Radovan Jirik

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

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.

Quantitative Contrast-Enhanced Ultrasound Comparison Between Inflammatory and Fibrotic Lesions in Patients with Crohn's Disease

The aim of this study was to determine whether there are differences in absolute blood flow between patients with Crohns disease with inflammation or fibrosis using contrast-enhanced ultrasound. Eighteen patients with fibrotic disease and 19 patients with inflammation were examined. Video sequences of contrast data were analyzed using a pharmacokinetic model to extract the arterial input and tissue residue functions with a custom software, enabling calculation of the absolute values for mean transit time, blood volume and flow. Feasibility of the examination was 89%. The fibrosis group had lower blood volume (0.9 vs. 3.4 mL per 100 mL tissue; p = 0.001) and flow (22.6 vs. 45.3 mL/min per 100 mL tissue; p = 0.003) compared with the inflammation group. There was no significant difference in mean transit time (3.9 vs. 5.5 s). In conclusion, absolute perfusion measurement in the gastrointestinal wall using contrast-enhanced ultrasound is feasible. There seems to be reduced blood volume and blood flow in patients with fibrotic disease.

Two-dimensional blind Bayesian deconvolution of medical ultrasound images

A new approach to 2-D blind deconvolution of ultrasonic images in a Bayesian framework is presented. The radio-frequency image data are modeled as a convolution of the point-spread function and the tissue function, with additive white noise. The deconvolution algorithm is derived from statistical assumptions about the tissue function, the point-spread function, and the noise. It is solved as an iterative optimization problem. In each iteration, additional constraints are applied as a projection operator to further stabilize the process. The proposed method is an extension of the homomorphic deconvolution, which is used here only to compute the initial estimate of the point-spread function. Homomorphic deconvolution is based on the assumption that the point-spread function and the tissue function lie in different bands of the cepstrum domain, which is not completely true. This limiting constraint is relaxed in the subsequent iterative deconvolution. The deconvolution is applied globally to the complete radiofrequency image data. Thus, only the global part of the point-spread function is considered. This approach, together with the need for only a few iterations, makes the deconvolution potentially useful for real-time applications. Tests on phantom and clinical images have shown that the deconvolution gives stable results of clearly higher spatial resolution and better defined tissue structures than in the input images and than the results of the homomorphic deconvolution alone.

Superresolution of ultrasound images using the first and second harmonic signal

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/spl times/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.

Ultrasound perfusion analysis combining bolus-tracking and burst-replenishment

A new signal model and processing method for quantitative ultrasound perfusion analysis is presented, called bolus-and-burst. The method has the potential to provide absolute values of blood flow, blood volume, and mean transit time. Furthermore, it provides an estimate of the local arterial input function which characterizes the arterial tree, allowing accurate estimation of the bolus arrival time. The method combines two approaches to ultrasound perfusion analysis: bolus-tracking and burst-replenishment. A pharmacokinetic model based on the concept of arterial input functions and tissue residue functions is used to model both the bolus and replenishment parts of the recording. The pharmacokinetic model is fitted to the data using blind deconvolution. A preliminary assessment of the new perfusion-analysis method is presented on clinical recordings.

High-resolution ultrasonic imaging using two-dimensional homomorphic filtering

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

Single-Channel Blind Estimation of Arterial Input Function and Tissue Impulse Response in DCE-MRI

Multipass dynamic MRI and pharmacokinetic modeling are used to estimate perfusion parameters of leaky capillaries. Curve fitting and nonblind deconvolution are the established methods to derive the perfusion estimates from the observed arterial input function (AIF) and tissue tracer concentration function. These nonblind methods are sensitive to errors in the AIF, measured in some nearby artery or estimated by multichannel blind deconvolution. Here, a single-channel blind deconvolution algorithm is presented, which only uses a single tissue tracer concentration function to estimate the corresponding AIF and tissue impulse response function. That way, many errors affecting these functions are reduced. The validity of the algorithm is supported by simulations and tests on real data from mouse. The corresponding nonblind and multichannel methods are also presented.

Ultrasonic attenuation tomography based on log-spectrum analysis

The paper presents a new ultrasonic attenuation imaging method which might be used as a new imaging modality, targeted at breast cancer diagnostics. Two approaches based on ultrasonic imaging are combined together, namely the estimation of ultrasound attenuation coefficients from pulse-echo B-mode imaging data and an ultrasound computer tomography imaging technique. A recently published method for estimation of the ultrasound attenuation coefficient using the log--spectrum analysis is applied to radiofrequency signals acquired by an ultrasound computer tomography system to estimate images of the attenuation coefficients. The examined volume (e.g. female breast) is enclosed by several thousand ultrasound transducers. Radiofrequency signals from all transducers using all sending positions are recorded. Compared to the known ultrasound attenuation tomography methods, not only the directly transmitted signal, but also the reflected and scattered signals are processed here, i.e. substantially more information is used. The method is presented in its initial stage. The applied algorithm is derived using simplifying assumptions which will be relaxed in further research. However, even at this stage the resulting attenuation image is of higher quality than the standard attenuation imaging methods applied to the same data set.

Parametric ultrasound perfusion analysis combining bolus tracking and replenishment

The paper presents a new perfusion analysis method using ultrasound which combines burst-replenishment and bolustracking acquisition methods. It allows absolute quantification of the mean transit time, blood flow and blood volume. It is based on the concept of arterial input function and tissue residue function and is formulated as a blind-deconvolution problem. It is illustrated on recordings from Crohns disease patients.

Calibrating an Ultrasonic Computed Tomography System Using a Time-of-Flight Based Positioning Algorithm

This paper presents a method for geometrical and time-delay auto-calibration of an ultrasonic computed tomography (USCT) system. The algorithms used for the calibration are based on the principles similar to the global positioning system (GPS) navigation. Ultrasonic transmitters and receivers in USCT can be viewed like satellite transmitters and mobile receiver units in GPS. However, unlike in GPS, none of the positions of the transmitters or receivers in USCT are assumed to be known and all are the to-be-calibrated unknowns. The presented method is capable of calibrating the positions of all ultrasonic transducers and their individual time delays at once. No calibration phantoms are necessary.