Ioannis Sechopoulos

A review of breast tomosynthesis. Part I. The image acquisition process

Mammography is a very well-established imaging modality for the early detection and diagnosis of breast cancer. However, since the introduction of digital imaging to the realm of radiology, more advanced, and especially tomographic imaging methods have been made possible. One of these methods, breast tomosynthesis, has finally been introduced to the clinic for routine everyday use, with potential to in the future replace mammography for screening for breast cancer. In this two part paper, the extensive research performed during the development of breast tomosynthesis is reviewed, with a focus on the research addressing the medical physics aspects of this imaging modality. This first paper will review the research performed on the issues relevant to the image acquisition process, including system design, optimization of geometry and technique, x-ray scatter, and radiation dose. The companion to this paper will review all other aspects of breast tomosynthesis imaging, including the reconstruction process.

A review of breast tomosynthesis. Part II. Image reconstruction, processing and analysis, and advanced applications

Many important post-acquisition aspects of breast tomosynthesis imaging can impact its clinical performance. Chief among them is the reconstruction algorithm that generates the representation of the three-dimensional breast volume from the acquired projections. But even after reconstruction, additional processes, such as artifact reduction algorithms, computer aided detection and diagnosis, among others, can also impact the performance of breast tomosynthesis in the clinical realm. In this two part paper, a review of breast tomosynthesis research is performed, with an emphasis on its medical physics aspects. In the companion paper, the first part of this review, the research performed relevant to the image acquisition process is examined. This second part will review the research on the post-acquisition aspects, including reconstruction, image processing, and analysis, as well as the advanced applications being investigated for breast tomosynthesis.

Computation of the glandular radiation dose in digital tomosynthesis of the breast

Tomosynthesis of the breast is currently a topic of intense interest as a logical next step in the evolution of digital mammography. This study reports on the computation of glandular radiation dose in digital tomosynthesis of the breast. Previously, glandular dose estimations in tomosynthesis have been performed using data from studies of radiation dose in conventional planar mammography. This study evaluates, using Monte Carlo methods, the normalized glandular dose (DgN) to the breast during a tomosynthesis study, and characterizes its dependence on breast size, tissue composition, and x-ray spectrum. The conditions during digital tomosynthesis imaging of the breast were simulated using a computer program based on the Geant4 toolkit. With the use of simulated breasts of varying size, thickness and tissue composition, the DgN to the breast tissue was computed for varying x-ray spectra and tomosynthesis projection angle. Tomosynthesis projections centered about both the cranio-caudal (CC) and medio-lateral oblique (MLO) views were simulated. For each projection angle, the ratio of the glandular dose for that projection to the glandular dose for the zero degree projection was computed. This ratio was denoted the relative glandular dose (RGD) coefficient, and its variation under different imaging parameters was analyzed. Within mammographic energies, the RGD was found to have a weak dependence on glandular fraction and x-ray spectrum for both views. A substantial dependence on breast size and thickness was found for the MLO view, and to a lesser extent for the CC view. Although RGD values deviate substantially from unity as a function of projection angle, the RGD averaged over all projections in a complete tomosynthesis study varies from 0.91 to 1.01. The RGD results were fit to mathematical functions and the resulting equations are provided.

Clinical digital breast tomosynthesis system: dosimetric characterization.

PURPOSE To comprehensively characterize the dosimetric properties of a clinical digital breast tomosynthesis (DBT) system for the acquisition of mammographic and tomosynthesis images. MATERIALS AND METHODS Compressible water-oil mixture phantoms were created and imaged by using the automatic exposure control (AEC) of the Selenia Dimensions system (Hologic, Bedford, Mass) in both DBT and full-field digital mammography (FFDM) mode. Empirical measurements of the x-ray tube output were performed with a dosimeter to measure the air kerma for the range of tube current-exposure time product settings and to develop models of the automatically selected x-ray spectra. A Monte Carlo simulation of the system was developed and used in conjunction with the AEC-chosen settings and spectra models to compute and compare the mean glandular dose (MGD) resulting from both imaging modalities for breasts of varying sizes and glandular compositions. RESULTS Acquisition of a single craniocaudal view resulted in an MGD ranging from 0.309 to 5.26 mGy in FFDM mode and from 0.657 to 3.52 mGy in DBT mode. For a breast with a compressed thickness of 5.0 cm and a 50% glandular fraction, a DBT acquisition resulted in an only 8% higher MGD than an FFDM acquisition (1.30 and 1.20 mGy, respectively). For a breast with a compressed thickness of 6.0 cm and a 14.3% glandular fraction, a DBT acquisition resulted in an 83% higher MGD than an FFDM acquisition (2.12 and 1.16 mGy, respectively). CONCLUSION For two-dimensional-three-dimensional fusion imaging with the Selenia Dimensions system, the MGD for a 5-cm-thick 50% glandular breast is 2.50 mGy, which is less than the Mammography Quality Standards Act limit for a two-view screening mammography study.

Optimization of the acquisition geometry in digital tomosynthesis of the breast

Digital tomosynthesis of the breast continues to be intensively studied as an adjunct or replacement of conventional mammography. Although many of the acquisition parameters found in tomosynthesis imaging are also found in conventional mammography and therefore most of the traditional values from mammography have been used in the former, two acquisition geometry parameters, the angular range covered during acquisition and the number of projections per projection set, are applicable only to tomosynthesis. Therefore, in the preclinical and clinical studies reported on tomosynthesis of the breast, a wide variety of values have been used for these two parameters. In this study, 63 different combinations of angular range and number of projections were evaluated using computer simulation methods to characterize how these two parameters affect reconstruction quality and to find which of these combinations maximize it. For this, a computer simulation of a digital tomosynthesis system that included empirically determined system response characteristics was developed and used to generate 9450 different breast tissue volume reconstructions. These reconstructions were analyzed objectively using metrics for in-plane lesion visibility and vertical resolution in the form of the contrast-to-noise ratio and artifact spread function (ASF). It was found that although maximizing the angular range covered does always increase the vertical resolution in tomosynthesis, increasing the number of projections in the acquisition set beyond a relatively low threshold does not further improve the vertical resolution. This threshold value for the minimal number of projections needed to minimize the ASF was found to vary proportionally with angular range. For example, for a 60 degrees angular range, the threshold number of projections was found to be 13. Given the clear inverse relationship between the number of projections and in-plane reconstruction quality under a limited total glandular dose condition, the optimum acquisition geometry in tomosynthesis imaging of the breast is that which maximizes the angular range while maintaining the number of projections close to the threshold values found. Finally, of the 63 acquisition geometries studied, the one that resulted in the highest quality reconstruction, considering both in-plane quality and vertical resolution, consisted of the acquisition of 13 projections over a 60 degrees angular range.

Imaging Nanoprobe for Prediction of Outcome of Nanoparticle Chemotherapy by Using Mammography

PURPOSE To prospectively predict the effectiveness of a clinically used nanochemotherapeutic agent by detecting and measuring the intratumoral uptake of an x-ray contrast agent nanoprobe by using digital mammography. MATERIALS AND METHODS All animal procedures were approved by the institutional animal care and use committee. A long-circulating 100-nm-scale injectable liposomal probe encapsulating 155 mg/mL iodine was developed. Preliminary studies were performed to identify the agent dose that would result in adequate tumor enhancement without enhancement of the normal vasculature in rats. This dose was used to image a rat breast tumor (n = 14) intermittently for 3 days by using a digital mammography system; subsequently, the animals were treated with liposomal doxorubicin. The predictive capability of the probe was characterized by creating good- and bad-prognosis subgroups, on the basis of tumor enhancement found during imaging, and analyzing the tumor growth after treatment of the animals in these two subgroups. RESULTS A dose of 455 mg of iodine per kilogram of body weight was found to produce an undetectable signal from the blood while achieving enough intratumoral accumulation of the probe to produce adequate signal for detection. The good- and bad-prognosis subgroups demonstrated differential tumor growth rates (P < .003). An inverse linear relationship between the contrast enhancement rate constant during imaging and the tumor growth rate constant during treatment was found (slope = -0.576, R(2) = 0.838). CONCLUSION In this animal model, quantitative measurement of vascular permeability enabled prediction of therapeutic responsiveness of tumors to liposomal doxorubicin.

Scatter radiation in digital tomosynthesis of the breast

Digital tomosynthesis of the breast is being investigated as one possible solution to the problem of tissue superposition present in planar mammography. This imaging technique presents various advantages that would make it a feasible replacement for planar mammography, among them similar, if not lower, radiation glandular dose to the breast; implementation on conventional digital mammography technology via relatively simple modifications; and fast acquisition time. One significant problem that tomosynthesis of the breast must overcome, however, is the reduction of x-ray scatter inclusion in the projection images. In tomosynthesis, due to the projection geometry and radiation dose considerations, the use of an antiscatter grid presents several challenges. Therefore, the use of postacquisition software-based scatter reduction algorithms seems well justified, requiring a comprehensive evaluation of x-ray scatter content in the tomosynthesis projections. This study aims to gain insight into the behavior of x-ray scatter in tomosynthesis by characterizing the scatter point spread functions (PSFs) and the scatter to primary ratio (SPR) maps found in tomosynthesis of the breast. This characterization was performed using Monte Carlo simulations, based on the Geant4 toolkit, that simulate the conditions present in a digital tomosynthesis system, including the simulation of the compressed breast in both the cranio-caudal (CC) and the medio-lateral oblique (MLO) views. The variation of the scatter PSF with varying tomosynthesis projection angle, as well as the effects of varying breast glandular fraction and x-ray spectrum, was analyzed. The behavior of the SPR for different projection angle, breast size, thickness, glandular fraction, and x-ray spectrum was also analyzed, and computer fit equations for the magnitude of the SPR at the center of mass for both the CC and the MLO views were found. Within mammographic energies, the x-ray spectrum was found to have no appreciable effect on the scatter PSF and on the SPR. Glandular fraction and compressed breast size were found to have a small effect, while compressed breast thickness and projection angle, as expected, introduced large variations in both the scatter PSF and SPR. The presence of the breast support plate and the detector cover plate in the simulations introduced important effects on the SPR, which are also relevant to the scatter content in planar mammography.

Tumor Vascular Permeability to a Nanoprobe Correlates to Tumor-Specific Expression Levels of Angiogenic Markers

Background Vascular endothelial growth factor (VEGF) receptor-2 is the major mediator of the mitogenic, angiogenic, and vascular hyperpermeability effects of VEGF on breast tumors. Overexpression of VEGF and VEGF receptor-2 is associated with the degree of pathomorphosis of the tumor tissue and unfavorable prognosis. In this study, we demonstrate that non-invasive quantification of the degree of tumor vascular permeability to a nanoprobe correlates with the VEGF and its receptor levels and tumor growth. Methodology/Principal Findings We designed an imaging nanoprobe and a methodology to detect the intratumoral deposition of a 100 nm-scale nanoprobe using mammography allowing measurement of the tumor vascular permeability in a rat MAT B III breast tumor model. The tumor vascular permeability varied widely among the animals. Notably, the VEGF and VEGF receptor-2 gene expression of the tumors as measured by qRT-PCR displayed a strong correlation to the imaging-based measurements of vascular permeability to the 100 nm-scale nanoprobe. This is in good agreement with the fact that tumors with high angiogenic activity are expected to have more permeable blood vessels resulting in high intratumoral deposition of a nanoscale agent. In addition, we show that higher intratumoral deposition of the nanoprobe as imaged with mammography correlated to a faster tumor growth rate. This data suggest that vascular permeability scales to the tumor growth and that tumor vascular permeability can be a measure of underlying VEGF and VEGF receptor-2 expression in individual tumors. Conclusions/Significance This is the first demonstration, to our knowledge, that quantitative imaging of tumor vascular permeability to a nanoprobe represents a form of a surrogate, functional biomarker of underlying molecular markers of angiogenesis.

Dosimetric characterization of a dedicated breast computed tomography clinical prototype

PURPOSE To investigate the glandular dose magnitudes and characteristics resulting from image acquisition using a dedicated breast computed tomography (BCT) clinical prototype imaging system. METHODS The x-ray spectrum and output characteristics of a BCT clinical prototype (Koning Corporation, West Henrietta, NY) were determined using empirical measurements, breast phantoms, and an established spectrum model. The geometry of the BCT system was replicated in a Monte Carlo-based computer simulation using theGEANT4 toolkit and was validated by comparing the simulated results for exposure distribution in a standard 16 cm CT head phantom with those empirically determined using a 10 cm CT pencil ionization chamber and dosimeter. The computer simulation was further validated by replicating the results of a previous BCT dosimetry study. Upon validation, the computer simulation was modified to include breasts of varying sizes and homogeneous compositions spanning those encountered clinically, and the normalized mean glandular dose resulting from BCT was determined. Using the systems measured exposure output determined automatically for breasts of different size and density, the mean glandular dose for these breasts was computed and compared to the glandular dose resulting from mammography. Finally, additional Monte Carlo simulations were performed to study how the glandular dose values vary within the breast tissue during acquisition with both this BCT prototype and a typical craniocaudal (CC) mammographic acquisition. RESULTS This BCT prototype uses an x-ray spectrum with a first half-value layer of 1.39 mm Al and a mean x-ray energy of 30.3 keV. The normalized mean glandular dose for breasts of varying size and composition during BCT acquisition with this system ranges from 0.278 to 0.582 mGy/mGy air kerma with the reference air kerma measured in air at the center of rotation. Using the measured exposure outputs for the tube currents automatically selected by the system for the breasts of different sizes and densities, the mean glandular dose for a BCT acquisition with this prototype system varies from 5.6 to 17.5 mGy, with the value for a breast of mean size and composition being 17.06 mGy. The glandular dose throughout the breast tissue of this mean breast varies by up to ±50% of the mean value. During a typical CC view mammographic acquisition of an equivalent mean breast, which typically results in a mean glandular dose of 2.0-2.5 mGy, the glandular dose throughout the breast tissue varies from∼15% to ∼400% of the mean value. CONCLUSIONS Acquisition of a BCT image with the automated tube output settings for a mean breast with the Koning Corp. clinical prototype results in mean glandular dose values approximately equivalent to three to five two-view mammographic examinations for a similar breast. For all breast sizes and compositions studied, this glandular dose ratio between acquisition with this BCT prototype and two-view mammography ranges from 1.4 to 7.2. In mammography, portions of the mean-sized breast receive a considerably higher dose than the mean value for the whole breast. However, only a small portion of a breast undergoing mammography would receive a glandular dose similar to that from BCT.

Multifunctional nanocarriers for mammographic quantification of tumor dosing and prognosis of breast cancer therapy

Nanoscale therapeutic interventions are increasingly important elements in the portfolio of cancer therapeutics. The efficacy of nanotherapeutics is dictated, in part, by the access they have to tumors via the leaky tumor vasculature. Yet, the extent of tumor vessel leakiness in individual tumors varies widely resulting in a correspondingly wide tumor dosing and resulting range of responses to therapy. Here we report the design of a multifunctional nanocarrier that simultaneously encapsulates a chemotherapeutic and a contrast agent which enables a personalized nanotherapeutic approach for breast cancer therapy by permitting tracking of the nanocarrier distribution by mammography, a widely used imaging modality. Following systemic administration in a rat breast tumor model, imaging demonstrated a wide range of intratumoral deposition of the nanocarriers, indicating variable tumor vessel leakiness. Notably, specific tumors that exhibited high uptake of the nanocarrier as visualized by imaging were precisely the animals that responded best to the treatment as quantified by low tumor growth and prolonged survival.