Introdução: O miocárdio não-compactado é uma doença genética rara de fisiopatologia desconhecida e controversa. Vários fatores têm sido implicados na fisiopatologia, como a disfunção da microcirculação, a perda da torção ventricular, distúrbios mitocondriais e mutações. A alteração do metabolismo cardíaco ocorre precocemente a disfunção diastólica e sistólica, reforçando a relevância desse estudo na análise combinada de tomografia de emissão de pósitron (PET) com 18F-Fluor-2-desoxiglicose e cintilografia de perfusão miocárdica com 99mTc-sestamibi pela tomografia por emissão de fóton simples (SPECT) e suas implicações clínicas. Métodos: Trinta pacientes com miocárdio não-compactado (41 ± 12 anos, 53% do sexo masculino), diagnosticados pelos critérios da ressonância magnética cardíaca, e 8 indivíduos saudáveis (42 ± 12 anos, 50% do sexo masculino) foram recrutados prospectivamente para serem submetidos a análise de perfusão miocárdica pelo SPECT e da captação miocárdica de glicose marcada pela PET. Resultados: Os pacientes apresentaram valores de captação de glicose miocárdica (CMG) menor que os controles (36.9 +- 8.8 vs. 44.6 +- 5.4 umol/min/100g, respectivamente, P = 0.02). Analisando a captação nos 17 segmentos de ambos os grupos, a CGM foi significativamente reduzida em 8 segmentos dos pacientes (P < 0,05). A diferença da média da captação miocárdica de glicose de todos os segmentos do grupo controle em relação a média dos segmentos compactados dos pacientes foi de 8,3 ?mol/min/100g (p < 0,001). Déficit de perfusão foi demonstrado em 15 (50%) dos pacientes, correspondendo a 45 segmentos do ventrículo esquerdo, destes 64,4% com padrão match e 35,6% com padrão mismatch pela análise de perfusão e metabolismo cardíaco. Nas análises univariada e multivariada foram observadas que o betabloqueador aumenta a CMG (coeficiente beta = 10.1, P = 0.008), como também ocorre um aumento gradual da CMG naqueles com doses mais elevadas (P para tendência linear = 0.01). Conclusão: A redução da captação miocárdica de glicose suporta a hipótese de que um mecanismo metabólico celular possa ter um papel na fisiopatologia do miocárdio não compactado. O betabloqueador demonstrou um efeito incremental dosedependente na captação miocárdica de glicose nos pacientes com miocárdio não-compactado, essa modulação do substrato cardíaco necessita de mais estudos para comprovação do benefício clínico nessa população / Background: Noncompaction cardiomyopathy (NCC) is a rare genetic disease with unknown and controversial pathophysiology. Several factors have been implicated such as microvascular dysfunction, loss of ventricular torsion, mitochondrial disorders, and genetic mutations. The change in cardiac metabolism occurs before the diastolic and systolic dysfunction, reinforcing the relevance of this study by the combined analysis of positron emission tomography with 18F-Fluor-2-deoxyglucose (PET) and myocardial perfusion scintigraphy with 99mTc-sestamibi by single-photon emission computed tomography (SPECT) and their clinical implications. Methods: Thirty patients (41 ± 12 years, 53% male) with NCC, diagnosed by cardiovascular magnetic resonance criteria, and 8 age-matched healthy controls (42 ± 12 years, 50% male) were prospectively recruited to undergo FDG-PET with measurement of the myocardial glucose uptake rate (MGU) and SPECT in order to investigate perfusion-metabolism patterns. Result: Patients with LVNC had lower global MGU compared with that in controls (36.9 +- 8.8 vs. 44.6 +- 5.4 +-mol/min/100g, respectively, P = 0.02). Of 17 LV segments, MGU levels were significantly reduced in 8, and also a reduction was observed when compacted segments from LVNC were compared with the segments from control subjects (P < 0,05). The difference in mean myocardial glucose uptake of all segments of the control group compared to the mean of the compact segments of the patients was 8.3 ?mol/min/100g (p < 0,001). Perfusion defects were also found in 15 (50%) patients (45 LV segments: 64.4% match, and 35.6% mismatch perfusionmetabolism pattern). Univariate and multivariate analyses showed that betablocker therapy was associated with increased MGU (beta coefficient=10.1, P = 0.008). Moreover, a gradual increase occurred in MGU across the beta-blocker dose groups (P for trend = 0.01). Conclusions: The reduction of MGU documented by FDG-PET in LVNC supports the hypothesis that a cellular metabolic pathway may play a role in the pathophysiology of LVNC. Betablocker demonstrated an incremental dose-dependent effect on myocardial glucose uptake in patients with NCC. The beneficial effect of beta-blocker mediating myocardial metabolism in the clinical course of LVNC requires further investigation

Apesar dos avanços no entendimento da fisiopatologia e dos recursos terapêuticos atualmente disponíveis, a cardiomiopatia dilatada (CMD) permanece como uma condição com alta mortalidade, sendo que a disfunção microvascular é um dos mecanismos relacionados à piora da função cardíaca. Nos últimos anos, novas técnicas de ecocardiografia vêm sendo utilizadas para avaliação da disfunção microvascular, incluindo a medida de velocidade de fluxo coronário pelo Doppler da artéria coronária descendente anterior (ADA), e a análise quantitativa do fluxo miocárdico pela ecocardiografia com perfusão miocárdica em tempo-real (EPMTR). No presente estudo, avaliamos o valor prognóstico da reserva de velocidade de fluxo coronário (RVFC), obtida pelo Doppler da ADA, e da reserva de fluxo miocárdico (RFM), obtida pela EPMTR, para predizer morte e transplante cardíaco em pacientes com CMD de origem não isquêmica. Adicionalmente, avaliamos se as medidas de reserva de fluxo acrescentam valor prognóstico sobre variáveis clínicas e ecocardiográficas que já são conhecidas como preditores de eventos nesta população. Estudamos 195 pacientes com CMD (130 homens, média etária 54 ± 12 anos) que apresentavam fração de ejeção do ventrículo esquerdo inferior a 35% pelo ecocardiograma e ausência de sinais de doença arterial coronária obstrutiva por angiografia coronária invasiva ou por método não invasivo (cintilografia de perfusão miocárdica ou angiotomografia de coronárias). Foram analisados parâmetros ecocardiográficos convencionais de função sistólica e diastólica do ventrículo esquerdo em repouso. A velocidade de fluxo coronário foi determinada pelo Doppler pulsado na ADA e a dinâmica das microbolhas no miocárdio foi quantificada pela EPMTR utilizando programas computacionais específicos, tanto em repouso como durante o estresse pelo dipiridamol (0,84 mg/Kg). As RVFC, RFM e reserva de velocidade de repreenchimento de microbolhas no miocárdio (reserva ) foram obtidas pela relação entre os parâmetros de fluxo durante a hiperemia e em repouso, sendo consideradas diminuídas quando os valores estavam abaixo de 2,0. O tempo médio de acompanhamento foi de 29 meses (variando de 6 a 69 meses). Neste período, 45 pacientes (24%) apresentaram eventos, sendo 43 mortes de causa cardíaca e 2 transplantes cardíacos. Na análise univariada foram preditores de eventos: etiologia chagásica, classe funcional de insuficiência cardíaca, uso de inibidores da enzima conversora de angiotensina e/ou bloqueadores dos receptores de angiotensina II (fator protetor), diâmetros ventriculares e do átrio esquerdo, volumes ventriculares, fração de ejeção, disfunção diastólica, grau de insuficiência mitral, RVFC, RFM e reserva . Na análise multivariada, foram preditores independentes de eventos o diâmetro do átrio esquerdo (razão de chances = 1,16 por unidade de aumento; intervalo de confiança 95% = 1,078 1,264; p<0,001) e a reserva diminuída (razão de chances = 3,219; intervalo de confiança 95% = 1,178 8,795; p<0,001). No modelo sequencial de predição de eventos, fração de ejeção e diâmetro do átrio esquerdo adicionaram valor prognóstico às variáveis clínicas (aumento do qui-quadrado de 15,2 para 58,5; p < 0,001). A reserva adicionou poder ao modelo (qui-quadrado de 70,2; p<0,001). Concluímos que tanto a RVFC, obtida pelo Doppler da ADA, como a RFM e reserva , obtidas pela EPMTR sob estresse pelo dipiridamol, são preditoras de morte e transplante cardíaco em pacientes com CMD não isquêmica. Entretanto, somente o diâmetro do átrio esquerdo e a reserva mostraram valor prognóstico independente e incremental sobre variáveis clínicas e ecocardiográficas que já são conhecidas como preditores de eventos nesta população / Despite advances in understanding of the pathophysiology and therapeutic approaches, dilated cardiomyopathy (DCM) remains as a condition with high mortality and one of the mechanisms involved in this process seems to be microvascular dysfunction. Recently, new echocardiographic techniques have been incorporated in the clinical practice and used for the assessment of microvascular dysfunction, including evaluation of left anterior descending coronary artery (LAD) by Doppler and quantitative analysis of myocardial flow by real-time myocardial perfusion echocardiography (RTMPE). In the present study, we evaluated the prognostic value of coronary flow velocity reserve (CFVR), obtained by transthoracic echocardiography, and parameters of myocardial flow reserve (MFR), obtained by RTMPE for predicting cardiac death and heart transplantation in patients with nonischemic DCM. In addition, we sought to detect the incremental value of flow reserve over clinical and echocardiographic parameters already known as predictors of events in this population. We studied 195 patients with DCM (130 men, mean age 54 ± 12 years) who had left ventricular ejection fraction (LVEF) less than 35% by echocardiography and no signs of obstructive coronary artery disease by invasive coronary angiography or noninvasive methods (nuclear medicine or angiography by computed tomography). We assessed conventional echocardiographic parameters of systolic and diastolic left ventricular function at rest. Coronary flow velocity was determined by pulsed Doppler in LAD and dynamics of microbubbles in the myocardium was measured by RTMPE using specific computer programs, both at rest and during dipyridamole stress (0.84 mg/kg). CFVR, MFR and the reserve of velocity of microbubbles in the myocardium ( reserve) were obtained as the ratio between parameters of flow during hyperemia and at rest, being considered abnormal when these were below 2.0. The mean follow-up was 29 months (ranging from 6 to 69 months). During this period, 45 patients (24%) had events, 43 cardiac deaths and 2 heart transplantations. In the univariate analysis, predictors of events were: Chagas disease, New York Heart Association functional class, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker (protective effect), left ventricular and atrial diameters, left ventricular volumes, LVEF, diastolic dysfunction, degree of mitral regurgitation, CVFR, MFR and reserve. By multivariate analysis, the only independent predictors of events were the left atrial diameter (OR = 1.16, 95% confidence interval = 1.078 to 1.264, p <0.001) and reserve 2.0 (OR = 3.219, confidence interval 95 % = 1.178 to 8.795, p <0.001). In the sequential model of events prediction, LVEF and left atrial diameter added prognostic value over clinical factors (chi-square from 15.2 to 58.5; p<0.001). reserve added power to the model (chi-square = 70.2, p<0.001). We concluded that CVFR, obtained by Doppler in LAD, MFR and reserve, obtained by dipyridamole stress RTMPE, are predictors of cardiac death and heart transplantation in patients with nonischemic DCM. However, only left atrial diameter and depressed reserve showed independent and incremental predictive value beyond that provided by current known prognostic clinical and echocardiographic factors

Perfusion magnetic resonance imaging is a medical diagnostic method which requires high spatial and temporal resolution simultaneously to capture dynamics of an intravenous contrast agent which is used to perfusion measurement. However, magnetic resonance imaging has physical limits which do not allow to have this resolution simultaneously. This thesis deals with compressed sensing which enables to reconstruct measured data from relatively few acquired samples (below Nyquist rate) while resolution required to perfusion analysis is increased. This aim could be achieved with suitably proposed apriory information about sensed data and model proposal. The reconstruction is then done as an optimization problem. Doctoral thesis brings several new reconstruction models, further proposes method to debias this estimates and examines influence of compressed sensing onto perfusion parameters. Whole thesis is ended with extension of compressed sensing into three-dimensional data. Here, the influence of reconstruction onto perfusion parameters is also described. In summary, the thesis shows that due to compressed sensing, temporal resolution can be increased with the fixed spatial resolution or spatial resolution can be increased with the fixed temporal resolution.

This work focuses on issues relating to the perfusion analysis. The aim of this work is to perform experimental measurements of the phantom and then evaluate the perfusion curves. This curves are used to himation of perfusion hemodynamic parameters, which indicates important informatik about monitoring area. All processes associated with the designation and evaluation are performed in a program named Matlab. The output of work is a system that provides the reader into the problem of perfusion analysis and allows him to understand and know what is the meaning od analysis, what demands are placed on the evaluation and what is the result of this perfusion analysis.

Les études de perfusion du myocarde en tomographie par émission de positons (TEP) sont utilisées pour diagnostiquer l’étendue de maladies coronariennes. La TEP peut aussi mesurer le débit sanguin myocardique en valeur absolue, au repos et en période d’effort. Une des limitations réside dans le fait que l’activité résiduelle de l’examen de repos ne doit pas contaminer l’examen réalisé en phase d’effort. Il est donc nécessaire de séparer les deux acquisitions de 3 à 5 périodes radioactives. Il est maintenant possible d’utiliser de nouveaux traceurs marqués au fluor 18 pour quantifier le débit sanguin myocardique avec précision. Leur période offre la possibilité d’une distribution régionale mais complique la logistique des examens, en rallongeant la durée d’attente entre les deux acquisitions. Pour s’affranchir de cette contrainte, une nouvelle méthode a récemment été proposée (Alpert et al. 2012). Cette méthode permet de mesurer le débit sanguin myocardique au repos et en phase d’effort lors d’une seule session d’imagerie. Le but de cette thèse était de démontrer la faisabilité expérimentale de cette technique et de l’améliorer pour une éventuelle application clinique. Nous avons validé la méthode dans un modèle animal (cochon) pour le traceur 18F-Flurpiridaz puis, nous avons développé un algorithme pour générer rapidement des images paramétriques et des images standard de perfusion au repos et pendant effort. Nous avons ensuite validé nos méthodes pour le traceur 13NH3 qui est utilisé en clinique dans certains pays. Enfin, nous avons proposé une méthode pour la création d’un atlas multimodal 4D dans le but de faciliter les comparaisons entre acquisitions et sujets. / Positron emission tomography (PET) cardiac perfusion studies are used in the clinic to diagnose the extent of coronary artery disease. PET can also measure absolute myocardial blood flow (MBF) at rest and during stress. One limitation is that radioactivity from the rest scan must not affect the stress scan, making it necessary to wait 3 to 5 half-lives between studies for sufficient radioactive decay to occur. With the advent of new myocardial flow tracers, it is now possible to use 18F- tracers for myocardial perfusion imaging and accurate MBF quantification. Their physical half-life does not require the need of on-site cyclotron but constitutes a logistical complication for rest/stress measurements because of the between scan waiting period needed. To address this issue an alternative protocol was previously proposed (Alpert et al. 2012). In the new method rest and stress MBF is measured during a single-scan session. The goal of this thesis was to demonstrate the feasibility of this technique in experimental measurements and to improve its practicality for future clinical application. First, we demonstrated the use of the method in a porcine model for standard bull’s eye, segmental analysis using the novel flow tracer 18F-Flurpiridaz. We then extended the method and developed a computationally efficient algorithm to provide rest/stress MBF parametric maps and to generate rest/stress standard perfusion images in a timely manner. Third, we demonstrated the applicability of our methods to the clinically used radiotracer 13NH3. Lastly, we developed a framework for the construction of a 4D multimodal probabilistic atlas to facilitate inter- and intra-subjects comparisons.

Mirbazel SH. Jämförelse mellan kvinnor och mäns överlevnad baserad på resultat från arbetsprov och myokardscintigrafi. Examensarbete i Biomedicinsk Laboratorievetenskap, 15 högskolepoäng. Malmö högskola: Hälsa och Samhälle, utbildningsområde för Biomedicinsk Laboratorievetenskap, 2011.En av de vanligaste orsakerna till död både i utvecklingsländerna och i västvärlden är hjärtinfarkt som drabbar vanligtvis individer över 65 år. Hjärtischemi är den vanligaste orsaken till hjärtinfarkt/ plötsligt hjärtstopp. För diagnostik av hjärtischemi används oftast arbetsprov som förstahandsval, eftersom metoden är billig, icke-invasiv och relativt ofarlig. Myokardscintigrafi utförs ofta efter arbetsprovet, om detta varit inkonklusivt. Syftet i denna retrospektiva studie var att ta reda på om prognosen och överlevnaden skiljer sig åt mellan kvinnor och män beroende på undersökningsresultat från arbetsprov och myokardscintigrafi. I denna studie analyserades 2045 patienter som var registrerade att utföra arbetsprov för misstänkt eller tidigare känd koronarkärlssjukdom under 2006 & 2007. Patienternas resultat delades i tre grupper: normalt, patologiskt och intermediärt enligt bestämda kriterier. Intermediärgruppen analyserades också om de hade utfört ett myokardscintigrafi inom 6 månader. Intermediärgruppen delades därefter in i tre grupper: de med normal myokardscintigrafi, de med patologisk och de som inte hade utfört någon. Patienter med normalt arbetsprov var 1110, med intermediärt arbetsprov 540 och med patologiskt arbetsprov 254 personer. Det finns statistiskt signifikanta skillnader av antal levande och avlidna mellan män och kvinnor i intermediärt arbetsprov (p < 0,001) och i undergruppen, intermediär utan utförd myokardscintigrafi (p < 0,001). Det finns också en statistiskt signifikant skillnad i överlevnad i huvudgruppen med intermediärt arbetsprov(p < 0,01). Inga analyser av överlevad utfördes för undergrupperna. Sammanfattningsvis har denna studie visat att det inte finns några statistiskt säkerställda skillnader i överlevnad mellan män och kvinnor med normalt och patologiskt arbetsprov däremot finns det en signifikant skillnad i intermediärgruppen. / Mirbazel SH. Comparison between men and women’s survival based on the results from the exercise tests and myocardial perfusion imaging. Degree Project in Biomedical Laboratory Science, 15 points. Malmö University: Health and Society, Department of Biomedical Laboratory Science, 2011.One of the most common causes of death in both developing countries and in the Western world is heart attack that hits usually individuals over 65 years. Cardiac ischemia is the most common cause of myocardial infarction/sudden cardiac arrest. For the diagnosis of cardiac ischemia, exercise test is the first choice, because the method is inexpensive, non-invasive and relatively harmless. Myocardial perfusion imaging is often performed after an inconclusive exercise test. The purpose of this retrospective study was to determine if the prognosis and survival differ between women and men depending on the outcome of the investigation from the exercise test, and the myocardial perfusion imaging. In this study 2045 patients were analyzed who were registered to perform the exercise tests for a suspected or previously known coronary artery disease in 2006/2007. Patient’s results were divided into three groups: normal, pathological and intermediate findings. The intermediary group was further divided according to results of myocardial perfusion imaging within 6 months of the exercise test: those with normal, those with pathologic and those who had not carried out any myocardial perfusion imaging. Patients with normal exercise test were 1110, with intermediate exercise test 540 and with pathologic exercise test were 254 people. There are statistically significant differences in the number of living and deceased between men and women in intermediate exercise tests (p < 0, 001) and in the subgroup, intermediary without myocardial perfusion imaging (p < 0,001). There is also a statistically significant difference in survival in the main group with the intermediate exercise tests (p < 0.01). No analysis was performed for sub-groups. In conclusion, this study has shown that there are no statistically significant differences in survival between men and women with normal and pathological exercise test. However there is a significant difference in intermediary group.

99mTecknetium-tetrofosmin är ett radiofarmaceutiskt medel som används vid myokardscintigrafi för att bedöma myokardperfusionen genom att avbilda vänsterkammarens blodflöde. Radiofarmakat uppvisar ett lågt myokardiellt upptag på endast 1,2%, där majoriteten av resterande radiofarmaka rensas ut genom levern och utsöndras via gallsystemet. Det extrakardiella upptaget i buken kan minska bildkvalitén, dölja defekter och försämra diagnostisk noggrannhet. GE StarGuide är en SPECT/CT-kamera utrustad med avancerad detektorteknologi som möjliggör fokuserad fotoninsamling, vilket bidrar till högre bildupplösning. Syftet med den här studien var att undersöka effekten av bukupptag vid bedömning av vänsterkammarens blodfördelning vid myokardscintigrafi med hjälp av SPECT/CT-kameran StarGuide. För att uppnå detta användes en thoraxmodell med ett fantomhjärta och en slang som simulerade bukupptag. Slangen fylldes med varierande aktivitetskoncentrationer och avståndet mellan slangen och fantomhjärtat varierades systematiskt. Vårdpersonal inom området bedömde sedan om bildomtagning var nödvändig, baserat på bildkvalitén och effekten av bukupptaget. Resultatet från studien indikerar en kvalitativ och kvantitativ påverkan av bukupptag vid bedömning av blodfördelningen i vänsterkammaren för de olika undersökta aktivitetskoncentrationerna och avstånden. Däremot observerades ingen statistisk signifikant skillnad mellan aktivitetskoncentrationerna vad gäller den kvantitativt påverkan. Vidare studier krävs för att validera dessa fynd och ge nya riktlinjer för att optimera användningen av StarGuide inom den nuklearmedicinska verksamheten. / 99mTechnetium-tetrofosmin is a radiopharmaceutical agent used for myocardial perfusion scintigraphy to assess myocardial perfusion by imaging the left ventricular bloodflow. The agent exhibits a low myocardial uptake of only 1,2%, with the majority of the agent being cleared through the liver and excreted via the biliary system. The extracardiac uptake in the abdomen can reduce image quality, conceal defects, and compromise diagnostic accuracy. The GE StarGuide is a SPECT/CT-camera equipped with advanced detector technology that allows for focused photon collection, thus contributing to improved image resolution. The objective of the present phantomstudy was to investigate the effect of abdominal uptake on the assessment of blood distribution in the left ventricle during myocardial perfusion scintigraphy using the SPECT/CT-camera StarGuide. To acieve this, a thorax model containing a phantomheart was used, with a tube simulating abdominal uptake. The tube was filled with varying activity concentrations, and the distance between the tube and the phantomheart was systematically varied. Healthcare professionals within the field then assessed whether image retakes were necessary based on the image quality and the impact of the abdominal uptake. The results of the study indicated that there is a qualitative and quantitative effect of extracardiac uptake on the assessment of left ventricular blood distribution for the different activity concentrations and distances examined, however, no statistically significant difference was observed between the activity concentrations quantitatively. Further investigations are needed to validate these findings and provide guidance for optimizing the use of the StarGuide camera in nuclear medicine practice.

No description available.

[ES] Los tumores cerebrales son una de las enfermedades más devastadoras en la actualidad por el importante deterioro cognitivo que sufren los pacientes, la elevada tasa de mortalidad y el mal pronóstico. Los astrocitomas de grado 4 conllevan una supervivencia de cinco años en aproximadamente el 5% de los pacientes diagnosticados, siendo los tumores más agresivos y letales del Sistema Nervioso Central (SNC). Los astrocitomas de grado 4 siguen siendo un problema médico complejo aún sin resolver. A pesar de representar más del 60% de los tumores cerebrales malignos en adultos, estos tumores tienen una baja prevalencia relativa y se consideran una enfermedad huérfana, lo que dificulta el desarrollo de nuevos fármacos o tratamientos que puedan beneficiar a los pacientes. La agresividad de estos tumores se debe a diferentes características, como la fuerte angiogénesis, la necrosis, la microproliferación vascular, la capacidad de invasión e infiltración de las células tumorales y un microambiente inmunológico particular. Además, debido a la rápida progresión de los astrocitomas de grado 4, en la zona de la lesión coexisten diferentes regiones específicas que cambian con el tiempo. Esta naturaleza compleja, junto con la marcada heterogeneidad interpaciente, intratumoral y longitudinal, complica el éxito de un único tratamiento eficaz para todos los pacientes. La imagen de resonancia magnética (MRI) supone una técnica útil para caracterizar la morfología y la vascularidad del tumor. El uso de métodos avanzados y robustos para analizar las imágenes de MR recogidas en las fases iniciales del tratamiento de los pacientes permite la delimitación de las diferentes regiones de los astrocitomas de grado 4, convirtiéndose en herramientas útiles para investigadores, radiólogos y neurocirujanos. Además, el cálculo de biomarcadores vasculares de imagen, como los propuestos en esta tesis, facilitaría la caracterización del tumor, la estimación del pronóstico y los enfoques de tratamiento más personalizados. Esta tesis propone cuatro pilares fundamentales para avanzar en el manejo de los astrocitomas de grado 4. Estos incluyen I) la caracterización multinivel del tumor para mejorar las clasificaciones de los gliomas de alto grado del SNC; II) la búsqueda y desarrollo de biomarcadores robustos para estimar el pronóstico de los pacientes desde el momento prequirúrgico; III) así como para evaluar la respuesta a los tratamientos y la selección de los pacientes que pueden beneficiarse de terapias específicas; y IV) el diseño e implementación de estudios clínicos y protocolos para la recogida de datos a largo plazo de cohortes de pacientes notables a nivel internacional. Para abordar estos cuatro pilares, se ha utilizado un enfoque interdisciplinario que combina el análisis de imágenes médicas, técnicas avanzadas de inteligencia artificial y variables moleculares, histopatológicas y clínicas. En conclusión, hemos abordado la influencia de la heterogeneidad interpaciente e intratumoral del astrocitoma de grado 4 para la caracterización y clasificación del tumor, la estimación del pronóstico del paciente y la predicción de las respuestas al tratamiento. Además, se han diseñado e implementado diferentes estudios clínicos que permiten la recogida de datos multinivel de cohortes internacionales de pacientes con astrocitoma de grado 4. / [CA] Els tumors cerebrals són una de les malalties més devastadores en l'actualitat per la important deterioració cognitiva que pateixen els pacients, l'elevada taxa de mortalitat i el mal pronòstic. Els astrocitomes de grau 4 comporten una supervivència de cinc anys en aproximadament el 5% dels pacients diagnosticats, sent els tumors més agressius i letals del Sistema Nerviós Central (SNC). Els astrocitomes de grau 4 continuen sent un problema mèdic complex encara sense resoldre. Malgrat representar més del 60% dels tumors cerebrals malignes en adults, aquests tumors tenen una baixa prevalença relativa i es consideren una malaltia òrfena, la qual cosa dificulta el desenvolupament de nous fàrmacs o tractaments que puguen beneficiar als pacients. L'agressivitat d'aquests tumors es deu a diferents característiques, com la forta angiogènesis, la necrosi, la microproliferació vascular, la capacitat d'invasió i infiltració de les cèl·lules tumorals i un microambient immunològic particular. A més, a causa de la ràpida progressió dels astrocitomes de grau 4, en la zona de la lesió coexisteixen diferents regions específiques que canvien amb el temps. Aquesta naturalesa complexa, juntament amb la marcada heterogeneïtat interpacient, intratumoral i longitudinal fa que es complique l'èxit d'un únic tractament eficaç per a tots els pacients. L'imatge de ressonància magnètica (MRI) suposa una tècnica útil per a caracteritzar la morfologia i la vascularitat del tumor. L'ús de mètodes avançats i robustos per a analitzar les imatges de MR recollides en les fases inicials del tractament dels pacients permet la delimitació de les diferents regions dels astrocitomes de grau 4, convertint-se en eines útils per a investigadors, radiòlegs i neurocirugians. A més, el càlcul de biomarcadors vasculars d'imatge, com els proposats en aquesta tesi, facilitaria la caracterització del tumor, l'estimació del pronòstic i els enfocaments de tractament més personalitzats. Aquesta tesi proposa quatre pilars fonamentals per a avançar en el maneig dels astrocitomes de grau 4. Aquests inclouen I) la caracterització multinivell del tumor per a millorar les classificacions dels gliomes d'alt grau del SNC; II) la cerca i desenvolupament de biomarcadors robustos per a estimar el pronòstic dels pacients des del moment prequirúrgic; III) així com per a avaluar la resposta als tractaments i la selecció dels pacients que poden beneficiar-se de teràpies específiques; i IV) el disseny i implementació d'estudis clínics i protocols per a la recollida de dades a llarg termini de cohorts de pacients notables a nivell internacional. Per a abordar aquests quatre pilars, s'ha utilitzat un enfocament interdisciplinari que combina l'anàlisi d'imatges mèdiques, tècniques avançades d'intel·ligència artificial i variables moleculars, histopatològiques i clíniques. En conclusió, hem abordat la influència de l'heterogeneïtat interpacient i intratumoral del astrocitoma de grau 4 per a la caracterització i classificació del tumor, l'estimació del pronòstic del pacient i la predicció de les respostes al tractament. A més, s'han dissenyat i implementat diferents estudis clínics que permeten la recollida de dades multinivell de cohorts internacionals de pacients amb astrocitoma de grau 4. / [EN] Brain tumors are one of the most devastating diseases today because of the significant cognitive impairment suffered by patients, high mortality rates, and poor prognosis. Astrocytomas grade 4 bring five-year survival in approximately 5% of diagnosed patients, being the most aggressive and lethal tumors of the Central Nervous System (CNS). Astrocytomas grade 4 continue to be an unresolved complex medical problem. Despite accounting for more than 60% of malignant brain tumors in adults, these tumors have a low relative prevalence and are considered an orphan disease, making difficult developing new drugs or treatments that might benefit patients. The aggressiveness of these tumors is due to different characteristics, such as strong angiogenesis, necrosis, vascular microproliferation, the capacity of the tumor cells to invade and infiltrate, and a particular immune microenvironment. In addition, due to the rapid progression of astrocytomas grade 4, different specific regions coexist in the lesion area which change over time. This complex nature, along with the marked interpatient, intratumor, and longitudinal heterogeneity, makes complicate the success of a single efficient treatment for all patients. Magnetic Resonance Imaging (MRI) represents a useful technique to characterize tumor morphology and vascularity. Using advanced and robust methods to analyze MR images collected from initial stages of patient management allows the delineation of different regions of astrocytomas grade 4, becoming useful tools for researchers, radiologists and neurosurgeons. In addition, the calculation of imaging vascular biomarkers, such as those proposed in this thesis, would facilitate tumor characterization, prognosis estimation and more personalized treatment approaches. This thesis proposes four fundamental pillars to advance the management of astrocytomas grade 4. These include I) the multilevel characterization of the tumor to improve classifications of high-grade CNS gliomas; II) the search and development of robust biomarkers for estimating patient prognosis from the presurgical moment; III) as well as for evaluating the response to treatments and the selection of patients who may benefit from specific therapies; and IV) the design and implementation of clinical studies and protocols for long-term collecting data from internationally remarkable cohorts of patients. To address these four pillars, an interdisciplinary approach has been used that combines medical imaging analysis, advanced artificial intelligence techniques, and molecular, histopathological, and clinical variables. Concluding, we have addressed the influence of both interpatient and intratumor heterogeneity of astrocytoma grade 4 for tumor characterization and classification, patient prognosis estimation and predicting treatment responses. In addition, different clinical studies have been designed and implemented allowing the collection of multilevel data from international cohorts of patients with astrocytoma grade 4. / Álvarez Torres, MDM. (2022). Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/188957

Collateral blood flow is the compensatory flow of blood to the tissue through secondary channels when the primary channel is compromised. It is of vital importance in cerebrovascular disease where collateral flow can maintain large regions of brain tissue which would otherwise have suffered ischaemic damage. Traditional x-ray based techniques for visualising collateral flow are invasive and carry risks to the patient. In this thesis novel magnetic resonance imaging techniques for performing vessel-selective labelling of brain feeding arteries are explored and developed to reveal the source and extent of collateral flow in the brain non-invasively and without the use of contrast agents. Vessel-encoded pseudo-continuous arterial spin labelling (VEPCASL) allows the selective labelling of blood water in different combinations of brain feeding arteries that can be combined in post-processing to yield vascular territory maps. The mechanism of VEPCASL was elucidated and optimised through simulations of the Bloch equations and phantom experiments, including its sensitivity to sequence parameters, blood velocity and off-resonance effects. An implementation of the VEPCASL pulse sequence using an echo-planar imaging (EPI) readout was applied in healthy volunteers to enable optimisation of the post-labelling delay and choice of labelling plane position. Improvements to the signal-to-noise ratio (SNR) and motion-sensitivity were made through the addition of background suppression pulses and a partial-Fourier scheme. Experiments using a three-dimensional gradient and spin echo (3D-GRASE) readout were somewhat compromised by significant blurring in the slice direction, but showed potential for future work with a high SNR and reduced dropout artefacts. The VEPCASL preparation was also applied to a dynamic 2D angiographic readout, allowing direct visualisation of collateral blood flow in the brain as well as a morphological and functional assessment of the major cerebral arteries. The application of a balanced steady-state free precession (bSSFP) readout significantly increased the acquisition efficiency, allowing the generation of dynamic 3D vessel-selective angiograms. A theoretical model of the dynamic angiographic signal was also derived, allowing quantification of blood flow through specified vessels, providing a significant advantage over qualitative x-ray based methods. Finally, these methods were applied to a number of patient groups, including those with vertebro-basilar disease, carotid stenosis and arteriovenous malformation. These preliminary studies demonstrate that useful clinical information regarding collateral blood flow can be obtained with these techniques.