Microcirculatory fraction (MCF(I)) as a potential imaging marker for tumor heterogeneity in breast cancer

Cancer is a heterogeneous disease by nature. Current imaging studies usually ignore intratumor variability in imaging biomarkers. We postulate that quantifying tumor heterogeneity with imaging techniques can provide useful information about cancer biology and potentially serve as novel imaging biomarkers. In this retrospective study, we identify a potential imaging marker, the microcirculatory fraction (MCF(I)), that quantifies tumor heterogeneity in normoxic/hypoxic cellular composition. We demonstrate its application on a test population of 22 women with stage II/III HER-2 negative breast cancer receiving antiangiogenic-cytotoxic combination neoadjuvant chemotherapy. Early change in MCF(I) (ΔMCF(I)) is assessed with dynamic contrast enhanced magnetic resonance imaging at the end of Cycle 2 and associated with pathologic response. Its performance is compared with other established volumetric imaging biomarkers (initial tumor volume and volume change) by statistical and graphic methods. We demonstrate that a significant (P<.01) difference in ΔMCF(I) can be detected between good (median ΔMCF(I) 0.27) and poor (median ΔMCF(I) -0.12) responders, despite the limited population size. Differences in the volumetric biomarkers are not statistically significant. Receiver operating characteristic analysis also shows that ΔMCF(I) is a good predictor for pathologic response (AUC=0.86, 95% CI 0.69-1.00, P<.01), while predictions made with the established volumetric biomarkers are not significantly better than random guesses. We conclude that ΔMCF(I) has the potential of being a better predictive biomarker for therapeutic response assessment. Our findings support our postulation that quantifying tumor heterogeneity with imaging techniques can provide additional information that can serve as novel biomarkers.     

Spectroscopic measurement of blood volume and its oxygenation in a small volume of tissue using red laser lights and differential calculation between two point detections

An optical method for measuring blood volume and its oxygenation in a small volume of tissue (<1 cm³) based on the Beer–Lambert law is proposed. Three red laser lights are used because the difference of absorption by oxy- and deoxy-haemoglobin is large, but the absorption of the light by tissue itself causes a large offset value. The scattered light was detected at two receiving points, and the differential calculation between the values obtained from the receiving points were examined to eliminate the offset value. The result shows that the blood volume in skin is obtained from the regression analysis without the offset value. This method was evaluated by using a simple model which contained real blood. The relationship between the concentration of erythrocyte and the output of this method shows good linearity. Also, measuring depth as a function of the distance between incident and receiving points was estimated by using plastic plates having similar optical properties to skin. The maximum measuring depth was almost linear to the distance.     

Magnetic resonance imaging measurements of vascular permeability and extracellular volume fraction of breast tumors by dynamic Gd-DTPA-enhanced relaxometry

Vascular permeability (k(ep), min(-1)) and extracellular volume fraction (v(e)) are tissue parameters of great interest to characterize malignant tumor lesions. Indeed, it is well known that tumors with high blood supply better respond to therapy than poorly vascularized tumors, and tumors with large extracellular volume tend to be more malignant than tumors showing lower extracellular volume. Furthermore, the transport of therapeutic agents depends on both extracellular volume fraction and vessel permeability. Thus, before treatment, these tissue parameters may prove useful to evaluate tumor aggressiveness and to predict responsiveness to therapy and variations during cytotoxic therapies could allow to assess treatment efficacy and early modified therapy schedules in case of poor responsiveness. As a consequence, there is a need to develop methods that could be routinely used to determine these tissue parameters. In this work, blood-tissue permeability and extracellular volume fraction information were derived from magnetic resonance imaging dynamic longitudinal relaxation rate (R(1)) mapping obtained after an intravenous bolus injection of Gd-DTPA in a group of 92 female patients with breast lesions, 68 of these being histologically proven to be with carcinoma. For the sake of comparison, 24 benign lesions were studied. The measurement protocol based on two-dimensional gradient echo sequences and a monoexponential plasma kinetic model was that validated in the occasion of previous animal experiments. As a consequence of neoangiogenesis, results showed a higher permeability in malignant than in benign lesions, whereas the extracellular volume fraction value did not allow any discrimination between benign and malignant lesions. The method, which can be easily implemented whatever the imaging system used, could advantageously be used to quantify lesion parameters (k(ep) and v(e)) in routine clinical imaging. Because of its large reproducibility, the method could be useful for intersite comparisons and follow-up studies.     

Trabecular bone volume fraction measurements of a large number of subjects using a compact MRI

Trabecular bone volume fraction (TBVF) and speed of sound (SOS) were measured for the right calcanei of 416 female volunteers. The TBVF was measured with a compact MRI developed in our laboratory. The SOS was measured with a commercial quantitative ultrasound system. It was observed that the correlation coefficient between TBVF and SOS and that between TBVF and age varied depending on the location of region of interest (ROI) in the calcaneus. As a result, an optimum circular ROI with a diameter of 20 mm was determined so that the correlation coefficients were maximized. In the optimum ROI, transverse relaxation time (T₂) of the bone marrow protons of the calcaneus was found to be concentrated in a narrow range over the subjects. This result suggested that a 50% scan time reduction in the TBVF measurements could be made by skipping the T₂ correction procedure.     

Analysis of input functions from different arterial branches with gamma variate functions and cluster analysis for quantitative blood volume measurements

Regional cerebral blood volume (rCBV) provides valuable information about the nature and progress of diseases of the central nervous system. While relative rCBV maps can be derived directly from dynamic susceptibility contrast data, the arterial input function (AIF) has to be measured for absolute rCBV quantification. For determination of the AIF pixels located completely within a feeding artery must be selected. However, by using a region-of-interest (ROI) based selection some confounding effects can occur, especially if single shot echo planar imaging (EPI) with low spatial resolution is used. In this study we analyzed the influence of partial volume effects and spatial misregistration due to frequency shifts induced by paramagnetic contrast agents. We analyzed AIFs from the internal carotid artery (ICA), the vertebral artery (VA) and the middle cerebral artery (MCA) using gamma variate function based parameterization. The concentration time curves (CTC) of several pixels which were selected on the basis of strong signal drop appeared distorted during the bolus passage. Moreover, the amplitudes of input functions derived from the MCA were smaller by a factor of three as compared to those of the ICA and VA. Simulations revealed that these effects can be attributed to a spatial shift of the vessel along phase-encoding direction during the passage of the bolus. We therefore developed a procedure for a pixel selection based on cluster analysis which classifies pixels according to the parameters of the fitted gamma variate functions. This approach accounted for misregistration of the vessel and yielded very consistent results for a group of normal subjects.     

Determining uterine blood flow in pregnancy with magnetic resonance imaging

Objective

The purpose of this study is to determine the feasibility of measuring total uterine blood flow in pregnancy using magnetic resonance imaging (MRI) technique.

Methods

Uterine blood flow was determined in pregnant women in whom MRI was being carried out to assess a fetal anomaly. A two-dimensional time-of-flight magnetic resonance (MR) angiogram sequence was performed. Scout images and a peripherally gated phase contrast MR sequence were planned to study simultaneous blood flow in the uterine and ovarian arteries.

Results

The MR pelvic angiogram sequence was completed in 13 women. The uterine arteries were visualized and their cross-sectional area determined. The complexity of the pelvic blood supply prevented the calculation of blood flow velocity and, thus, total uterine blood flow.

Conclusion

The measurement of total uterine blood flow during pregnancy was not possible using our MR technique. The ovarian vessels were not consistently visualized. Doppler ultrasonography remains the best modality by which to estimate total uterine blood flow in pregnancy.     

Diffusion-weighted magnetic resonance imaging to evaluate microvascular density after transarterial embolization ablation in a rabbit VX2 liver tumor model

Objective

To evaluate the correlation between findings from diffusion weighted imaging (DWI) and microvascular density (MVD) measurements in VX2 liver tumors after transarterial embolization ablation (TEA).

Materials and Methods

Eighteen New Zealand white rabbits were used in this study. VX2 tumor cells were implanted in livers by percutaneous puncture under computed tomography (CT) guidance. Two weeks later, all rabbits underwent conventional magnetic resonance imaging (MRI) (T1 and T2 imaging), DWI, (b = 100, 600, and 1000 s/mm²) and TEA. MRI was performed again1 week after TEA. Liver tissue was then harvested and processed for hematoxylin and eosin (H&E) staining and immunohistochemical staining for CD31to determine MVD.

Results

VX2 liver tumors were successfully established in all 18 rabbits. Optimal contrast was achieved with a b value of 600 s/mm².The maximum pre-operative apparent diffusion coefficient (ADC)_difference value was 0.28 × 10^− 3 ± 0.10 × 10^− 3 mm²/s, and was significantly different (P < 0.001) from the maximum postoperative ADC_difference value of 0.47 × 10^− 3 ± 0.10 × 10^− 3 mm²/s. However, the mean ADC value for the entire tumor was not significantly correlated with MVD (r = 0.221, P = 0.379), nor was the ADC value for the regions of viable tumor (r = − 0.044, P = 0.862). However, the maximum postoperative ADC_difference value was positively correlated with MVD(r = 0.606, F = 12.247, P = 0.003).

Conclusion

DWI is effective to evaluate the therapeutic efficacy of TEA. The maximum ADC_difference offers a promising new method to noninvasively assess tumor angiogenesis.     

Development of a novel folate-modified nanobubbles with improved targeting ability to tumor cells

Conjugation of folate (FOL) to nanobubbles could enhance the selective targeting to tumors expressing high levels of folate receptor (FR). To further improve the selective targeting ability of FOL-modified nanobubbles, a novel FOL-targeted nanobubble ((FOL)₂-NB) with increasing FOL content (accomplished by linking two FOL molecules per DSPE-PEG2000 chain) was synthesized, through the methods of mechanical shaking and low-speed centrifugation based on lipid-stabilized perfluoropropane. The bubble size and distribution range were measured by dynamic light scattering (DLS). Enhanced imaging ability was evaluated using a custom-made agarose mold with a clinical US imaging system at mechanical indices of up to 0.12 at a center frequency of 9.0 MHz. Targeted ability was also carried out in human breast cancer MCF-7 cells, which over-express the FR, by fluorescence activated cell sorting (FACS) and fluorescence microscopy, respectively. (FOL)₂-NB with a particle size of 286.87 ± 22.96 nm were successfully prepared, and they exhibited superior contrast imaging effect. FACS and fluorescence microscopy studies showed greater cellular targeting ability in the group of (FOL)₂-NB than in their control group of Non-targeted-NB (no FOL targeted nanobubbles) and FOL-NB (one FOL molecule per DSPE-PEG2000 chain). These results suggest that a new type of stronger targeted nanobubble was successfully prepared by increasing the FOL content per DSPE-PEG2000 chain. This novel (FOL)₂-NBs are potentially useful for ultrasound molecular imaging and treatment of FR-positive tumors and are worthy for further investigation.     

Nonuniversality and continuity of the critical covered volume fraction in continuum percolation

We establish, using mathematically rigorous methods, that the critical covered volume fraction (CVF) for a continuum percolation model with overlapping balls of random sizes is not a universal constant independent of the distribution of the size of the balls. In addition, we show that the critical CVF is a continuous function of the distribution of the radius random variable, in the sense that if a sequence of random variables converges weakly to some random variable, then the critical CVF based on these random variables converges to the critical CVF of the limiting random variable.     

Simulation on simultaneous estimation of non-uniform temperature and soot volume fraction distributions in axisymmetric sooting flames

For visualizing non-uniform absorbing, emitting, non-scattering, axisymmetric sooting flames, because conventional two-color emission methods are no longer suitable, a three-color emission method for the simultaneous estimation of temperature and soot volume fraction distributions in these flames is studied in this paper. The spectral radiation intensities at wavelengths of red, green, and blue, which may be derived from color flame images, are simulated for the inverse analysis. Then the simultaneous estimation is carried out from the spectral radiation intensities by using a Newton-type iteration algorithm and the least-squares method. In this method, a factor is used to balance the wide variation of spectral radiation intensities due to both the wide ranges of temperature and wavelength of the flame radiation. The results indicate that the three-color method is suited for the reconstruction of flame structures with single or double peaks with small difference between the peak and valley. For a double-peaked flame structure with larger peak and valley difference, reasonable result can be obtained just when the mean square deviations of measurement data are small, for example, not more than 0.01.     

The SU(2) glueball spectrum in a small volume

We use lattice gauge theory simulation to evaluate the spectrum in pure gauge theory with an SU(2) colour group. Glueball states in all representations of the cubic group O_h are investigated. We compare our results for small spatial volumes with the analytic hamiltonian results of Koller and van Baal and with our large lattice results.     

Gas challenge-blood oxygen level-dependent (GC-BOLD) MRI in the rat Novikoff hepatoma model

Purpose

The purpose of the study was to investigate the relationship between gas challenge-blood oxygen level-dependent (GC-BOLD) response angiogenesis and tumor size in rat Novikoff hepatoma model.

Materials and Methods

Twenty adult male Sprague-Dawley rats (weighting 301-325 g) were used for our Animal Care and Use Committee-approved experiments. N1-S1 Novikoff hepatomas were grown in 14 rats with sizes ranging from 0.42 to 2.81 cm. All experiments were performed at 3.0 T using a custom-built rodent receiver coil. A multiple gradient-echo sequence was used for R2^? measurements, first during room air (78% N₂/20% O₂) breathing and then after 10 min of carbogen (95% O₂/5% CO₂) breathing. After image acquisition, rats were euthanized, and the tumors were harvested for histological evaluation.

Results

The R2^? change between air and carbogen breathing for small hepatomas was positive; R2^? changes changed to negative values for larger hepatomas. We found a significant positive correlation between tumor R2^? change and tumor microvessel density (MVD) (r=0.798, P=.001) and a significant inverse correlation between tumor R2^? change and tumor size (r=−0.840, P<.0001).

Conclusions

GC-BOLD magnetic resonance imaging measurements are well correlated to MVD levels and tumor size in the N1-S1 Novikoff hepatoma model; GC-BOLD measurements may serve as noninvasive biomarkers for evaluating angiogenesis and disease progression and/or therapy response.     

空间遥感器高体份SiC/Al复合材料反射镜组件设计

为消除反射镜与支撑结构材料线胀系数差异产生的热变形对反射镜面形精度、系统成像质量的影响, 采用高体份SiC/Al复合材料作为新型反射镜组件的材料。首先, 通过合理的结构设计及有限元分析比较, 确定了Ф600 mm口径反射镜结构参数, 然后, 对反射镜组件进行了静力学和动力学分析, 在1 g重力载荷作用下, 反射镜X、Y、Z方向去除刚体位移后的镜面变形RMS值分别为12.6, 12.7, 12.6 nm, 达到了λ/50(λ=632.8 nm)。最后, 为了验证高体份SiC/Al复合材料反射镜组件的结构性能及检验结构在振动条件下的抗干扰能力, 对反射镜组件进行了力学试验, 反射镜组件的一阶谐振频率为556.6 Hz。力学试验前后, 反射镜镜面面形误差RMS分别为0.021λ、0.025λ, 没有明显变化。实验结果表明:高体份SiC/Al复合材料反射镜达到了与SiC材料反射镜相同的设计指标要求, 能够满足空间应用。     

Tissue similarity maps (TSMs): A new means of mapping vascular behavior and calculating relative blood volume in perfusion weighted imaging

This study introduces a new processing means that uses the original signal (rather than contrast agent concentration) from dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) to calculate a relative cerebral blood volume map and a tissue similarity map (TSM). Ten healthy volunteers and eight multiple sclerosis (MS) patients were studied using high resolution PWI. The TSM is found by choosing a reference region in one slice and comparing its signal in a mean squared error sense to the signal from every pixel in all images throughout the brain. The TSMs provide a means to determine which tissues have similar flow characteristics with high contrast and signal-to-noise ratios. The effective blood volume measured from this approach is nearly identical to that from conventional relative cerebral blood volume (rCBV) maps but with better signal-to-noise. Of interest is the fact that choosing one MS lesion as the reference tissue appears to be enough to find nearly all lesions throughout the brain. That is, these lesions all behave the same from a vascular point of view. The TSM results are robust within and across slices properly nulling the same type of tissue throughout the brain for a given reference region. TSM derived rCBV agrees well with the conventional derived rCBV using contrast agent concentration. TSM may provide a new means to study similarities between blood flow patterns in tissue in the brain and in better diagnosing vascular differences between tissues and lesions.     

Limitations of the permeability-limited compartment model in estimating vascular permeability and interstitial volume fraction in DCE-MRI

Dynamic contrast-enhanced magnetic resonance imaging commonly uses compartment models to estimate tissue parameters in general and perfusion parameters in particular. Compartment models assume a homogeneous distribution of the injected tracer throughout the compartment volume. Since tracer distribution within a compartment cannot be assessed, the parameters obtained by means of a compartment model might differ from the actual physical values.This work systematically examines the widely used permeability-surface-limited one-compartment model to determine the reliability of the parameters obtained by comparing them with their actual values. A computer simulation was used to model spatial tracer distribution within the interstitial volume using diffusion of contrast agent in tissue. Vascular parameters were varied as well as tissue parameters. The vascular parameters used were capillary radius (4 and 12 μm), capillary permeability (from 0.03 to 3.3 μm/s) and intercapillary distances from 30 to 300 μm. The tissue parameters used were tortuosity (λ), porosity (α) and interstitial volume fraction (v_e).Our results suggest that the permeability-surface-limited compartment model generally underestimates capillary permeability for capillaries with a radius of 4 μm by factors from ≈0.03 for α=0.04, to ≈ 0.1 for α=0.2, to ≈ 0.5 for α=1.0. An overestimation of actual capillary permeability for capillaries with a radius of 12 μm by a factor of ≥1.3 was found for α=1.0, while α=0.2 yielded an underestimation by a factor of ≈0.3 and α=0.04 by a factor of ≈ 0.03. The interstitial volume fraction, v_e, obtained by the compartment model differed with increasing intercapillary distances and for low vessel permeability, whereas v_e was found to be estimated approximately accurately for P=0.3 μm/s and P=3.3 μm/s for vessel distances <100 μm.     

On the relationship between the apparent diffusion coefficient and extravascular extracellular volume fraction in human breast cancer

MRI techniques have been developed that can noninvasively probe the apparent diffusion coefficient (ADC) of water via diffusion-weighted MRI (DW-MRI). These methods have found much application in cancer where it is often found that the ADC within tumors is inversely correlated with tumor cell density, so that an increase in ADC in response to therapy can be interpreted as an imaging biomarker of positive treatment response. Dynamic contrast enhanced MRI (DCE-MRI) methods have also been developed and can noninvasively report on the extravascular extracellular volume fraction of tissues (denoted by v_e). By conventional reasoning, the ADC should therefore also be directly proportional to v_e. Here we report measurements of both ADC and v_e obtained from breast cancer patients at both 1.5 and 3.0 T. The 1.5-T data were acquired as part of normal standard of care, while the 3.0-T data were obtained from a dedicated research protocol. We found no statistically significant correlation between ADC and v_e for the 1.5- or 3.0-T patient sets on either a voxel-by-voxel or a region-of-interest (ROI) basis. These data, combined with similar results from other disease sites in the literature, may indicate that the conventional interpretation of either ADC, v_e or their relationship is not sufficient to explain experimental findings.     

Analysis of uncertainties in instantaneous soot volume fraction measurements using two-dimensional, auto-compensating, laser-induced incandescence (2D-AC-LII)

Laser-induced incandescence (LII) is an optical measurement technique capable of measuring soot volume fraction over a wide range of conditions. However, development of two-dimensional auto-compensating LII (2D-AC-LII) in the literature has been limited and until now, instantaneous measurements have not been demonstrated. In this paper, we successfully demonstrate instantaneous 2D-AC-LII soot volume fraction (SVF) measurements in an ethylene-air co-annular diffusion flame. Results were then used to support a detailed uncertainty analysis based on a Monte-Carlo simulation. Agreement between both the instantaneous and average SVF measurements with published data from attenuation measurements under identical conditions was found to be good. Uncertainties are discussed both in terms of an overall accuracy of the SVF measurement, which is strongly dominated by uncertainty in the optical properties of soot, and the comparative uncertainties with optical properties fixed. The uncertainty in an instantaneous 2D determination of SVF for a comparative measurement is dominated by photon shot noise, and in regions of high soot volume fraction it is below 25% (95% confidence interval). Shot noise uncertainty could be further reduced with additional pixel averaging at the expense of spatial resolution. This diagnostic shows significant promise for quantitative planar soot concentration measurements within turbulent flames.     

(Higgs)2, 3 quantum fields in a finite volume

This is the third paper of a series, and contains a proof of the bounds on the effective actions needed in the two previous papers. The proof is based on perturbative analysis of renormalization.     

Sonochemical synthesis of a novel nanoscale 1D lead(II) [Pb2(L)2(I)4]n coordination Polymer,survey of temperature,reaction time parameters

One new lead(II) coordination supramolecular complex (CSC) (1D), [Pb₂(L)₂(I)₄]_n, L = C₄H₆N₂ (1-methyl imidazole), has been synthesized under different experimental conditions. Micrometric crystals (bulk) or nano-sized materials have been obtained depending on using the branch tube method or sonochemical irradiation. All materials have been characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and FT-IR spectroscopy. Single crystal X-ray analyses on complex 1 showed that Pb²⁺ ion is 4-coordinated. Topological analysis shows that the complex 1 is 2,3,5C2 net. Finally, the role of reaction time and temperature on the growth and final morphology of the structures obtained by sonochemical irradiation have been studied.