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PURPOSE: K trans $$ {K}^{\mathrm{trans}} $$ has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for K trans $$ {K}^{\mathrm{trans}} $$ quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize K trans $$ {K}^{\mathrm{trans}} $$ measurement. METHODS: A framework was created to evaluate K trans $$ {K}^{\mathrm{trans}} $$ values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for K trans $$ {K}^{\mathrm{trans}} $$ quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' K trans $$ {K}^{\mathrm{trans}} $$ values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in K trans $$ {K}^{\mathrm{trans}} $$ analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within K trans $$ {K}^{\mathrm{trans}} $$ estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology.
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Meios de Contraste , Imageamento por Ressonância Magnética , Humanos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética/métodos , Software , AlgoritmosRESUMO
PURPOSE: The Tofts and the extended Tofts models are the pharmacokinetic models commonly used in dynamic contrast-enhanced MRI (DCE-MRI) perfusion analysis, although they do not provide two important biological markers, namely, the plasma flow and the permeability-surface area product. Estimates of such markers are possible using advanced pharmacokinetic models describing the vascular distribution phase, such as the tissue homogeneity model. However, the disadvantage of the advanced models lies in biased and uncertain estimates, especially when the estimates are computed voxelwise. The goal of this work is to improve the reliability of the estimates by including information from neighboring voxels. THEORY AND METHODS: Information from the neighboring voxels is incorporated in the estimation process through spatial regularization in the form of total variation. The spatial regularization is applied on five maps of perfusion parameters estimated using the tissue homogeneity model. Since the total variation is not differentiable, two proximal techniques of convex optimization are used to solve the problem numerically. RESULTS: The proposed algorithm helps to reduce noise in the estimated perfusion-parameter maps together with improving accuracy of the estimates. These conclusions are proved using a numerical phantom. In addition, experiments on real data show improved spatial consistency and readability of perfusion maps without considerable lowering of the quality of fit. CONCLUSION: The reliability of the DCE-MRI perfusion analysis using the tissue homogeneity model can be improved by employing spatial regularization. The proposed utilization of modern optimization techniques implies only slightly higher computational costs compared to the standard approach without spatial regularization.
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Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Meios de Contraste/farmacologia , Glioblastoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Algoritmos , Animais , Simulação por Computador , Processamento de Imagem Assistida por Computador , Perfusão , Permeabilidade , Imagens de Fantasmas , Ratos , Reprodutibilidade dos Testes , Razão Sinal-RuídoRESUMO
BACKGROUND: Perfusion assessment of the pancreas is challenging and poorly evaluated. Pancreatic affection is a prevalent feature of cystic fibrosis (CF). Little is known about pancreatic perfusion in CF. We aimed to assess pancreatic perfusion by contrast-enhanced ultrasound (CEUS) analysed in the bolus-and-burst model and software. METHODS: We performed contrast enhanced ultrasound of the pancreas in 25 CF patients and 20 healthy controls. Perfusion data was analysed using a dedicated perfusion model providing the mean capillary transit-time (MTT), blood flow (BF) and blood-volume (BV). CF patients were divided according to exocrine function. RESULTS: The pancreas insufficient CF patients had longer MTT (p ≤ 0.002), lower BF (p < 0.001) and lower BV (p < 0.05) compared to the healthy controls and sufficient CF patients. Interrater analysis showed substantial agreement for the analysis of mean transit time. CONCLUSION: The bolus-and-burst method used on pancreatic CEUS-examinations demonstrates reduced perfusion in CF patients with pancreas affection. The perfusion model and software requires further optimization and standardization to be clinical applicable for the assessment of pancreatic perfusion.
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Fibrose Cística/diagnóstico por imagem , Pâncreas/diagnóstico por imagem , Imagem de Perfusão/métodos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Software , UltrassonografiaRESUMO
PURPOSE: One of the main challenges in quantitative dynamic contrast-enhanced (DCE) MRI is estimation of the arterial input function (AIF). Usually, the signal from a single artery (ignoring contrast dispersion, partial volume effects and flow artifacts) or a population average of such signals (also ignoring variability between patients) is used. METHODS: Multi-channel blind deconvolution is an alternative approach avoiding most of these problems. The AIF is estimated directly from the measured tracer concentration curves in several tissues. This contribution extends the published methods of multi-channel blind deconvolution by applying a more realistic model of the impulse residue function, the distributed capillary adiabatic tissue homogeneity model (DCATH). In addition, an alternative AIF model is used and several AIF-scaling methods are tested. RESULTS: The proposed method is evaluated on synthetic data with respect to the number of tissue regions and to the signal-to-noise ratio. Evaluation on clinical data (renal cell carcinoma patients before and after the beginning of the treatment) gave consistent results. An initial evaluation on clinical data indicates more reliable and less noise sensitive perfusion parameter estimates. CONCLUSION: Blind multi-channel deconvolution using the DCATH model might be a method of choice for AIF estimation in a clinical setup.
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Algoritmos , Imageamento por Ressonância Magnética/métodos , Modelos Biológicos , Capilares/diagnóstico por imagem , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/diagnóstico por imagem , Meios de Contraste , Humanos , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/diagnóstico por imagem , Imagem de PerfusãoRESUMO
Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.
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Anticorpos Monoclonais/farmacologia , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bevacizumab , Volume Sanguíneo/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Meios de Contraste , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Glioblastoma/enzimologia , Glioblastoma/ultraestrutura , Humanos , Imageamento por Ressonância Magnética , Invasividade Neoplásica , Neovascularização Patológica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Nus , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Wnt/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Dynamic Contrast-Enhanced (DCE) MRI with 2nd generation pharmacokinetic models provides estimates of plasma flow and permeability surface-area product in contrast to the broadly used 1st generation models (e.g. the Tofts models). However, the use of 2nd generation models requires higher frequency with which the dynamic images are acquired (around 1.5 s per image). Blind deconvolution can decrease the demands on temporal resolution as shown previously for one of the 1st generation models. Here, the temporal-resolution requirements achievable for blind deconvolution with a 2nd generation model are studied. METHODS: The 2nd generation model is formulated as the distributed-capillary adiabatic-tissue-homogeneity (DCATH) model. Blind deconvolution is based on Parker's model of the arterial input function. The accuracy and precision of the estimated arterial input functions and the perfusion parameters is evaluated on synthetic and real clinical datasets with different levels of the temporal resolution. RESULTS: The estimated arterial input functions remained unchanged from their reference high-temporal-resolution estimates (obtained with the sampling interval around 1 s) when increasing the sampling interval up to about 5 s for synthetic data and up to 3.6-4.8 s for real data. Further increasing of the sampling intervals led to systematic distortions, such as lowering and broadening of the 1st pass peak. The resulting perfusion-parameter estimation error was below 10% for the sampling intervals up to 3 s (synthetic data), in line with the real data perfusion-parameter boxplots which remained unchanged up to the sampling interval 3.6 s. CONCLUSION: We show that use of blind deconvolution decreases the demands on temporal resolution in DCE-MRI from about 1.5 s (in case of measured arterial input functions) to 3-4 s. This can be exploited in increased spatial resolution or larger organ coverage.
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Meios de Contraste , Imageamento por Ressonância Magnética , Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética/métodos , Perfusão , Fatores de Tempo , AlgoritmosRESUMO
PURPOSE: The composite vascular transport function of a brain voxel consists of one convolutional component for the arteries, one for the capillaries and one for the veins in the voxel of interest. Here, the goal is to find each of these three convolutional components and the associated arterial input function. PHARMACOKINETIC MODELLING: The single voxel vascular transport functions for arteries, capillaries and veins were all modelled as causal exponential functions. Each observed multipass tissue contrast function was as a first approximation modelled as the resulting parametric composite vascular transport function convolved with a nonparametric and voxel specific multipass arterial input function. Subsequently, the residue function was used in the true perfusion equation to optimize the three parameters of the exponential functions. DECONVOLUTION METHODS: For each voxel, the parameters of the three exponential functions were estimated by successive iterative blind deconvolutions using versions of the Lucy-Richardson algorithm. The final multipass arterial input function was then computed by nonblind deconvolution using the Lucy-Richardson algorithm and the estimated composite vascular transport function. RESULTS: Simulations showed that the algorithm worked. The estimated mean transit time of arteries, capillaries and veins of the simulated data agreed with the known input values. For real data, the estimated capillary mean transit times agreed with known values for this parameter. The nonparametric multipass arterial input functions were used to derive the associated map of the arrival time. The arrival time map of a healthy volunteer agreed with known arterial anatomy and physiology. CONCLUSION: Clinically important new voxelwise hemodynamic information for arteries, capillaries and veins separately can be estimated using multipass tissue contrast functions and the iterative blind Lucy-Richardson deconvolution algorithm.
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Capilares , Meios de Contraste , Algoritmos , Artérias/patologia , Encéfalo/diagnóstico por imagem , Capilares/diagnóstico por imagem , Circulação Cerebrovascular , Meios de Contraste/farmacocinética , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Imagem de PerfusãoRESUMO
The temporomandibular joint (TMJ) is typically involved in 45-87% of children with Juvenile Idiopathic Arthritis (JIA). Accurate diagnosis of JIA is difficult as various clinical tests, including MRI, disagree. The purpose of this study is to optimize the methodological aspects of Dynamic Contrast Enhanced (DCE) MRI of the TMJ in children. In this cross-sectional study, including data from 73 JIA affected children, aged 6-15 years, effects of motion correction, sampling rate and parametric modelling on DCE-MRI data is investigated. Consensus among three radiologists determined the regions of interest. Quantitative perfusion parameters were estimated using four perfusion models; the Adiabatic Approximation to Tissue Homogeneity (AATH), Distributed Capillary Adiabatic Tissue Homogeneity (DCATH), Gamma Capillary Transit Time (GCTT) and Two Compartment Exchange (2CXM) models. Effects of motion correction were evaluated by a sum of least squares between corrected raw data and the GCTT model. The effect of systematically down sampling the raw data was tested. The sum of least squares was computed across all pharmacokinetic models. Relative difference perfusion parameters between the left and right TMJ were used for an unsupervised k-means based stratification of the data based on a principal component analysis, as well as for a supervised random forest classification. Diagnostic sensitivity and specificity were computed relative to structural image scorings. Paired sample t-tests, as well as ANOVA tests, were used (significant threshold: p < 0.05) with Tukeys post hoc test. High-level elastic motion correction provides the best least square fit to the GCTT model (percental improvement: 72-84%). A 4 s sampling rate captures more of the potentially disease relevant signal variations. The various parametric models all leave comparable residues (relative standard deviation: 3.4%). In further evaluation of DCE-MRI as a potential diagnostic tool for JIA a high-level elastic motion correction scheme should be adopted, with a sampling rate of at least 4 s. Results suggest that DCE-MRI data can be a valuable part in JIA diagnostics in the TMJ.
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Artrite Juvenil/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Modelos Estatísticos , Movimento , Articulação Temporomandibular/diagnóstico por imagem , Adolescente , Artefatos , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Sensibilidade e EspecificidadeRESUMO
Diseases with the highest burden for society such as stroke, myocardial infarction, pulmonary embolism, and others are due to blood clots. Preclinical and clinical techniques to study blood clots are important tools for translational research of new diagnostic and therapeutic modalities that target blood clots. In this study, we employed a three-dimensional (3D) printed middle cerebral artery model to image clots under flow conditions using preclinical imaging techniques including fluorescent whole-body imaging, magnetic resonance imaging (MRI), and computed X-ray microtomography (microCT). Both liposome-based, fibrin-targeted, and non-targeted contrast agents were proven to provide a sufficient signal for clot imaging within the model under flow conditions. The application of the model for clot targeting studies and thrombolytic studies using preclinical imaging techniques is shown here. For the first time, a novel method of thrombus labeling utilizing barium sulphate (Micropaque®) is presented here as an example of successfully employed contrast agents for in vitro experiments evaluating the time-course of thrombolysis and thus the efficacy of a thrombolytic drug, recombinant tissue plasminogen activator (rtPA). Finally, the proof-of-concept of in vivo clot imaging in a middle cerebral artery occlusion (MCAO) rat model using barium sulphate-labelled clots is presented, confirming the great potential of such an approach to make experiments comparable between in vitro and in vivo models, finally leading to a reduction in animals needed.
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PURPOSE: One of the main obstacles for reliable quantitative dynamic contrast-enhanced (DCE) MRI is the need for accurate knowledge of the arterial input function (AIF). This is a special challenge for preclinical small animal applications where it is very difficult to measure the AIF without partial volume and flow artifacts. Furthermore, using advanced pharmacokinetic models (allowing estimation of blood flow and permeability-surface area product in addition to the classical perfusion parameters) poses stricter requirements on the accuracy and precision of AIF estimation. This paper addresses small animal DCE-MRI with advanced pharmacokinetic models and presents a method for estimation of the AIF based on blind deconvolution. METHODS: A parametric AIF model designed for small animal physiology and use of advanced pharmacokinetic models is proposed. The parameters of the AIF are estimated using multichannel blind deconvolution. RESULTS: Evaluation on simulated data show that for realistic signal to noise ratios blind deconvolution AIF estimation leads to comparable results as the use of the true AIF. Evaluation on real data based on DCE-MRI with two contrast agents of different molecular weights showed a consistence with the known effects of the molecular weight. CONCLUSION: Multi-channel blind deconvolution using the proposed AIF model specific for small animal DCE-MRI provides reliable perfusion parameter estimates under realistic signal to noise conditions.
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Artérias/diagnóstico por imagem , Meios de Contraste/farmacocinética , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Algoritmos , Animais , Simulação por Computador , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Necrose/patologia , Perfusão , Farmacocinética , Análise de Regressão , Reprodutibilidade dos Testes , Razão Sinal-RuídoRESUMO
OBJECTIVE: An extension of single- and multi-channel blind deconvolution is presented to improve the estimation of the arterial input function (AIF) in quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). METHODS: The Lucy-Richardson expectation-maximization algorithm is used to obtain estimates of the AIF and the tissue residue function (TRF). In the first part of the algorithm, nonparametric estimates of the AIF and TRF are obtained. In the second part, the decaying part of the AIF is approximated by three decaying exponential functions with the same delay, giving an almost noise free semi-parametric AIF. Simultaneously, the TRF is approximated using the adiabatic approximation of the Johnson-Wilson (aaJW) pharmacokinetic model. RESULTS: In simulations and tests on real data, use of this AIF gave perfusion values close to those obtained with the corresponding previously published nonparametric AIF, and are more noise robust. CONCLUSION: When used subsequently in voxelwise perfusion analysis, these semi-parametric AIFs should give more correct perfusion analysis maps less affected by recording noise than the corresponding nonparametric AIFs, and AIFs obtained from arteries. SIGNIFICANCE: This paper presents a method to increase the noise robustness in the estimation of the perfusion parameter values in DCE-MRI.
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Meios de Contraste/farmacocinética , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Algoritmos , Animais , Artérias/patologia , Simulação por Computador , Meios de Contraste/química , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Perfusão , Reprodutibilidade dos TestesRESUMO
Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth factor (VEGF) blocking agents has been shown to lead to morphological vascular normalisation resulting in a reduction of contrast enhancement as seen by magnetic resonance imaging (MRI). Yet the functional consequences of this normalisation and its potential for improved delivery of cytotoxic agents to the tumour are not known. The presented study aimed at determining the early physiologic changes following bevacizumab treatment. A time series of perfusion MRI and hypoxia positron emission tomography (PET) scans were acquired during the first week of treatment, in two human GBM xenograft models treated with either high or low doses of bevacizumab. We show that vascular morphology was normalised over the time period investigated, but vascular function was not improved, resulting in poor tumoural blood flow and increased hypoxia.
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Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Neovascularização Patológica/patologia , Animais , Feminino , Humanos , Masculino , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Dynamic contrast-enhanced ultrasound (DCE-US) can be used for calculating organ perfusion. By combining bolus injection with burst replenishment, the actual mean transit time (MTT) can be estimated. Blood volume (BV) can be obtained by scaling the data to a vessel on the imaging plane. The study aim was to test interobserver agreement for repeated recordings using the same ultrasound scanner and agreement between results on two different scanner systems. MATERIALS AND METHODS: Ten patients under evaluation for exocrine pancreatic failure were included. Each patient was scanned two times on a GE Logiq E9 scanner, by two different observers, and once on a Philips IU22 scanner, after a bolus of 1.5 ml Sonovue. A 60-second recording of contrast enhancement was performed before the burst and the scan continued for another 30 s for reperfusion. We performed data analysis using MATLAB-based DCE-US software. An artery in the same depth as the region of interest (ROI) was used for scaling. The measurements were compared using the intraclass correlation coefficient (ICC) and Bland Altman plots. RESULTS: The interobserver agreement on the Logiq E9 for MTT (ICC=0.83, confidence interval (CI) 0.46-0.96) was excellent. There was poor agreement for MTT between the Logiq E9 and the IU22 (ICC=-0.084, CI -0.68-0.58). The interobserver agreement for blood volume measurements was excellent on the Logiq E9 (ICC=0.9286, CI 0.7250-0.98) and between scanners (ICC=0.86, CI=0.50-0.97). CONCLUSION: Interobserver agreement was excellent using the same scanner for both parameters and between scanners for BV, but the comparison between two scanners did not yield acceptable agreement for MTT. This was probably due to incomplete bursting of bubbles in some of the recordings on the IU22.
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A new method for two-dimensional deconvolution of medical ultrasonic images is presented. The spatial resolution of the deconvolved images is much higher compared to the common images of the fundamental and second harmonic. The deconvolution also results in a more distinct speckle pattern. Unlike the most published deconvolution algorithms for ultrasonic images, the presented technique can be implemented using currently available hardware in real-time imaging, with a rate up to 50 frames per second. This makes it attractive for application in the current ultrasound scanners. The algorithm is based on two-dimensional homomorphic deconvolution with simplified assumptions about the point spread function. Broadband radio frequency image data are deconvolved instead of common fundamental harmonic data. Thus, information of both the first and second harmonics is used. The method was validated on image data recorded from a tissue-mimicking phantom and on clinical image data.
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Algoritmos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Armazenamento e Recuperação da Informação/métodos , Processamento de Sinais Assistido por Computador , Ultrassonografia/métodos , Humanos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Ultrassonografia/instrumentaçãoRESUMO
BACKGROUND: Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. METHODS: In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. RESULTS: In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. CONCLUSIONS: The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.
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Neoplasias Encefálicas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Neovascularização Patológica/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Evolução Molecular , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Imagem Multimodal , Mutação , Invasividade Neoplásica , Análise de Sobrevida , Regulação para CimaRESUMO
This study presents three methods for absolute quantification in ultrasound perfusion analysis based on bolus tracking. The first two methods deconvolve the perfusion time sequence with a measured AIF, using a nonparametric or a parametric model of the tissue residue function, respectively. The third method is a simplified approach avoiding deconvolution by assuming a narrow AIF. A phantom with a dialyzer filter as a tissue-mimicking model was used for evaluation. Estimated mean transit times and blood volumes were compared with the theoretical values. A match with a maximum error of 12% was achieved.
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Processamento de Imagem Assistida por Computador/métodos , Imagem de Perfusão/métodos , Imagens de Fantasmas , Ultrassonografia/métodos , Desenho de Equipamento , Humanos , Modelos Cardiovasculares , Imagem de Perfusão/instrumentação , Processamento de Sinais Assistido por Computador , Ultrassonografia/instrumentaçãoRESUMO
This paper presents a system for correcting motion influences in time-dependent 2D contrast-enhanced ultrasound (CEUS) images to assess tissue perfusion characteristics. The system consists of a semi-automatic frame selection method to find images with out-of-plane motion as well as a method for automatic motion compensation. Translational and non-rigid motion compensation is applied by introducing a temporal continuity assumption. A study consisting of 40 clinical datasets was conducted to compare the perfusion with simulated perfusion using pharmacokinetic modeling. Overall, the proposed approach decreased the mean average difference between the measured perfusion and the pharmacokinetic model estimation. It was non-inferior for three out of four patient cohorts to a manual approach and reduced the analysis time by 41% compared to manual processing.
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Abdome/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Doença de Crohn/diagnóstico por imagem , Fibrose Cística/diagnóstico por imagem , Bases de Dados Factuais , Interpretação de Imagem Assistida por Computador/métodos , Feminino , Humanos , Masculino , Movimento (Física) , UltrassonografiaRESUMO
This paper presents a new method of blind two-dimensional (2-D) homomorphic deconvolution and speckle reduction applied to medical ultrasound images. The deconvolution technique is based on an improved 2-D phase unwrapping scheme for pulse estimation. The input images are decomposed into minimum-phase and allpass components. The 2-D phase unwrapping is applied only to the allpass component. The 2-D phase of the minimum-phase component is derived by a Hilbert transform. The accuracy of 2-D phase unwrapping is also improved by processing small (16 x 16 pixels) overlapping subimages separately. This takes the spatial variance of the ultrasound pulse into account. The deconvolution algorithm is applied separately to the first and second harmonic images, producing much sharper images of approximately the same resolution and different speckle patterns. Speckle reduction is made by adding the envelope images of the deconvolved first and second harmonic images. Neither the spatial resolution nor the frame rate decreases, as the common compounding speckle reduction techniques do. The method is tested on sequences of clinical ultrasound images, resulting in high-resolution ultrasound images with reduced speckle noise.
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Algoritmos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Processamento de Sinais Assistido por Computador , Ultrassonografia/métodos , Ecocardiografia/métodos , Humanos , Rim/diagnóstico por imagem , Pâncreas/diagnóstico por imagem , Controle de Qualidade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The present trend in dynamic contrast-enhanced MRI is to increase the number of estimated perfusion parameters using complex pharmacokinetic models. However, less attention is given to the precision analysis of the parameter estimates. In this paper, the distributed capillary adiabatic tissue homogeneity pharmacokinetic model is extended by the bolus arrival time formulated as a free continuous parameter. With the continuous formulation of all perfusion parameters, it is possible to use standard gradient-based optimization algorithms in the approximation of the tissue concentration time sequences. This new six-parameter model is investigated by comparing Monte-Carlo simulations with theoretically derived covariance matrices. The covariance-matrix approach is extended from the usual analysis of the primary perfusion parameters of the pharmacokinetic model to the analysis of the perfusion parameters derived from the primary ones. The results indicate that the precision of the estimated perfusion parameters can be described by the covariance matrix for signal-to-noise ratio higher than~20dB. The application of the new analysis model on a real DCE-MRI data set is also presented.
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Meios de Contraste/farmacocinética , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Modelos Cardiovasculares , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/fisiopatologia , Algoritmos , Velocidade do Fluxo Sanguíneo , Simulação por Computador , Humanos , Aumento da Imagem/métodos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
This paper is focused on quantitative perfusion analysis using MRI and ultrasound. In both MRI and ultrasound, most approaches allow estimation of rate constants (Ktrans, kep for MRI) and indices (AUC, TTP) that are only related to the physiological perfusion parameters of a tissue (e.g. blood flow, vessel permeability) but do not allow their absolute quantification. Recent methods for quantification of these physiological perfusion parameters are shortly reviewed. The main problem of these methods is estimation of the arterial input function (AIF). This paper summarizes and extends the current blind-deconvolution approaches to AIF estimation. The feasibility of these methods is shown on a small preclinical study using both MRI and ultrasound.