanoparticles. The size measurements performed with the DLS instrument resulted very robust for multiple acquisition configurations with and error typically below 1%. A very good agreement was obtained when comparing the results with the values obtained with reference techniques. Therefore, accurate and reproducible size measurements can be performed with the DLS instrument developed in this work for a wide range of nanoparticle sizes and materials while significantly reducing the cost.

Objective: 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18 F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18 F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18 F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and Results: Gain-of-function PCSK9 D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18 F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18 F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18 F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications. Conclusions: 18 F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.

Full exploitation of the therapeutic potential of protontherapy is still prevented by uncertainties in the determination of the proton range within the patient's body. Several methods have been proposed to verify the proton range in-vivo by measuring the secondary activity (either PET or prompt-gamma) induced by proton fields. However, none of the presented solutions has yet reached clinical maturity, due to low activity counts and different spatial distributions of dose and proton-induced activity profiles. The quality of verification images can be largely improved by the use of contrast agents that provide an increased induced radioactivity near the Bragg peak region. Iodine is a contrast agent already approved for a number of medical applications. It presents a promising proton reaction channel producing the metastable isomer 127mXe, with a half-life of 69.2(9) s, which could be used for online range verification. However, cross section production for this reaction has not been measured down to small proton energies present near the Bragg peak. To overcome this lack of data, we put in place a specific set-up consisting of two pairs of collinear opposed LaBr3(Ce) detectors and a fully digital acquisition system and performed irradiations in the low energy (4–10 MeV) range in the microbeam line at the Center for Micro Analysis of Materials (Madrid, Spain). We report on a new measurement of the 127I(p,n)127mXe reaction cross section in the 4.5–10 MeV energy region using the activation technique. The accuracy of the measured cross sections is better than 30%, and the observed values are in agreement with theoretical calculations using the default parameters of the TALYS code. Significant activity was observed for proton energies above 4.5 MeV, corresponding to a range in water of less than 0.3 mm. Our results support the viability of 127I as a contrast agent for proton radiotherapy.

In this paper, the technicalities performed to obtain a pulsed beam at the CMAM facility will be explained. The pulsed beam has been characterized with an 8 MeV proton beam, using an existing equipment at CMAM: two pairs of electrostatic plates (RASTER) that deflect the beam, commonly used for homogeneous irradiation of large areas. A pulsed beam is used in many areas such as nuclear physics, material science and, in particular, for proton-therapy medical studies. Rectangular and pyramidal functions have been used to generate different pulses and characterize the response of the RASTER. The results point out that the pulses obtained are suitable for preclinical proton-therapy studies in the FLASH regime, which consists on fractionating the dose in time with short and intense pulses. The set-up for the characterization has been a function generator and a Si-PM outside the chamber.

Background Atherosclerosis is a chronic inflammatory disease and colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease. Purpose Our aim was to assess the anti-inflammatory effects of colchicine on atherosclerotic vascular disease. Methods Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. The study protocol lasted 36 weeks. After 18 weeks rabbits were randomized to receive either colchicine or placebo. Two animals died in each group. At randomization and at the end of the study, all animals underwent MRI and positron 18F-FDG PET/CT. In this post-hoc subgroup analyses, animals of each group in the first quartile of cholesterol levels were excluded. For MRI plaque volume values were expressed as Normalized Wall Index (NWI) and for 18F-FDG PET/CT values were expressed as mean maximum standard uptake (meanSUVmax). Statistical comparisons were made by using the Mann-Whitney U test for unpaired data and Wilcoxon signed-rank test for paired data. Results Results are summarized in Table 1. Animals with higher levels of cholesterol (6 per group) showed significant differences in favor to colchicine group, both as NWI at the end of the protocol 0.47 (IQR 0.05) in the colchicine group versus 0.52 (IQR 0.03) in the placebo; p=0.01] and as relative increase in meanSUVmax [−4.0% (IQR 30.1) in the colchicine group versus 35.1 (IQR 59.0) in the placebo; p 0.041] (Figure 1). Conclusions Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This work was supported by a grant from the Sociedad Española de Cardiología and a grant from the Carlos III Institute of Health of Spain and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”)

BACKGROUND: Conventional PET imaging has usually been limited to a single tracer per scan. We propose a new technique for multi-tracer PET imaging that uses dynamic imaging and multi-tracer compartment modeling including an explicitly derived arterial input function (AIF) for each tracer using blood sampling spectroscopy. For that purpose, at least one of the co-injected tracers must be based on a non-pure positron emitter. METHODS: The proposed technique was validated in vivo by performing cardiac PET/CT studies on three healthy pigs injected with 18FDG (viability) and 68Ga-DOTA (myocardial blood flow and extracellular volume fraction) during the same acquisition. Blood samples were collected during the PET scan, and separated AIF for each tracer was obtained by spectroscopic analysis. A multi-tracer compartment model was applied to the myocardium in order to obtain the distribution of each tracer at the end of the PET scan. Relative activities of both tracers and tracer uptake were obtained and compared with the values obtained by ex vivo analysis of excised myocardial tissue segments. RESULTS: A high correlation was obtained between multi-tracer PET results, and those obtained from ex vivo analysis (18FDG relative activity: r = 0.95, p < 0.0001; SUV: r = 0.98, p < 0.0001). CONCLUSIONS: The proposed technique allows performing PET scans with two tracers during the same acquisition obtaining separate information for each tracer. This work was supported by grants from the Carlos III Institute of Health of Spain and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (FIS-FEDER PI14-01427) and from the Comunidad de Madrid (2016-T1/TIC-1099). CV holds a fellowship from the Spanish Ministry of Education (FPU014/01794). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

espanolObjetivos La precision cuantitativa en PET requiere una adecuada aplicacion de la correccion de atenuacion, lo cual representa uno de los mayores retos que aun estan por resolver en la tecnica PET/RM. El proposito de este estudio es evaluar el efecto de utilizar mapas de atenuacion basados en RM y el uso de antenas flexibles sobre la precision cuantitativa en PET con especial hincapie en grandes arterias. Materiales y metodos Se utilizaron datos PET/TC de 8 pacientes oncologicos. Los datos PET fueron reconstruidos utilizando mapas de atenuacion con diferente nivel de detalle emulando las distintas aproximaciones utilizadas actualmente por lo equipos PET/RM. Las imagenes PET obtenidas con mapas de atenuacion basados en TC y RM fueron comparadas para evaluar las desviaciones cuantitativas obtenidas. El efecto producido por las antenas flexibles fue tambien estudiado. Resultados El uso de mapas de atenuacion mas simplificados da lugar a un incremento en las desviaciones cuantitativas en grasa, tejido blando y hueso. Las desviaciones en pulmon son altas debido a su heterogeneidad y a la variabilidad entre pacientes. La cuantificacion en grandes arterias muestra pequenas desviaciones excepto en el caso de utilizar antenas flexibles. La cuantificacion mediante TBR proporciona menores desviaciones al cancelarse las desviaciones medidas en arterias y las venas utilizadas como referencia. Conclusiones Los mapas de atenuacion simplificados que se utilizan en PET/RM producen un incremento significativo de variabilidad cuantitativa especialmente en pulmones y huesos. La cuantificacion aplicada al estudio de la aterosclerosis produce pequenas desviaciones, especialmente cuando se utiliza el TBR. EnglishObjectives 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.

Liposomes encapsulating magnetic nanoparticles (MNPs), known as magnetoliposomes (MLs), have become a hot topic in biomedical research for applications in remote-triggered drug delivery and diagnostic imaging. One of the most crucial steps in the preparation of MLs is the purification of non-encapsulated MNPs, as a non-efficient purification can lead to misleading results. Purification is challenging especially when MNPs are loaded in the liposome lumen due to the small size differences between the MLs and the non-encapsulated MNPs. This work presents a comparison of three well known purification techniques, namely size exclusion chromatography, centrifugation and salt-induced aggregation, using five commercial MNPs with different configurations. The optimal purification techniques for two MNPs were studied further in the synthesis of MLs. In conclusion, we show that an efficient MLs purification requires the performance of a detailed study to select a valid method that is strongly dependent upon MNPs choices.

Colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease. Our aim was to evaluate the effects of colchicine on atherosclerotic plaque stabilization. Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. Rabbits were randomized to receive either colchicine or placebo. All animals underwent MRI, 18F-FDG PET/CT, optical coherence tomography (OCT), and histology. Similar progression of atherosclerotic burden was observed in the two groups as relative increase of normalized wall index (NWI). Maximum 18F-FDG standardized uptake value (meanSUVmax) decreased after colchicine treatment, while it increased in the placebo group with a trend toward significance. Animals with higher levels of cholesterol showed significant differences in favor to colchicine group, both as NWI at the end of the protocol and as relative increase in meanSUVmax. Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden, without altering macrophage infiltration or plaque typology. This work was supported by a grant from the Sociedad Española de Cardiología, a grant from the Instituto de Salud Carlos III of Spain and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (FIS-FEDER PI14-01427 to J. Mateo) and a grant from Fundación BBVA to J. Ruiz-Cabello. The CNIC is supported by the Instituto de Salud Carlos III, the Ministry of Science and Innovation and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is supported by the Spanish State Research Agency of MICIN under the María de Maeztu Units of Excellence Program from MDM-2017-0720. Sí

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). The PESA study is cofunded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Banco Santander. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019) and the European Regional Development Fund (ERDF) “A way to make Europe.” The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Sanchez-González is an employee of Philips Healthcare. Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 & PI17/01799), AstraZeneca, Bristol-Myers Squibb, Janssen, and Novartis; has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Novartis, and MEDSCAPE-the heart.org. Sí

PeneloPET is a Monte Carlo simulation tool for positron emission tomography based on PENELOPE. It was developed by the Nuclear Physics Group at University Complutense of Madrid and its initial version was released in 2009. In this work, we present PeneloPET v3.0, which is now available precompiled for Microsoft Windows, MacOS and Linux OS. This new release includes improved simulations of the positron range in different materials and an accurate description of the decay cascades for many radioactive nuclei including the most common non-pure positron emitters used in PET. This enables the simulation of PET acquisitions with positron-gamma emitters. This release also includes many different fully-working examples, of both clinical and preclinical scanners, as well as several numerical phantoms. Due to the simplicity of the input the output files, and the installation process, PeneloPET v3.0 can be perfectly used not only for research, but also as an educational tool in class.

We propose the use of 18O-enriched water as a suitable contrast agent for potential in-vivo range verification in proton therapy. The low energy production threshold of 18F (2.6 MeV, proton range in water of 115 μm) leads to tissue activation in very close proximity to the maximum dose deposition, facilitating accurate range verification with off-line PET imaging. This idea has been explored in a phantom experiment. A 3D-printed phantom containing inserts with 18O-enriched water was irradiated with a 100-MeV, 8 × 8 cm2 proton beam, and the induced activity was measured with a small-animal PET-CT 30 min after irradiation. The images obtained were compared against Monte Carlo simulation using TOPAS. Good agreement was observed between reconstructed and simulated activity profiles (within 40% for specific 18F activity), with excellent spatial match to the simulated dose deposition. Because of the long half-life of 18F, the specific activity of the contrast agent could be separated and was clearly observed for more than 2 h after irradiation. Activity distribution maps were used to determine the position of the Bragg peak within 2 mm for three different regions of interest. These results show the potential of 18O-enriched water as a contrast agent in proton therapy.

Here we evaluated the feasibility of PET with Gallium-68 (8 healthy pigs underwent three sequentialMBF assessed with

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.

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.

Background: In vivo determination of regional pulmonary blood flow (PBF) is a valuable tool for the evaluation of many lung diseases. In this study, the use of Ga-68-DOTA PET for the in vivo quantitative determination of regional PBF is proposed. This methodology was implemented and tested in healthy pigs and validated using fluorescent microspheres. The study was performed on young large white pigs (n = 4). To assess the reproducibility and consistency of the method, three PET scans were obtained for each animal. Each radiotracer injection was performed simultaneously to the injection of fluorescent microspheres. PBF images were generated applying a two-compartment exchange model over the dynamic PET images. PET and microspheres values were compared by regression analysis and Bland-Altman plot. Results: The capability of the proposed technique to produce 3D regional PBF images was demonstrated. The correlation evaluation between Ga-68-DOTA PET and microspheres showed a good and significant correlation (r = 0.74, P < 0.001). Conclusions: Assessment of PBF with the proposed technique allows combining the high quantitative accuracy of PET imaging with the use of Ga-68/Ge-68 generators. Thus, Ga-68-DOTA PET emerges as a potential inexpensive method for measuring PBF in clinical settings with an extended use. This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-58920-R) and a grant from the Carlos III Institute of Health (FIS-FEDER PI14-01427). C. Velasco is a recipient of a fellowship from the Spanish Ministry of Education (FPU014/01794). S. Espana and A. Santos are recipients of M+Vision Advanced fellowships from the community of Madrid. The CNIC is supported by the MINECO and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Sí

The majority of current whole-body PET scanners are based on pixelated scintillator arrays with a transverse pixel size of 4mm. However, recent studies have shown that decreasing the pixel size to 2mm 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 376ps 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.Keywords: digital silicon photomultiplier array, dSiPM, PET, high resolution, TOF, time of flight, LYSO(Some figures may appear in colour only in the online journal)

Monte Carlo (MC) simulations are widely used in positron emission tomography (PET) for optimizing detector design, acquisition protocols, and evaluating corrections and reconstruction methods. PeneloPET is a MC code based on PENELOPE, for PET simulations which considers detector geometry, acquisition electronics and materials, and source definitions. While PeneloPET has been successfully employed and validated with small animal PET scanners, it required a proper validation with clinical PET scanners including time-of-flight (TOF) information. For this purpose, we chose the family of Biograph PET/CT scanners: the Biograph True-Point (B-TP), Biograph True-Point with TrueV (B-TPTV) and the Biograph mCT. They have similar block detectors and electronics, but a different number of rings and configuration. Some effective parameters of the simulations, such as the dead-time and the size of the reflectors in the detectors, were adjusted to reproduce the sensitivity and noise equivalent count (NEC) rate of the B-TPTV scanner. These parameters were then used to make predictions of experimental results such as sensitivity, NEC rate, spatial resolution, and scatter fraction (SF), from all the Biograph scanners and some variations of them (energy windows and additional rings of detectors). Predictions agree with the measured values for the three scanners, within 7% (sensitivity and NEC rate) and 5% (SF). The resolution obtained for the B-TPTV is slightly better (10%) than the experimental values. In conclusion, we have shown that PeneloPET is suitable for simulating and investigating clinical systems with good accuracy and short computational time, though some effort tuning of a few parameters of the scanners modeled may be needed in case that the full details of the scanners studied are not available., Comunidad de Madrid, Spanish Ministry of Science and Innovation, Human Frontier Science Program, CPAN, Innovative Medicines Initiative Joint Undertaking, 10.13039/501100004963-European Union’s Seventh Framework Programme, EFPIA companies, UCM, EU FP7-PEOPLE-2011-COFUND Program

Positron range (PR) is one of the important factors that limit the spatial resolution of positron emission tomography (PET) preclinical images. Its blurring effect can be corrected to a large extent if the appropriate method is used during the image reconstruction. Nevertheless, this correction requires an accurate modelling of the PR for the particular radionuclide and materials in the sample under study. In this work we investigate PET imaging with 68Ga and 66Ga radioisotopes, which have a large PR and are being used in many preclinical and clinical PET studies. We produced a 68Ga and 66Ga phantom on a natural zinc target through (p,n) reactions using the 9-MeV proton beam delivered by the 5-MV CMAM tandetron accelerator. The phantom was imaged in an ARGUS small animal PET/CT scanner and reconstructed with a fully 3D iterative algorithm, with and without PR corrections. The reconstructed images at different time frames show significant improvement in spatial resolution when the appropriate PR is applied for each frame, by taking into account the relative amount of each isotope in the sample. With these results we validate our previously proposed PR correction method for isotopes with large PR. Additionally, we explore the feasibility of PET imaging with 68Ga and 66Ga radioisotopes in proton therapy. We acknowledge support from the Spanish MINECO through projects FPA2010-17142, FPA2013-41267-P, CSD-2007-00042 (CPAN), and the RTC-2015-3772-1 grant. We also acknowledge support from Comunidad de Madrid via the TOPUS S2013/MIT-3024 project.

Technological advances have improved the assembly process of PET detectors, resulting in quite small mechanical tolerances. However, in high-spatialresolution 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. This work was partially funded by the AMIT project (CEN-20101014) from the CDTICENIT program, RECAVA-RETIC Network (RD09/0077/00087), projects TEC2010-21619-C04-01 and TEC2011-28972-C02-01 from the Spanish Ministerio de Ciencia e Innovación, PRECISION grant IPT-300000-2010-3, CPAN (CSD-2007-00042@Ingenio2010), MEC (FPA2010-17142) and ARTEMIS program (S2009/DPI-1802) from the Spanish Comunidad de Madrid and EU-ERDF program. Publicado

Positron range limits the spatial resolution of PET images and has a different effect for different isotopes and positron propagation materials. Therefore it is important to consider it during image reconstruction, in order to obtain optimal image quality. Positron range distributions for most common isotopes used in PET in different materials were computed using the Monte Carlo simulations with PeneloPET. The range profiles were introduced into the 3D OSEM image reconstruction software FIRST and employed to blur the image either in the forward projection or in the forward and backward projection. The blurring introduced takes into account the different materials in which the positron propagates. Information on these materials may be obtained, for instance, from a segmentation of a CT image. The results of introducing positron blurring in both forward and backward projection operations was compared to using it only during forward projection. Further, the effect of different shapes of positron range profile in the quality of the reconstructed images with positron range correction was studied. For high positron energy isotopes, the reconstructed images show significant improvement in spatial resolution when positron range is taken into account during reconstruction, compared to reconstructions without positron range modeling. © 2010 Elsevier B.V. All rights reserved., This work has been supported by the MEC (FPA2007-62216), the UCM (Grupos UCM, 910059), the CPAN (Consolider-Ingenio 2010)CSPD-2007-00042, the RECAVA-RETIC network, ARTEMISS2009/DPI-1802, the European Regional Development and ENTEPRASE grant, PSE-300000-2009-5 and the Ministerio de Ciencia e Innovación, Spanish Government.

We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to

Super Bialkali (SBA) photocathode is a new technology that improves the spectral response characteristics of position sensitive PMTs, boosting their quantum efficiency up to 35%. In this experiment, two SBA tubes were introduced into a production line of PET detectors mixed with the regular tubes. The detectors were assembled using the standard factory protocols for detector mounting, calibration and testing. We report an evaluation of the improvement introduced by the SBA photocathode comparing the spatial and energy resolution and the depth-of-interaction (DOI) performance of PET detector modules with DOI capabilities.We conclude that the superior performance of the SBA tube may enable the use of arrays with a larger number of crystals of smaller footprint, thus potentially improving the detector intrinsic spatial resolution without degrading the energy resolution or the phoswich (DOI) discrimination capability. This work was supported in part by the CENIT Program (Ministerio de Industria), Comunidad de Madrid program ARTEMIS-P2009/DPI-1802, TEC2007-64731/TCM (Ministerio de Educación y Ciencia), and the RETIC-RECAVA, ISCIII. The contribution of J. Seidel wa supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. Publicado

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 This project was supported by the CENIT Program (Ministerio de Industria), CIBER CB07/09/0031 (Ministerio de Sanidad y Consumo), TEC2007-64731/TCM and TEC2008- 06715-C02-01 (Ministerio de Educaci´on y Ciencia) Publicado

In this work we show that there is a limit for the maximum resolution achievable with a high resolution PET scanner, as well as for the best signal-to-noise ratio, which are ultimately related to the physical effects involved in the emission and detection of the radiation and thus they cannot be overcome with any particular reconstruction method. These effects prevent the spatial high frequency components of the imaged structures to be recorded by the scanner. Therefore, the information encoded in these high frequencies cannot be recovered by any reconstruction technique. Within this framework, we have determined the maximum resolution achievable for a given acquisition as a function of data statistics and scanner parameters, like the size of the crystals or the inter-crystal scatter. In particular, the noise level in the data as a limitation factor to yield high-resolution images in tomographs with small crystal sizes is outlined. These results have implications regarding how to decide the optimal number of voxels of the reconstructed image or how to design better PET scanners Publicado

Positron emission tomography (PET) is an important technique in cardiovascular research. Vascular inflammation detected by fluorodeoxyglucose (FDG)-PET has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. The use of PET imaging in mouse models of atherosclerosis is challenged by the reduced size of the scanned organs. However, the last generation of dedicated PET scanners has an improved spatial resolution (1 mm) and increased sensitivity allowing those studies to be performed. Here, we describe a procedure to perform FDG-PET experiments in atherosclerosis mouse models, the required equipment for animal handling and imaging, and the tools and procedures for image analysis and validation of the results.

Plaque development has been extensively studied using magnetic resonance imaging (MRI) in animal models of rapidly progressing atherosclerosis, such as apolipoprotein E-knockout (apoE-KO) mice. Preclinical MRI plays a significant role in the study of experimental atherosclerosis. Currently, MRI is capable of detecting luminal narrowing, plaque size, and morphology with high accuracy and reproducibility, providing reliable measurements of plaque burden. Therefore, MRI offers a noninvasive approach to serially monitor the progression of the disease. Compared with other imaging modalities, MRI appears to have the greatest potential for plaque characterization, through the use of multiple contrast weightings (e.g., T1, T2, and proton density). Here, we illustrate a standard procedure to image the aorta of atherosclerotic mice using noninvasive MRI.

Plaque development has been extensively studied using magnetic resonance imaging (MRI) in animal models of rapidly progressing atherosclerosis, such as apolipoprotein E-knockout (apoE-KO) mice. Preclinical MRI plays a significant role in the study of experimental atherosclerosis. Currently, MRI is capable of detecting luminal narrowing, plaque size, and morphology with high accuracy and reproducibility, providing reliable measurements of plaque burden. Therefore, MRI offers a noninvasive approach to serially monitor the progression of the disease. Compared with other imaging modalities, MRI appears to have the greatest potential for plaque characterization, through the use of multiple contrast weightings (e.g., T1, T2, and proton density). Here, we illustrate a standard procedure to image the aorta of atherosclerotic mice using noninvasive MRI.

Positron emission tomography (PET) is an important technique in cardiovascular research. Vascular inflammation detected by fluorodeoxyglucose (FDG)-PET has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. The use of PET imaging in mouse models of atherosclerosis is challenged by the reduced size of the scanned organs. However, the last generation of dedicated PET scanners has an improved spatial resolution (

Fully 3D iterative tomographic image reconstruction is computationally very demanding. Graphics Processing Unit(GPU) has be enproposed formany years as potential accelerators incomplex scientific problems, but it has not be enuseduntil there cent advances in the programmability of GPU sthat the best available reconstruction code shave started tobe implemented toberunon GPUs. This work presents a GPU based fully 3D PET iterative reconstruction sofware. This new code may reconstruct sinogram data from several commercially available PET scanners. The most important and time consuming part soft he code,the forward and backward projection operations, arebasedonan accurate model of the scanner obtained with the MonteCarlo code PeneloPET and they have been massively parallelize don the GPU.For the PET scanners considered, the GPU based code is more than 70 times faster than asimilar code running on a single core of a fast CPU, obtainingin both cases the same images. The code has been designed to be easily adapted to reconstruct sinograms from any other PET scanner, including scanner prototypes. This work has been supported by MEC(FPA200762216), UCM (Grupos UCM,910059), CPAN(Consolider Ingenio 2010) CSPD 200700042,the RECAVARETIC network, ARTEMISS2009/ DPI 1802, European Regional Development,ENTEPRASE grant, PSE 30000020095 and TEC20080675C0201, Ministerio de Ciencia e Innovación, Spanish Government. Publicado

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.

A new preclinical PET system based on dSiPMs, called DigiPET, is presented. The system is based on thin monolithic scintillation crystals and exhibits superior spatial resolution at low-cost compared to systems based on pixelated crystals. Current dedicated small-rodent PET scanners have a spatial resolution in the order of 1 mm. Most of them have a large footprint, requiring considerable laboratory space. For rodent brain imaging, a PET scanner with sub-millimeter resolution is desired. To achieve this, crystals with a pixel pitch down to 0.5 mm have been used. However, fine pixels are difficult to produce and will render systems expensive. In this work, we present the first results with a high-resolution preclinical PET scanner based on thin monolithic scintillators and a large solid angle. The design is dedicated to rat-brain imaging and therefore has a very compact geometry. Four detectors were placed in a square arrangement with a distance of 34.5 mm between two opposing detector modules, defining a field of view (FOV) of 32 × 32 × 32 mm(3). Each detector consists of a thin monolithic LYSO crystal of 32 × 32 × 2 mm(3) optically coupled to a digital silicon photomultiplier (dSiPM). Event positioning within each detector was obtained using the maximum likelihood estimation (MLE) method. To evaluate the system performance, we measured the energy resolution, coincidence resolving time (CRT), sensitivity and spatial resolution. The image quality was evaluated by acquiring a hot-rod phantom filled with (18)F-FDG and a rat head one hour after an (18)F-FDG injection. The MLE yielded an average intrinsic spatial resolution on the detector of 0.54 mm FWHM. We obtained a CRT of 680 ps and an energy resolution of 18% FWHM at 511 keV. The sensitivity and spatial resolution obtained at the center of the FOV were 6.0 cps kBq(-1) and 0.7 mm, respectively. In the reconstructed images of the hot-rod phantom, hot rods down to 0.7 mm can be discriminated. In conclusion, a compact PET scanner was built using dSiPM technology and thin monolithic LYSO crystals. Excellent spatial resolution and acceptable sensitivity were demonstrated. Promising results were also obtained in a hot-rod phantom and in rat-brain imaging.

A typical high resolution PET detector consists of a matrix of scintillator elements which are connected to a light guide in order to spread the light onto the pixels of a photo detector. In this work we introduce a matrix that works without light guide but has defined internal light leaks in order to allow controlled light sharing between the individual scintillator elements. This is especially useful when used together with the Philips digital SiPM DPC 3200. We show that better position determination is achieved and in addition higher count rates should be possible compared to a classical light guide solution.

Silicon photomultipliers (SiPM) are a promising alternative light sensor for the classic photomultiplier tubes currently used as single photon emission computed tomography (SPECT) detectors due to their compact dimensions and smaller pixelization. Furthermore, these SiPMs are also known to be MR-hard which brings on new possibilities for simultaneous SPECT-MR imaging. In contrast to other research on SiPMs which is mainly focussed on PET applications, we will focus on SPECT imaging. The detector used in this work, consists of a dSiPM (DPC-3200-22-44, Philips Digital Photon Counting) optically coupled to a monolithic LYSO scintillator of 2mm thick. Using a collimated 57Co source, a filter was developed to remove the dark count events from the spectrum and a comparison was made between the detection efficiency of the DPC-based detector and a PSPMT-based detector. Furthermore, the intrinsic spatial resolution was determined using both a resolution collimator and beam source measurements. The same beam source measurements were also used to calculate the energy resolution across the detector. Finally, the count rate performance of the DPC was investigated by measuring a decaying 99mTc source in front of the detector. Measurements showed that, despite the presence of dark count events in the spectrum, the DPCs have approximately the same detection efficiency as our gold standard, the PSPMT. Furthermore, we demonstrate that the detector has an intrinsic spatial resolution of 0.486mm and an energy resolution of 22.3 %. This work demonstrates the usefulness of the DPCs as SPECT detectors.

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 (18F, 11C, 13N, 15O, 68Ga and 82Rb) 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. We kindly acknowledge support from Comunidad de Madrid (ARTEMIS S2009/DPI-1802), Spanish Ministry of Science and Innovation (grants FPA2010-17142 and ENTEPRASE, PSE-300000-2009-5), by European Regional Funds, by CDTI under the CENIT Programme (AMITProject) and by CPAN, CSPD-2007-00042@Ingenio2010. Part of the calculations of this work were performed in the “Cluster de Cálculo de Alta Capacidad para Técnicas Físicas” funded in part by UCM and in part by UE under FEDER programme. This is a contribution to the Campus of International Excellence of Moncloa Publicado

Monolithic scintillation detectors for positron emission tomography and single-photon emission computed tomography (SPECT) imaging have many advantages over pixelated detectors. The use of monolithic crystals allows for reducing the scintillator cost per unit volume and increasing the sensitivity along with the energy and timing resolution of the detector. In addition, on thick detectors the depth-of-interaction can be determined without additional hardware. However, costly and complex calibration procedures have been proposed to achieve optimal detector performance for monolithic detectors. This hampers their use in commercial systems. There is thus, a need for simple calibration routines that can be performed on assembled systems. The main goal of this work is to develop a simplified calibration procedure based on acquired training data. In comparison with other methods that use training data acquired with beam sources attached to robotic stages, the proposed method uses a static un-collimated activity source with simple geometry acquiring in a reasonable time. Once the data are acquired, the calibration of the detector is accomplished in three steps: energy calibration based on the k-means clustering method, self-organization based on the self-organizing maps algorithm, and distortion correction based on the Monge-Kantorovich grid adaptation. The proposed calibration method was validated for 2D positioning using a SPECT detector. Similar results were obtained by comparison with an existing calibration method (maximum likelihood estimation). In conclusion, we proposed a novel calibration method for monolithic scintillation detectors that greatly simplifies their use with optimal performance in SPECT systems.

Proton relative biological effectiveness (RBE) is known to depend on the (alpha/beta)(x) of irradiated tissues, with evidence of similar to 60% variation over (alpha/beta)(x) values from 1-10 Gy. The range of (alpha/beta)(x) values reported for prostate tumors (1.2-5.0 Gy), brain tumors (10-15 Gy) and liver tumors (13-17 Gy) imply that the proton RBE for these tissues could vary significantly compared to the commonly used generic value of 1.1. Our aim is to evaluate the impact of this uncertainty on the proton dose in Gy(RBE) absorbed in normal and tumor tissues. This evaluation was performed for standard and hypofractionated regimens. RBE-weighted total dose (RWTD) distributions for 15 patients (five prostate tumors, five brain tumors and five liver tumors) were calculated using an in-house developed RBE model as a function of dose, dose-averaged linear energy transfer (LETd) and (alpha/beta)(x). Variations of the dose-volume histograms (DVHs) for the gross tumor volume (GTV) and the organs at risk due to changes of (alpha/beta)(x) and fractionation regimen were calculated and the RWTD received by 10% and 90% of the organ volume reported. The goodness of the plan, bearing the uncertainties, was then evaluated compared to the delivered plan, which considers a constant RBE of 1.1. For standard fractionated regimens, the prostate tumors, liver tumors and all critical structures in the brain showed typically larger RBE values than 1.1. However, in hypofractionated regimens lower values of RBE than 1.1 were observed in most cases. Based on DVH analysis we found that the RBE variations were clinically significant in particular for the prostate GTV and the critical structures in the brain. Despite the uncertainties in the biological input parameters when estimating RBE values, the results show that the use of a variable RBE with dose, LETd and (alpha/beta)(x) could help to further optimize the target dose in proton treatment planning. Most importantly, this study shows that the consideration of RBE variations could influence the comparison of proton and photon treatments in clinical trials, in particular in the case of the prostate.