Accurate,robust and harmonized implementation of morpho-functional imaging in treatment planning for personalized radiotherapy

In this work we present a methodology able to use harmonized PET/CT imaging in dose painting by number (DPBN) approach by means of a robust and accurate treatment planning system. Image processing and treatment planning were performed by using a Matlab-based platform, called CARMEN, in which a full Monte Carlo simulation is included. Linear programming formulation was developed for a voxel-by-voxel robust optimization and a specific direct aperture optimization was designed for an efficient adaptive radiotherapy implementation. DPBN approach with our methodology was tested to reduce the uncertainties associated with both, the absolute value and the relative value of the information in the functional image. For the same H&N case, a single robust treatment was planned for dose prescription maps corresponding to standardized uptake value distributions from two different image reconstruction protocols: One to fulfill EARL accreditation for harmonization of [18F]FDG PET/CT image, and the other one to use the highest available spatial resolution. Also, a robust treatment was planned to fulfill dose prescription maps corresponding to both approaches, the dose painting by contour based on volumes and our voxel-by-voxel DPBN. Adaptive planning was also carried out to check the suitability of our proposal. Different plans showed robustness to cover a range of scenarios for implementation of harmonizing strategies by using the highest available resolution. Also, robustness associated to discretization level of dose prescription according to the use of contours or numbers was achieved. All plans showed excellent quality index histogram and quality factors below 2%. Efficient solution for adaptive radiotherapy based directly on changes in functional image was obtained. We proved that by using voxel-by-voxel DPBN approach it is possible to overcome typical drawbacks linked to PET/CT images, providing to the clinical specialist confidence enough for routinely implementation of functional imaging for personalized radiotherapy.Junta de Andalucía (FISEVI, reference project CTS 2482)European Regional Development Fund (FEDER

Production yields at the distal fall-off of the β+ emitters 11C and 13N for in-vivo range verification in proton therapy

In proton therapy, Positron Emission Tomography (PET) range verification relies on the comparison of the measured and estimated activity distributions from β+ emitters produced by the proton beam in the patient. The accuracy of the estimated activity distributions is basically that of the underlying reaction cross section data. In this context, we have developed a new method for measuring β+ production yields combining the multi-foil technique with a clinical PET scanner, resulting in energy differential cross sections from a single irradiation. The method has been applied to the production of (t1/2 = 20.36 min) and (t1/2 = 9.97 min), the main candidates for off-line PET range verification, in carbon, nitrogen and oxygen, the main elements of the human body. The energy range studied with the 18 MeV CNA cyclotron corresponds to the distal fall-off of the activity curve, i.e. near the Bragg peak.Ministerio de Economía y Competitividad RYC-2014-15271, FPA2016- 77689-C2-1-R, RTI2018-098117-B-C2

Computer Tomography for avoiding fractures, controlling ice and monitoring cryoprotectant in organ cryopreservation

Abstract presented at the Organ Preservation Alliance’s Organ Banking Summit, held February 26–28, 2015, Silicon Valley, California, USA.From an engineering point of view, the challenge of organ cryopreservation is a problem of heat and mass transfer. However, from a technical point of view, there are four major goals: avoiding fractures, controlling ice, monitoring the cryoprotectant concentration and having a fast and uniform rewarming. Computer Tomography (CT) can help at least with the first three of these four topics; in the case of DMSO based cryoprotectant, the high number of electrons in the sulfur atom of this molecule makes it visible at energies around 70 KeV, where the photoelectric effect is dominant. Water, DMSO and air (fractures) have very different CT values, offering the possibility of drawing a 3D map of the status of the organ not only after the cryopreservation, but also during the loading and/or cooling steps. Kidneys and cryopreserved ovarian tissue have been monitored with a nanoCT. A spectacle of patterns and structures is revealed under the light of the X-rays.Peer Reviewe

18F Labeling of a new naphthalene derivative as potential Alzheimer Disease PET imaging agent. Synthesis and preclinical studies

Resumen del póster presentado al 28th Annual Congress of the European Association of Nuclear Medicine (EANM), celebrado en Hamburgo (Alemania) del 10 al 14 de octubre de 2015.-- et al.[Introduction]: Radiotracers for β-amyloid plaques PET imaging with best results include naphthalene derivative structures. CNEURO has developed and patented some naphthalene derivative molecules for the diagnosis of Alzheimer Disease at early stages (CU/P/2009/57, CU/P/2013/27, EP 2 436 666 A20, South Africa P58243ZA00. A successful 18F-labelling of such molecules by nucleophilic substitution synthesis was developed at CNA, for β-amyloid plaques PET imaging. [Matherial and methods]: 3-(6-methoxy-2-naphtyl)propyl-4-methylbenzenesulphonate was used as precursor for the labelling process. 18F- was obtained from a Cyclone 18/9 MeV cyclotron (IBA, Belgium) and nucleophilic substitution took place in a modified TracerLab FXFN module (GE, USA). Azeotropic distillation was performed at 100°C in vacuum and with helium flushing. Fluorination of precursor took place at 70°C for ten minutes, with subsequent acidic hydrolysis and neutralization using NaOH 1N. The intermediate compound (before hydrolysis) was dried to avoid any presence of acetonitrile (precursor solvent). The radiotracer 2-(3-[18F]fluoropropyl)-6-methoxynaphtalene was purified by solid phase extraction cartridges (SPE), connecting two alumina Sep-Pack and a SCX Sep-Pack to retain unreacted 18F- and cationic impurities. The labeled compound was retained in a C18 Sep-Pack, and eluted in absolute ethanol. The solution of radiotracer was diluted with saline for injection. Quality controls were performed before injection to the animals; pH, absence of particles, and radiochemical purity (RCP). RCP was determined with a Dionex HPLC system and a coupled radiation detector. The stationary phase was a C18 reverse phase analytical column and acetonitrile/water (75/25) as mobile phase. Two transgenic mice APPSwe/PS1dE8 with amyloid plaques and two wild type mice for control were injected with the radiotracer for PET/CT studies. Whole body images of biodistribution were obtained, and kinetic curves of radioactivity at several cerebral regions were performed. [Results]: Radiochemical yield reached 49,8% (uncorrected decay), and radiochemical purity was higher than 95% in all batches. In vitro stability cromatograms demonstrated that 2-(3-[18F]fluoropropyl)-6-methoxynaphtalene is stable for more than ten hours. Comparison between transgenic and control mice was established by cortexcerebellum SUVratio (SUVr) curve. [Conclusions]: Radiosynthesis of 2-(3-[18F]fluoropropyl)-6-methoxynaphtalene by nucleophilic substitution of tosyl group at the precursor gives good radiochemical yields and radiochemical purity higher than 95%, which makes the radiotracer useful for brain β-amyloid PET imaging. Its in vitro stability (more than 10h) allows several patient studies from the same batch. PET/CT studies show that 2-(3-[18F]fluoropropyl)-6-methoxynaphtalene crosses blood brain barrier, with higher brain uptake in transgenic mice, in comparison with control animals.Peer Reviewe

Biodistribution of [18F]Amylovis®, a new radiotracer for PET imaging of ß-amyloid plaques

Resumen del trabajo presentado al 18th European Sympossium in Radiopharmacy and Radiopharmaceuticals, celebrado en Salzburgo (Austria) del 7 al 10 de abril de 2016.-- et al.[Aim]: [18F]-2-(3-fluoropropyl)-6-methoxynaphtalene ([18F]Amylovis®) is a new naphthalene-derivative for detecting β-amyloid plaques in Alzheimer’s disease. The aim of the study is the assessment of the animal biodistribution of this new radiotracer. [Material and methods]: [18F]Amylovis® was synthesized by nucleophilic substitution of the tosyl group of the precursor. Thirty five healthy male Balb/C mice of 10-12 weeks were divided into 6 groups of 5 animals each and injected with similar doses of [18F]Amylovis® through a lateral tail vein. Blood samples were collected and the animals were sacrificed at 5, 15, 30, 45, 70 and 180 minutes. Organs of interest were removed and washed with saline. Radioactivity of blood, plasma, urine, faeces, brain, cerebellum, heart, liver, stomach, spleen, bowel, colon, left kidney, muscle, bone and tail was measured in a well counter. To assess protein binding, plasma samples were diluted with acetonitrile and centrifuged at 4000 g. Pellets of proteins and supernatants were separated and their radioactivity measured in a well counter. RadioTLC analysis of plasma were performed for the same purpose in silicagel 60 and mobile phase of acetonitrile/water (95/5). 20μL of each supernatant was analysed by HPLC-RP using a C18 column and acetonitrile/water (75/25) as mobile phase to identify plasma metabolites. Pharmacokinetic parameters (AUC, t1/2, Cmax, Cl, Vss) were calculated using non-compartmental analysis (NCA). Dynamic PET/CT images of healthy and transgenic APPSwe/PS1dE9 mice were acquired for 2.5 h after i.v. administration. Immunohistochemistry of control and transgenic mice brains were performed to identify β-amyloid plaques. [Results]: [18F]Amylovis® crossed blood brain barrier. PET/CT images showed significant differences between healthy and transgenic mice, expressed in Cortex to cerebellum SUV ratio, with maximum difference at 30 minutes. Postmortem studies of immunohistochemistry showed also differences in healthy vs transgenic mice (amyloid positive). Plasma T1/2 of 37 min. No significant protein binding was observed. Renal and hepatic pathways were the main excretion routes. Some amount of in vivo degradation metabolites appeared in blood from 1 h post-administration. [Conclusion]: [18F]Amylovis® could be a promising PET radiotracer for amyloid plaques visualization.Peer Reviewe

Towards new protocols of ovarian tissue cryopreservation assisted by X-ray Computed Tomography

Trabajo presentado en CRYO 2018, 55th Annual Meeting of the Society for Cryobiology, celebrado en Madrid (España), del 10 al 13 de julio de 2018Peer reviewe

An optimized controlled rate slow cooling protocol for bovine ovarian tissue cryopreservation by means of X-ray computed tomography

Cryopreservation and subsequent transplantation of ovarian tissue is the only option to preserve fertility in certain patients facing gonadotoxic treatment. So far, cryopreservation of ovarian tissue has been carried out mostly by a controlled rate slow cooling process, typically known as slow freezing. Even though there are still some concerns about the iatrogenic damage on the follicle population, this technique has been used in the more than 100 live births reported to date. It is well known that the control of the cryoprotectant loading in the tissue is crucial to in a cryopreservation procedure. We have used the technology of X-ray computed tomography to assess the concentration and distribution of dimethyl sulfoxide (one of the cryoprotectants most used in fertility preservation) inside pieces of bovine ovarian tissue after its cryopreservation. The low voltage used in our device (75 kV) and the high electronic density of this cryoprotectant makes the X-ray attenuation proportional to its concentration. By assessing and comparing the permeation and homogeneity of the cryoprotectant inside ovarian tissue fragments subjected to a controlled rate slow cooling process, we have characterized the effect of variations in the main parameters involved in the process, with the goal of achieving an optimized protocol with higher permeation of the cryoprotectant in the tissue. The most promissory results were obtained by increasing the initial concentration of dimethyl sulfoxide in the vehicle solution from 10 to 20%v/v

New model for PET/CT image processing and radiotherapy planning based on dose painting

Resumen del póster presentado a la international conference on imaging techniques in subatomic physics, astrophysics, medicine, biology and industry; celebrada en Estocolmo (Suecia) del 13 al 16 de junio de 2016.-- et al.[Introduction]: Dose Painting (DP) is a radiotherapy treatment strategy for delivering a nonuniform dose distribution with a prescription based on the new concept of biological target volumes (BTVs) from medical images. Two approaches are being evaluated: threshold-based dose painting by contours (DPBC), and voxel-based dose painting by numbers (DPBN). The study of the impact of different developed PET image reconstruction protocols on the segmentation of the BTVs for DPBC, and the generation of the dose prescription maps for DPBN are topics under study in processing image for nuclear medicine and radiotherapy. [Purpose]: To present a new model for assessing the effect on the radiotherapy treatment planning of using different acquisition and reconstruction protocols for morpho-functional image from PET/CT before incorporating their use in the clinical routine. [Material and methods]: We used Siemens Biograph mCT PET/CT clinical scanner with Syngo V51C acquisition software. Acquisition and reconstruction methods for EARL (ResEARch for Life R , http://earl.eanm.org) [18F]FDG-PET/CT accreditation were carried out and a protocol for maximize Recovery Coefficient (RC) in Image Quality NEMA 2007 phantom was also implemented. The scanner and software apart from typical corrections allows Time of Flight correction, iterative OSEM reconstruction and application of Point Spread Function. Beyond the deviations already observed between dose prescriptions maps and the different reconstructed SUV images, in order to assess the impact of different reconstruction methods on the treatment planning algorithm, actual clinical cases should be also planned for both a dose painting by contours (DPBC) and a dose painting by numbers (DPBN) strategy. However, as far as we know, planning of DPBN is not supported by commercial treatment planning system. To make possible this evaluation, a novel algorithm has been developed for planning based on inverse planning, including an optimization method at the voxel level, so restriction of dose to volumes from a previous segmentation process in the image is not necessary. The software was implemented in our in-house platform CARMEN, based on Matlab (http://grupos.us.es/medicalphysics/) for radiotherapy research. New image processing methods for generating the previous maps to the optimization process and new metrics for the evaluation of results were implemented in CARMEN platform. The platform was developed for the easy implementation of new algorithms under evaluation and then, to be applied to imported clinical cases. [Results]: The different reconstruction methods for the generation of prescription dose maps for DPBN and different semiautomatic segmentation algorithms for DBPN showed relevant discrepancies in covering tumor and unwished doses in healthy tissue and organs at risk. These results evidenced the need to incorporate standard protocols in the processing of PET/CT images for radiotherapy planning. [Conclusions]: A new model was presented for the correct evaluation of the influence in the radiotherapy planning of the implementation of different reconstruction methods and thresholds of morpho-functional information by PET/CT image processing.Peer Reviewe

Tissue and organ cryopreservation by means of X-ray computed tomography

Trabajo presentado en la Society for Low Temperature Biology Meeting (SLTB), celebado en Cambridge (Reino Unido) del 19 al 20 de septiembre de 2017Peer reviewe

X-ray Computed Tomography applied to tissue and organ cryopreservation

Trabajo presentado en International Longevity and Cryopreservation Summit 2017, celebrado en Madrid (España) del 25 al 27 de Mayo de 2017Peer reviewe