Near-Infrared Characterization of Breast Tumors In Vivo using Spectrally-Constrained Reconstruction

Multi-wavelength Near-Infrared (NIR) Tomography was utilized in this study to non-invasively quantify physiological parameters of breast tumors using direct spectral reconstruction. Frequency domain NIR measurements were incorporated with a new spectrally constrained direct chromophore and scattering image reconstruction algorithm, which was validated in simulations and experimental phantoms. Images of total hemoglobin, oxygen saturation, water, and scatter parameters were obtained with higher accuracy than previously reported. Using this spectral approach, in vivo NIR images are presented and interpreted through a series of case studies (n=6 subjects) having differing abnormalities. The corresponding mammograms and ultrasound images are also evaluated. Three of six cases were malignant (infiltrating ductal carcinomas) and showed higher hemoglobin (34–86% increase), a reduction in oxygen saturation, an increase in water content as well as scatter changes relative to surrounding normal tissue. Three of six cases were benign, two of which were diagnosed with fibrocystic disease and showed a dominant contrast in water, consistent with fluid filled cysts. Scatter amplitude was the main source of contrast in the volunteer with the benign condition fibrosis, which typically contains denser collagen tissue. The changes monitored correspond to physiological changes associated with angiogenesis, hypoxia and cell proliferation anticipated in cancers. These changes represent potential diagnostic indicators, which can be assessed to characterize breast tumors

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Iliocaval venous obstruction, cardiac preload reserve, and exercise limitation

Cardiac output during exercise increases by as much as five-fold in the untrained man, and by as much as eight-fold in the elite athlete. Increasing venous return is a critical but much overlooked component of the physiological response to exercise. Cardiac disorders such as constrictive pericarditis, restrictive cardiomyopathy and pulmonary hypertension are recognised to impair preload and cause exercise limitation, however the effects of peripheral venous obstruction on cardiac function have not been well described. This manuscript will discuss how obstruction of the iliocaval venous outflow can lead to impairment in exercise tolerance; how such obstructions may be diagnosed, the potential implications of chronic obstructions on sympathetic nervous system activation, and relevance of venous compression syndromes in heart failure with preserved ejection fraction

Effects of refractive index on near-infrared tomography of the breast

Near infrared (NIR) optical tomography is an imaging technique in which internal images of optical properties are reconstructed with the boundary measurements of light propagation through the medium. Recent advances in instrumentation and theory have led to the use of this method for the detection and characterization of tumors within the female breast tissue. Most image reconstruction approaches have used the diffusion approximation and have assumed that the refractive index of the breast is constant, with a bulk value of approximately 1.4. We have applied a previously reported modified diffusion approximation, in which the refractive index for different tissues can be modeled. The model was used to generate NIR data from a realistic breast geometry containing a localized anomaly. Using this simulated data, we have reconstructed optical images, both with and without correct knowledge of the refractiveindex distribution to show that the modified diffusion approximation can accurately recover the anomaly given a priori knowledge of refractive index. But using a reconstruction algorithm without the use of correct a priori information regarding the refractive-index distribution is shown as recovering the anomaly but with a degraded quality, depending on the degree of refractive index mismatch. The results suggest that provided the refractive index of breast tissue is approximately 1.3-1.4, their exclusion will have minimal effect on the reconstructed images.</p

Effects of refractive index on near-infrared tomography of the breast

Near infrared (NIR) optical tomography is an imaging technique in which internal images of optical properties are reconstructed with the boundary measurements of light propagation through the medium. Recent advances in instrumentation and theory have led to the use of this method for the detection and characterization of tumors within the female breast tissue. Most image reconstruction approaches have used the diffusion approximation and have assumed that the refractive index of the breast is constant, with a bulk value of approximately 1.4. We have applied a previously reported modified diffusion approximation, in which the refractive index for different tissues can be modeled. The model was used to generate NIR data from a realistic breast geometry containing a localized anomaly. Using this simulated data, we have reconstructed optical images, both with and without correct knowledge of the refractiveindex distribution to show that the modified diffusion approximation can accurately recover the anomaly given a priori knowledge of refractive index. But using a reconstruction algorithm without the use of correct a priori information regarding the refractive-index distribution is shown as recovering the anomaly but with a degraded quality, depending on the degree of refractive index mismatch. The results suggest that provided the refractive index of breast tissue is approximately 1.3-1.4, their exclusion will have minimal effect on the reconstructed images.</p

Internal refractive index changes affect light transport in tissue

This investigation explores the effect of index of refraction, as an optical property, on light transport through optically turbid media. We describe a model of light propagation that incorporates the influence of refractive index mismatch at boundaries within a domain. We measure light transmission through turbid cylindrical phatoms with different distributions of refractive index. These distributions approximate the heterogeneous, layered nature of biological tissue. Finite element method model calculations of diffuse transmittance through these phantoms show good agreement with the trends observed experimentally. We see that phase measurements of light that propagates through approximately 90 (mm) of scatter-dominated media may vary by 10 degrees depending upon the values of refractive index of the medium. Amplitude measurements are not as sensitive to this parameter as phase. Model calculations of diffuse reflectance from a semi-infinite slab geometry with different layers also shows good agreement with Monte Carlo simulations. We conclude that incorporating refractive index into light transport models may be worthwhile. Applying such a model in tomographic image reconstruction may improve the estimation of optical properties of biological tissues.</p

Three-dimensional optical tomography:Resolution in small-object imaging

Near-infrared (NIR) optical tomography can provide estimates of the internal distribution of optical absorption and transport scattering from boundary measurements of light propagation within biological tissue. Although this is a truly three–dimensional (3D) imaging problem, most research to date has concentrated on two-dimensional modeling and image reconstruction. More recently, 3D imaging algorithms are demonstrating better estimation of the light propagation within the imaging region and are providing the basis of more accurate image reconstruction algorithms. As 3D methods emerge, it will become increasingly important to evaluate their resolution, contrast, and localization of optical property heterogeneity. We present a concise study of 3D reconstructed resolution of a small, low-contrast, absorbing and scattering anomaly as it is placed in different locations within a cylindrical phantom. The object is an 8–mm–diameter cylinder, which represents a typical small target that needs to be resolved in NIR mammographic imaging. The best resolution and contrast is observed when the object is located near the periphery of the imaging region (12–22 mm from the edge) and is also positioned within the multiple measurement planes, with the most accurate results seen for the scatter image when the anomaly is at 17 mm from the edge. Furthermore, the accuracy of quantitative imaging is increased to almost 100% of the target values when a priori information regarding the internal structure of imaging domain is utilized.</p

Image reconstruction strategies using dual modality MRI-NIR data

An imaging system which simultaneously performs near infrared (NIR) tomography and magnetic resonance imaging (MRI) has been developed at Dartmouth College, to study breast tissue of women in vivo. A NIR image reconstruction technique which exploits the combined multi-wavelength data set is presented which implements the MR structure as a soft-constraint in the NIR property estimation. The benefits of spatial and spectral priors, applied independently and together, in NIR diffuse tomography image reconstruction of in vivo measurements are presented. When both spatial and spectral priors are applied in a healthy volunteer, glandular tissue shows higher total blood content, water, and scattering power compared to fatty tissue.</p

The effects of internal refractive index variation in near-infrared optical tomography:A finite element modelling approach

Near-infrared (NIR) tomography is a technique used to measure light propagation through tissue and generate images of internal optical property distributions from boundary measurements. Most popular applications have concentrated on female breast imaging, neonatal and adult head imaging, as well as muscle and small animal studies. In most instances a highly scattering medium with a homogeneous refractive index is assumed throughout the imaging domain. Using these assumptions, it is possible to simplify the model to the diffusion approximation. However, biological tissue contains regions of varying optical absorption and scatter, as well as varying refractive index. In this work, we introduce an internal boundary constraint in the finite element method approach to modelling light propagation through tissue that accounts for regions of different refractive indices. We have compared the results to data from a Monte Carlo simulation and show that for a simple two-layered slab model of varying refractive index, the phase of the measured reflectance data is significantly altered by the variation in internal refractive index, whereas the amplitude data are affected only slightly.</p