Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women.

BACKGROUND: Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women. METHODS: A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception (n = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone-binding globulin, prolactin). Testosterone (n = 330) and sex hormone-binding globulin (n = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels. RESULTS: Estradiol at age 21.5 and sex hormone-binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%-7%) and 3% (1%-5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%-4%) and 4% (1%-7%), respectively]. CONCLUSIONS: The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women. IMPACT: The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.

Growth Trajectories, Breast Size, and Breast-Tissue Composition in a British Prebirth Cohort of Young Women.

Mammographic percent density, the proportion of fibroglandular tissue in the breast, is a strong risk factor for breast cancer, but its determinants in young women are unknown. We examined associations of magnetic resonance imaging (MRI) breast-tissue composition at age 21 years with prospectively collected measurements of body size and composition from birth to early adulthood and markers of puberty (all standardized) in a sample of 500 nulliparous women from a prebirth cohort of children born in Avon, United Kingdom, in 1991-1992 and followed up to 2011-2014. Linear models were fitted to estimate relative change in MRI percent water, which is equivalent to mammographic percent density, associated with a 1-standard-deviation increase in the exposure of interest. In mutually adjusted analyses, MRI percent water was positively associated with birth weight (relative change (RC) = 1.03, 95% confidence interval (CI): 1.00, 1.06) and pubertal height growth (RC = 1.07, 95% CI: 1.02, 1.13) but inversely associated with pubertal weight growth (RC = 0.86, 95% CI: 0.84, 0.89) and changes in dual-energy x-ray absorptiometry percent body fat mass (e.g., for change between ages 11 years and 13.5 years, RC = 0.96, 95% CI: 0.93, 0.99). Ages at thelarche and menarche were positively associated with MRI percent water, but these associations did not persist upon adjustment for height and weight growth. These findings support the hypothesis that growth trajectories influence breast-tissue composition in young women, whereas puberty plays no independent role.

Multiscale biphasic modelling of peritumoural collagen microstructure: The effect of tumour growth on permeability and fluid flow.

We present an in-silico model of avascular poroelastic tumour growth coupled with a multiscale biphasic description of the tumour-host environment. The model is specified to in-vitro data, facilitating biophysically realistic simulations of tumour spheroid growth into a dense collagen hydrogel. We use the model to first confirm that passive mechanical remodelling of collagen fibres at the tumour boundary is driven by solid stress, and not fluid pressure. The model is then used to demonstrate the influence of collagen microstructure on peritumoural permeability and interstitial fluid flow. Our model suggests that at the tumour periphery, remodelling causes the peritumoural stroma to become more permeable in the circumferential than radial direction, and the interstitial fluid velocity is found to be dependent on initial collagen alignment. Finally we show that solid stresses are negatively correlated with peritumoural permeability, and positively correlated with interstitial fluid velocity. These results point to a heterogeneous, microstructure-dependent force environment at the tumour-peritumoural stroma interface.

Breast MRI segmentation for density estimation: Do different methods give the same results and how much do differences matter?

PURPOSE: To compare two methods of automatic breast segmentation with each other and with manual segmentation in a large subject cohort. To discuss the factors involved in selecting the most appropriate algorithm for automatic segmentation and, in particular, to investigate the appropriateness of overlap measures (e.g., Dice and Jaccard coefficients) as the primary determinant in algorithm selection. METHODS: Two methods of breast segmentation were applied to the task of calculating MRI breast density in 200 subjects drawn from the Avon Longitudinal Study of Parents and Children, a large cohort study with an MRI component. A semiautomated, bias-corrected, fuzzy C-means (BC-FCM) method was combined with morphological operations to segment the overall breast volume from in-phase Dixon images. The method makes use of novel, problem-specific insights. The resulting segmentation mask was then applied to the corresponding Dixon water and fat images, which were combined to give Dixon MRI density values. Contemporaneously acquired T1 - and T2 -weighted image datasets were analyzed using a novel and fully automated algorithm involving image filtering, landmark identification, and explicit location of the pectoral muscle boundary. Within the region found, fat-water discrimination was performed using an Expectation Maximization-Markov Random Field technique, yielding a second independent estimate of MRI density. RESULTS: Images are presented for two individual women, demonstrating how the difficulty of the problem is highly subject-specific. Dice and Jaccard coefficients comparing the semiautomated BC-FCM method, operating on Dixon source data, with expert manual segmentation are presented. The corresponding results for the method based on T1 - and T2 -weighted data are slightly lower in the individual cases shown, but scatter plots and interclass correlations for the cohort as a whole show that both methods do an excellent job in segmenting and classifying breast tissue. CONCLUSIONS: Epidemiological results demonstrate that both methods of automated segmentation are suitable for the chosen application and that it is important to consider a range of factors when choosing a segmentation algorithm, rather than focus narrowly on a single metric such as the Dice coefficient.

Automated Classification of Breast Cancer Stroma Maturity From Histological Images.

OBJECTIVE: The tumor microenvironment plays a crucial role in regulating tumor progression by a number of different mechanisms, in particular, the remodeling of collagen fibers in tumor-associated stroma, which has been reported to be related to patient survival. The underlying motivation of this work is that remodeling of collagen fibers gives rise to observable patterns in hematoxylin and eosin (H&E) stained slides from clinical cases of invasive breast carcinoma that the pathologist can label as mature or immature stroma. The aim of this paper is to categorise and automatically classify stromal regions according to their maturity and show that this classification agrees with that of skilled observers, hence providing a repeatable and quantitative measure for prognostic studies. METHODS: We use multiscale basic image features and local binary patterns, in combination with a random decision trees classifier for classification of breast cancer stroma regions-of-interest (ROI). RESULTS: We present results from a cohort of 55 patients with analysis of 169 ROI. Our multiscale approach achieved a classification accuracy of 84%. CONCLUSION: This work demonstrates the ability of texture-based image analysis to differentiate breast cancer stroma maturity in clinically acquired H&E-stained slides at least as well as skilled observers.

3D volume reconstruction from serial breast specimen radiographs for mapping between histology and 3D whole specimen imaging.

PURPOSE: In breast imaging, radiological in vivo images, such as x-ray mammography and magnetic resonance imaging (MRI), are used for tumor detection, diagnosis, and size determination. After excision, the specimen is typically sliced into slabs and a small subset is sampled. Histopathological imaging of the stained samples is used as the gold standard for characterization of the tumor microenvironment. A 3D volume reconstruction of the whole specimen from the 2D slabs could facilitate bridging the gap between histology and in vivo radiological imaging. This task is challenging, however, due to the large deformation that the breast tissue undergoes after surgery and the significant undersampling of the specimen obtained in histology. In this work, we present a method to reconstruct a coherent 3D volume from 2D digital radiographs of the specimen slabs. METHODS: To reconstruct a 3D breast specimen volume, we propose the use of multiple target neighboring slices, when deforming each 2D slab radiograph in the volume, rather than performing pairwise registrations. The algorithm combines neighborhood slice information with free-form deformations, which enables a flexible, nonlinear deformation to be computed subject to the constraint that a coherent 3D volume is obtained. The neighborhood information provides adequate constraints, without the need for any additional regularization terms. RESULTS: The volume reconstruction algorithm is validated on clinical mastectomy samples using a quantitative assessment of the volume reconstruction smoothness and a comparison with a whole specimen 3D image acquired for validation before slicing. Additionally, a target registration error of 5 mm (comparable to the specimen slab thickness of 4 mm) was obtained for five cases. The error was computed using manual annotations from four observers as gold standard, with interobserver variability of 3.4 mm. Finally, we illustrate how the reconstructed volumes can be used to map histology images to a 3D specimen image of the whole sample (either MRI or CT). CONCLUSIONS: Qualitative and quantitative assessment has illustrated the benefit of using our proposed methodology to reconstruct a coherent specimen volume from serial slab radiographs. To our knowledge, this is the first method that has been applied to clinical breast cases, with the goal of reconstructing a whole specimen sample. The algorithm can be used as part of the pipeline of mapping histology images to ex vivo and ultimately in vivo radiological images of the breast.

Microstructural models for diffusion MRI in breast cancer and surrounding stroma: an ex vivo study.

The diffusion signal in breast tissue has primarily been modelled using apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and diffusion tensor (DT) models, which may be too simplistic to describe the underlying tissue microstructure. Formalin-fixed breast cancer samples were scanned using a wide range of gradient strengths, durations, separations and orientations. A variety of one- and two-compartment models were tested to determine which best described the data. Models with restricted diffusion components and anisotropy were selected in most cancerous regions and there were no regions in which conventional ADC or DT models were selected. Maps of ADC generally related to cellularity on histology, but maps of parameters from more complex models suggest that both overall cell volume fraction and individual cell size can contribute to the diffusion signal, affecting the specificity of ADC to the tissue microstructure. The areas of coherence in diffusion anisotropy images were small, approximately 1 mm, but the orientation corresponded to stromal orientation patterns on histology.

Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines. CONCLUSIONS: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non-constant and reader-specific difference.

Pre-natal exposures and breast tissue composition: findings from a British pre-birth cohort of young women and a systematic review.

BACKGROUND: Breast density, the amount of fibroglandular tissue in the adult breast for a women's age and body mass index, is a strong biomarker of susceptibility to breast cancer, which may, like breast cancer risk itself, be influenced by events early in life. In the present study, we investigated the association between pre-natal exposures and breast tissue composition. METHODS: A sample of 500 young, nulliparous women (aged approximately 21 years) from a U.K. pre-birth cohort underwent a magnetic resonance imaging examination of their breasts to estimate percent water, a measure of the relative amount of fibroglandular tissue equivalent to mammographic percent density. Information on pre-natal exposures was collected throughout the mothers' pregnancy and shortly after delivery. Regression models were used to investigate associations between percent water and pre-natal exposures. Mediation analysis, and a systematic review and meta-analysis of the published literature, were also conducted. RESULTS: Adjusted percent water in young women was positively associated with maternal height (p for linear trend [p t] = 0.005), maternal mammographic density in middle age (p t = 0.018) and the participant's birth size (p t < 0.001 for birthweight). A 1-SD increment in weight (473 g), length (2.3 cm), head circumference (1.2 cm) and Ponderal Index (4.1 g/cm3) at birth were associated with 3 % (95 % CI 2-5 %), 2 % (95 % CI 0-3 %), 3 % (95 % CI 1-4 %) and 1 % (95 % CI 0-3 %), respectively, increases in mean adjusted percent water. The effect of maternal height on the participants' percent water was partly mediated through birth size, but there was little evidence that the effect of birthweight was primarily mediated via adult body size. The meta-analysis supported the study findings, with breast density being positively associated with birth size. CONCLUSIONS: These findings provide strong evidence of pre-natal influences on breast tissue composition. The positive association between birth size and relative amount of fibroglandular tissue indicates that breast density and breast cancer risk may share a common pre-natal origin.

Multiscale Mechano-Biological Finite Element Modelling of Oncoplastic Breast Surgery-Numerical Study towards Surgical Planning and Cosmetic Outcome Prediction.

Surgical treatment for early-stage breast carcinoma primarily necessitates breast conserving therapy (BCT), where the tumour is removed while preserving the breast shape. To date, there have been very few attempts to develop accurate and efficient computational tools that could be used in the clinical environment for pre-operative planning and oncoplastic breast surgery assessment. Moreover, from the breast cancer research perspective, there has been very little effort to model complex mechano-biological processes involved in wound healing. We address this by providing an integrated numerical framework that can simulate the therapeutic effects of BCT over the extended period of treatment and recovery. A validated, three-dimensional, multiscale finite element procedure that simulates breast tissue deformations and physiological wound healing is presented. In the proposed methodology, a partitioned, continuum-based mathematical model for tissue recovery and angiogenesis, and breast tissue deformation is considered. The effectiveness and accuracy of the proposed numerical scheme is illustrated through patient-specific representative examples. Wound repair and contraction numerical analyses of real MRI-derived breast geometries are investigated, and the final predictions of the breast shape are validated against post-operative follow-up optical surface scans from four patients. Mean (standard deviation) breast surface distance errors in millimetres of 3.1 (±3.1), 3.2 (±2.4), 2.8 (±2.7) and 4.1 (±3.3) were obtained, demonstrating the ability of the surgical simulation tool to predict, pre-operatively, the outcome of BCT to clinically useful accuracy.

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

A review of biomechanically informed breast image registration.

Breast radiology encompasses the full range of imaging modalities from routine imaging via x-ray mammography, magnetic resonance imaging and ultrasound (both two- and three-dimensional), to more recent technologies such as digital breast tomosynthesis, and dedicated breast imaging systems for positron emission mammography and ultrasound tomography. In addition new and experimental modalities, such as Photoacoustics, Near Infrared Spectroscopy and Electrical Impedance Tomography etc, are emerging. The breast is a highly deformable structure however, and this greatly complicates visual comparison of imaging modalities for the purposes of breast screening, cancer diagnosis (including image guided biopsy), tumour staging, treatment monitoring, surgical planning and simulation of the effects of surgery and wound healing etc. Due primarily to the challenges posed by these gross, non-rigid deformations, development of automated methods which enable registration, and hence fusion, of information within and across breast imaging modalities, and between the images and the physical space of the breast during interventions, remains an active research field which has yet to translate suitable methods into clinical practice. This review describes current research in the field of breast biomechanical modelling and identifies relevant publications where the resulting models have been incorporated into breast image registration and simulation algorithms. Despite these developments there remain a number of issues that limit clinical application of biomechanical modelling. These include the accuracy of constitutive modelling, implementation of representative boundary conditions, failure to meet clinically acceptable levels of computational cost, challenges associated with automating patient-specific model generation (i.e. robust image segmentation and mesh generation) and the complexity of applying biomechanical modelling methods in routine clinical practice.

Multiscale modelling of solid tumour growth: the effect of collagen micromechanics.

Here we introduce a model of solid tumour growth coupled with a multiscale biomechanical description of the tumour microenvironment, which facilitates the explicit simulation of fibre-fibre and tumour-fibre interactions. We hypothesise that such a model, which provides a purely mechanical description of tumour-host interactions, can be used to explain experimental observations of the effect of collagen micromechanics on solid tumour growth. The model was specified to mouse tumour data, and numerical simulations were performed. The multiscale model produced lower stresses than an equivalent continuum-like approach, due to a more realistic remodelling of the collagen microstructure. Furthermore, solid tumour growth was found to cause a passive mechanical realignment of fibres at the tumour boundary from a random to a circumferential orientation. This is in accordance with experimental observations, thus demonstrating that such a response can be explained as purely mechanical. Finally, peritumoural fibre network anisotropy was found to produce anisotropic tumour morphology. The dependency of tumour morphology on the peritumoural microstructure was reduced by adding a load-bearing non-collagenous component to the fibre network constitutive equation.

Symmetric Biomechanically Guided Prone-to-Supine Breast Image Registration.

Prone-to-supine breast image registration has potential application in the fields of surgical and radiotherapy planning, image guided interventions, and multi-modal cancer diagnosis, staging, and therapy response prediction. However, breast image registration of three dimensional images acquired in different patient positions is a challenging problem, due to large deformations induced to the soft breast tissue caused by the change in gravity loading. We present a symmetric, biomechanical simulation based registration framework which aligns the images in a central, virtually unloaded configuration. The breast tissue is modelled as a neo-Hookean material and gravity is considered as the main source of deformation in the original images. In addition to gravity, our framework successively applies image derived forces directly into the unloading simulation in place of a subsequent image registration step. This results in a biomechanically constrained deformation. Using a finite difference scheme avoids an explicit meshing step and enables simulations to be performed directly in the image space. The explicit time integration scheme allows the motion at the interface between chest and breast to be constrained along the chest wall. The feasibility and accuracy of the approach presented here was assessed by measuring the target registration error (TRE) using a numerical phantom with known ground truth deformations, nine clinical prone MRI and supine CT image pairs, one clinical prone-supine CT image pair and four prone-supine MRI image pairs. The registration reduced the mean TRE for the numerical phantom experiment from initially 19.3 to 0.9 mm and the combined mean TRE for all fourteen clinical data sets from 69.7 to 5.6 mm.

An Inverse Finite Element u/p-Formulation to Predict the Unloaded State of In Vivo Biological Soft Tissues.

Physically realistic patient-specific biomechanical modelling is of paramount importance for many medical applications, where the geometry of tissues or organs is usually constructed from in vivo images. However, it is common for such biological structures to correspond to a deformed state due to being under external loadings. This necessitates the determination of the stress distribution of the known deformed state through an inverse analysis approach. To achieve this, we propose here a generalised finite element displacement/pressure (u/p)-formulation for evaluating the unloaded configuration of in vivo biological soft tissues that exhibit quasi-incompressible behaviour under finite deformations. Validity and applicability of the proposed numerical framework to practical inverse analysis problems in biomechanics is demonstrated through various numerical examples. The corresponding simulations utilise in vivo measurements of patient-specific geometries derived from different medical imaging modalities, and include recovery of the pressure-free configuration of human aortas and the gravity-free shape of the female breast.

Low-cost surface reconstruction for aesthetic results assessment and prediction in breast cancer surgery.

The high incidence and low mortality of breast cancer surgery has led to an increasing emphasis on the cosmetic outcome of surgical treatment. Advances in aesthetic evaluation, as well as surgical planning and outcome prediction, have been investigated by using geometrically precise 3D modelling of the breast surface prior to surgery and after the procedure. However, existing solutions are based on expensive site specific setups and remain weakly validated. In this paper, we explore the possibility of using low-cost RGBD cameras as an affordable and mobile system for breast surface reconstruction. The methodology relies on sensor calibration, uncertainty-driven point filtering, dense reconstruction and subsequent multi-view joint optimization to diffuse residual pose errors. Results from a phantom study, with ground truth obtained through commercially available scanners, indicate that the approach is promising with RMS errors in order of 2 mm. A clinical study shows the practical applicability of our method and compares favourably to high-end scanning solutions.

A nonlinear biomechanical model based registration method for aligning prone and supine MR breast images.

Preoperative diagnostic magnetic resonance (MR) breast images can provide good contrast between different tissues and 3-D information about suspicious tissues. Aligning preoperative diagnostic MR images with a patient in the theatre during breast conserving surgery could assist surgeons in achieving the complete excision of cancer with sufficient margins. Typically, preoperative diagnostic MR breast images of a patient are obtained in the prone position, while surgery is performed in the supine position. The significant shape change of breasts between these two positions due to gravity loading, external forces and related constraints makes the alignment task extremely difficult. Our previous studies have shown that either nonrigid intensity-based image registration or biomechanical modelling alone are limited in their ability to capture such a large deformation. To tackle this problem, we proposed in this paper a nonlinear biomechanical model-based image registration method with a simultaneous optimization procedure for both the material parameters of breast tissues and the direction of the gravitational force. First, finite element (FE) based biomechanical modelling is used to estimate a physically plausible deformation of the pectoral muscle and the major deformation of breast tissues due to gravity loading. Then, nonrigid intensity-based image registration is employed to recover the remaining deformation that FE analyses do not capture due to the simplifications and approximations of biomechanical models and the uncertainties of external forces and constraints. We assess the registration performance of the proposed method using the target registration error of skin fiducial markers and the Dice similarity coefficient (DSC) of fibroglandular tissues. The registration results on prone and supine MR image pairs are compared with those from two alternative nonrigid registration methods for five breasts. Overall, the proposed algorithm achieved the best registration performance on fiducial markers (target registration error, 8.44 ±5.5 mm for 45 fiducial markers) and higher overlap rates on segmentation propagation of fibroglandular tissues (DSC value > 82%).

Development of patient-specific biomechanical models for predicting large breast deformation.

Physically realistic simulations for large breast deformation are of great interest for many medical applications such as cancer diagnosis, image registration, surgical planning and image-guided surgery. To support fast, large deformation simulations of breasts in clinical settings, we proposed a patient-specific biomechanical modelling framework for breasts, based on an open-source graphics processing unit-based, explicit, dynamic, nonlinear finite element (FE) solver. A semi-automatic segmentation method for tissue classification, integrated with a fully automated FE mesh generation approach, was implemented for quick patient-specific FE model generation. To solve the difficulty in determining material parameters of soft tissues in vivo for FE simulations, a novel method for breast modelling, with a simultaneous material model parameter optimization for soft tissues in vivo, was also proposed. The optimized deformation prediction was obtained through iteratively updating material model parameters to maximize the image similarity between the FE-predicted MR image and the experimentally acquired MR image of a breast. The proposed method was validated and tested by simulating and analysing breast deformation experiments under plate compression. Its prediction accuracy was evaluated by calculating landmark displacement errors. The results showed that both the heterogeneity and the anisotropy of soft tissues were essential in predicting large breast deformations under plate compression. As a generalized method, the proposed process can be used for fast deformation analyses of soft tissues in medical image analyses and surgical simulations.

Localized fibroglandular tissue as a predictor of future tumor location within the breast.

BACKGROUND: Mammographic density (MD) is a strong marker of breast cancer risk, but it is unclear whether tumors arise specifically within dense tissue. METHODS: In 231 British women diagnosed with breast cancer after at least one negative annual screening during a mammographic screening trial, we assessed whether tumor location was related to localized MD 5 years prior to diagnosis. Radiologists identified tumor locations on digitised films. We used a validated algorithm to align serial images from the same woman to locate the corresponding point on the prediagnostic film. A virtual 1 cm square grid was overlaid on prediagnostic films and MD calculated for each square within a woman's breast (mean = 271 squares/film). Conditional logistic regression, matching on a woman's breast, was used to estimate the odds of a tumor arising in a square in relation to its prediagnostic square-specific MD. RESULTS: Median (interquartile range) prediagnostic MD was 98.2% (46.8%-100%) in 1 cm-squares that subsequently contained the tumor and 41.0% (31.5%-53.9%) for the whole breast. The odds of a tumor arising in a 1 cm-square were, respectively, 6.1 (95% CI: 1.9-20.1), 16.6 (5.2-53.2), and 25.5-fold (8.1-80.3) higher for squares in the second, third, and fourth quartiles of prediagnostic MD relative to those in the lowest quartile within that breast (P(trend) < 0.001). The corresponding odds ratios were 2.3 (1.3-4.0), 3.9 (2.3-6.4), and 4.6 (2.8-7.6) if a 3 cm-square grid was used. CONCLUSION: Tumors arise predominantly within the radiodense breast tissue. IMPACT: Localized MD may be used as a predictor of subsequent tumor location within the breast.

Automated registration of diagnostic to prediagnostic x-ray mammograms: evaluation and comparison to radiologists' accuracy.

PURPOSE: To compare and evaluate intensity-based registration methods for computation of serial x-ray mammogram correspondence. METHODS: X-ray mammograms were simulated from MRIs of 20 women using finite element methods for modeling breast compressions and employing a MRI/x-ray appearance change model. The parameter configurations of three registration methods, affine, fluid, and free-form deformation (FFD), were optimized for registering x-ray mammograms on these simulated images. Five mammography film readers independently identified landmarks (tumor, nipple, and usually two other normal features) on pairs of diagnostic and corresponding prediagnostic digitized images from 52 breast cancer cases. Landmarks were independently reidentified by each reader. Target registration errors were calculated to compare the three registration methods using the reader landmarks as a gold standard. Data were analyzed using multilevel methods. RESULTS: Between-reader variability varied with landmark (p < 0.01) and screen (p = 0.03), with between-reader mean distance (mm) in point location on the diagnostic/prediagnostic images of 2.50 (95% CI 1.95, 3.15)/2.84 (2.24, 3.55) for nipples and 4.26 (3.43, 5.24)/4.76 (3.85, 5.84) for tumors. Registration accuracy was sensitive to the type of landmark and the amount of breast density. For dense breasts (> or = 40%), the affine and fluid methods outperformed FFD. For breasts with lower density, the affine registration surpassed both fluid and FFD. Mean accuracy (mm) of the affine registration varied between 3.16 (95% CI 2.56, 3.90) for nipple points in breasts with density 20%-39% and 5.73 (4.80, 6.84) for tumor points in breasts with density < 20%. CONCLUSIONS: Affine registration accuracy was comparable to that between independent film readers. More advanced two-dimensional nonrigid registration algorithms were incapable of increasing the accuracy of image alignment when compared to affine registration.