Vessel Size Imaging Research Articles

Biomarkers and perfusion – training-induced changes after stroke (BAPTISe): protocol of an observational study accompanying a randomized controlled trial

BackgroundPhysical activity is believed to exert a beneficial effect on functional and cognitive rehabilitation of patients with stroke. Although studies have addressed the impact of physical exercise in cerebrovascular prevention and rehabilitation, the underlying mechanisms leading to improvement are poorly understood. Training-induced increase of cerebral perfusion is a possible mediating mechanism. Our exploratory study aims to investigate training-induced changes in blood biomarker levels and magnetic resonance imaging in patients with subacute ischemic stroke.Methods/designThis biomarker-driven study uses an observational design to examine a subgroup of patients in the randomized, controlled PHYS-STROKE trial. In PHYS-STROKE, 215 patients with subacute stroke (hemorrhagic and ischemic) receive either 4 weeks of physical training (aerobic training, 5 times a week, for 50 minutes) or 4 weeks of relaxation sessions (5 times a week, for 50 minutes). A convenience sample of 100 of these patients with ischemic stroke will be included in BAPTISe and will receive magnetic resonance imaging (MRI) scans and an additional blood draw before and after the PHYS-STROKE intervention. Imaging scans will address parameters of cerebral perfusion, vessel size imaging, and microvessel density (the Q factor) to estimate the degree of neovascularization in the brain. Blood tests will determine several parameters of immunity, inflammation, endothelial function, and lipometabolism. Primary objective of this study is to evaluate differential changes in MRI and blood-derived biomarkers between groups. Other endpoints are next cerebrovascular events and functional status of the patient after the intervention and after 3 months assessed by functional scores, in particular walking speed and Barthel index (co-primary endpoints of PHYS-STROKE). Additionally, we will assess the association between functional outcomes and biomarkers including imaging results. For all endpoints we will compare changes between patients who received physical fitness training and patients who had relaxation sessions.DiscussionThis exploratory study will be the first to investigate the effects of physical fitness training in patients with ischemic stroke on MRI-based cerebral perfusion, pertinent blood biomarker levels, and functional outcome. The study may have an impact on current patient rehabilitation strategies and reveal important information about the roles of MRI and blood-derived biomarkers in ischemic stroke.Trial registrationNCT01954797.

Vessel Size Imaging (VSI) by Robust Magnetic Resonance (MR) Relaxometry: MR-VSI of Solid Tumors in Correlation with Immunohistology and Intravital Microscopy

The aim of this study was to evaluate a robust magnetic resonance (MR) vessel size imaging (VSI) method for the noninvasive assessment of mean vessel size in solid tumors in a clinical dose range of ultrasmall superparamagnetic particles of iron oxide (USPIO). Therefore, USPIO-enhanced MR-VSI was performed on DU-4475, MDA-MB-435, and EOMA tumor-bearing mice xenografts with known differences in angiogenic activity and vessel morphology. MR results were compared to vessel sizes determined by immunohistochemistry (anti-CD31) and by intravital microscopy (IVM). MR-VSI revealed significantly different mean vessel sizes between the xenograft models at both USPIO doses (DU-4475: 20.6 ± 4.9 μm; MDA-MB-435: 37.4 ± 8.8 μm; and EOMA: 60.3 ±9.6 μm at 80 μmol/kg; p < .05). Immunohistochemistry revealed lower values for all tumor entities, whereas the size distribution was in line with MR-measurements. IVM corroborated the MR results for DU-4475 and MDA-MB435, but showed similar vessel sizes for MDA-MB-435 and EOMA. Our MR-VSI method allowed a noninvasive estimation of the mean vessel size in mice xenograft solid tumors with variable vascularity using a clinically relevant USPIO dose range.

The influence of noise on BOLD-mediated vessel size imaging analysis methods.

Vessel size imaging (VSI) is a magnetic resonance imaging (MRI) technique that aims to provide quantitative measurements of tissue microvasculature. An emerging variation of this technique uses the blood oxygenation level-dependent (BOLD) effect as the source of the imaging contrast. Gas challenges have the advantage over contrast injection techniques in that they are noninvasive and easily repeatable because of the fast washout of the contrast. However, initial results from BOLD-VSI studies are somewhat contradictory, with substantially different estimates of the mean vessel radius. Owing to BOLD-VSI being an emerging technique, there is not yet a standard processing methodology, and different techniques have been used to calculate the mean vessel radius and reject uncertain estimates. In addition, the acquisition methodology and signal modeling vary from group to group. Owing to these differences, it is difficult to determine the source of this variation. Here we use computer modeling to assess the impact of noise on the accuracy and precision of different BOLD-VSI calculations. Our results show both potential overestimates and underestimates of the mean vessel radius, which is confirmed with a validation study at 3T.

Combretastatin A-4 Phosphate Affects Tumor Vessel Volume and Size Distribution as Assessed Using MRI-Based Vessel Size Imaging

Combretastatin A-4 disodium phosphate (CA4P) is a promising vascular disrupting agent (VDA) in clinical trials. As CA4P acts on dividing endothelial cells, we hypothesize that CA4P affects vessels of certain sizes. The aim of this study was to evaluate the effect of CA4P by the MRI-based vessel size imaging (VSI). C3H mammary carcinomas were grown to 200 mm(3) in the right rear foot of female CDF(1) mice. A control group of mice received no treatment, and a treatment group had CA4P administered intraperitoneally at a dose of 250 mg/kg. VSI was conducted on a 3 Tesla MR scanner to estimate the tumor blood volume (ζ(0)) and mean vessel radius (R). Vascularization was also estimated histologically by endothelial and Hoechst 33342 staining. ζ(0) and R showed different spatial heterogeneity. Tumor median and quartile values of ζ(0) were all significantly reduced by about 35% in the CA4P-treated group as compared with the control group, and the median and upper quartile of R were significantly increased. Histograms of ζ(0) and R showed a general decrease in ζ(0) following treatment, and values of R in a certain range (≈20-30 μm) were decreased in the treatment group. The drug-induced change in ζ(0) was in agreement with histology and our previous dynamic contrast enhanced MRI (DCE-MRI) data. Tumor blood volume and mean vessel radius showed a clear response following treatment with CA4P. VSI may prove valuable in estimation of tumor angiogenesis and prediction of response to VDAs.

Highlights of This Issue

The impact of pretransplantation iron overload on patient outcome after allogeneic stem cell transplantation is controversially discussed, because recent studies were retrospective in nature and relied on interference prone surrogate markers. Wermke and colleagues report prospective data based on liver MRI to quantify the extent of body iron in this context. In their cohort, surrogate parameters failed to accurately identify iron overloaded patients. Moreover, only liver iron as determined by MRI but not serum ferritin or transfusion burden predicted for survival. It will be important to understand the mechanisms by which excessive iron contributes to a worse outcome after transplantation.Measurement of HER family signaling is critically important in the clinical management of a significant number of breast cancer patients. Using a highly sensitive protein array, Wulfkuhle and colleagues identified a new subgroup of breast cancer patients with HER2 pathway activation in an otherwise HER2- negative cohort. These patients are not identified by current clinically approved or genomic tests for HER2, and are thus excluded from anti-HER2 therapies. Protein pathway activation mapping of receptor tyrosine kinases and linked signaling pathways may identify new patient cohorts that could benefit from existing FDA cleared and/or experimental molecular targeted inhibitors, if these measurements prove clinically useful.The novel magnetic resonance imaging method of vessel size imaging (VSI) provides in vivo images of blood volume and mean vessel radius. Using an intravascular contrast agent of the ultrasmall paramagnetic iron oxide class, Nielsen and colleagues utilized VSI for investigating the effect of the vascular disrupting agent combretastatin in a murine tumor model. Treatment with combretastatin reduced blood volume and indicated a change in the distribution of vessel sizes. VSI may be valuable in assessing tumor angiogenesis, prediction of response to vascular disrupting agents, and treatment monitoring.Adjuvant setting represents the optimal set to test the tumor vaccines because of the more conserved immune conditions of early cancer patients. In this phase II randomized trial, Filipazzi and colleagues used modified tumor peptides to immunize stage II–III melanoma patients. However, in spite of a prompt and persisting immune response, no evident clinical benefit was detected in vaccinated versus control patients. The limited number of true antitumor T cells induced by vaccination, unraveled by an extensive immunologic monitoring, shows that the choice of the immunization strategy is a critical step and that the use of modified peptides should be reconsidered.

Monitoring Molecular, Functional and Morphologic Aspects of Bone Metastases Using Non-Invasive Imaging

Bone is among the most common locations of metastasis and therefore represents an important clinical target for diagnostic follow-up in cancer patients. In the pathogenesis of bone metastases, disseminated tumor cells proliferating in bone interact with the local microenvironment stimulating or inhibiting osteoclast and osteoblast activity. Non-invasive imaging methods monitor molecular, functional and morphologic changes in both compartments of these skeletal lesions - the bone and the soft tissue tumor compartment. In the bone compartment, morphologic information on skeletal destruction is assessed by computed tomography (CT) and radiography. Pathogenic processes of osteoclast and osteoblast activity, however, can be imaged using optical imaging, positron emission tomography (PET), single photon emission CT (SPECT) and skeletal scintigraphy. Accordingly, conventional magnetic resonance imaging (MRI) and CT as well as diffusion- weighted MRI and optical imaging are used to assess morphologic aspects on the macroscopic and cellular level of the soft tissue tumor compartment. Imaging methods such as PET, MR spectroscopy, dynamic contrast-enhanced techniques and vessel size imaging further elucidate on pathogenic processes in this compartment including information on metabolism and vascularization. By monitoring these aspects in bone lesions, new insights in the pathogenesis of skeletal metastases can be gained. In translation to the clinical situation, these novel methods for the monitoring of bone metastases might be applied in patients to improve follow-up of these lesions, in particular after therapeutic intervention. This review summarizes established and experimental imaging techniques for the monitoring of tumor and bone cell activity including molecular, functional and morphological aspects in bone metastases.

The Potential of Microvessel Density in Prediction of Infarct Growth: A Two-Month Experimental Study in Vessel Size Imaging

Objectives: Vessel size imaging is a novel technique to evaluate pathological changes of the microvessel density quantity Q and the mean vessel size index (VSI). As a follow-up study, we assessed these parameters for microscopic description of ischemic penumbra and their potentials in predicting lesion growth. Methods: Seventy-five patients with a perfusion-diffusion mismatch were examined within 24 h from symptom onset. We defined three regions of interest: the initial infarct (INF), the ischemic penumbra (IPE), and the healthy region (HEA) symmetric to the IPE. For 23 patients with a 6th-day follow-up, IPE regions were divided into areas of infarct growth and areas of oligemia. Result: The median values of Q and VSI were: for INF 0.29 s^-1/3 and 15.8 µm, for IPE 0.33 s^-1/3 and 20.6 µm and for HEA 0.36 s^-1/3 and 17.4 µm. The Q in the IPE was significantly smaller than in HEA, and VSI was significantly larger. The Q with a threshold of 0.32 s^-1/3 predicted the final infarction with a sensitivity of 69% and a specificity of 64%. Conclusions: The reduced Q and increased VSI in the IPE confirmed our previous pilot results. Although Q showed a trend to identify the severity of ischemia in an overall voxel population, its potential in predicting infarct growth needs to be further tested in a larger cohort including a clear status of reperfusion and recanalization.

Combined spin‐ and gradient‐echo perfusion‐weighted imaging

In this study, a spin- and gradient-echo echo-planar imaging (SAGE EPI) MRI pulse sequence is presented that allows simultaneous measurements of gradient-echo and spin-echo dynamic susceptibility-contrast perfusion-weighted imaging data. Following signal excitation, five readout trains were acquired using spin- and gradient-echo echo-planar imaging, all of them with echo times of less than 100 ms. Contrast agent concentrations in brain tissue were determined based on absolute R2* and R(2) estimates rather than relative changes in the signals of individual echo trains, producing T(1)-independent dynamic susceptibility-contrast perfusion-weighted imaging data. Moreover, this acquisition technique enabled vessel size imaging through the simultaneous quantification of R2* and R(2), without an increase in acquisition time. In this work, the concepts of SAGE EPI pulse sequence and results in stroke and tumor imaging are presented. Overall, SAGE EPI combined the advantages of higher sensitivity to contrast agent passage of gradient-echo perfusion-weighted imaging with better microvascular selectivity of spin-echo perfusion-weighted imaging.

Vascular component analysis of hyperoxic and hypercapnic BOLD contrast

Hyperoxia or hypercapnia provides a useful experimental tool to systematically alter the blood oxygenation level dependent (BOLD) contrast. Typical applications include calibrated functional magnetic resonance imaging (fMRI), BOLD sensitivity mapping, vessel size imaging or cerebrovascular reactivity mapping. This article describes a novel biophysical model of hyperoxic and hypercapnic BOLD contrast, which accounts for the magnetic susceptibility effects of molecular oxygen that is dissolved in blood and tissue, in addition to the well-established effects caused by the paramagnetic properties of deoxyhaemoglobin. Furthermore, the concept of vascular component analysis (VCA) is introduced and is shown to provide a computationally efficient tool for investigating the vascular specificity of hyperoxic and hypercapnic BOLD contrast. A theoretical investigation of gradient and spin echo BOLD contrast based on computer simulations was performed to compare three different conditions (hypercapnia induced by breathing 6% CO2, hyperoxia induced by breathing 100% O2, and simultaneous hypercapnia and hyperoxia induced by breathing carbogen, i.e. 5% CO2 in 95% CO2) with baseline (breathing air). Simulations were carried out for different levels of metabolic oxygen extraction fraction (OEF) ranging from 0 to 0.5. The key findings can be summarised as follows: (i) for hyperoxia the susceptibility of dissolved O2 may lead to a significant arterial BOLD contrast; (ii) under normoxic conditions the susceptibility of dissolved O2 is negligible; (iii) an almost complete loss of BOLD sensitivity may occur at lower OEF values in all parts of the vascular tree, whereas hyperoxic BOLD sensitivity is largely maintained; (iv) under hyperoxic conditions, a transition from positive to negative BOLD contrast occurs with decreasing OEF values. These findings have important implications for experimental applications of hyperoxic and hypercapnic BOLD contrast and may enable new clinical applications in ischemic stroke and other forms of acquired brain injury.

S.14.02 Imaging modalities to determine pathophysiological changes in the brain and the blood–brain barrier

In the context of neurologic disorders, dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE) MRI provide valuable insights into cerebral vascular function, integrity, and architecture. Even after two decades of use, these modalities continue to evolve as their biophysical and kinetic basis is better understood, with improvements in pulse sequences and accelerated imaging techniques and through application of more robust and automated data analysis strategies. Here, we systematically review each of these elements, with a focus on how their integration improves kinetic parameter accuracy and the development of new hemodynamic biomarkers that provide sub-voxel sensitivity (e.g., capillary transit time and flow heterogeneity). Regarding contrast mechanisms, we discuss the dipole-dipole interactions and susceptibility effects that give rise to simultaneous T1, T2 and T2∗ relaxation effects, including their quantification, influence on pulse sequence parameter optimization, and use in methods such as vessel size and vessel architectural imaging. The application of technologic advancements, such as parallel imaging, simultaneous multi-slice, undersampled k-space acquisitions, and sliding window strategies, enables improved spatial and/or temporal resolution of DSC and DCE acquisitions. Such acceleration techniques have also enabled the implementation of, clinically feasible, simultaneous multi-echo spin- and gradient echo acquisitions, providing more comprehensive and quantitative interrogation of T1, T2 and T2∗ changes. Characterizing these relaxation rate changes through different post-processing options allows for the quantification of hemodynamics and vascular permeability. The application of different biophysical models provides insight into traditional hemodynamic parameters (e.g., cerebral blood volume) and more advanced parameters (e.g., capillary transit time heterogeneity). We provide insight into the appropriate selection of biophysical models and the necessary post-processing steps to ensure reliable measurements while minimizing potential sources of error. We show representative examples of advanced DSC- and DCE-MRI methods applied to pathologic conditions affecting the cerebral microcirculation, including brain tumors, stroke, aging, and multiple sclerosis. The maturation and standardization of conventional DSC- and DCE-MRI techniques has enabled their increased integration into clinical practice and use in clinical trials, which has, in turn, spurred renewed interest in their technological and biophysical development, paving the way towards a more comprehensive assessment of cerebral hemodynamics.

Quantitative phenomenological model of the BOLD contrast mechanism

Different theoretical models of the BOLD contrast mechanism are used for many applications including BOLD quantification (qBOLD) and vessel size imaging, both in health and disease. Each model simplifies the system under consideration, making approximations about the structure of the blood vessel network and diffusion of water molecules through inhomogeneities in the magnetic field created by deoxyhemoglobin-containing blood vessels. In this study, Monte-Carlo methods are used to simulate the BOLD MR signal generated by diffusing water molecules in the presence of long, cylindrical blood vessels. Using these simulations we introduce a new, phenomenological model that is far more accurate over a range of blood oxygenation levels and blood vessel radii than existing models. This model could be used to extract physiological parameters of the blood vessel network from experimental data in BOLD-based experiments. We use our model to establish ranges of validity for the existing analytical models of Yablonskiy and Haacke, Kiselev and Posse, Sukstanskii and Yablonskiy (extended to the case of arbitrary time in the spin echo sequence) and Bauer et al. (extended to the case of randomly oriented cylinders). Although these models are shown to be accurate in the limits of diffusion under which they were derived, none of them is accurate for the whole physiological range of blood vessels radii and blood oxygenation levels. We also show the extent of systematic errors that are introduced due to the approximations of these models when used for BOLD signal quantification.

Vessel Size Imaging Reveals Pathological Changes of Microvessel Density and Size in Acute Ischemia

The aim of this study was to test the feasibility of vessel size imaging with precise evaluation of apparent diffusion coefficient and cerebral blood volume and to apply this novel technique in acute stroke patients within a pilot group to observe the microvascular responses in acute ischemic tissue. Microvessel density-related quantity Q and mean vessel size index (VSI) were assessed in 9 healthy volunteers and 13 acute stroke patients with vessel occlusion within 6 hours after symptom onset. Our results in healthy volunteers matched with general anatomical observations. Given the limitation of a small patient cohort, the median VSI in the ischemic area was higher than that in the mirrored region in the contralateral hemisphere (P<0.05). Decreased Q was observed in the ischemic region in 2 patients, whereas no obvious changes of Q were found in the remaining 11 patients. In a patient without recanalization, the VSI hyperintensity in the subcortical area matched well with the final infarct. These data reveal that different observations of microvascular response in the acute ischemic tissue seem to emerge and vessel size imaging may provide useful information for the definition of ischemic penumbra and have an impact on future therapeutic approaches.

Magnetic resonance imaging of the mean venous vessel size in the human brain using transient hyperoxia

Vessel size imaging is an emerging magnetic resonance imaging (MRI) technique which has been demonstrated to provide clinically relevant information about microvascular morphology. While previous studies of vessel size in humans relied on MRI contrast agents or hypercapnia-induced changes in blood oxygenation, the technique described here uses transient hyperoxia to alter the venous blood oxygenation. The experimental paradigm consisted of two 3-minute intervals of breathing 100% O2 interleaved with three 2-minute intervals of breathing room air. Parametric maps of the mean venous vessel radius were calculated from changes in the blood oxygenation level dependent (BOLD) contrast which were measured using a combined spin-echo (SE) and gradient echo (GE) echo-planar imaging (EPI) sequence. The corresponding mean values in grey and white matter were r=6.5±0.3μm and r=6.2±0.3μm (n=6). While the hypercapnia technique requires a specialised gas mixture containing a low concentration of CO2 (typically 5–6%), the hyperoxia technique presented here uses the inhalation of medical oxygen (100% O2) which is routinely available in a clinical environment. Furthermore, 100% O2 is generally better tolerated than low doses of CO2 which makes this technique particularly suitable for applications in critically ill patients.

Sorafenib tosylate and paclitaxel induce anti-angiogenic, anti-tumour and anti-resorptive effects in experimental breast cancer bone metastases

Purpose In this study we investigated sorafenib tosylate and paclitaxel as single and combination therapies regarding their effects on tumour growth and vasculature as well as their potency to inhibit osteolysis in experimental breast cancer bone metastases. Experimental design Nude rats bearing breast cancer bone metastases were treated with sorafenib tosylate (7 mg/kg, n = 11), paclitaxel (5 mg/kg, n = 11) or the combination of both ( n = 10) and were compared to untreated controls ( n = 11). In a longitudinal study, volumes of osteolyses and respective soft tissue tumours were measured in these groups by MRI and volume CT, while changes in cellularity within bone metastases were assessed by diffusion-weighted imaging. Dynamic contrast-enhanced MRI and vessel size imaging was performed to determine changes of tumour vasculature within osseous lesions non-invasively. Results Animals treated with sorafenib tosylate or paclitaxel showed significantly reduced growth of both, the osteolytic lesions and the soft tissue tumours as well as a decreased cellularity in bone metastases compared to control rats. Effects on the tumour vasculature of these drugs included significantly reduced blood volume as well as significant changes of the vessel permeability and the mean vessel calibers. When combining sorafenib tosylate with paclitaxel for the treatment of bone metastases positive combination effects were observed, particularly on reducing vessel permeability in these lesions. Conclusion The application of sorafenib tosylate monotherapy or in combination with paclitaxel is effective against experimental breast cancer bone metastases resulting in anti-angiogenic, anti-tumour and anti-resorptive effects.

Drug-Induced Vessel Remodeling in Bone Metastases as Assessed by Dynamic Contrast Enhanced Magnetic Resonance Imaging and Vessel Size Imaging: A LongitudinalIn vivoStudy

The aim of this study was to assess the antiangiogenic treatment effects of zoledronic acid (ZA) and sunitinib malate (SM) noninvasively in experimental breast cancer bone metastases by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging. Nude rats bearing bone metastases after inoculation of MDA-MB-231 breast cancer cells were treated with ZA (40 microg/kg weekly; n = 8 rats), SM (20 mg/kg daily; n = 8 rats), or their combination (ZA and SM; n = 8 rats) and compared with sham-treated controls (n = 10 rats). Vascular changes in bone metastases were longitudinally imaged in vivo using DCE-MRI [amplitude (A) and exchange rate coefficient (k(ep))] and vessel size imaging [blood volume (BV) and vessel size index (VI)]. In addition, antiresorptive and antitumor changes were assessed in these lesions by flat-panel volumetric computed tomography as well as morphologic MRI and diffusion-weighted imaging. In bone metastases, significant changes in A, k(ep), BV, and VI in accordance with decreased blood volume and vessel permeability as well as with increased mean vessel diameters were observed after application of ZA and SM as compared with controls. In this longitudinal study, antiangiogenic changes preceded the inhibition of osteolysis and antitumor effects after treatment. These results indicate vessel remodeling in breast cancer bone metastases on ZA and SM treatment and implicate substantial effects on imaging and treatment of malignant bone lesions.

Highlights of This Issue

Angiogenesis plays a crucial role in the development of bone metastases. To examine vascular changes in experimental breast cancer bone metastases upon treatment with zoledronic acid and sunitinib malate, Bäuerle and colleagues used dynamic contrast enhanced MRI and vessel size imaging in a longitudinal in vivo study. Resulting parameters from noninvasive imaging indicated vessel remodeling in these osseous lesions after application of zoledronic acid and sunitinib malate, which could be assessed before antiresorptive and antitumor effects of these treatments were detected. These results suggest that imaging could be used for early assessment of treatment response in malignant bone lesions.In recent years, the study of cancer stem cells (CSCs) has garnered much attention. In this issue of CCR Focus, guest editor Percy Ivy provides an overview of research surrounding CSCs and addresses some of the controversies in the field. Topics in CSC biology are discussed, including CSC identification and characterization, the CSC self-renewal pathway, and interaction of CSCs with the microenvironment. A particular emphasis is placed on translating our underlying knowledge of CSC biology into the development of anticancer therapeutics, and efforts to target several pathways involved in CSCs, including the Wnt, Notch, and Hedgehog signaling pathways, are described.Histone deacetylases (HDACs) 1–11 are differentially expressed in cancer tissues; however, more research is needed on the role of individual HDACs in tumor biology. In this study, Milde and colleagues found that class II HDACs 5 and 9 were significantly upregulated in medulloblastoma tumors with poor prognosis, and high HDAC5 and HDAC9 mRNA expression was an independent risk factor for poor survival in multifactorial analysis. Furthermore, siRNA-mediated knockdown of HDAC5 or HDAC9 resulted in decreased tumor cell growth. These findings implicate HDAC5 and HDAC9 as potential therapeutic targets in medulloblastoma.Local CD40-directed therapies, which aim to tilt tumor-induced immunosuppression in favor of antitumor responses, have shown promise in experimental models. Malmström and colleagues used adenovector-based gene therapy to introduce the human CD40 ligand (CD40L) gene into the tumor milieu. In a Phase I/IIa trial of patients with urinary bladder carcinoma, they found that AdCD40L therapy was safe and that it stimulated a massive immune cell infiltration into the bladder wall. Further, several patients had few, or no, remaining high-grade malignant cells following treatment. These results suggest that AdCD40L therapy has potential for local application on patients with solid tumors.

Evaluation of magnetic resonance vessel size imaging by two-photon laser scanning microscopy

MR vessel size imaging (MR-VSI) is increasingly applied to noninvasively assess microvascular properties of tumors and to evaluate tumor response to antiangiogenic treatment. MR-VSI provides measures for the microvessel radius and fractional blood volume of tumor tissue. However, data have not yet been evaluated with three-dimensional microscopy techniques. Therefore, three-dimensional two-photon laser scanning microscopy (TPLSM) was performed to assess microvascular radius and fractional vessel volume in tumor and muscle tissue. TPLSM data displayed a mazelike architecture of the tumor microvasculature and mainly parallel oriented muscle microvessels. For both MR-VSI and TPLSM, a larger vessel radius and fractional blood volume were found in the tumor rim than in the core. The microvessel radius was approximately six times larger in tumor and muscle for MR-VSI than for TPLSM. The tumor blood volume was 4-fold lower with MR-VSI than with TPLSM, whereas muscle blood volume was comparable for both techniques. Differences between the tumor rim, core, and muscle tissue showed similar trends for both MR-VSI and TPLSM parameters. These results indicate that MR-VSI does not provide absolute measures of microvascular morphology; however, it does reflect heterogeneity in microvascular morphology. Hence, MR-VSI may be used to assess differences in microvascular morphology.

The Assessment of Vessel Size Imaging and Its Application in Patients with Ischemic Stroke

The Assessment of Vessel Size Imaging and Its Application in Patients with Ischemic Stroke

Whole-brain mapping of venous vessel size in humans using the hypercapnia-induced BOLD effect

Measuring the morphology of the cerebral microvasculature by vessel-size imaging (VSI) is a promising approach for clinical applications, such as the characterization of tumor angiogenesis and stroke. Despite the great potential of VSI, this method has not yet found widespread use in practice due to the lack of experience in testing it on healthy humans. Since this limitation derives mainly from the need for an invasive injection of a contrast agent, this work explores the possibility to employ instead the easily accessible blood oxygenation level dependent (BOLD) effect for VSI of the venous microstructure. It is demonstrated that BOLD-VSI in humans can be realized by a hypercapnic challenge using a fast gradient-echo (GE) and spin-echo (SE) sequence at 7T. Reproducible maps of the mean venous vessel radius, based on the BOLD-induced changes in GE and SE relaxation rates, could be obtained within a scan time of 10min. Moreover, the method yields maps of venous blood volume and vessel density. Owing to its non-invasive character, BOLD-VSI provides a low-risk method to analyze the venous microstructure, which will not only be useful in clinical applications, but also provide a better understanding of BOLD effect.

Vessel size imaging using dual contrast agent injections

To investigate the feasibility of a vessel size imaging (VSI) technique with separate contrast agent injections for evaluation of the vessel caliber in normal tissues and in brain tumors. Computer simulation was first performed to assess the potential errors in the estimation of vessel caliber that could result from time shifts between the dual contrast agent injections. Eight patients (four female, four male, 37-77 years old) with brain tumors (three high-grade gliomas, two low-grade gliomas, and three meningiomas) were recruited for clinical study. Dynamic susceptibility contrast magnetic resonance imaging (MRI) using gradient echo (GE) and spin echo (SE) echo-planar imaging sequences were performed separately with a 10-minute interval on a 3.0T scanner. Vessel caliber maps were calculated and analyzed in regions of interest at cortical gray matter (GM), thalamus, white matter (WM), and tumors. From the computer simulation, the error of vessel caliber measurement was less than 8% when the difference between the time-to-peak of the GE and the SE studies was 1.5 seconds, and reduced to within 5% when the difference was 1 second. From the patient datasets of a 64 x 64 matrix, the estimated vessel calibers were 37.4 +/- 12.9 microm for cortical gray matter, 20.7 +/- 8.8 microm for thalamus, and 15.0 +/- 5.1 microm for white matter, comparable to results in the literature. Two patients had a VSI with 128 x 128 matrix and showed similar results in vessel calibers of normal tissues. All the tumors had larger mean vessel diameter than normal-appearing tissues. The difference in vascular size between normal tissue and tumor was demonstrated clearly in both the VSIs of regular and high spatial resolution. This study suggests that VSI with a dual injection method is a feasible technique for estimating microvascular calibers of normal tissues and brain tumors in clinical scanners.