Repeatability of arterial input functions and kinetic parameters in muscle obtained by dynamic contrast enhanced MR imaging of the head and neck

BACKGROUND: Quantification of pharmacokinetic parameters in dynamic contrast enhanced (DCE) MRI is heavily dependent on the arterial input function (AIF). In the present patient study on advanced stage head and neck squamous cell carcinoma (HNSCC) we have acquired DCE-MR images before and during chemo radiotherapy. We determined the repeatability of image-derived AIFs and of the obtained kinetic parameters in muscle and compared the repeatability of muscle kinetic parameters obtained with image-derived AIF's versus a population-based AIF. MATERIALS AND METHODS: We compared image-derived AIFs obtained from the internal carotid, external carotid and vertebral arteries. Pharmacokinetic parameters (ve, Ktrans, kep) in muscle-located outside the radiation area-were obtained using the Tofts model with the image-derived AIFs and a population averaged AIF. Parameter values and repeatability were compared. Repeatability was calculated with the pre- and post-treatment data with the assumption of no DCE-MRI measurable biological changes between the scans. RESULTS: Several parameters describing magnitude and shape of the image-derived AIFs from the different arteries in the head and neck were significantly different. Use of image-derived AIFs led to higher pharmacokinetic parameters compared to use of a population averaged AIF. Median muscle pharmacokinetic parameters values obtained with AIFs in external carotids, internal carotids, vertebral arteries and with a population averaged AIF were respectively: ve (0.65, 0.74, 0.58, 0.32), Ktrans (0.30, 0.21, 0.13, 0.06), kep (0.41, 0.32, 0.24, 0.18). Repeatability of pharmacokinetic parameters was highest when a population averaged AIF was used; however, this repeatability was not significantly different from image-derived AIFs. CONCLUSION: Image-derived AIFs in the neck region showed significant variations in the AIFs obtained from different arteries, and did not improve repeatability of the resulting pharmacokinetic parameters compared with the use of a population averaged AIF. Therefore, use of a population averaged AIF seems to be preferable for pharmacokinetic analysis using DCE-MRI in the head and neck area

Perfusion magnetic resonance neuroimaging

The clinical appliance of perfusion is being continuously developed and it is closely related to technology development. The role of perfusion neuroimaging in the management of acute stroke has been to prove reduced regional blood flow and to give the contribution in the identification of ischemic areas, respectively the regions of hypoperfusion that can be treated by thrombolytic and/or endovascular recanalization therapy. There are two main approaches to the measurement of cerebral perfusion by magnetic resonance. The aim of this article is to compare different measuring approaches of MR perfusion neuroimaging

Magnetic resonance imaging and the development of vascular targeted treatments for cancer.

The main subject of the work presented in this thesis is the further development of magnetic resonance imaging (MRI) as a non-invasive method of investigating tumour microcirculation. Two different MR techniques were used: dynamic contrast enhanced (DCE)-MRI and Blood Oxygen Level Dependent (BOLD)-MRI. Intravital microscopy was used to help interpret BOLD-MRI results. The ultimate aims were to determine whether MRI methods could be relied upon to define a drug as having vascular disrupting activity and to develop techniques to predict the effectiveness of vascular disruptive agents (VDA). In DCE-MRI, tissue enhancement is continuously monitored over several minutes after intravenous injection of contrast medium. Modelling of contrast agent kinetics generates quantitative parameters related to tissue blood flow rate and permeability, e.g. Ktrans (transfer constant). In a clinical study, patients had DCE-MRI examinations before and 24 hours after cytotoxic chemotherapy to establish whether any acute ami-vascular effects could be detected. No acute reductions in Ktrans were seen. In this project, the acute effects of the VDA, combretastatin A-4-phosphate, were investigated using DCE-MRI in SW1222 tumours in mice. Responses were seen both at a clinically relevant dose and at higher doses, and a dose-response relationship established. BOLD-MRI can detect changes in oxygenation and blood flow within tumours using deoxygenated haemoglobin as an intrinsic contrast agent. Tumours contain a variable proportion of immature vessels, which may explain differential sensitivity to VDAs. In this project, BOLD-MRI was used to assess tumour vessel maturity using consequent vasoreactivity to angiotensin II and carbon dioxide (as air-5%C02 or as carbogen) in an animal model. Intravital microscopy was used to directly observe response to these agents in mouse window chambers. Results suggest that response to vasoactive agents is useful for assessing vascular maturity in tumours but that more sensitive non-invasive imaging methods than BOLD-MRI are required for clinical use

Current status in spatiotemporal analysis of contrast‐based perfusion MRI

In perfusion MRI, image voxels form a spatially organized network of systems, all exchanging indicator with their immediate neighbors. Yet the current paradigm for perfusion MRI analysis treats all voxels or regions-of-interest as isolated systems supplied by a single global source. This simplification not only leads to long-recognized systematic errors but also fails to leverage the embedded spatial structure within the data. Since the early 2000s, a variety of models and implementations have been proposed to analyze systems with between-voxel interactions. In general, this leads to large and connected numerical inverse problems that are intractible with conventional computational methods. With recent advances in machine learning, however, these approaches are becoming practically feasible, opening up the way for a paradigm shift in the approach to perfusion MRI. This paper seeks to review the work in spatiotemporal modelling of perfusion MRI using a coherent, harmonized nomenclature and notation, with clear physical definitions and assumptions. The aim is to introduce clarity in the state-of-the-art of this promising new approach to perfusion MRI, and help to identify gaps of knowledge and priorities for future research

短時間の造影ダイナミック灌流画像を用いた脳腫瘍の質的診断について

This study sought to determine the diagnostic utility of perfusion parameters derived from dynamic contrast-enhanced (DCE) perfusion MRI with a short acquisition time (approximately 3.5 min) in patients with glioma, brain metastasis, and primary CNS lymphoma (PCNSL). Twenty-six patients with 29 lesions (4 low-grade glioma, 13 high-grade glioma, 7 metastasis, and 5 PCNSL) underwent DCE-MRI in a 3 T scanner. A ROI was placed on the hotspot of each tumor in maps for volume transfer contrast Ktrans, extravascular extracellular volume Ve, and fractional plasma volume Vp. We analyzed differences in parameters between tumors using the Mann–Whitney U test. We calculated sensitivity and specificity using receiver operating characteristics analysis. Mean K trans values of LGG, HGG, metastasis and PCNSL were 0.034, 0.31, 0.38, 0.44, respectively. Mean Ve values of each tumors was 0.036, 0.57, 0.47, 0.96, and mean Vp value of each tumors was 0.070, 0.086, 0.26, 0.17, respectively. Compared with other tumor types, low-grade glioma showed lower Ktrans (P < 0.01, sensitivity = 88%, specificity = 100%) and lower Ve (P < 0.01, sensitivity = 96%, specificity = 100%). PCNSL showed higher Ve (P < 0.01, sensitivity = 100%, specificity = 88%), but the other perfusion parameters overlapped with those of different histology. Kinetic parameters derived from DCE-MRI with short acquisition time provide useful information for the differential diagnosis of brain tumors

Assessing Antiangiogenic Therapy Response by DCE-MRI: Development of a Physiology Driven Multi-Compartment Model Using Population Pharmacometrics

Dynamic contrast enhanced (DCE-) MRI is commonly applied for the monitoring of antiangiogenic therapy in oncology. Established pharmacokinetic (PK) analysis methods of DCE-MRI data do not sufficiently reflect the complex anatomical and physiological constituents of the analyzed tissue. Hence, accepted endpoints such as Ktrans reflect an unknown multitude of local and global physiological effects often rendering an understanding of specific local drug effects impossible. In this work a novel multi-compartment PK model is presented, which for the first time allows the separation of local and systemic physiological effects. DCE-MRI data sets from multiple, simultaneously acquired tissues, i.e. spinal muscle, liver and tumor tissue, of hepatocellular carcinoma (HCC) bearing rats were applied for model development. The full Markov chain Monte Carlo (MCMC) Bayesian analysis method was applied for model parameter estimation and model selection was based on histological and anatomical considerations and numerical criteria. A population PK model (MTL3 model) consisting of 3 measured and 6 latent (unobserved) compartments was selected based on Bayesian chain plots, conditional weighted residuals, objective function values, standard errors of model parameters and the deviance information criterion. Covariate model building, which was based on the histology of tumor tissue, demonstrated that the MTL3 model was able to identify and separate tumor specific, i.e. local, and systemic, i.e. global, effects in the DCE-MRI data. The findings confirm the feasibility to develop physiology driven multi-compartment PK models from DCE-MRI data. The presented MTL3 model allowed the separation of a local, tumor specific therapy effect and thus has the potential for identification and specification of effectors of vascular and tissue physiology in antiangiogenic therapy monitoring

Intraoperative Quantification of Bone Perfusion in Lower Extremity Injury Surgery

Orthopaedic surgery is one of the most common surgical categories. In particular, lower extremity injuries sustained from trauma can be complex and life-threatening injuries that are addressed through orthopaedic trauma surgery. Timely evaluation and surgical debridement following lower extremity injury is essential, because devitalized bones and tissues will result in high surgical site infection rates. However, the current clinical judgment of what constitutes “devitalized tissue” is subjective and dependent on surgeon experience, so it is necessary to develop imaging techniques for guiding surgical debridement, in order to control infection rates and to improve patient outcome. In this thesis work, computational models of fluorescence-guided debridement in lower extremity injury surgery will be developed, by quantifying bone perfusion intraoperatively using Dynamic contrast-enhanced fluorescence imaging (DCE-FI) system. Perfusion is an important factor of tissue viability, and therefore quantifying perfusion is essential for fluorescence-guided debridement. In Chapters 3-7 of this thesis, we explore the performance of DCE-FI in quantifying perfusion from benchtop to translation: We proposed a modified fluorescent microsphere quantification technique using cryomacrotome in animal model. This technique can measure bone perfusion in periosteal and endosteal separately, and therefore to validate bone perfusion measurements obtained by DCE-FI; We developed pre-clinical rodent contaminated fracture model to correlate DCE-FI with infection risk, and compare with multi-modality scanning; Furthermore in clinical studies, we investigated first-pass kinetic parameters of DCE-FI and arterial input functions for characterization of perfusion changes during lower limb amputation surgery; We conducted the first in-human use of dynamic contrast-enhanced texture analysis for orthopaedic trauma classification, suggesting that spatiotemporal features from DCE-FI can classify bone perfusion intraoperatively with high accuracy and sensitivity; We established clinical machine learning infection risk predictive model on open fracture surgery, where pixel-scaled prediction on infection risk will be accomplished. In conclusion, pharmacokinetic and spatiotemporal patterns of dynamic contrast-enhanced imaging show great potential for quantifying bone perfusion and prognosing bone infection. The thesis work will decrease surgical site infection risk and improve successful rates of lower extremity injury surgery

Measurement of the vascular input function in mice for DCE-MRI

DCE-MRI is an important technique in the study of small animal cancer models because its sensitivity to vascular changes opens the possibility of quantitative assessment of early therapeutic response. However, extraction of physiologically descriptive parameters from DCE-MRI data relies upon measurement of the vascular input function (VIF), which represents the contrast agent concentration time course in the blood plasma. This is difficult in small animal models due to artifacts associated with partial volume, inflow enhancement, and the limited temporal resolution achievable with MR imaging. In this work, the development of a suite of techniques for high temporal resolution, artifact resistant measurement of the VIF in mice is described. One obstacle in VIF measurement is inflow enhancement, which decreases the sensitivity of the MR signal to the presence of contrast agent. Because the traditional techniques used to suppress inflow enhancement degrade the achievable spatiotemporal resolution of the pulse sequence, improvements can be achieved by reducing the time required for the suppression. Thus, a novel RF pulse which provides spatial presaturation contemporaneously with the RF excitation was implemented and evaluated. This maximizes the achievable temporal resolution by removing the additional RF and gradient pulses typically required for suppression of inflow enhancement. A second challenge is achieving the temporal resolution required for accurate characterization of the VIF, which exceeds what can be achieved with conventional imaging techniques while maintaining adequate spatial resolution and tumor coverage. Thus, an anatomically constrained reconstruction strategy was developed that allows for sampling of the VIF at extremely high acceleration factors, permitting capture of the initial pass of the contrast agent in mice. Simulation, phantom, and in vivo validation of all components were performed. Finally, the two components were used to perform VIF measurement in the murine heart. An in vivo study of the VIF reproducibility was performed, and an improvement in the measured injection-to-injection variation was observed. This will lead to improvements in the reliability of quantitative DCE-MRI measurements and increase their sensitivity

Translational studies on the vascular targeting agent combretastatin A4 phosphate

This thesis describes in vitro experiments with the novel vascular targeting agent Combretastatin A4 Phosphate (CA4P) and non-invasive magnetic resonance imaging (MRI) measurements in patients treated with CA4P to derive parameters which reflect tumour and normal tissue blood flow and permeability. Shape changes induced following tubulin depolymerisation by CA4P are quantified in human umbilical vein endothelial cells (HUVECs) and are measurable after only 10 minutes exposure. The effect is more marked in proliferating than confluent HUVECs, and begins at doses that have no anti-proliferative activity. In contrast, human smooth muscle cells show no shape change after treatment. The similar time course of HUVEC shape changes in vitro and tumour vascular shutdown in vitro suggest that this might be an early event involved in vascular shutdown. The effects and recovery rates of several other tubulin-binding agents are compared with CA4P. Colchicine and vinblastine also induce changes in HUVEC shape but unlike CA4P, HUVECs do not recover after drug removal. For these drugs, shape change and antiproliferative effects occur at similar doses. ZD6126, which like CA4P also has vascular targeting activity at well tolerated doses, induces recoverable changes in HUVEC shape at doses with no anti-proliferative activity. The difference in recovery rates with different tubulin-binding agents might therefore be related to their therapeutic window. The reproducibility of dynamic contrast enhanced MRI is measured in 21 patients who had 2 pre treatment scans within a week. Comparing the technique in rats with an established method for measuring absolute blood flow provides verification that the kinetic parameters derived from this technique reflect blood flow changes. Significant reductions in these parameters in patients' tumours are seen 4 and 24 hours after treatment at well tolerated doses of CA4P at 52mg/m2 to 68 mg/m2. No significant mean changes are seen in kidney, liver, spleen or skeletal muscle, although a small proportion of patients have significant reductions which are generally not maintained, and not associated with clinical consequences