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Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2022-2023. Tutor/Director: Niñerola Baizán, Aida, Aguiar Fernández, Pablo, Silva-Rodríguez, Jesús, Nowadays, Nuclear Medicine techniques are of great importance in the clinical practice, especially in Neurology and Oncology, for both Diagnostics and Treatment. Focusing on imaging techniques, quantitative methods have shown to be an alternative to the traditional interpreting of images to give support to the clinician for a more accurate diagnostic. The lack of ground-truths has difficulted the implementation of these quantitative methods in the clinical practice, and consequently the use of simulation has raised as a solution for obtaining reference images. In particular, SimPET is a platform that aims to simulate and reconstruct Positron Emission Tomograph (PET) images while being able to model any scanner by introducing its parameters. The introduction of a new scanner requires a validation process to ensure it works in accordance of the manufacturer’s specifications. To do so, the NEMA protocols are a set of tests to allow a comparison with these specifications. In this work we are developing an implementation in Python and automatization of these tests to allow the easy validation of new scanners for SimPET. Four of the five specified tests were implemented, concerning the Spatial Resolution and the Sensitivity of the tomograph, and the Image Quality and the fraction of Scattering of the reconstructed images. The results were tested and compared with the experimental ones of the Discovery ST scanner. The results show that the values of Resolution and Sensitivity do not strictly coincide with the experimental ones, and further work on tuning the adjustments of the simulation need to be done. For the Image Quality test we obtained parameters that seem to be in accordance with the theoretical behaviour, but the lack of comparative results does not allow us to extract relevant conclusions. In the case of the Scatter Fraction test, we have shown that the suggested method does not work for very low activities. Thus, due to time and computational limitations further work needs to be done in the development of the techniques, but this work has shown the feasibility of its implementation.

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson’s disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD−). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD−, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD− was significantly lower than HC in all these regions. PD-RBD− showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

[ES] Desde su creación en la década de 1950, las imágenes tomográficas han resultado muy valiosas en el ámbito médico ayudando tanto en el diagnóstico como en el tratamiento de múltiples enfermedades. Dentro de la imagen molecular, los escáneres PET (Tomografía por Emisión de Positrones) generan información detallada de la interacción de los radio-trazadores con el tejido de estudio, pudiendo combinar dicha información con imagen anatómica de escáneres TC (Tomografía Computarizada) o RM (Resonancia Magnética). Con el fin de aumentar las prestaciones de estos equipos, como la sensibilidad y la resolución espacial, los PET de cuerpo completo recientemente aumentan su cobertura axial. Sin embargo, el precio de estos dispositivos se multiplica, dificultando su compra en muchos hospitales y centros de investigación. Como alternativa, los escáneres PET específicos de órganos manejan un menor número de detectores haciéndolos más económicos. El objetivo de este tipo de escáneres es mejorar el rendimiento de los dispositivos acercando los detectores al paciente lo máximo posible, optimizando su diseño para un órgano en específico. Otra ventaja es la posible portabilidad de los aparatos. En esta tesis introducimos dos posibles diseños de PET específicos orientados a distintos órganos y con diferente tecnología y geometría y además un escáner preclínico con una geometría novedosa. El primer escáner fue construido de un proyecto nacional llamado PROSPET, fue diseñado y optimizado para hacer imagen de la próstata, debido a la conocida elevada tasa de cáncer de próstata en hombres. El 17% de la población masculina sufrirá cáncer de próstata. El detector escogido para este diseño está compuesto por cristales centelladores monolíticos acoplados a una matriz de fotomultiplicadores de silicio. Inicialmente se pensó en crear un escáner compuesto por dos palas. Sin embargo, los resultados con pacientes no fueron satisfactorios debido a la falta de información angular y la ausencia de información temporal precisa en los detectores. Por tanto, se construyó una configuración de anillo con un diámetro reducido en comparación con escáneres de cuerpo completo. Se apreció un aumento en la sensibilidad y la resolución espacial, así como una buena calidad de imagen utilizando fantomas. El segundo escáner, llamado proyecto CardioPET, está orientado a visualizar el corazón cuando el paciente está sometido a condiciones de estrés farmacológico. Para este dispositivo se utilizó el diseño de dos palas, pero usando cristales pixelados, mejorando la resolución temporal, permitiendo implantar algoritmos de tiempo de vuelo. Se han montado y testeado dos palas tanto con simulaciones como experimentalmente con buenas prestaciones. Además, se procedió a registrar el movimiento de las fuentes de radiación con el fin de aplicar correcciones de movimiento con la ayuda de una cámara externa y unos marcadores ARUCO. Los algoritmos de corrección de movimiento fueron testeados, demostrando un buen funcionamiento. El último dispositivo fue diseñado para optimizar la configuración PET de anillo lo máximo posible. Para ello, se eliminaron los espaciados entre detectores en un escáner pequeño de animales, creando un único detector centellador de forma cilíndrica. Con esto se busca aumentar la sensibilidad, pues ya no se pierden interacciones en los huecos, y también la resolución espacial. Dos prototipos fueron testeados con simulaciones, y validados experimentalmente. El primero con caras de salida planas y el segundo totalmente cilíndrico. En ambos diseños se observaron efectos debidos a la curvatura del detector que necesariamente han de ser compensados con una calibración., [CA] Des de la seua creació en la dècada de 1950, les imatges tomogràfiques hi han resultat molt valuoses en àmbit mèdic ajudant tant en el diagnòstic com en el tractament de moltes malalties. Dins de la imatge molecular, els escàners PET (Tomografia per Emissió de Positrons) generen informació detallada de la interacció dels traçadors amb el teixit del pacient, podent combinar aquesta informació amb imatge anatòmica d'escàners TC (Tomografia Axial Automatitzada) o RM (Ressonancia Magnètica). Amb el fi d'augmentar les prestacions d’aquests equips, els PET de cos complet augmenten la seua cobertura axial, multiplicant el preu dels dispositius i dificultant la seua compra en hospitals i centres d’investigació. Com a alternativa, els escàners PET específics d'òrgans utilitzen un menor nombre de detectors resultant així un preu més econòmic. Un altre avantatge és la possible portabilitat dels aparells. En aquesta tesi abordem tres possibles dissenys de PET específics orientats a diferents òrgans i amb diferent tecnologia i geometria. El primer de tots, un projecte nacional denominat PROSPET, ha sigut dissenyat i optimitzat per a fer imatge de la pròstata, ja que és molt coneguda l'elevada taxa de càncer de pròstata en homes. El 17% de población masculina patirà càncer de pròstata. El detector escollit per a aquest disseny està format per cristals centellejadors monolítics acoblats a una matriu de fotomultiplicadors de silici. De primeres es va pensar a crear un escàner compost per dues pales, ja que permetria disposar els detectors molt a prop del pacient. El resultat no va ser molt satisfactori a causa de la falta d'informació angular i l'absència d'informació temporal precisa. Per tant, l'última iteració va consistir en una configuració d'anell amb un diàmetre reduït en comparació amb els escàners de cos complet. Es va observar una millora en la sensibilitat i la resolució espacial, així com una qualitat d'imatge acceptable. El segon dispositiu va ser dissenyat per a optimitzar la configuració d'anell el màxim possible. Per això es van llevar els espaiats entre detectors, creant un únic detector de forma cilíndrica. Amb aquest disseny es busca augmentar la sensibilitat, ja que no es perden interaccions en els espaiats, i també la resolució espacial. Dos prototips van ser testejats amb simulacions i validats experimentalment. El primer amb cares d'eixida planars i el segon totalment cilíndric. En els dos dissenys es va observar efectes deguts a la curvatura del detector que necessàriament ha de ser compensat amb una calibració. L’últim escàner, denominat projecte CardioPET, està orientat a visualitzar el cor durant el pacient quan és sotmés a condicions d'estrés farmacologic. escàner, denominat projecte CardioPET, està orientat a visualitzar el cor durant el pacient quan és sotmés a condicions d'estrés. Es va recuperar el disseny de les pales per aquest dispositiu, però utilitzant cristals pixelats, millorant la resolució temporal. Dues pales van ser muntades i testejades tant amb simulacions com experimentalment amb bones prestacions. A més, es va registrar el moviment de les fonts de radiació amb la fi d'aplicar correcció de moviment amb l'ajuda d'una càmera externa i uns marcadors ARUCO. Els algoritmes de correcció de moviment també van ser testejats, demostrant un bon funcionament. L'últim dispositiu va ser dissenyat per a optimitzar la configuració d'anell el màxim possible. Per això es van llevar els espaiats entre detectors, creant un únic detector de forma cilíndrica. Amb aquest disseny es busca augmentar la sensibilitat, ja que no es perden interaccions en els espaiats, i també la resolució espacial. Dos prototips van ser testejats amb simulacions i validats experimentalment. El primer amb cares d'eixida planars i el segon totalment cilíndric. En els dos dissenys es va observar efectes deguts a la curvatura del detector que necessàriament ha de ser compensat amb una calibració., [EN] Since their introduction in the 1950-decade, tomographic images have become very valuable in the medical field helping both in diagnostics and in a variety of illnesses treatment. In the molecular imaging field, Positron Emission Tomography (PET) provides accurate information of the radio-tracers interactions with the patient tissue. Moreover, it is possible to combine this information with anatomical images provided by CT (Computed Tomography) or MR (Magnetic Resonance) scanners. With the aim to improve PET systems performance, such as the spatial resolution and the sensitivity, whole body (WB) PET scanners with large axial coverage are recently proposed. However, the system cost increases and, thus, makes difficult their installation in many hospitals or research centers. Organ-dedicated PET scanners, as an alternative to such large systems, use a lower number of detectors, so their price is considerably more economical. The goal of this kind of systems is to boost PET performance by placing the detectors as close as possible to the patient, optimizing the design for a specific organ instead of a large volume. Other advantage of these scanners is their portability. In this thesis we have worked in the design and validation of two organ-dedicated PET scanners with different geometries and technologies, as well as in a novel pre-clinical PET. The first scanner was the result from a national project called PROSPET. A PET system was designed and optimized to image the prostate area. Notice there is a high incidence rate of prostate cancer in the male population. 17% of male population will suffer prostate cancer. For this scanner, the detector modules were composed by a monolithic LYSO scintillation block coupled to a photosensor array based on silicon photomultipliers (SiPM). The first design configuration was made by two panels. However, patient results were not satisfactory due to the lack of angular information and the poor detector time resolution. Therefore, it was rebuilt in a ring configuration with a reduced diameter in comparison with WB-PET scanners. A high sensitivity and spatial resolution were found, as well as a good image quality using phantoms. The second PET scanner, called CardioPET, also arose from a national grant, and it was implemented to visualize the heart area when the patient is under stress condition. The two panels geometry was also implemented for this system, but using pixelated crystals, therefore improving the detector time resolution and allowing to use time of flight (TOF) reconstruction algorithms. Two panels were mounted and tested with both simulation and experimental data with good results. Furthermore, the patient motion was registered applying movement correction techniques with the help of an external optical camera device and ARUCO markers. These algorithms were tested showing a good performance. The last device that we worked within this PhD thesis was designed to optimize the classical ring PET configuration as much as possible. To do so, the gaps between the detector modules in a small animal PET were eliminated by building a single detector with a cylindrical scintillator shape. The goal is to improve the sensitivity, given that there are no event losses in the gaps and to also boost the spatial resolution since there are not edges. Two prototypes were tested with simulations, and experimentally validated as well. The first of them was built with planar outer faces whereas the second was fully cylindrical. In both designs some effects originated from the detector curvature were observed and successfully corrected during the calibration., This thesis was supported by a FPI grant under 2017-08582 reference in the PhD program: “Programa de Doctorado en Tecnologías para la Salud y el Bienestar” belonging to the Polytechnic University of Valencia. The grant was supported by the “Consejo Superior de Investigaciones Científicas” together with the “Agencia Estatal de Investigación” and the “Fondo Social Europeo”.

IntroductionMultiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT.MethodsWe retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as “long-term responders” (LTRs). In the non-LTR group, a cohort referred to as “prolonged responders” (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data.ResultsTwo hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I–II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by polysomnography-confirmed REM sleep without atonia and dream-enacting behaviors. This disorder is considered a prodromal syndrome of alpha-synucleinopathies like Parkinson's disease (PD), where it affects more than 50% of PD patients. The underlying pathology of RBD has been generally understood to involve the pontine nuclei within the brainstem. However, the complete pathophysiology beyond the brainstem remains unclear as does its relationship with PD pathology. Therefore, this review aims to survey the neuroimaging literature involving PET, SPECT, and MR imaging techniques to provide an updated understanding of the neuro-chemical, structural, and functional changes in both RBD and PD patients comorbid with RBD. This review found neuroimaging evidence that indicate alterations to the dopaminergic and cholinergic system, blood perfusion, and glucose metabolism in both RBD patients and PD patients with RBD. Beyond the brainstem, structural and functional changes were found to involve the nigrostriatal system, limbic system, and the cortex-suggesting that RBD is a multi-systemic neurodegenerative process. Future investigations are encouraged to follow RBD patients longitudinally using multimodal imaging techniques to enhance our understanding of this parasomnia disorder. Uncovering which individuals are most likely to develop an alpha-synuclein disorder in the prodromal phase will improve patient outcomes and potentially aid in the development of novel treatments for patients affected by RBD.

[cat] INTRODUCCIÓ: Aproximadament, un 40% dels pacients amb epilèpsia focal son fàrmac-resistents. En aquests casos, la cirurgia de l’epilèpsia pot controlar o reduir significativament les crisis. La zona epileptògena (ZE) és la regió cerebral que la seva resecció implicaria la llibertat de crisis. Malauradament, no hi ha cap prova que determini amb precisió la ZE. HIPÒTESIS: Les alteracions de la DTI que valora la integritat de la substància blanca i les anomalies corticals determinades per la PET-FDG estan relacionades. Per altra banda, el PISCOM té una utilitat similar al SISCOM per detectar la zona d’inici ictal, però evitant la realització de la SPECT interictal. Aquests dos nous processaments de la neuroimatge cerebral permetrien determinar amb major precisió la ZE. OBJECTIUS: Valorar la utilitat de la combinació de la DTI amb la PET-FDG i el PISCOM a l’avaluació pre-quirúrgica de l’epilèpsia fàrmac-resistent. De forma més específica, es pretén determinar la localització de les alteracions de la DTI i la seva relació amb l’hipometabolisme cortical de la PET- FDG i la resecció de la potencial ZE, en pacient adults amb epilèpsia temporal medial amb esclerosi de hipocamp (ETM + EH). En el cas del PISCOM, l’objectiu es valorar la validesa del PISCOM per a identificar la potencial ZE, comparat amb el SISCOM ¡ la PET-FDG, en pacients pediàtrics amb una epilèpsia focal fàrmac-resistent. MÈTODES: De forma retrospectiva, els resultats de la DTI i la PET-FDG en una mostra de 21 pacients adults amb ETM + EH es van comparar amb un grup control sa, i a 18 d’aquests pacients se’ls havia realitzat una cirurgia d’epilèpsia. Respecte al PISCOM, la mostra estava formada per 22 pacients pediàtrics amb epilèpsia focal fàrmac-resistent, majoritàriament extra-temporal. Els resultats del PISCOM es van comparar amb les alteracions determinades pel SISCOM i la PET- FDG, realitzades durant l’avaluació pre-quirúrgica, i amb la ZE determinada per la resecció quirúrgica, la histologia, i el seguiment clínic post-quirúrgic favorable. RESULTATS: Les anomalies determinades per la combinació de la DTI i la PET-FDG van ser extenses, però sent més difuses quan la ETM + EH estava lateralitzada a l’hemisferi esquerre. Segons l’extensió de l’hipometabolisme de la PET-FDG al lòbul temporal epilèptic, es van diferenciar tres grups: anterior, mig i posterior. El grup anterior es relacionava amb alteracions de la DTI més anteriors, a diferència dels altes dos grups on les anomalies de la DTI eren tant anteriors com posteriors. No es va objectivar una relació clara entre les troballes de la DTI i la PET-FDG, i els resultats post-quirúrgics. El PISCOM va localitzar de forma exitosa la ZE en un major número de casos que el SISCOM (86% vs 54%, respectivament), i en una proporció similar a la PET-FDG. La ZE va ser identificada en tots els pacients només sent necessaris els resultats de la PET-FDG i el PISCOM. Es va observar una major concordança global entre observadors a l’analitzar els resultats del PISCOM, comparats amb els de la PET-FDG i el SISCOM. CONCLUSIONS: Els resultats de la combinació de la DTI i la PET-FDG mostren una relació entre ambdues tècniques, permetent identificar diferents xarxes neuronals implicades en una mateixa patologia (ETM + EH), en funció de l’extensió de l’hipometabolisme de la PET-FDG, però sense una clara relació amb el resultats post-quirúrgics. Els resultats del PISCOM suggereixen que podria ser una tècnica complementària per inferir la ZE als casos amb una PET-FDG dubtosa o negativa, substituint al SISCOM i evitant la realització de la SPECT interictal. Ambdues noves tècniques de neuroimatge podrien tenir una utilitat a l’avaluació pre-quirúrgica de l’epilèpsia per ajudar a inferir de forma més precisa la localització de la ZE., [eng] PURPOSE: In drug-resistant epilepsy, surgery can control or significantly reduce seizures. The epileptogenic zone (EZ) is the brain region whose resection would imply freedom from seizures. Unfortunately, there is no evidence to accurately determine EZ. The aim of this study is to determine whether the extent of 18F-FDG-PET hypometabolism combined to DTI abnormalities, and the PISCOM, a new nuclear imaging processing technique, could be useful to try to locate the EZ. METHODS: Twenty-one patients with MTLE-HS underwent comprehensive preoperative evaluation; 18 (86%) of these underwent epilepsy surgery. We analyzed and compared the pattern of white matter (WM) alterations on DTI and cortical hypometabolism on 18F-FDG-PET. Twenty-two children with pharmacorefractory epilepsy, mainly extratemporal, who had undergone presurgical assessment including SISCOM and 18F-FDG-PET and with postsurgical favorable outcome (Engel class I or II) for at least two years, were included. RESULTS: Widespread temporal and extratemporal 18F-FDG-PET and DTI abnormalities were found, involved similar brain regions, being more extensive in the left than the right MTLE-HS. Three groups were determined according to temporal 18F-FDG-PET patterns: hypometabolism restricted to the anterior third, to the middle third, and extending to the posterior third. Patients with anterior temporal hypometabolism showed DTI abnormalities in anterior tracts while patients with posterior hypometabolism showed WM alterations in anterior and posterior tracts. PISCOM concordance with the known EZ was significantly higher than SISCOM (p

Aims Diagnosis of prosthetic valve endocarditis (PVE) by positron emission computed tomography angiography (PET/CTA) is based on visual and quantitative morpho-metabolic features. However, the fluorodeoxyglucose (FDG) uptake pattern can be sometimes visually unclear and susceptible to subjectivity. This study aimed to validate a new parameter, the valve uptake index [VUI, maximum standardized uptake value (SUVmax)−mean standardized uptake value (SUVmean)/SUVmax], designed to provide a more objective indication of the distribution of metabolic activity. Secondly, to re-evaluate the utility of traditionally used PVE imaging criteria and determine the potential value of adding the VUI in the diagnostic algorithm of PVE. Methods and results Retrospective analysis of 122 patients (135 prosthetic valves) admitted for suspicion of endocarditis, with a conclusive diagnosis of definite (N = 57) or rejected (N = 65) PVE, and who had undergone a cardiac PET/CTA scan as part of the diagnostic evaluation. We measured the VUI and recorded the SUVmax, SUVratio, uptake pattern, and the presence of endocarditis-related anatomic lesions. The VUI, SUVmax, and SUVratio values were 0.54 ± 0.1 vs. 0.36 ± 0.08, 7.68 ± 3.07 vs. 3.72 ± 1.11, and 4.28 ± 1.93 vs. 2.16 ± 0.95 in the ‘definite’ PVE group vs. the ‘rejected’ group, respectively (mean ± SD; P < 0.001). A cut-off value of VUI > 0.45 showed a sensitivity, specificity, and diagnostic accuracy for PVE of 85%, 88%, and 86.7% and increased diagnostic ability for confirming endocarditis when combined with the standard diagnostic criteria. Conclusions The VUI demonstrated good diagnostic accuracy for PVE, even increasing the diagnostic power of the traditionally used morphometabolic parameters, which also confirmed their own diagnostic performance. More research is needed to assess whether the integration of the VUI into the PVE diagnostic algorithm may clarify doubtful cases and thus improve the diagnostic yield of PET/CTA.

Purpose A Monte Carlo (MC) modeling of single axial and helical CT scan modes has been developed to compute single and accumulated dose distributions. The radiation emission characteristics of an MDCT scanner has been modeled and used to evaluate the dose deposition in infinitely long head and body PMMA phantoms. The simulated accumulated dose distributions determined the approach to equilibrium function, H(L). From these urn:x-wiley:00942405:media:mp15306:mp15306-math-0001 curves, dose-related information was calculated for different head and body clinical protocols. Methods The PENELOPE/penEasy package has been used to model the single axial and helical procedures and the radiation transport of photons and electrons in the phantoms. The bowtie filters, heel effect, focal-spot angle, and fan-beam geometry were incorporated. Head and body protocols with different pitch values were modeled for x-ray spectra corresponding to 80, 100, 120, and 140 kV. The analytical formulation for the single dose distributions and experimental measurements of single and accumulated dose distributions were employed to validate the MC results. The experimental dose distributions were measured with OSLDs and a thimble ion chamber inserted into PMMA phantoms. Also, the experimental values of the urn:x-wiley:00942405:media:mp15306:mp15306-math-0002 along the center and peripheral axes of the CTDI phantom served to calibrate the simulated single and accumulated dose distributions. Results The match of the simulated dose distributions with the reference data supports the correct modeling of the heel effect and the radiation transport in the phantom material reflected in the tails of the dose distributions. The validation of the x-ray source model was done comparing the CTDI ratios between simulated, measured and CTDosimetry data. The average difference of these ratios for head and body protocols between the simulated and measured data was in the range of 13-17% and between simulated and CTDosimetry data varied 10-13%. The distributions of simulated doses and those measured with the thimble ion chamber are compatible within 3%. In this study, it was demonstrated that the efficiencies of the urn:x-wiley:00942405:media:mp15306:mp15306-math-0003 measurements in head phantoms with nT = 20 mm and 120 kV are 80.6% and 87.8% at central and peripheral axes, respectively. In the body phantoms with urn:x-wiley:00942405:media:mp15306:mp15306-math-0004= 40 mm and 120 kV, the efficiencies are 56.5% and 86.2% at central and peripheral axes, respectively. In general terms, the clinical parameters such as pitch, beam intensity, and voltage affect the Deq values with the increase of the pitch decreasing the Deq and the beam intensity and the voltage increasing its value. The H(L) function does not change with the pitch values, but depends on the phantom axis (central or peripheral). Conclusions The computation of the pitch-equilibrium dose product, urn:x-wiley:00942405:media:mp15306:mp15306-math-0005, evidenced the limitations of the urn:x-wiley:00942405:media:mp15306:mp15306-math-0006 method to determine the dose delivered by a CT scanner. Therefore, quantities derived from the urn:x-wiley:00942405:media:mp15306:mp15306-math-0007 propagate this limitation. The developed MC model shows excellent compatibility with both measurements and literature quantities defined by AAPM Reports 111 and 200. These results demonstrate the robustness and versatility of the proposed modeling method.

Cardiovascular risk; Myocardial insulin resistance; Non-alcoholic fatty liver disease Riesgo cardiovascular; Resistencia a la insulina del miocardio; Enfermedad del higado graso no alcoholico Risc cardiovascular; Resistència a la insulina del miocardi; Malaltia del fetge gras no alcohòlic Background: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D. This work was supported by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064, PI20/01588) and the Agency for Management of University and Research Grants (AGAUR) of Catalonia (2017SGR1303).

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival in treatment-naive diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer progression-free survival, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71 [95% CI, 1.35-2.18]; total lesion glycolysis hazard ratio: 1.46 [95% CI, 1.15-1.86]). Total metabolic tumor volume was prognostic for progression-free survival in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of progression-free survival in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.

Antecedents La captació de 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol pel teixit cerebral a través d’una tomografia per emissió de positrons (TEP) està acceptada per agències reguladores per avaluar la càrrega d’amiloide en persones amb demència, essent aquesta càrrega amiloide una de les troballes histopatològiques en la malaltia d’Alzheimer. El seu valor afegit es demostra principalment quan la captació d’amiloide és negativa, fet que permet excloure la patologia d’Alzheimer en un diagnòstic de demència establert. No obstant això, l’Institut Nacional sobre l’Envelliment i l’Associació d’Alzheimer van establir que la presència de patologia amiloide, detectada per algun d’aquests marcadors en una persona amb un quadre de deteriorament cognitiu lleu (DCL) estaria determinada per una malaltia d’Alzheimer. Objectius Determinar la exactitud de la prova diagnòstica (EPD) de la TEP amb 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol per detectar persones amb un DCL i que progressaran clínicament a una demència per malaltia d’Alzheimer (DMA). Mètodes Es van elaborar tres revisions sistemàtiques seguint els estàndards metodològics Cochrane, una per a cada un dels marcadors esmentats. Resultats 18F-Florbetapir: En avaluar el risc de biaix, es va considerar que la selecció de pacients i l’estàndard de referència en els tres estudis va ser poc clar. Pel que fa al domini del flux de pacients, es va considerar que dos estudis tenien un alt risc de biaix. La progressió de DCL a DMA en aquells amb un seguiment entre dos i menys de quatre anys va tenir una sensibilitat del 67% (IC 95%: 30 a 93) i una especificitat del 71% (IC 95%: 54 a 85 ) segons l’avaluació visual. La progressió de DCL a DMA en aquells amb un seguiment entre un i menys de dos anys va tenir una sensibilitat del 89% (IC 95%: 78 a 95) i una especificitat del 58% (IC 95%: 53 a 64) per avaluació visual i una sensibilitat del 87% (IC 95%: 76 a 94) i una especificitat del 51% (IC 95%: 45 a 56) mitjançant l’avaluació quantitativa. 18F-Florbetaben: En avaluar el risc de biaix es va considerar que l’estudi tenia un alt risc de biaix en els dominis de l’estàndard de referència, el flux i el temps. La progressió de DCL a DMA per avaluació visual va tenir una sensibilitat del 100% (IC 95%: 84 a 100) i una especificitat del 83% (IC 95%: 63 a 98). Analitzada quantitativament, la sensibilitat va ser del 100% (IC 95%: 84 a 100) i l’especificitat del 88% (IC 95%: 68 a 97) en el seguiment a quatre anys. 18F-Flutemetamol: Es van incloure dos estudis que van avaluar la progressió de DCL a DMA. Es va considerar que tots dos estudis tenien un alt risc de biaix en els dominis de flux i temps. La progressió de DCL a DMA al cap de dos anys de seguiment va tenir una sensibilitat del 89% (IC 95%: 52 a 100) i una especificitat del 80% (IC 95%: 44 a 97) segons l’avaluació quantitativa. La progressió de DCL a DMA al cap de tres anys de seguiment va tenir una sensibilitat del 64% (IC 95%: 53 a 75) i una especificitat del 69% (IC 95%: 60 a 76) segons l’avaluació visual. Conclusions A causa de les sensibilitats i especificitats variables per predir la progressió de DCL a DMA i a les poques dades disponibles, no es pot recomanar l’ús rutinari de 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol en la pràctica clínica. Els biomarcadors 18F-Florbetapir, 18F-Florbetaben i 18F-Flutemetamol són d’alt cost econòmic; per tant, és important demostrar amb suficient certesa la seva exactitud diagnòstica i estandarditzar les seves modalitats de procés abans de ser usats en forma àmplia. Antecedentes La captación de 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol por el tejido cerebral a través de una tomografía por emisión de positrones (TEP) está aceptada por agencias reguladoras para evaluar la carga de amiloide en personas con demencia. Su valor añadido se demuestra principalmente cuando la captación de amiloide es negativa, lo que permite excluir la patología Alzheimer en un diagnóstico de demencia establecido. Sin embargo, el Instituto Nacional sobre el Envejecimiento y la Asociación de Alzheimer establecieron que la presencia de patología amiloidea, detectada por alguno de estos marcadores en una persona con un cuadro de deterioro cognitivo leve (DCL) estaría determinada por una enfermedad de Alzheimer. Objetivos Determinar la exactitud de la prueba diagnóstica (EPD) TEP con 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol para detectar personas con un DCL y que progresarán clínicamente a una DEA. Métodos Se elaboraron tres revisiones sistemáticas siguiendo los estándares metodológicos Cochrane, una para cada uno de los marcadores mencionados. Resultados 18F-Florbetapir: Al evaluar el riesgo de sesgo, se consideró que la selección de pacientes y el estándar de referencia en los tres estudios fue poco claro. Con respecto al dominio del flujo de pacientes, se consideró que dos estudios tenían un alto riesgo de sesgo. La progresión desde un DCL a una DEA en aquellos con un seguimiento de entre dos y menos de cuatro años tuvo una sensibilidad de 67% (IC 95%: 30 a 93) y una especificidad de 71% (IC 95%: 54 a 85) según la evaluación visual. La progresión desde un DCL a una DEA en aquellos con un seguimiento entre uno y menos de dos años tuvo una sensibilidad de 89% (IC 95%: 78 a 95) y una especificidad de 58% (IC 95%: 53 a 64) por evaluación visual y una sensibilidad de 87% (IC 95%: 76 a 94) y una especificidad de 51% (IC 95%: 45 a 56) mediante la evaluación cuantitativa. 18F-Florbetaben: Al evaluar el riesgo de sesgo se consideró que el estudio tenía un alto riesgo de sesgo en los dominios del estándar de referencia, el flujo y el tiempo. La progresión desde un DCL a una DEA por evaluación visual tuvo una sensibilidad de 100% (IC 95%: 84 a 100) y una especificidad de 83% (IC 95%: 63 a 98). Analizada cuantitativamente, la sensibilidad fue de 100% (IC 95%: 84 a 100) y la especificidad de 88% (IC 95%: 68 a 97) en el seguimiento a cuatro años. 18F-Flutemetamol: Se incluyeron dos estudios que evaluaron la progresión desde un DCL a una DEA. Ambos estudios se consideraron con un alto riesgo de sesgo en los dominios de flujo y tiempo. La progresión desde un DCL a una DEA a los dos años de seguimiento tuvo una sensibilidad de 89% (IC 95%: 52 a 100) y una especificidad de 80% (IC 95%: 44 a 97) según la evaluación cuantitativa. La progresión desde un DCL a una DEA a los tres años de seguimiento tuvo una sensibilidad de 64% (IC 95%: 53 a 75) y una especificidad de 69% (IC 95%: 60 a 76) según la evaluación visual. Conclusiones Debido a las sensibilidades y especificidades variables para predecir la progresión desde un DCL a una DEA y a los pocos datos disponibles, no se puede recomendar el uso rutinario de 18F-Florbetapir, 18F-Florbetaben o 18F-Flutemetamol en la práctica clínica. Los biomarcadores 18F-Florbetapir, 18F-Florbetaben y 18F-Flutemetamol son de alto costo económico; por lo tanto, es importante demostrar con suficiente certidumbre su exactitud diagnóstica y estandarizar sus modalidades de proceso antes de ser usados en forma amplia. Background 18F-Florbetapir, 18F-Florbetaben or 18F-Flutemetamol uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer’s pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer’s Association established the diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease if the amyloid pathology is present when using some amyloid biomarkers tests. Objectives To determine the diagnostic test accuracy (DTA) of the 18F-Florbetapir, 18F-Florbetaben or 18F-Flutemetamol PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD. Methods Three systematic reviews were performed following Cochrane methodological standards, one for each biomarker. plus some additional items to assess the methodological quality of the included studies. Results 18F-Florbetapir: Regarding the risk of bias, for the patient selection and reference standard domain, all three studies were considered to have an unclear risk of bias. Regarding the domains of flow and timing, two studies were considered at high risk of bias. Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment. Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment. 18F-Florbetaben: We considered the study to be at high risk of bias in the domains of the reference standard, flow, and timing. Progression from MCI to ADD had a sensitivity of 100% (95% CI 84 to 100) and a specificity of 83% (95% CI 63 to 98) by visual assessment, and a sensitivity of 100% (95% CI 84 to 100) and a specificity of 88% (95% CI 68 to 97) by quantitative assessment at four years of follow up. 18F-Flutemetamol: Two studies evaluated the progression from MCI to ADD. Regarding the domains of flow and timing, both studies were considered at high risk of bias. Progression from MCI to ADD at two years of follow-up had a sensitivity of 89% (95% CI 52 to 100) and a specificity of 80% (95% CI 44 to 97) by quantitative assessment (n = 19, 1 study). Progression from MCI to ADD at three years of follow-up had a sensitivity of 64% (95% CI 53 to 75) and a specificity of 69% (95% CI 60 to 76) by visual assessment (n = 224, 1 study). Conclusion Due to the varying sensitivity and specificity for predicting the progression from MCI to ADD and the limited data available, we cannot recommend routine use of 18F-Florbetapir, 18F-Florbetaben, and 18F-Flutemetamol in clinical practice. 18F-Florbetapir, 18F-Florbetaben, and 18F-Flutemetamol have high financial costs; therefore, clearly demonstrating the DTA and standardising the process modalities is important prior the wider use of these biomarkers. Universitat Autònoma de Barcelona. Programa de Doctorat en Metodologia de la Recerca Biomèdica i Salut Pública

[eng] Alzheimer's disease (AD) is the leading cause of dementia worldwide. This disease, however, starts decades before any clinical symptom appears with the accumulation in the brain of aggregates of two main proteins: amyloid-β (Aβ) and tau. In recent years, the appearance of in vivo biomarkers capable to track biological changes has boosted the research interest to earlier phases of the disease. With these concepts in mind, the general objective of this thesis was to investigate Aβ deposition and its downstream effects in the earliest stages of the Alzheimer's continuum. To this aim, the four studies of the thesis include participants of the ALFA (from Alzheimer and Families) cohort, who are characterized as being cognitively unimpaired, (late) middle-aged, and to be enriched in risk factors for AD. Thus, increasing the probability of incorporating participants with lowintermediate burden of Aβ. In the first two studies of this thesis, our focus was set on the early detection of Aβ deposition using PET scans. We first used automated quantification methods, as typically done in the research setting and, second, we used visual assessment, which is more often used in the clinical context. Our results lead to the identification of quantitative thresholds for the detection of early abnormalities in amyloid PET scans significantly lower than previously proposed. We also concluded that visual inspection of Aβ PET scans is sensitive to detect and grade early Aβ deposition in the brain. In the third study, Aβ PET images were used to investigate whether risk factors for Alzheimer's dementia promoted the deposition of insoluble, fibrillar aggregates of Aβ in the brain for similar levels of Aβ in the cerebrospinal fluid (CSF), reflecting the production/clearance rate of soluble Aβ species. We found that that the main unmodifiable risk factors for Alzheimer's dementia -older age, female sex, and APOE-ε4 allele carriership- increased deposited fibrillar Aβ for similar levels of soluble Aβ as measured in the CSF. However, while older age and female sex promoted the deposition in typical AD-related areas, thus suggesting an additive effect, APOE-ε4 allele facilitated the spread of Aβ in the entorhinal area, which has been described as an area vulnerable to tau deposition. This result suggests that APOE-ε4 allele-related mechanisms might accelerate the propagation of Aβ pathology to these areas, facilitating the spread of tau through the neocortex and thus, contributing to raise the risk of developing AD. Finally, in our last study, we investigated Aβ-downstream effects in the earliest stages of the Alzheimer's continuum. To this aim, we analysed core and novel AD CSF biomarkers. These included: Aβ42/40 and phosphorylated tau (p-tau) as markers of Aβ and tau pathology, respectively; total tau (t-tau) and neurofilament light (NfL) as markers of neurodegeneration; neurogranin for synaptic dysfunction; glial fibrillary acidic protein (GFAP), YKL-40, soluble triggering receptor on myeloid cells 2 (sTREM2), S100b, interleukin 6 (IL-6) as glial activity biomarkers and, total α-synuclein as marker of α-synuclein pathology. We observed that, although studying participants with low Aβ load, many pathophysiological pathways, such as inflammation, were already altered. Of note, our results suggest a direct link between Aβ deposition in the brain and neurodegeneration that is independent of tau pathology. Further, we described their direct and/or indirect associations with Aβ deposition, as well as the moderation effects of some Alzheimer’s dementia risk factors on these relationships., [cat] La malaltia d'Alzheimer és la causa principal de demència en tot el món. Aquesta malaltia però, comença dècades abans de l'aparició de qualsevol símptoma clínic amb l'acumulació en el cervell de l'agregat de dues proteïnes: l'amiloide-β (Aβ) i la tau. En els últims anys, l'aparició de biomarcadors in vivo capaços de monitoritzar aquests, entre d'altres, canvis biològics ha estimulat l'interès cap a etapes més inicials de la malaltia. Amb aquests conceptes en ment, l'objectiu general d'aquesta tesis era el d'investigar l'acumulació d'Aβ i els seus efectes derivats en les etapes més incipients del continu de la malaltia d'Alzheimer. Amb aquest objectiu, els quatre estudis d'aquesta tesis inclouen participants de la cohort ALFA (per Alzheimer i Famílies), els quals es caracteritzen per ser cognitivament sans, ser de mitjana edat avançada i per estar prioritàriament seleccionats per tenir factors de risc per l'Alzheimer incrementant, d'aquesta manera, la possibilitat d'incorporar participants amb càrrega baixa o intermitja d'Aβ. En els primers dos estudis d'aquesta tesis, el nostre focus era la detecció precoç de l'acumulació d'Aβ utilitzant imatges PET. Primer utilitzant mètodes de quantificació automàtica, típicament utilitzats en la recerca i, segon, mitjançant l'avaluació visual, que és més sovint utilitzada en el context clínic. Els nostres resultats ens van portar a la identificació de llindars quantitatius per a la detecció precoç d'anormalitats en les imatges PET d'Aβ significativament inferiors als prèviament proposats. A més, també vam concloure que la inspecció visual d'aquestes imatges és sensible per detectar i qualificar el dipòsit inicial d'Aβ en el cervell. En el tercer estudi, les imatges PET d'Aβ van ser utilitzades per investigar si factors de risc per la demència d'Alzheimer promovien l'acumulació d'agregats fibril·lars insolubles d'Aβ en el cervell per nivells similars d'Aβ mesurat en el líquid cefalorraquidi (LCR), els quals reflecteixen el rati de producció/eliminació d'espècies solubles d'Aβ. La nostra conclusió en aquest estudi és que els tres principals factors de risc no modificables per a la demència d'Alzheimer -edat avançada, sexe femení i ser portador de l'al·lel APOE-ε4- incrementen la càrrega fibril·lar d'Aβ dipositat per nivells similars d'Aβ soluble mesurat en el LCR. Tanmateix, mentre que l'edat avançada i el sexe femení promouen el dipòsit d'Aβ en àrees típiques de la malaltia d'Alzheimer i, per tant, suggereixen un efecte additiu; l'al·lel APOE-ε4 facilita l'expansió de l'Aβ en l'escorça entorínica, que ha sigut descrita per ser especialment vulnerable al dipòsit de la proteïna tau. Aquest últim resultat suggereix que, els mecanismes relacionats amb l'al·lel APOE-ε4 podrien accelerar la propagació de la patologia Aβ a aquestes àrees, facilitant la futura propagació de la proteïna tau pel neocòrtex i contribuir així, a l'augment de risc de desenvolupar la malaltia d'Alzheimer. Finalment, en el nostre últim estudi, vam investigar els efectes derivats de l'acumulació d'Aβ en les primeres etapes del continu de la malaltia d'Alzheimer. Amb aquest objectiu, vam analitzar marcadors bàsics i novells en LCR de la malaltia d'Alzheimer. Aquests inclouen: Aβ42/40 i tau fosforilat (p-tau) com a marcadors de patologia Aβ i tau, respectivament; tau total (t-tau) i neurofilament lleuger (NfL) com a biomarcadors de neurodegeneració; neurogranina per disfunció sinàptica; GFAP, YKL-40, sTREM2, S100b i IL-6 com marcadors d'activitat glial i, α-synucleïna total com a marcador de patologia d'α-synucleïna. Val a destacar que els nostres resultats suggereixen una relació directe entre el dipòsit d'Aβ en el cervell i la neurodegeneració que és independent de la patologia tau. A més, també vam descriure les associacions directes i/o indirectes amb la càrrega d'Aβ, així com l'efecte moderador d'alguns factors de risc en aquestes relacions.

Interstitial lung diseases (ILDs) that present in childhood (chILD) are seen far less frequently than ILDs presenting in adults which themselves constitute rare disorders [1]. Histopathological [2, 3] and imaging [4] characterisation of chILD disease subtypes therefore lags behind adult ILDs. The field has also been constrained by comparisons with disease morphology in adults, despite the developmental differences in terms of growth and healing in the paediatric lung, which may alter disease patterns and distributions. The American Thoracic Society [5] and European [1] chILD management guidelines both specify a pivotal role for computed tomography (CT) imaging in the work-up of chILD patients to: 1) determine whether a chILD is present or not; and 2) where possible, to make a specific diagnosis of the underlying cause. For the second aim to be achieved, diagnostic reviews need to be reproducible between experts. Our study uniquely examined agreement between observers of varying experience in the CT evaluation of chILD to inform whether the current status of CT imaging and knowledge can be diagnostic of specific chILDs. We hypothesised that observer agreement for chILD groups and diagnoses would be limited. The study was not designed to relate CT agreement to final diagnosis. As a secondary analysis, we examined how CT interpretation differed between observers in children under and over 2 years of age., Making chILD diagnoses on CT is poorly reproducible, even amongst sub-specialists. CT might best improve diagnostic confidence in a multidisciplinary team setting when augmented with clinical, functional and haematological results. http://bit.ly/327jRCw

[eng] Time-of-Flight Positron Emission Tomography (TOF-PET) scanners demand fast and efficient photo-sensors and scintillators coupled to fast readout electronics. Nowadays, there are two main configurations regarding the scintillator crystal geometry: the segmented or pixelated and the monolithic approach. Depending on the cost, spatial resolution and time requirements of the PET module, one can choose between one or another. The pixelated crystal is the most extensive configuration on TOF-PET scanners as the coincidence time resolution is better compared to the monolithic. On the contrary, monolithic scintillator crystals for Time-of-Flight Positron Emission Tomography (ToF-PET) are increasing in popularity this last years due to their performance potential and price in front of the commonly used segmented crystals. On one hand, monolithic blocks allows to determine 3D information of the gamma-ray interaction inside the crystal, which enables the possibility to correct the parallax error (radial astigmatism) at off-center positions within a PET scanner, resulting in an improvement of the spatial resolution of the device. On the other hand, due to the simplicity during the crystal manufacturing process as well as for the detector design, the price is reduced compared to a regular pixelated detector. The thesis starts with the use of HRFlexToT, an ASIC developed in this group, as the readout electronics for measurements with single pixelated crystals coupled to different SiPMs. These measurements show an energy linearity error of 3% and an energy resolution below 10% of the 511 keV photopeak. Single Photon Time Resolution (SPTR) measurements performed using an FBK SiPM NUV-HD (4 mm x 4 mm pixel size) and a Hamamatsu SiPM S13360-3050CS gave a 141 ps and 167 ps FWHM respectively. Coincidence Time Resolution (CTR) measurements with small cross-section pixelated crystals (LFS crystal, 3 m x 3 mm x 20 mm ) coupled to a single Hamamatsu SiPM S13360-3050CS provides a CTR of 180 ps FWHM. Shorter crystals (LSO:Ce Ca 0.4%) coupled to a Hamamatsu S13360-3050CS SiPM or FBK-NUVHD yields a CTR of 117 ps and 119 ps respectively. Then, the results with different monolithic crystals and SiPM sensors using HRFlexToT ASIC will be presented. A Lutetium Fine Silicate (LFS) of 25 mm x 25 mm x 20 mm, a small LSO:Ce Ca 0.2% of 8 mm x 8 mm x 5 mm and a Lutetium-Yttrium Oxyorthosilicate (LYSO) of 25 mm x 25 mm x 10 mm has been experimentally tested. After subtracting the TDC contribution (82 ps FWHM), a coincidence time resolution of 244 ps FWHM for the small LFS crystal and 333 ps FWHM for the largest LFS one is reported. Additionally, a novel time calibration correction method for CTR improvement that involves a pico-second pulsed laser will be detailed. In the last part of the dissertation, a new developed simulation framework that will enable the cross-optimization of the whole PET system will be explained. It takes into consideration the photon physics interaction in the scintillator crystal, the sensor response (sensor size, pixel pitch, dead area, capacitance) and the readout electronics behavior (input impedance, noise, bandwidth, summation). This framework has allowed us to study a new promising approach that will help reducing the CTR parameter by segmenting a large area SiPM into "m" smaller SiPMs and then summing them to recover all the signal spread along these smaller sensors. A 15% improvement on time resolution is expected by segmenting a 4 mm x 4 mm single sensor into 9 sensors of 1.3 mm x 1.3 mm with respect to the case where no segmentation is applied., [cat] Aquesta tesi tenia com a objectiu la fabricació i avaluació d'un prototip per a detecció de fotons gamma en aplicació per imatge mèdica, més concretament en Tomografia per Emissió de Positrons amb mesura de temps de vol (TOF-PET). L'avaluació del mòdul va començar fent una caracterització completa del chip (ASIC) anomenat HRFlexToT, una versió nova i millorada de l'antic chip FlexToT, desenvolupat i fabricat pel grup de la Unitat Tecnològica del ICC de la Universitat de Barcelona. Aquesta avaluació inicial del chip compren des de la comprovació de les funcionalitats bàsiques fins a la generació d'un test automàtic per generar les gràfiques de linealitat corresponents durant el test elèctric. Un cop donat per bo, es va muntar en una placa demostrada, també ideada per l'equip d'enginyers del grup, i ja quedava llesta per realitzar les mesures pertinents. Tot seguit, es varen realitzar les mesures òptiques, que incloïa mesures de Singe Photon Time Resolution (SPTR) i de Coincidence Time Resolution (CTR). Aquest valors actuen com a figures de mèrit a l'hora de comparar les prestacions amb d'altres ASICs competidors del HRFlexToT. Es van obtenir valors de 60 ps de resposta pel que respecta al SPTR i de 115 ps de CTR en cristalls segmentats, una millora entorn del 20-30% respecte a la versió predecessora del chip. Aquests valors mostren ser el límit de l'estat de l'art actual i amb aquesta idea es van començar a fer altres mesures, en aquest cas amb cristall monolítics, blocs grans llegits per diversos fotosensors de les empreses Hamamatsu i FBK. Per altra banda, es va provar el funcionament del ASIC en configuració anomenada monolítica, on el cristall centellejador s'utilitza en blocs grans en coptes d’emprar cristalls segmentats, això abarateix el cost total del detector. Aquesta configuració degrada les propietats de CTR, un paràmetre crític a l'hora de tenir un producte bo i eficient. S’han obtingut mesures de 250 ps de CTR amb aquesta configuració, d’on es pot dir que l’HRFlexToT es trobar a l’estat de l’art de la tecnologia electrònica dedicada a TOF-PET amb cristalls segmentats i monolítics. Finalment, es va desenvolupar una nova eina simulació que consisteix en un sistema híbrid entre un simulador físic i un electrònic per tal de tenir una idea del comportament complet del mòdul detector. Una solució que ningú havia provat fins ara o que no es pot trobar en la literatura.

Treballs Finals de Grau de Física, Facultat de Física, Universitat de Barcelona, Curs: 2020, Tutor: Eugeni Graugés, The HRFlexToT control software was designed to be used through command-line. In this project a graphical interface has been programmed in order to simplify the software configuration process. The interface has been programmed via PyQt libraries. It also includes a new feature to plot the data registered by the HRFlexToT board. Finally it's explained how to calibrate by the HRFlexToT acquisition system.

The HRFlexToT is a 16-channel ASIC for SiPM anode readout designed for Positron Emission Tomography (PET) applications that features high dynamic range (>8 bits), low input impedance, common cathode connection, high speed and low power (~3.5 mW/ch). The ASIC has been manufactured using XFAB 0.18 mm CMOS technology. The main characteristics of the HRFlexToT, compared to its predecessor, are a new energy measurement readout providing a linear Time Over Threshold (ToT) with an extended dynamic range, lower power consumption and better timing response. Initial measurements show a linearity error below 3%. Single Photon Time Resolution (SPTR) measurements performed using a Hamamatsu MPPC S13360-3050CS (3x3 mm2 pixel, 50 umm cell) shows 30% improvement with respect to the previous version of the ASIC, setting this specification in the order of 141 ps FWHM and reducing 3 times power consumption. It is important to highlight that an SPTR of 141 ps FWHM is, according to the best of our knowledge, the best resolution achieved so far for this sensor. Coincidence Time Resolution (CTR) measurements are expected to be performed during 2018.

La endocarditis infecciosa (EI) es una patología grave que continúa teniendo mal pronóstico a pesar de los avances en el tratamiento médico y quirúrgico y cuyo diagnóstico es siempre un desafío clínico. De la misma manera, la infección de dispositivos intracardíacos es un problema creciente que también comporta una alta morbimortalidad y que posee importantes dificultades diagnósticas. Por este motivo el desarrollo de una nueva técnica de imagen que contribuya a mejorar la detección de estas patologías constituye un tema de relevancia en el momento actual. La presente tesis doctoral se compone de dos artículos que analizan diferentes aspectos de la utilidad de la tomografía por emisión de positrones con 18F-fluordesoxiglucosa/ Angiotomografía computarizada cardíaca (18F-FDG-PET/CTA (PET/CTA) para el diagnóstico de EI y la infección de dispositivos intracardíacos. El primer artículo demuestra que que el PET-CT/CTA es una técnica útil en el diagnóstico de los pacientes con sospecha de EI portadores de válvulas protésicas o dispositivos intracardíacos y que la combinación de sus hallazgos con los Criterios de Duke modificados mejora la sensibilidad diagnóstica del 52% al 90,7% permitiendo establecer un diagnóstico concluyente en el 95% de los casos en esta población de enfermos. Asimismo, demuestra que la combinación de la gran sensibilidad para detectar inflamación de la 18F-FDG-PET/CT con la alta resolución espacial del CTA cardíaco para definir el daño estructural es la mejor estrategia para el diagnóstico y la detección de complicaciones periprotésicas, con resultados superiores al PET/CT convencional (sensibilidad diagnóstica del 88,6% para la combinación de los Criterios de Duke y los estudios de PET/CT sin contraste y del 91% para la combinación de los primeros con el PET/CTA). El segundo artículo aborda la utilidad de esta técnia en un grupo particularmente complejo de pacientes adultos con cardiopatías congénitas y portadores de materiales protésicos, observándose también un incremento de la sensibilidad diagnóstica en estos últimos del 39,1% al 87%, con un diagnóstico concluyente en el 92% de los casos. Dicho incremento representa un impacto superior al demostrado en la población general. En forma adicional y en ambos grupos, el PET-CT/CTA permitió documentar eventos embólicos y metástasis sépticas en un 15% de los casos, identificó la puerta de entrada de la bacteriemia en casos concretos y ofreció un diagnóstico alternativo en el 54% de los casos de EI o infección de dispositivos intracardíacos rechazadas. Infectious endocarditis (IE) is a serious pathology that continues to have a poor prognosis despite advances in medical and surgical treatment and its diagnosis poses always a clinical challenge. In the same way, the infection of intracardiac devices is a growing problem that also entails a high morbidity and mortality and that has important diagnostic difficulties. For this reason, the development of a new imaging technique that contributes to improve the detection of these pathologies is an issue of relevance at the present time. This doctoral thesis is composed of two articles that analyze different aspects of the usefulness of the positron emission tomography with 18F-fluorodeoxyglucose/cardiac computed tomography (18F-FDG-PET/CTA (PET CTA) for the diagnosis of IE and the infection of intracardiac devices. The first article shows that PET-CT/CTA is a useful technique in the diagnosis of patients with suspected prosthetic valve IE or intracardiac device infection and that the combination of its findings with the modified Duke Criteria improves the diagnostic sensitivity from 52% to 90.7%, making it possible to establish a conclusive diagnosis in 95% of the cases in this patient population. Besides, it demonstrates that the combination of the high sensitivity of the 18F-FDG-PET/CT to detect inflammation with the high spatial resolution of the cardiac CTA to define structural damage is the best strategy for the diagnosis and the detection of periprosthetic complications, with superior results to the conventional PET/CT technique (diagnostic sensitivity of 88.6% for the combination of the Duke Criteria and non-enhance PET/CT and 91% for the combination of the former with the PET/CTA). The second article addresses the usefulness of this technique in a particularly complex group of adult patients with congenital heart disease that have several prosthetic materials also observing an increase in the diagnostic sensitivity in this specific cohort, from 39.1% to 87%, with a conclusive diagnosis in 92% of the cases. This increase represents a greater impact than that observed in the general population. Additionally and in both groups, the PET-CT/CTA allowed the detection of embolic events and septic metastases in 15% of the cases, identified the source of the bacteremia in some specific cases and elucidated an alternative diagnosis in 54% of the rejected IE or device infection cases.

[spa] La epilepsia es una enfermedad con una elevada prevalencia e impacto sociosanitario. Aproximadamente un tercio de los pacientes son resistentes al tratamiento farmacológico y en estos casos debe considerarse la cirugía como la única opción potencialmente curativa. El éxito de la cirugía de la epilepsia está directamente relacionado con la precisa localización y resección del córtex epileptógeno, por lo que es crucial realizar una exhaustiva valoración prequirúrgica considerando varias modalidades diagnósticas. Los estudios de neuroimagen funcional como la PET, analizados visual y objetivamente mediante programas informáticos específicos, pueden desempeñar un papel decisivo en este contexto. Este trabajo de investigación se ha basado en la publicación dos estudios. En el primer estudio se incluyeron retrospectivamente 55 pacientes con epilepsia resistente al tratamiento farmacológico a los que se les realizó una PET con 18F-FDG que se interpretó como normal o con hallazgos muy sutiles o dudosos al análisis visual. De entre los pacientes incluidos, 20 habían sido operados con buenos resultados postquirúrgicos (Engel I-II). Se analizaron todos los estudios PET con SPM. Se usaron como dinteles de segmentación un valor de p corregido de p50 y p no corregida 100. Como PET-analysis procesa rápidamente varias combinaciones de dinteles de significación, se usaron múltiples dinteles basados en combinaciones de diferentes desviaciones estándar y tamaños de cluster. PET-analysis obtuvo un 66,7% (20/30) de estudios correctamente localizadores de la ZE, comparable con el 70,0% (21/30) obtenido mediante el análisis visual y significativamente superior (p100, que obtuvo 36,7% (11/30). Sólo un estudio fue positivo, aunque no localizador, con el dintel de SPM p50. En cuanto a la RM, un 16/30 (53,3%) de los estudios fueron correctamente localizadores. La concordancia de la ZE posquirúrgica fue sustancial con PET-analysis (к=0,643, IC95% 0,439-0,847) y la interpretación visual (к=0,622, IC95% 0,367-0,877), pero fue débil con SPM (к=0,242, IC95% 0,028-0,455) y moderada con la RM (к=0,520, IC95% 0,268-0,772). En comparación con SPM, PET-analysis podría ser superior para la localización de la ZE con su procesado rápido y sencillo de diferentes combinaciones de dinteles de significación. Los resultados de este estudio validan el uso clínico de PET-analysis como una herramienta robusta complementaria al análisis visual en la localización de la ZE., [eng] FIRST ARTICLE SUMMARY Seizure onset zone localization by Statistical Parametric Mapping in visually normal 18F-FDG PET studies Introduction and objective: Neuroimaging is crucial in the presurgical evaluation of patients with medically refractory epilepsy. To improve the moderate sensitivity of [18F]fluorodeoxyglucose (18F-FDG) positron emission tomograpghy (PET) our aim was to evaluate the usefulness of Statistical Parametric Mapping (SPM) to localize the seizure onset zone (SOZ) in PET studies deemed normal by visual assessment. Methods: Fifty-five patients with medically refractory epilepsy whose 18F-FDG PET was visually evaluated as normal were retrospectively included. Twenty of these patients were surgically-intervened. PET images were analysed by SPM8 using a corrected p value of p0, k>20, k>100 and k>200, respectively. The SPM-identified potential seizure zone (SZ) was compared to the SOZ, which was determined by consensus during patient management meetings in the Epilepsy Unit, taking into account presurgical tests. Studies in which the SPM-identified potential SZ was concordant with the SOZ were considered “correctly localizing”. Results: The SPM threshold combination with the least restrictive p-value and greatest minimum cluster size achieved the highest rate of correctly localizing studies. When p200 was used, 40% (22/55) of studies were correctly localizing, and the concordance obtained in the surgically-intervened subgroup was substantial (к=0.607, CI95% 0.258,0.957), which was comparable to the concordance obtained by MRI (к=0.783, CI95% 0.509,1.000). Conclusion: SPM offers improved SOZ localization in 18F-FDG PET studies that are negative on visual assessment. For this purpose, statistical parametric maps could be thresholded with liberal p-values and restrictive cluster sizes. SECOND ARTICLE SUMMARY Epileptogenic Zone Localization with 18FDG PET Using a New Dynamic Parametric Analysis Introduction and objective: [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is part of the regular preoperative work-up in medically refractory epilepsy. As a complement to visual evaluation of PET, statistical parametric maps can help in the detection of the epileptogenic zone (EZ). However, software packages currently available are time-consuming and little intuitive for physicians. We develop a user-friendly software (referred as PET-analysis) for EZ localization in PET studies that allows dynamic real-time statistical parametric analysis. To evaluate its performance, the outcome of PET-analysis was compared with the results obtained by visual assessment and Statistical Parametric Mapping (SPM). Methods: Thirty patients with medically refractory epilepsy who underwent presurgical 18F-FDG PET with good postoperative outcomes were included. The 18F-FDG PET studies were evaluated by visual assessment, with SPM8 and PET-analysis. In SPM, parametric T-maps were thresholded at corrected p

Individuals with autosomal dominant Alzheimer's disease (ADAD) present amyloid deposits before symptoms onset. We aimed to investigate efficacy and safety of 18F-florbetaben (FBB) for assessing amyloid deposition in ADAD. We acquired FBB positron emission tomography and magnetic resonance imaging of 25 individuals from PSEN1 families (NCT02362880). We studied individual uptake patterns, group differences, and correlation with estimated years to symptoms onset, as well as adverse events. We found that asymptomatic carriers (N = 14) showed increased FBB uptake across the cerebral cortex and in the caudate. FBB accumulation appeared more than 15 years before onset in the precuneus and bankssts, among other regions, overlapping regions showing increased cortical thickness in the same subjects. FBB uptake correlated with estimated years to symptoms onset in several areas, especially the rostral anterior cingulate. Symptomatic carriers (N = 7) had an elevated FBB uptake plateau. No adverse events were reported. Overall, we found progressive FBB uptake in ADAD starting 2 decades before symptoms. The rostral anterior cingulate is a candidate area to track Aβ deposition in addition to the precuneus.

Introduction The aim of this study was to evaluate the behavior of a penalized-likelihood image reconstruction method (Q.Clear) under different count statistics and lesion-to-background ratios (LBR) on a BGO scanner, in order to obtain an optimum penalization factor (β value) to study and optimize for different acquisition protocols and clinical goals. Methods Both phantom and patient images were evaluated. Data from an image quality phantom were acquired using different Lesion-to-Background ratios and acquisition times. Then, each series of the phantom was reconstructed using β values between 50 and 500, at intervals of 50. Hot and cold contrasts were obtained, as well as background variability and contrast-to-noise ratio (CNR). Fifteen 18 F-FDG patients (five brain scans and 10 torso acquisitions) were acquired and reconstructed using the same β values as in the phantom reconstructions. From each lesion in the torso acquisition, noise, contrast, and signal-to-noise ratio (SNR) were computed. Image quality was assessed by two different nuclear medicine physicians. Additionally, the behaviors of 12 different textural indices were studied over 20 different lesions. Results Q.Clear quantification and optimization in patient studies depends on the activity concentration as well as on the lesion size. In the studied range, an increase on β is translated in a decrease in lesion contrast and noise. The net product is an overall increase in the SNR, presenting a tendency to a steady value similar to the CNR in phantom data. As the activity concentration or the sphere size increase the optimal β increases, similar results are obtained from clinical data. From the subjective quality assessment, the optimal β value for torso scans is in a range between 300 and 400, and from 100 to 200 for brain scans. For the recommended torso β values, texture indices present coefficients of variation below 10%. Conclusions Our phantom and patients demonstrate that improvement of CNR and SNR of Q.Clear algorithm which depends on the studied conditions and the penalization factor. Using the Q.Clear reconstruction algorithm in a BGO scanner, a β value of 350 and 200 appears to be the optimal value for 18F-FDG oncology and brain PET/CT, respectively.

[eng] Positron emission tomography (PET) is a molecular imaging technique used for several decades in nuclear medicine that provides precise physiological information of the human body, what is crucial in oncology, cardiology, and neuropsychiatry. Due to physical, the best spatial resolution of PET is approximately 1 mm for human brain scanners. Unfortunately, the minimum resolution of the best commercial PET scanners for humans is 4-5 mm due to technological limitations. In this thesis, an application specific integrated circuit (ASIC) to readout the energy and the time stamp of a high-density and highly-granulated Cadmium Telluride detector for a novel PET scanner design is presented. The research presented here was realized within the framework of Voxel Imaging PET pathfinder ERC project to develop detector modules for positron emission tomography applications and reach their actual physical limits. The VIP PET scanner is based on the stacking of 2-mm thickness pixelated hybrid detectors. Every CdTe detector is pixelated into an array of 10 x 10 voxels of 1 mm x 1 mm x 2 mm size and is connected to a pixelated ASIC to readout independently the energy and the time stamp of every photon interaction. The VIP PET is based on more than 6 million voxels with independent energy and timing readout to reach the physical limits of PET. The simulated performance based on the properties of CdTe detectors shows a scatter fraction of approximately 4 % due to an excellent energy resolution of 1.6 % FWHM of the CdTe detectors. By simulation, the VIP PET is able to distinguish 1 mm size radioactive point-like source. The characterization of 2-mm thickness CdTe detectors using commercially available single-channel readout electronics is reported. Using a Sodium-22 radioactive source, the 511 keV photopeak resolution and the coincidence time resolution of back-to-back photons were measured with – 1000 V/mm detector bias voltage at -8 Celsius degree. An energy resolution of 1.6 % FWHM and a time coincidence resolution of 6 ns FWHM were obtained for photoelectric interactions. The architecture of the VIPPIX ASIC, i.e. the ASIC developed for VIP project, is based on an array of 10 x 10 independent pixel electronics controlled by a global controller and a common time to digital converter (TDC). Additional voltage and current references are generated in the ASIC’s back-end with a temperature sensor and a chip-ID cell. Every pixel electronics composes of a programmable gain preamplifier with detector’s leakage dynamic compensation, a tuneable peak-time pulse shaper connected to a peak-and-detect circuit, a 10-bit analog-to- digital converter (ADC), a pulse discriminator with adjustable offset, and a local pixel digital controller. The measured equivalent noise charge (ENC) of the pixel is 150 e- RMS and the trigger time jitter is approximately 1 ns for energy depositions larger than 200 keV. The time resolution of the integrated TDC is 600 ps FWHM. Twelve wafers of VIPPIX ASIC has been fabricated and characterized. Best quality ASICs have been mounted on 720 CdTe detectors and stacked in 18 detector modules with 40 hybrid detectors each to build the VIP PET prototype. Five modules have been characterized with a Sodium-22 radioactive source. The performance of approximately 18000 pixels shows a resolution of 2.2 % FWHM and a coincidence time resolution of 60 ns FWHM for 511 keV photopeak at -250 V/mm detector bias. Therefore, the main goal of the research has been accomplished. A new PET design based on pixelated Cadmium Telluride detectors using dedicated readout ASICs has been successfully fabricated, partly characterized, and is ready for image acquisition.

[spa] Las infecciones cardiovasculares (ICV) son entidades de difícil manejo que presentan un alto riesgo de mortalidad y de complicaciones severas. Dentro de estas complicaciones, el diagnóstico temprano de posibles embolias sépticas hematógenas (ESH) es un reto en la práctica clínica diaria y resulta crucial para el correcto manejo de estos pacientes, principalmente aquellas con clínica silente como es el caso de las espondilodiscitis. Los hemocultivos y los hallazgos del ecocardiograma continúan siendo los pilares en la sospecha y en el diagnóstico inicial. Sin embargo, el rendimiento de las pruebas diagnósticas actuales no es óptimo, persistiendo un alto porcentaje de pacientes sin un diagnóstico de confirmación. Las dificultades radican en la interpretación de los estudios microbiológicos y ecocardiográficos, principalmente en los pacientes portadores de válvulas protésicas (VP) y dispositivos de electroestimulación cardiaca (DEC). Publicamos estudios prospectivos observacionales de dos grupos de pacientes: En el primer artículo se estudiaron 80 pacientes consecutivos con sospecha de endocarditis infecciosa (EI) y/o infección de DEC (EI-DEC). Se les realizó PET/TC con inhibición miocárdica, de acuerdo a las siguientes indicaciones: sospecha de EI sobre válvulas nativas (VN) (n:21), EI-VP (n:29) o infección de DEC (n= 30). El diagnóstico final de infección se estableció en 31/80 pacientes: EI-VN (n:6), EI-VP (n:12), EI-DEC (n:8) e infección de DEC (n= 5). Los valores de sensibilidad, especificidad, VPP y VPN de la PET/TC fueron 82%, 96%, 94% y 87%, si se excluyeran las VN estos valores fueran 96%, 94%, 93% y 97%, respectivamente. La PET/TC identificó 8 casos de embolismos sépticos en los pacientes con infección (4 embolias pulmonares, 2 esplénicas y 2 vertebrales) y 3 casos de cáncer colo-rectal en estadios iniciales . La PET/TC fue capaz de reclasificar 63/70 casos (90%) inicialmente clasificados como posibles EI por los criterios de Duke modificados. En el segundo artículo se estudiaron a 26 pacientes con sospecha clínica de espondilodiscitis. Se realizaron estudios PET/TC y RM de columna a todos los pacientes, y se compararon sus resultados. El diagnóstico de espondilodiscitis se confirmo en 18/26 pacientes. Los valores de sensibilidad, especificidad, VPP, y VPN para la PET/TC fueron de 83%, 88%, 94% y 70 %. La RM obtuvo valores del 94%, 38%, 77% y 75%, respectivamente. Se encontraron diferencias estadísticamente significativas en lo valores de media del SUVmax entre los pacientes infectados y no infectados (6,52 y 3,67, respectivamente; p= 0,0013). La combinación de la PET/TC y la RM identificó correctamente la infección en el 100% de los pacientes con espondilodiscitis. La baja especificidad de la RM en el estudio (38%), se debió al numero de falsos positivos (5/8), dado principalmente a la dificultad que presenta la RM de diferenciar infección en aquellos pacientes con antecedentes de fracturas vertebrales previas y enfermedades degenerativas severas de la columna. De acuerdo a la experiencia y a los resultados de nuestras series, consideramos que la PET/TC debe incluirse en el algoritmo diagnóstico de EI, tanto en la sospecha de infección de las VP como de los DEC, reduciendo la tasa de pacientes mal diagnosticados. También consideramos que la técnica debe ser de elección en la detección de complicaciones sistémicas, tales como ESH y neoplasias insospechadas, influenciando de forma sustancial el manejo y el pronóstico de los pacientes. Pese a que la técnica no demuestra ser útil en el diagnóstico de EI-VN, en este grupo de pacientes mejora significativamente la detección del origen de la infección. Los resultados de nuestra serie indican que la PET/TC es una técnica complementaria a la RM en el diagnóstico de espondilodiscitis infecciosa., [eng] Cardiovascular infections are devastating diseases with high risk of mortality. Moreover, early diagnosis and detection of posible complications such as hematogenous septic embolism (HSE) remain a challenge in clinical practice. Diagnosis is based on the yielding of blood cultures and echocardiographic findings. However, they have limitations and sometimes the diagnosis is inconclusive, particularly in patients with prosthetic valves (PV) and implantable cardiac electronic devices (ICED) We conducted propective studies on two groups of patients: In the first article we included 80 patients with suspected native valve (NV) infective endocarditis (IE) (n:21), PV-IE (n:29), and ICED-related infection (n:30). For the total group, sensitivity, specificity, PPV, and NPV of 82%, 96%, 94%, and 87%, respectively, were reported. In the subgroup of patients with intracardiac prosthetic material, these numbers were 96%, 94%, 93%, and 97%, respectively. PET/CT was able to reclassify 90% of the patients initially classified as possible IE according to the modified Duke criteria (63/70). Aditionally, PET/CT identified 26% of (HSE) and 10% of malignant foci. In the second article we included 26 patients with suspicion of spondylodiscitis. Whole- body PET/CT and an MRI scan of the spine were performed in all patients. Spondylodiscitis was confirmed in 18/26 patients. The sensitivity, specificity,PPV and NPV were 83 %, 88 %, 94 % and 70 % for PET/CT, and 94 %, 38 %, 77 % and 75 % for MRI, respectively. The combination of 18F-FDG PET/CT and MRI detected the infection in 100 % of the patients. According to our results, we consider that PET/CT should be included in the diagnostic workup of patients suspected of having IE or ICED-related infection. Aditionally, PET/CT must be of choice in the detection of HSE, mainly in spondylodiscitis.

Tuberculosis; Positron emission tomography (PET); FDG Tuberculosis; Tomografía por emisión de positrones (PET); FDG Tuberculosi; Tomografia per emissió de positrons (PET); FDG BACKGROUND: The aim of our study is to describe the FDG-PET/CT findings in patients with tuberculosis and to correlate them with the patient's prognosis. METHODS: We retrospectively collected data from patients with tuberculosis, who had an FDG-PET/CT performed prior to treatment initiation from 2010 to 2015. RESULTS: Forty-seven out of 504 patients with active tuberculosis diagnosis (9.33%) underwent an FDG-PET/CT. The reasons for performing the FDG-PET/CT were: characterization of a pulmonary nodule (24; 51.1%), study of fever of unknown origin (12; 25.5%), study of lymph node enlargement (5; 10.6%) and others (6; 12.8%). Median age was 64 (IQR 50-74) years and 31 (66%) patients were male. Twenty-six (55.3%) patients had an immunosuppressant condition. According to the FDG-PET/CT, 48.6% of the patients had more than 1 organ affected and 46.8% had lymph node involvement. Median SUVmax of the main lesion was 5 (IQR 0.28-11.85). We found an association between the FDG accumulation and the size of the main lesion with a correlation coefficient of 0.54 (p

[F-18]-AV-1451 es un nuevo trazador para la detección de patología tau en vida del sujeto mediante tomografía por emisión de positrones (PET). [F-18]-AV-1451 fue originalmente creado para detectar tau en forma de filamentos de hélices pareadas (PHF) que conforman los ovillos neurofibrilares (ONF), una de las lesiones características de la Enfermedad de Alzheimer (EA). Pacientes con EA tienen una mayor captación in vivo de [F-18]-AV-1451 en la neocorteza comparados con ancianos cognitivamente sanos. En este trabajo se investigaron los sustratos neuropatológicos y los patrones regionales de la señal de [F-18]-AV-1451 en tejido cerebral de casos con y sin presencia de tau usando autoradiografía con pantalla de fósforo, autoradiografía con emulsión nuclear, ensayos de unión in vitro y cuantificación bioquímica de tau con SDD-AGE. También se estudiaron tres individuos que fueron evaluados con PET-[F-18]-AV-1451 en vida y al fallecer se sometieron a autopsia. Los resultados sugieren que [F-18]-AV-1451 se une intensamente a agregados formados por tau-PHF, incluyendo ONFs y neuritas distróficas, en los cerebros con EA. [F-18]-AV-1451 no tiene una afinidad significativa por filamentos rectos (FR) de tau en taupatías distintas a la EA ni por β-amiloide, TDP-43 o α-sinucleína. Se identificó una señal fuera de diana en la neuromelanina que podría explicar la captación in vivo hallada en la sustancia negra. Los tres sujetos que fueron evaluados con PET-[F-18]-AV-1451 en vida y al fallecer se les realizó autopsia tenían un diagnóstico clínico de Parálisis Supranuclear Progresiva (n=2) y Demencia frontotemporal portador de la mutación del gen MAPT P301L (n=1). La neuroimagen con PET mostró intensa captación en los ganglios basales y el mesencéfalo, y menor señal en otras regiones frontales y temporales. El examen neuropatológico confirmó el diagnóstico de PSP en dos casos mientras que en el portador de la mutación P301L se evidenciaron pequeños granos tau+ de predominio en los ganglios basales. La autoradiografía no detectó señal significativa de [F-18]-AV-1451 ni unión a las lesiones de tau-FR, con la excepción de señal en la corteza entorrinal (ONFs relacionados con el envejecimiento) y en la sustancia negra. Los análisis de correlación entre la captación regional del trazador in vivo con los ensayos de unión in vitro y el SDD-AGE no mostraron ninguna asociación significativa. En resumen, estos datos de sugieren que [F-18]-AV-1451 se une principalmente a los agregados de tau-PHF en la EA y tiene una afinidad relativamente baja para las lesiones de tau formadas por FR en taupatías distintas a la EA. También se evidenció la señal de [F-18]-AV-1451 en las neuronas con neuromelanina en la sustancia negra, que podría explicar la señal in vivo en el mesencéfalo., [F-18]-AV-1451 is a novel tracer for the in vivo detection of tau pathology using emission positron tomography (PET). [F-18]-AV-1451 was originally raised against paired helical filament (PHF)-tau, which if found in neurofibrillary tangles (NFTs), one of the characteristic lesions in Alzheimer´s disease (AD). AD patients show higher in vivo [F-18]-AV-1451 retention compared to elderly cognitively normal individuals in neocortical regions. In this project we investigated the neuropathological substrate and regional patterns of [F-18]-AV-1451 signal in brain tissue from cases with and without tau, using phosphor screen autoradiography, nuclear emulsion autoradiography, in vitro binding assays and biochemical quantifications of tau with SDD-AGE. We also analyzed three individuals who were evaluated with PET-[F-18]-AV-1451 when alive and came to autopsy. The results suggest that [F-18]-AV-1451 strongly binds to PHF-tau including both NFTs and dystrophic neurites in AD brains. [F-18]-AV-1451 does not have a significant affinity for straight filaments (ST) of tau in non-AD tauopathies, neither for β-amyloid, TDP-43 and α-synuclein. We identified an off-target signal to neuromelanin that could explain the in vivo uptake detected in the substantia nigra. The three subjects who were evaluated with PET-[F-18]-AV-1451 when alive and came to autopsy had a clinical diagnosis of Progressive Supranuclear Palsy (PSP, n=2) and frontotemporal dementia carrier of the MAPT P301L mutation (n=1). PET showed the highest in vivo uptake in the basal ganglia and the midbrain, and milder signal in other frontal and temporal regions. The neuropathological exam confirmed the PSP diagnosis in two cases, and the exam of the carrier of the P301L mutation showed small tau+ grains predominantly in the basal ganglia. Autoradiography failed to detect a significant [F-18]-AV-1451 signal, neither binding to SF-tau lesions. The only exceptions were the entorhinal cortex (age-related NFTs) and the substantia nigra. The correlation analysis between the in vivo tracer uptake with in vitro binding assays and SDD-AGE did not show any significant association. To conclude, these data suggest that [F-18]-AV-1451 mainly binds to tau-PHF aggregates in AD and has a relatively low affinity to SF-tau lesions in non-AD tauopathies. We also detected [F-18]-AV-1451 off-target signal in the neuromelanin-containing neurons of the substantia nigra, which could explain the universal in vivo midbrain uptake.

INTRODUCCIÓN El cáncer de próstata (CaP) es la neoplasia más frecuente en el hombre y la segunda causa de muerte oncológica. La decisión terapéutica está condicionada por la edad/comorbilidad, clasificación d´Amico y TNM. La elevación de PSA tras la terapia radical es muy sensible pero no permite localizar la recidiva. La sensibilidad de TC/RM es limitada en la infiltración adenopática. La especificidad de la gammagrafía es baja en las metástasis óseas. OBJETIVOS Evaluar si es factible la realización de un estudio “doble fase” 11C-Colina PET/TC. Evaluar la utilidad del 11C-Colina PET/TC en: -la detección de la diseminación linfática o hematógena en pacientes afectos de CaP de riesgo medio/alto. - la tasa de detección de la recurrencia bioquímica del CaP tras la terapia radical. METODOLOGÍA Este estudio comprende los 1016 estudios 11C-Colina PET/TC (junio´2006-octubre´2014). El motivo de la exploración fue recidiva bioquímica (73,2%), estadificación inicial (19,2%) y respuesta terapéutica (7,6%). La 11C-Colina se ha producido en el ciclotrón situado en la misma instalación. La dosis del trazador (296±185 MBq) se ha administrado con el paciente intracámara iniciando la adquisición inmediatamente después. Tras la realización de la TC se han efectuado dos adquisiciones PET de cuerpo completo consecutivas, sin movilización del paciente (ambos estudios PET se reconstruyeron con la TC inicial). Se han valorado las imágenes precoces y tardías, visualmente y calculando el SUVmáximo, considerado dos comportamientos dinámicos: Estable/aumento o descenso. Los hallazgos de la 11C-Colina PET/TC se compararon con otras técnicas de imagen y/o monitorización del PSA. Por cuestiones éticas únicamente las lesiones que suponían un cambio en la estadificación han sido confirmadas histológicamente. RESULTADOS “Doble fase” 11C-Colina PET/TC. Identificamos 106 focos hipermetabólicos: 34 local, 10 inguinal, 34 infradiafragmaticos, 14 supradiafragmaticos, 14 óseos, En el análisis ROC, SUVvariación discriminó mejor entre las lesiones benignas y malignas (área:0,993) seguido por SUVtardío (0,933) y finalmente SUVprecoz (0,665). Extensión inicial El 24,6% de los pacientes presentaron enfermedad extra-prostática. 40% multifocal. 60% en una sola localización: 66.7% infradiafragmáticas; 11,1% supradiafragmática; 22,2% metástasis óseas. Para manejo terapéutico fueron categorizados como: 40% enfermedad loco-regional, 33,3% oligo-metastásica, 16,7% multi-metastásica. A los pacientes con enfermedad loco-regional y oligo-metastásica (73,3%) se les realizo radioterapia de intensidad modulada según los depósitos de 11C-Colina. Recidiva bioquímica El 67% de los pacientes mostraron uno o más depósitos de 11C-Colina: 30% recurrencia local, 16% infradiafragmática, 14% supradiafragmática, 7% ósea. La relación entre el PSA y la tasa de detección de la recurrencia fue: 40% PSA4ng/ml. Comparamos la 11C-Colina PET/TC con la 18F-FDG PET/TC, la RM multiparamétrica pélvica y la gammagrafía ósea: El 41% de los pacientes mostraron uno o más depósitos de 18F-FDG: 14% recurrencia local, 9% infradiafragmática, 11% supradiafragmática, 7% ósea. En el 29% de los pacientes la RM y la 11C-Colina PET/TC fueron discordantes: 50% sólo RM positive por recurrencia local (, OBJECTIVES Feasibility of “Dual Phase” 11Cho-PET. Usefulness of 11Cho-PET in detecting lymphatic/haematogenous involvement in intermediate/high-risk PCa, Diagnostic performance in detection rate of biochemical recurrence. METHODOLOGY 1016 PCa who underwent 11Cho-PET (June/2006-october/2014) for biochemical recurrence (73.2%) initial staging (19.2%) and treatment response (7.6%). 11C-Choline was synthesized in onsite-cyclotron. 296±185MBq was administered with patient placed in PET-camera. Acquisition was immediately started: after CT, two whole-body PET were acquired without moving patient (Both-PETs reconstructed with initial-CT). Early/Delayed images were visually and SUVmax evaluated. Two dynamic patterns: stable/increasing and decreasing. 11Cho-PET were compared with imaging techniques and/or monitoring-PSA. Due to ethical reasons, only lesions that would change staging were histologically confirmed. RESULTS “Dual Phase”-11Cho-PET. We identified 106 hypermetabolic foci: 34 local, 10 inguinal, 34 infradiaphragmatic, 14 supradiaphragmatic, 14 bone. On the ROC analysis, SUVvariation best discriminated benign from malignant lesions (area:0,993) followed by SUVdelay (0,933) and finally SUVearly (0,665). Initial staging Extraprostatic disease was found in 24.6%: 40% Multifocal disease and 60% Single site: 66.7% infradiaphragmatic; 11.1% supradiaphragmatic; 22.2% bone metastases. For treatment purposes, patients were classified as: 40% locoregional disease; 33.3% oligometastasic; 16.7% multimetastasic. Locoregional/oligometastatic patients (73.3%) underwent intensity-modulated-radiation-therapy based on 11C-Choline uptake. Biochemical recurrence In 67% of patients, 11C-Choline foci were found: 30% Local recurrenc, 16% infradiaphragmatic, 14% supradiaphragmatic, 7% bone metastases. Relationship between PSA and rate of detection was: 40% PSA4ng/ml. Compared 11Cho-PET with 18F-FDG PET/CT, multiparametric pelvic MRI and BS: In 41% of patients, one or more 18F-FDG foci were found: 14% Local recurrence, 9% infradiaphragmatic, 11% supradiaphragmatic, 7% bone metastases. In 29% MRI and 11Cho-PET were discordant: 50% only MRI local recurrence positive (

Treballs Finals de Grau de Física, Facultat de Física, Universitat de Barcelona, Any: 2015, Tutor: Domènec Ros, The surgical removal of the epileptogenic region is considered as a possible treatent in intractable partial epilepsy. To guarantee surgery to be successful, an accurate localization of epileptogenic focus is crucial. A new proposal for its location is described and discussed. Six patients were used in the evaluation and the results were compared with other techniques routinely used for this purpose. All the processed studies showed a good agreement. As a result, it is seen great promise in this new methodology and further evaluation makes sense.

La cirugía de la epilepsia es una alternativa terapéutica en pacientes con epilepsia focal refractaria a los fármacos antiepilépticos, y para su correcta realización es indispensable localizar de forma precisa la zona cerebral responsable de las crisis epilépticas (Zona Epileptógena, ZE). La Tomografía por emisión de positrones (PET) es una técnica de neuroimagen funcional que puede aportar información diagnóstica y localizadora en los casos en que la Resonancia magnética (RM) cerebral y los registros vídeo-electroencefalográficos (EEG) no son capaces de localizar o caracterizar la ZE. El presente trabajo pretende evaluar la utilidad clínica de la PET en la localización de la ZE en casos de epilepsias sin lesión aparente por RM (epilepsia no lesional) y en casos de múltiples lesiones por RM (epilepsia asociada a esclerosis tuberosa, ET), así como en la caracterización de tumores cerebrales epileptógenos cuyo correcto diagnóstico diferencial tiene implicaciones en la planificación quirúrgica. En el caso de la epilepsia no lesional, se han estudiado 31 pacientes pediátricos mediante PET con el radiofármaco 2-[18F]fluoro-2-desoxi-D-glucosa (18F-FDG), la cual es capaz de mostrar áreas hipometabólicas corticales relacionadas con la ZE. Se estudió además el valor añadido de la fusión de imágenes PET con la RM del mismo paciente (PET/RM). Tanto la PET-FDG como la fusión PET/RM detectaron algún área hipometabólica en el 68% de pacientes. En el 58% de los pacientes el hipometabolismo tuvo algún grado de co-localización con la ZE según los hallazgos por vídeo-EEG. Se demostró además que las imágenes de fusión PET/RM son capaces de guiar una re-inspección dirigida de las RM previamente consideradas normales, poniendo de manifiesto pequeñas displasias corticales inicialmente no detectadas en 9 pacientes. En el caso de la epilepsia en pacientes con ET, una enfermedad que cursa con múltiples tumores hamartomatosos o túbers en el cerebro, se analizaron 12 pacientes mediante PET con alfa-[11C]metil-L-triptófano (11C-AMT). Trabajos previos han sugerido que un aumento de captación de 11C-AMT en un túber cortical en concreto lo identifica como la lesión responsable de las crisis epilépticas. En nuestro estudio, se detectaron 2 túbers intensamente hipercaptantes en 2 pacientes, y otros túbers con hipercaptación discreta en 4 pacientes. Solamente los túbers con hipercaptación intensa mostraron ser epileptogénicos según los registros EEG. En un análisis por lesiones (126 túbers en los 12 pacientes), la PET-AMT mostró una sensibilidad del 12% y una especificidad del 100% en la detección del túber epileptógeno. En el caso de los tumores epileptógenos, se revisaron 52 pacientes operados por tumores de lento crecimiento (21 gliomas, 10 gangliogliomas y 21 tumores disembrioplásticos neuroepiteliales o DNET) a los que se les había realizado una PET con [11C]metil-L-metionina (11C-MET), un radiotrazador habitualmente utilizado en neurooncología. Todos los gliomas y gangliogliomas mostraron hipercaptación moderada o intensa en la PET-MET, mientras que solamente los DNET mostraron un nivel de captación normal de 11C-MET (en 9 de los 21 DNETs). Un análisis semicuantitativo de las imágenes PET-MET mostró una sensibilidad de 89% y una especificidad de 90% para la discriminación de los DNET frente a otros tipos tumorales. En conclusión, la PET con diferentes radiotrazadores es una técnica útil en la valoración prequirúrgica de pacientes con epilepsia refractaria en diferentes situaciones clínicas: -La PET-FDG detecta áreas hipometabólicas relacionadas con la ZE en una proporción significativa de pacientes, y la fusión PET/RM es capaz de revelar pequeñas lesiones previamente no detectadas. -La PET-AMT es una técnica poco sensible pero altamente específica en la detección del túber responsable de las crisis en pacientes epilépticos con ET. -La detección de una captación normal por PET-MET en tumores epileptógenos de lento crecimiento es muy sugestiva de una histología de DNET., Epilepsy surgery is an alternative approach in patients with medically-resistant focal epilepsy, and its goal is the removal of the cortical region causing the seizures, i.e., the epileptogenic zone (EZ). Positron Emission Tomography (PET) is a functional neuroimaging technique which can contribute to the presurgical detection and characterization of the EZ. The aim of this study was to evaluate the clinical utility of PET in the presurgical evaluation of epilepsy in different clinical settings: (1) patients with no detectable lesion by Magnetic Resonance Imaging (non-lesional MRI), (2) patients with tuberous-sclerosis (TS) related epilepsy and multiple brain lesions, and (3) patients with epileptogenic tumors. All patients had received at least one MRI scan and scalp video-electroencephalographic (EEG) recordings as part of their presurgical work-up. The non-lesional cohort comprised 31 pediatric patients who underwent PET with 2­[18F]fluoro-2-deoxy-D-glucose radiotracer (18F-FDG). PET-FDG images detected hypometabolic cortical areas in 21/31 (68%) patients, and this hypometabolism showed some degree of concordance with the EZ defined by video-EEG in 18 patients. Through the spatial coregistration of PET with the MRI of the same patient, a second interpretation of MRI studies was carried out focusing on the exact anatomic region in which the hypometabolism was located. This analysis led to the detection of previously missed focal cortical dysplasias in 9 cases. The TS-related epilepsy cohort comprised 12 patients with multiple cortical hamartomas or “tubers”, who underwent PET with alpha-[11C]methyl-L-tryptophan (11C-AMT), a radiotracer whose uptake is supposed to be selectively increased in the tuber responsible of the seizures. Two of 12 patients demonstrated a tuber with clearly increased 11C-AMT uptake, and tubers with mild increased uptake were also detected in 4 patients. Only those two tubers with clearly increased 11C-AMT uptake proved to be epileptogenic on intracerebral EEG recordings, thus yielding a PET-AMT per-lesion sensitivity of 12% and specificity of 100%. Finally, we reviewed 52 patients with epileptogenic tumors (21 gliomas, 10 gangliogliomas and 21 dysembryoplastic-neuroepithelial-tumors or DNT) which had undergone a PET with [11C]methyl-L-methionine (11C-MET) prior to surgical resection. All gliomas and gangliogliomas were associated with increased 11C-MET uptake, whereas 9/21 DNTs had normal 11C-MET uptake. Semiquantitative PET ratios showed a cutoff threshold that distinguished DNTs from other tumor types with 90% specificity and 89% sensitivity. In conclusion, PET with the evaluated radiotracers is a useful neuroimaging tool in the presurgical work-up of patients with refractory epilepsy, as it significantly contributes to the localization and characterization of the EZ.

[cat] L’objectiu d’aquesta tesi és presentar una solució per a la lectura de matrius de fotomultiplicadors de silici (SiPM) millorant les característiques de sistemes actuals. Amb aquesta finalitat s’ha dissenyat i provat el circuit d’una nova etapa d’entrada. En primer lloc s’ha dissenyat pensant en aplicacions genèriques i per a imatge mèdica, concretament per a escàners PET (Positron Emission Tomography). Però més endavant s’aplica la mateixa topologia per a una aplicació més concreta i específica com és un detector de partícules (l’actualització del Tracker a l’experiment LHCb). Els SiPM són uns dispositius electrònics relativament nous amb la possibilitat de comptar fotons i millorant algunes característiques dels sensors actuals, com serien la tensió d’operació més baixa, més guany o immunitat a camps magn`etics, mentre manté unes prestacions excel•lents respecte el guany, resolució temporal i rang dinàmic. Aquest tipus de dispositius es troben en constant evolució encara i una gran varietat de fabricants intenten millorar les prestacions, sobretot respecte la eficiència en la detecció de llum, reduir el corrent d’obscuritat, construir matrius més grans i augmentar l’espectre al qual són sensibles. En aquest document es presenta el disseny d’un circuit integrat específic amb les següents característiques: gran rang dinàmic, alta velocitat, multicanal, amb entrada en corrent i baixa impedància d’entrada, baix consum, control de la tensió de polarització del SiPM i amb les sortides de; temps, càrrega i apilament., [eng] The aim of this thesis is to present a solution for the readout of Silicon Photo-Multipliers (SiPMs) arrays improving currently implemented systems. Using as a starting point previous designs with similar objectives a novel current mode input stage has been designed and tested. To start with the design a valid model has been used to generate realistic output from the SiPMs depending on light input. Design has been performed in first place focusing in general applications for medical imaging Positron Emission Tomography (PET) and then using the same topology for a more constrained design in particle detectors (upgrade of Tracker detector at LHCb experiment). A 16 channel ASIC for PET applications including the novel input stage has demonstrated an excellent timing measurement with good energy resolution measurement and pile-up detection. This document starts with the analysis of the requirements needed to fit such a system, followed by a detailed description of the input stage and analog processing. Signal is divided in the input stage into three different signal paths: timing, energy and pileup. Every channel performs different signal analysis to deliver; a fast time signal output (digital edge), energy output (a linear time over threshold digital output) and a digital bit to signal pile-up. The time information is then ORed between all channels to generate a single timing output. All the pile-up bits are combined in a digital word ready to be readout for the 16 channels. Design has been optimized for reduced power consumption and no components needed to interface inputs and outputs. Digital slow control to tune the circuit behaviour is also included. The prototype measurements have proved to be a valid option for integration in a full system scanner. An adapted prototype of the input stage using different technology and adapted to the different constraints from a particle detector is also presented. Only simulation results are available since device is still under production. An analysis of the different requirements needed by the SciFi tracker design is summarized. Current specifications are still evolving since final sensor is still not defined, but other requirements and some tunable elements permits to design such prototypes.

Treballs Finals de Grau d'Enginyeria Informàtica, Facultat de Matemàtiques, Universitat de Barcelona, Any: 2014, Director: Anna Puig Puig i Frederic Sampedro Santaló, Visual analysis of medical volume datasets performed by medical experts provides valuable information in research and clinical settings such as radiology or nuclear medicine. Computer visualization methods seek to present to the user an informative display of a given dataset, trying to minimize both the computation time and the user interaction. The goal of this project is to analyze, design and implement a volume visualitzation system that proposes a new method to improve the visualitzation of segmented volume datasets. In this scenario, two common volume visualization methods included in commercial medical software are the Direct Volume Rendering (DVR), and the Maximum Intensity Projection (MIP). DVR allows to have a spatial context and MIP is an easy-­to­implement method. Both methods display good visualitzations but have several drawbacks. This project develops a new method called Maximum Intensity Difference Accumulation (MIDA) that exploits the data characteristics to generate good visualitzation results. The basic idea behind the MIDA approach is combining the advantatges of DVR and MIP and therefore provide an improved visualization framework with reduced limitations. Also, in this project an adaptation of the MIDA framework is proposed to visualize the volume in conjuntion with any segmentation mask of it. MIDA is a general method that can be applied to several types of volume datasets. In particular, this project focuses on the application of the proposed method in Positron Emission Tomography (PET) volumes obtained from the Nuclear Medicine Department at the H. Sant Pau. PET is a commonly used nuclear medicine diagnosis test to detect and quantify the presence of any tumor volume within a patient’s body, where physicians may also provide tumor segmentation masks. Visualization of segmented PET scans using our proposed MIDA­based system provided superior visual results with respect to DVR and MIDA approaches. A GPU implementation provides substancial runtime improvement with respect to a CPU approach, obtaining the real­time visualization needed in the clinical setting.

Molecular imaging receives increased attention for selecting patients who will benefit from targeted anticancer therapies. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) enrolled 455 women with invasive human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared rates of pathologic complete response (pCR) to neoadjuvant lapatinib, trastuzumab, and their combination. Each anti-HER2 therapy was given alone for 6 wk, followed by 12 wk of the same therapy plus weekly paclitaxel. The early metabolic effects of the anti-HER2 therapies on the primary tumors and their predictive values for pCR were assessed in a subset of patients. Methods: eighty-six patients underwent (18)F-FDG PET/CT at baseline and weeks 2 and 6 of anti-HER2 treatment. An imaging core laboratory provided central validation, and 2 independent reviewers, masked to assigned treatment arm and clinical outcomes, performed consensus (18)F-FDG PET/CT readings. Maximum standardized uptake value (SUVmax) reductions from baseline were used to measure metabolic response. Results: seventy-seven of the 86 enrolled patients presented an evaluable baseline (18)F-FDG PET/CT scan; of these, 68 and 66 were evaluable at weeks 2 and 6, respectively. Metabolic responses in the primary tumors were evident after 2 wk of targeted therapy and correlated highly with metabolic responses at week 6 (R(2) = 0.81). pCRs were associated with greater SUVmax reductions at both time points. Mean SUVmax reductions for pCR and non-pCR, respectively, were 54.3% versus 32.8% at week 2 (P = 0.02) and 61.5% versus 34.1% at week 6 (P = 0.02). (18)F-FDG PET/CT metabolic response rates at weeks 2 and 6 were 71.6% and 60%, respectively using European Organization for Research and Treatment of Cancer criteria; pCR rates were twice as high for (18)F-FDG PET/CT responders than nonresponders (week 2: 42% vs. 21%, P = 0.12; week 6: 44% vs. 19%, P = 0.05). Conclusion: early metabolic assessment using (18)F-FDG PET/CT can identify patients with an increased likelihood of pCR after neoadjuvant trastuzumab, lapatinib, or their combination when given with chemotherapy.

The Voxel Imaging PET (VIP) Path nder project got the 4 year European Research Council FP7 grant in 2010 to prove the feasibility of using CdTe detectors in a novel conceptual design of PET scanner. The work presented in this thesis is a part of the VIP project and consists of, on the one hand, the characterization of a CdTe detector in terms of energy resolution and coincidence time resolution and, on the other hand, the simulation of the setup with the single detector in order to extend the results to the full PET scanner. An energy resolution of 0.98% at 511 keV with a bias voltage of 1000 V/mm has been measured at low temperature T=-8 ºC. The coincidence time distribution of two twin detectors has been found to be as low as 6 ns FWHM for events with energies above 500 keV under the same temperature and bias conditions. The measured energy and time resolution values are compatible with similar ndings available in the literature and prove the excellent potential of CdTe for PET applications. This results have been presented in form of a poster contribution at the IEEE NSS/MIC & RTSD 2011 conference in October 2011 in Valencia and at the iWoRID 2012 conference in July 2012 in Coimbra, Portugal. They have been also submitted for publication to "Journal of Instrumentation (JINST)" in September 2012.

La presente entrega de la serie de Nursing sobre las pruebas complementarias está dedicada a la tomografía por emisión de positrones o PET, acrónimo de positron emission tomography. La PET es una técnica de diagnóstico por la imagen de medicina nuclear en la cual se administra al paciente un radiofármaco emisor de positrones. Este radiofármaco se incorpora a los tejidos adecuados siguiendo una vía metabólica determinada. La radiactividad emitida por esos tejidos del paciente es detectable por los equipos PET y se obtienen imágenes que proporcionan una información funcional in vivo. El radiofármaco PET más habitual es un análogo de la glucosa que se llama F-18-fluordesoxiglucosa, conocido como FDG, el cual permite estudiar la actividad metabólica. La incorporación de la tomografía computarizada (TC) en el mismo equipo híbrido PET-TC permite obtener además la información anatómica del paciente. En el presente artículo se describen los fundamentos físicos y fisiológicos básicos de las exploraciones PET-TC con FDG en oncología, así como los procedimientos de enfermería necesarios para el cuidado del paciente y la correcta obtención de las imágenes.

Positron emission tomography (PET) is a functional imaging method that allows studying physiological, biochemical or pharmacological processes in vivo. PET is being used in both research and clinical practice. In the brain, it has been used to investigate metabolism, receptor binding, and alterations in regional blood flow. This thesis involves both preclinical and clinical dual-tracer PET imaging studies of different neurological disorders. In this way, different radiotracers were used along the projects. The first project focused on the implementation and in vivo validation of the simultaneous dual-tracer PET imaging technique on the rat brain and its applications in the study of cerebral ischemia. In particular, in this project two biological processes were studied at the same time: cerebral blood flow and cerebral glucose metabolism. The second project consisted in a clinical correlation study of the GABAergic and serotonin systems in a population with Essential Tremor (ET), the most commonly movement disorders., La tomografia per emissió de positrons (PET) és un mètode d'imatge funcional que permet l'estudi in vivo de processos fisiològics, bioquímics i farmacològics. La PET s'utilitza tant en la pràctica clínica com en la recerca. Al cervell, s'ha utilitzat per investigar el metabolisme, la neurotransmissió, i les alteracions en el flux sanguini regional. Aquesta tesi implica estudis preclínics i clínics de la tècnica PET en diversos trastorns neurològics. D'aquesta manera, es van utilitzar diferents radiotraçadors al llarg dels projectes. El primer projecte es va centrar en la implementació i validació in vivo de la tècnica PET del doble-marcador simultani en el cervell de rata i les seves aplicacions en l'estudi de la isquèmia cerebral. En particular, en aquest projecte es van estudiar en el mateix moment dos processos biològics: el flux sanguini cerebral i el metabolisme cerebral de la glucosa. El segon projecte va consistir en un estudi clínic de correlació dels sistemes GABAèrgic i serotoninèrgic en una població amb tremolor essencial (TE), el trastorn del moviment més comú

Tomografia per emissió de positrons; Diagnòstic per la imatge Tomografía por emisión de positrones; Diagnóstico por la imagen Positron emission tomography; Diagnostic Imaging La tomografia per emissió de positrons (PET) és una tècnica de diagnòstic per la imatge, no invasiva, que permet obtenir informació completa sobre el metabolisme cel·lular mitjançant l'administració de radiofàrmacs. Les indicacions més freqüents de la PET fan referència a les especialitat d’oncologia, neurologia i cardiologia. L'any 2002 el Servei Català de la Salut-CatSalut va incorporar la PET a la cartera de serveis amb un sistema de pagament transitori fins a l'any 2006, que finalment va ser considerada com a producte intermedi. En aquests darrers anys la demanda d’exploracions s’ha incrementat de forma important. A petició del Programa per al desenvolupament del diagnòstic per la imatge, creat pel Departament de Salut, l’Agència d’Informació, Avaluació i Qualitat en Salut (AIAQS) ha prioritzat les indicacions de les exploracions de PET o PET/TC (PET i tomografia computada) en oncologia, cardiologia i neurologia generades en el sector públic a Catalunya d’acord amb la validesa diagnòstica i l’impacte en el maneig clínic del malalt. La tomografía por emisión de positrones (PET) es una técnica de diagnóstico por la imagen, no invasiva, que permite obtener información completa sobre el metabolismo celular mediante la administración de radiofármacos. Las indicaciones más frecuentes de la PET hacen referencia a las especialidades de oncología, neurología y cardiología. En el año 2002 el Servicio Catalán de la Salud-CatSalut incorporó la PET a la cartera de servicios con un sistema de pago transitorio hasta el año 2006, que finalmente fue considerada como producto intermedio. En estos últimos años la demanda de exploraciones se ha incrementado de forma importante. A petición del Programa para el desarrollo del diagnóstico por la imagen, creado por el Departamento de Salud, la Agencia de Información, Evaluación y Calidad en Salud de Cataluña (AIAQS) ha priorizado las indicaciones de las exploraciones de PET o PET/TC (PET y tomografía computarizada) en oncología, cardiología y neurología generadas en el sector público en Cataluña de acuerdo con la validez diagnóstica y el impacto en el manejo clínico del enfermo.

La tomografia per emissió de positrons amb 18fluorodesoxiglucosa (PET-FDG) s'ha implantat com a tècnica d'estudi i estadificació d'elecció als pacients amb diagnòstic de carcinoma pulmonar no microcrític (CPNM) susceptibles de tractament quirúrgic. Mètodes: Per valorar l'eficàcia de la PET FDG realitzem un estudi retrospectiu incloent els pacients intervinguts al nostre centre entre setembre del 2007 i abril del 2009. Resultats: La PET-FDG va mostrar una sensibilitat i especificitat de 56% i 75% respectivament. Conclusions: El rendiment diagnòstic de la PET-FDG a la població estudiada ha estat baix. Aquest resultat pot estar condicionat per una mostra poc representativa. La tomografía por emisión de positrones con 18fluorodesoxiglucosa (PET-FDG) se ha implantado como técnica deestudio y estadificación de elección en los pacientes con diagnóstico de carcinoma pulmonar no microcítico (CPNM) susceptibles de tratamiento quirúrgico. Métodos: Para valorar la eficacia de la PET FDG realizamos un estudio retrospectivo incluyendo los pacientes intervenidos en nuestro centro entre septiembre del 2007 y abril del 2009. Resultados: La PET-FDG mostró una sensibilidad y especificidad de56% y 75% respectivamente. Conclusiones: El rendimiento diagnóstico de la PET-FDG en la población estudiada ha sido bajo. Este resultado puede estar condicionado por una muestra poco representativa.

Localization of sentinel lymph nodes can be challenging if they are in difficult anatomic locations or near high radiotracer activity. The purpose of this study was to assess the value of intraoperative real-time imaging using a portable gamma-camera in conjunction with a conventional gamma-counting probe when it is difficult to localize the sentinel node.After (99m)Tc-nanocolloid injection, patients with various malignancies underwent presurgical lymphoscintigraphy followed by surgery (usually the next day). We evaluated 20 patients who required sentinel lymph node biopsy and in whom the location or other characteristics of the sentinel node would make intraoperative retrieval difficult. During surgery, the sentinel node was localized using a portable gamma-camera together with a hand-held gamma-probe. A (153)Gd pointer or (125)I seed was used to better depict the sentinel node location in real time.Using only a conventional hand-held gamma-probe, surgeons were able to definitively localize the sentinel node in 15 of 20 patients. Intraoperatively, the portable gamma-camera showed uptake by the definite sentinel node in 19 of 20 patients and helped to precisely localize the node with the hand-held gamma-probe in 4 patients. In 1 of these patients, the sentinel node was metastatic.The combination of a standard hand-held gamma-probe and real-time imaging provided by a portable gamma-camera offers a high intraoperative detection rate in patients with difficult sentinel node localization as assessed by presurgical lymphoscintigraphy.

We propose and compare different registration approaches to align small-animal PET studies and a procedure to validate the results by means of objective registration consistency measurements. Procedures: We have applied a registration algorithm based on information theory, using different approaches to mask the reference image. The registration consistency allows for the detection of incorrect registrations. This methodology has been evaluated on a test dataset(FDG-PET rat brain images). Results: The results show that a multiresolution two-step registration approach based on the use of the whole image at the low resolution step, while masking the brain at the high resolution step, provides the best robustness (87.5% registration success) and highest accuracy (0.67-mm average). Conclusions: The major advantages of our approach are minimal user interaction and automatic assessment of the registration error, avoiding visual inspection of the results, thus facilitating the accurate, objective, and rapid analysis of large groups of rodent PET images This work was supported by projects CIBER CB06/01/0079 (Ministerio de Sanidad y Consumo) and CDTEAM (CENIT program, Ministerio de Industria). Further support came from NIAAA Intramural Research Program (AA 11034 and AA07574, AA07611) and the US Department of Energy (DE-AC02-98CH10886) Publicado

En el contexto de la técnica de SPECT, la simulación Monte Carlo es una herramienta que permite profundizar en el fundamento físico de la formación de la imagen, evaluando diversos aspectos que serían muy difíciles de medir experimentalmente. Monte Carlo es un método estadístico que parte del seguimiento de partículas, generadas aleatoriamente, en una distribución tridimensional. Este seguimiento se hace incluyendo toda la física implicada, modelizada con unas funciones de probabilidad para las diferentes interacciones posibles. Este método se utiliza en diversas especialidades relacionadas con la interacción radiación ionizante-materia como son la medicina nuclear, radioterapia, dosimetría y protección radiológica.Esta herramienta se empleará en dos aplicaciones: 1) Cuantificación de estudios de SPECT de neurotransmisión y 2) Localización del foco epileptógeno en el contexto de la epilepsia farmacorresistente.A) Cuantificación de estudios de SPECT de neurotransmisión:El estudio de los sistemas de neurotransmisión cerebral tiene una gran importancia en el diagnóstico de enfermedades neurológicas y psiquiátricas. En concreto, la disfunción del sistema dopaminérgico presináptico está relacionado con la Enfermedad de Parkinson. La valoración visual es a menudo suficiente para valorar las imágenes del transportador de dopamina (DAT), pero una cuantificación de las imágenes permitiría hacerla menos dependiente del observador. Los valores cuantitativos están afectados por la degradación de las imágenes debido a los efectos asociados a la interacción radiación-materia, a los efectos relacionados con la respuesta del sistema colimador/detector y al efecto de volumen parcial. Para alcanzar la cuantificación exacta de estas imágenes es necesario desarrollar algoritmos de reconstrucción y métodos de corrección de cada uno de los efectos degradantes que afectan a la técnica de SPECT. Para evaluar la fiabilidad y la exactitud de los algoritmos de reconstrucción y de los métodos de cuantificación se puede hacer uso de las técnicas de simulación Monte Carlo. Por medio de la simulación de maniquíes numérico se puede evaluar la exactitud de un método de cuantificación comparando los valores teóricos (del maniquí) con los valores calculados (en la imagen reconstruida).B) Localización del foco epileptógeno:Las crisis epilépticas parciales se caracterizan por presentar un origen focal y porque tienen una elevada farmacorresistencia, por lo que se plantea la búsqueda de otras alternativas terapéuticas. Una posibilidad es el tratamiento quirúrgico extrayendo el foco sin que se produzcan déficits neurológicos significativos. Por este motivo la detección y correcta localización del foco es fundamental para valorara la posibilidad de cirugía en estos pacientes. El método SISCOM permite localizar el foco mediante el registro de dos estudios de SPECT (ictal e interictal) para detectar los cambios de perfusión y esta información funcional registrarla con la imagen de resonancia magnética, que aporta el detalle estructural y así permite localización del foco detectado. La evaluación cuantitativa de los algoritmos de registro empleados en la técnica requiere el conocimiento de una transformación geométrica de referencia. Para obtener esta transformación algunos estudios emplean marcadores externos, otros marcos estereotácticos o el cálculo de la transformación geométrica a partir de los resultados de registros intermedios. Una manera de conseguir este gold standard es por medio de la simulación realista de datos de SPECT.

Se describen los principios de la tomografía por emisión de positrones (PET) como procedimiento diagnóstico de reciente introducción en el campo de las Ciencias de la Salud. Las aplicaciones clínicas principales se dan en un grupo concreto de especialidades: la cardiología, neurología, psiquiatría y sobre todo la oncología. La tomografía por emisión de positrones es una técnica de diagnóstico por la imagen no invasiva de uso clínico. Se trata de una excelente herramienta para el estudio de la estadificación y la posible malignización de los tumores de cabeza y cuello, la detección de metástasis y linfoadenopatías no valorables clínicamente, así como para el diagnóstico de recidivas tumorales. El único trazador que tiene aplicación clínica es la fluor-desoxiglucosa-F18 o FDG. La PET detecta la intensa acumulación de FDG que se produce en los tumores malignos, debido al mayor índice glicolítico que tienen las células neoplásicas. Con la introducción de sistemas híbridos que combinan la tomografía computadorizada o la resonancia magnética con la tomografía por emisión de positrones, se está produciendo un importante avance en el diagnóstico y el seguimiento de la patología oncológica de cabeza y cuello. The principles of positron emission tomography (PET), recently introduced as a diagnostic procedure into the health sciences, are described. The principle clinical applications apply to a particular group of specialties: cardiology, neurology, psychiatry, and above all oncology. Positron emission tomography is a non-invasive diagnostic imaging technique with clinical applications. It is an excellent tool for the study of the stage and possible malignancy of tumors of head and neck, the detection of otherwise clinically indeterminate metastases and lymphadenopathies, and likewise for the diagnosis of relapses. The only tracer with any practical clinical application is fluor-desoxyglucosa-F18 (FDG). PET detects the intense accumulation of FDG produced in malignant tumors due to the increased glycolytic rate of the neoplastic cells. With the introduction of hybrid systems that combine computerized tomography or magnetic resonance with positron emission tomography, important advances are being made in the diagnosis and follow-up of oncologic pathology of head and neck.

Se describen los principios de la tomografía por emisión de positrones (PET) como procedimiento diagnóstico de reciente introducción en el campo de las Ciencias de la Salud. Las aplicaciones clínicas principales se dan en un grupo concreto de especialidades: la cardiología, neurología, psiquiatría y sobre todo la oncología. La tomografía por emisión de positrones es una técnica de diagnóstico por la imagen no invasiva de uso clínico. Se trata de una excelente herramienta para el estudio de la estadificación y la posible malignización de los tumores de cabeza y cuello, la detección de metástasis y linfoadenopatías no valorables clínicamente, así como para el diagnóstico de recidivas tumorales. El único trazador que tiene aplicación clínica es la fluor-desoxiglucosa- F18 o FDG. La PET detecta la intensa acumulación de FDG que se produce en los tumores malignos, debido al mayor índice glicolítico que tienen las células neoplásicas. Con la introducción de sistemas híbridos que combinan la tomografía computadorizada o la resonancia magnética con la tomografía por emisión de positrones, se está produciendo un importante avance en el diagnóstico y el seguimiento de la patología oncológica de cabeza y cuello.

Purpose: to retrospectively compare morphologic and metabolic changes in bone metastases in response to systemic therapy in patients with metastatic breast cancer (MBC) with integrated positron emission tomography (PET)/computed tomography (CT). Materials and methods: the institutional review board waived the requirement for informed consent and approved this HIPAA-compliant study. A retrospective analysis was performed with 102 women (mean age, 55 years) with MBC who received systemic treatment. All patients underwent integrated PET/CT before and after treatment. Two reviewers analyzed the images in consensus. Morphologic changes, including morphologic patterns, and lesion attenuation were evaluated. Standardized uptake value (SUV) and total lesion glycolysis (TLG) were analyzed to evaluate metabolic changes. Uni- and multivariate analyses were performed to identify factors that enabled response duration (RD) to be predicted. Results: at baseline, the morphologic patterns of the target lesions were lytic (n = 33), sclerotic (n = 22), mixed (n = 42), and unclassified (n = 5). Progression of sclerotic change after treatment was identified in 49 patients (48%). After treatment, the mean attenuation of the lesion increased, whereas the mean SUV and TLG decreased. Increases in attenuation correlated significantly with decreases in SUV (r = -0.510, P < .001) and TLG (r = -0.491, P < . 001). Univariate analysis revealed that the increase in attenuation and the decrease in SUV were potential predictors of RD. Multivariate analysis revealed that an increase in the change in SUV was a significant predictor of RD (relative risk, 2.4; P = .003). Conclusion: a decrease in SUV after treatment was an independent predictor of RD in patients with MBC who had bone metastases.

The aim of this study was to assess the physical performance of a new PET/CT system, the Discovery IQ with 5-ring detector blocks. Methods: Performance was measured using the National Electrical Manufacturers Association NU2-2012 methodology. Image quality was extended by accounting for different acquisition parameters (lesion-to-background ratios [8:1, 4:1, and 2:1] and acquisition times) and reconstruction algorithms (VUE-point HD [VPHD], VPHD with point-spread-function modeling [VPHD-S], and Q.Clear). Tomographic reconstruction was also assessed using a Jaszczak phantom. Additionally, 30 patient lesions were analyzed to account for differences in lesion volume and SUV quantification between reconstruction algorithms. Results: Spatial resolution ranged from 4.2 mm at 1 cm to 8.5 mm at 20 cm. Sensitivity measured at the center and at 10 cm was 22.8 and 20.4 kps/kBq, respectively. The noise-equivalent counting rate peak was 124 kcps at 9.1 kBq/cm3 The scatter fraction was 36.2%. The accuracy of correction for count losses and randoms was 3.9%. In the image quality test, contrast recovery for VPHD, VPHD-S, and Q.Clear ranged from 18%, 18%, and 13%, respectively (hot contrast; 10-mm sphere diameter; ratio, 2:1), to 68%, 67%, and 81%, respectively (cold contrast; 37-mm sphere diameter; ratio, 8:1). Background variability ranged from 3.4%, 3.0%, and 2.1%, respectively (ratio, 2:1), to 5.5%, 4.8%, and 3.7%, respectively (ratio, 8:1). On Q.Clear reconstruction, the decrease in the penalty term (β) increased the contrast recovery coefficients and background variability. With the Jaszczak phantom, image quality increased overall when a reconstruction algorithm modeling the point-spread function was used, and use of Q.Clear increased the signal-to-noise ratio. Lesions analyzed using VPHD-S and Q.Clear had an SUVmean of 6.5 ± 3 and 7 ± 3, respectively (P < 0.01), and an SUVmax of 11 ± 4.8 and 12 ± 4, respectively (P < 0.01). No significant difference in mean lesion volume was found between algorithms. Conclusion: Among the various Discovery bismuth germanium oxide-based PET/CT scanners, the IQ with 5-ring detector blocks has the highest overall performance, with improved sensitivity and counting rate performance. Q.Clear reconstruction improves the PET image quality, with higher recovery coefficients and lower background variability.