Joint AAPM Task Group 282/EFOMP Working Group Report: Breast dosimetry for standard and contrast-enhanced mammography and breast tomosynthesis.

Currently, there are multiple breast dosimetry estimation methods for mammography and its variants in use throughout the world. This fact alone introduces uncertainty, since it is often impossible to distinguish which model is internally used by a specific imaging system. In addition, all current models are hampered by various limitations, in terms of overly simplified models of the breast and its composition, as well as simplistic models of the imaging system. Many of these simplifications were necessary, for the most part, due to the need to limit the computational cost of obtaining the required dose conversion coefficients decades ago, when these models were first implemented. With the advancements in computational power, and to address most of the known limitations of previous breast dosimetry methods, a new breast dosimetry method, based on new breast models, has been developed, implemented, and tested. This model, developed jointly by the American Association of Physicists in Medicine and the European Federation for Organizations of Medical Physics, is applicable to standard mammography, digital breast tomosynthesis, and their contrast-enhanced variants. In addition, it includes models of the breast in both the cranio-caudal and the medio-lateral oblique views. Special emphasis was placed on the breast and system models used being based on evidence, either by analysis of large sets of patient data or by performing measurements on imaging devices from a range of manufacturers. Due to the vast number of dose conversion coefficients resulting from the developed model, and the relative complexity of the calculations needed to apply it, a software program has been made available for download or online use, free of charge, to apply the developed breast dosimetry method. The program is available for download or it can be used directly online. A separate User's Guide is provided with the software.

Quantitative Breast Density in Contrast-Enhanced Mammography.

Contrast-enhanced mammography (CEM) demonstrates a potential role in personalized screening models, in particular for women at increased risk and women with dense breasts. In this study, volumetric breast density (VBD) measured in CEM images was compared with VBD obtained from digital mammography (DM) or tomosynthesis (DBT) images. A total of 150 women who underwent CEM between March 2019 and December 2020, having at least a DM/DBT study performed before/after CEM, were included. Low-energy CEM (LE-CEM) and DM/DBT images were processed with automatic software to obtain the VBD. VBDs from the paired datasets were compared by Wilcoxon tests. A multivariate regression model was applied to analyze the relationship between VBD differences and multiple independent variables certainly or potentially affecting VBD. Median VBD was comparable for LE-CEM and DM/DBT (12.73% vs. 12.39%), not evidencing any statistically significant difference (p = 0.5855). VBD differences between LE-CEM and DM were associated with significant differences of glandular volume, breast thickness, compression force and pressure, contact area, and nipple-to-posterior-edge distance, i.e., variables reflecting differences in breast positioning (coefficient of determination 0.6023; multiple correlation coefficient 0.7761). Volumetric breast density was obtained from low-energy contrast-enhanced spectral mammography and was not significantly different from volumetric breast density measured from standard mammograms.

Artifacts in contrast-enhanced mammography: are there differences between vendors?

PURPOSE: Contrast-Enhanced Mammography (CEM) produces a dual-energy subtracted (DES) image that demonstrates iodine uptake (neovascularity) in breast tissue. We aim to review a range of artifacts on DES images produced using equipment from two different vendors and compare their incidence and subjective severity. METHODS: We retrospectively reviewed CEM studies performed between September 2013 and March 2017 using GE Senographe Essential (n = 100) and Hologic Selenia Dimensions (n = 100) equipment. Artifacts were categorized and graded in severity by a subspecialist breast radiologist and one of two medical imaging technologists in consensus. The incidence of artifacts between vendors was compared by calculating the relative risk, and the severity gradings were compared using a Wilcoxon rank-sum test. RESULTS: Elephant rind, corrugations and the black line on chest wall artifact were seen exclusively in Hologic images. Artifacts such as cloudy fat, negative rim around lesion and white line on pectoral muscle were seen in significantly more Hologic images (p < 0.05) whilst halo, ripple, skin line enhancement, black line on pectoral muscle, bright pectorals, chest wall high-lighting and air gap were seen in significantly more GE images (p < 0.05). The severity gradings for cloudy fat had a significantly higher mean rank in Hologic images (p < 0.001) whilst halo and ripple artifacts had a significantly higher mean rank in GE images (p < 0.001 and p = 0.028 respectively). CONCLUSION: The type, incidence and subjective severity of CEM-specific artifacts differ between vendors. Further research is needed, but differences in algorithms used to produce the DE image are postulated to be a significant contributor.

Accuracy of mammography dosimetry in the era of the European Directive 2013/59/Euratom transposition.

PURPOSE: To evaluate the impact of increasing levels of accuracy for mean glandular dose (MGD) evaluation in the era of the European Directive 2013/59/Euratom transposition. METHOD: 4028 women who had a mammography examination by one of five mammography units using different detector technologies were included in this study. 16,006 images were processed by a software algorithm that determines breast glandularity quantitatively and uses this to estimate patient-specific MGD (psMGD). Entrance dose (ED) values and half value layers (HVLs) measured for each mammography system were collected to evaluate the effect of equipment calibration in psMGD calculation. The psMGD values adjusted for system calibration were compared with organ dose (OD) provided by manufacturers as image metadata. RESULTS: Overall median relative difference between calibrated psMGD and organ dose was below 3%, with larger differences for individual systems. The psMGD adjustment for system calibration was particularly useful for one system for which ED had an evident miscalibration issue. The mean difference between psMGD with calibration and organ dose provided by manufacturers was 4.1 %, ranging from -16.3 % to +24.5 %. The proportion of images for which organ dose was more than 10 % 'inaccurate' compared to psMGD was between 11 % and 46 %, depending on the mammography system. CONCLUSION: Patient-specific mean glandular dose, possibly adjusted for system calibration, allows more accurate individual breast dosimetry than what would be performed using organ dose provided by manufacturers. Conversely, definition of diagnostic reference levels could be achieved using either psMGD or organ dose.

A solid iodinated phantom material for use in tomographic x-ray imaging.

PURPOSE: Iodinated phantoms are of value in x-ray imaging for quality control measurements, system calibration, and for use in the research setting; however, the liquid phantoms that are most often used have several limitations including variability between repeated dilutions, inhomogeneities from air bubbles or precipitants, and long set up times. Although suitable materials have been investigated for projection radiography, quantitative measurements of contrast enhancement in computed tomography (CT) have become increasingly important in the clinic, and a need exists for a durable and reproducible iodinated phantom material. In this work, the authors describe a solid radiographic phantom material that has an accurately known concentration of iodine distributed uniformly throughout its volume and that has stable properties over time. This material can be molded or machined into a desired shape to create a test object or for use in an anthropomorphic phantom. METHODS: Two sets of calibration phantoms were produced with a clinically relevant range of iodine concentrations. Measurements were made on these phantoms to characterize the material properties in terms of accuracy of iodine concentration, radiographic uniformity, temporal stability of x-ray attenuation, and manufacturing repeatability. Experimentally measured linear x-ray attenuation coefficients were compared to those predicted by a theoretical model. The uniformity of the iodine distribution in the material was assessed by measuring image intensity variation, both in projection images and in reconstructed CT volumes. The reproducibility of manufacture was estimated on a set of independently produced samples. A longitudinal study was performed to assess the stability of the material x-ray characteristics over time by making measurements at 6 month intervals. RESULTS: Good agreement was seen between the experimental measurements of effective attenuation and the theoretically predicted values. It is estimated that a desired iodine concentration could be produced to within 0.04 mg/ml. Comparison of the measured effective linear iodine attenuation coefficients of eight 1.0 mg/ml samples indicated a manufacturing reproducibility of +/-0.03 mg/ml iodine. Variations in uniformity across each of the samples were on the order of image intensity fluctuations (sigma). No inhomogeneities due to mixing or settling were apparent. An analysis of longitudinal data collected for both calibration sets revealed no perceptible change in radiographic properties over the first 6 months after manufacture, nor over a subsequent 1.5 yr period from 1 yr postmanufacture onward. CONCLUSIONS: The uniformity, stability, and precision of this iodinated material suggest that it is suitable for use in accurate calibration tools for contrast tomographic imaging.

Anatomical noise in contrast-enhanced digital mammography. Part I. Single-energy imaging.

PURPOSE: The use of an intravenously injected iodinated contrast agent could help increase the sensitivity of digital mammography by adding information on tumor angiogenesis. Two approaches have been made for clinical implementation of contrast-enhanced digital mammography (CEDM), namely, single-energy (SE) and dual-energy (DE) imaging. In each technique, pairs of mammograms are acquired, which are then subtracted with the intent to cancel the appearance of healthy breast tissue to permit sensitive detection and specific characterization of lesions. Patterns of contrast agent uptake in the healthy parenchyma, and uncanceled signal from background tissue create a "clutter" that can mask or mimic an enhancing lesion. This type of "anatomical noise" is often the limiting factor in lesion detection tasks, and thus, noise quantification may be useful for cascaded systems analysis of CEDM and for phantom development. In this work, the authors characterize the anatomical noise in CEDM clinical images and the authors evaluate the influence of the x-ray energy used for acquisition, the presence of iodine in the breast, and the timing of imaging postcontrast administration on anatomical noise. The results are presented in a two-part report, with SE CEDM described here, and DE CEDM in Part II. METHODS: A power law is used to model anatomical noise in CEDM images. The exponent, ß, which describes the anatomical structure, and the constant α, which represents the magnitude of the noise, are determined from Wiener spectra (WS) measurements on images. A total of 42 SE CEDM cases from two previous clinical pilot studies are assessed. The parameters α and ß are measured both from unprocessed images and from subtracted images. RESULTS: Consistent results were found between the two SE CEDM pilot studies, where a significant decrease in ß from a value of approximately 3.1 in the unprocessed images to between about 1.1 and 1.8 in the subtracted images was observed. Increasing the x-ray energy from that used in conventional DM to those of typical SE CEDM spectra with mean energies above 33 keV significantly decreased α by about a factor of 19, in agreement with theory. Compared to precontrast images, in the unprocessed postcontrast images at 30 s postinjection, α was larger by about 7.4 × 10(-7) mm(2) and ß was decreased by 0.2. While α did not vary significantly with the time after contrast administration, ß from the unprocessed image WS increased linearly, and ß from subtracted image WS increased with an initial quadratic relationship that plateaued by about 5 min postinjection. CONCLUSIONS: The presence of an iodinated contrast agent in the breast produced small, but significant changes in the power law parameters of unprocessed CEDM images compared to the precontrast images. Image subtraction in SE CEDM significantly reduced anatomical noise compared to conventional DM, with a reduction in both α and ß by about a factor of 2. The data presented here, and in Part II of this work, will be useful for modeling of CEDM backgrounds, for systems characterization and for lesion detectability experiments using models that account for anatomical noise.

Towards a nanoscale mammographic contrast agent: development of a modular pre-clinical dual optical/x-ray agent.

Contrast-enhanced digital mammography (CEDM) can provide improved breast cancer detection and characterization compared to conventional mammography by imaging the effects of tumour angiogenesis. Current small-molecule contrast agents used for CEDM are limited by a short plasma half-life and rapid extravasation into tissue interstitial space. To address these limitations, nanoscale agents that can remain intravascular except at sites of tumour angiogenesis can be used. For CEDM, this agent must be both biocompatible and strongly attenuate mammographic energy x-rays. Nanoscale perfluorooctylbromide (PFOB) droplets have good x-ray attenuation and have been used in patients for other applications. However, the macroscopic scale of x-ray imaging (50-100 µm) is inadequate for direct verification that PFOB droplets localize at sites of breast tumour angiogenesis. For efficient pre-clinical optimization for CEDM, we integrated an optical marker into PFOB droplets for microscopic assessment (≪50 µm). To develop PFOB droplets as a new nanoscale mammographic contrast agent, PFOB droplets were labelled with fluorescent quantum dots (QDs). The droplets had mean diameters of 160 nm, fluoresced at 635 nm and attenuated x-ray spectra at 30.5 keV mean energy with a relative attenuation of 5.6 ± 0.3 Hounsfield units (HU) mg(-1) mL(-1) QD-PFOB. With the agent loaded into tissue phantoms, good correlation between x-ray attenuation and optical fluorescence was found (R(2) = 0.96), confirming co-localization of the QDs with PFOB for quantitative assessment using x-ray or optical methods. Furthermore, the QDs can be removed from the PFOB agent without affecting its x-ray attenuation or structural properties for expedited translation of optimized PFOB droplet formulations into patients.

Use of a computerized C-reactive protein (CRP) based sepsis evaluation in very low birth weight (VLBW) infants: a five-year experience.

BACKGROUND: Serial C-reactive protein (CRP) values may be useful for decision-making regarding duration of antibiotics in neonates. However, established standard of practice for its use in preterm very low birth weight (<1500 g, VLBW) infants are lacking. OBJECTIVE: Evaluate compliance with a CRP-guided computerized decision support (CDS) algorithm and compare characteristics and outcomes of compliant versus non-compliant cases. Measure correlation between CRPs and white blood count (WBC) indices. METHODS: We examined 3 populations: 1) all preterm VLBW infants born at Vanderbilt 2006-2011 - we assessed provider compliance with CDS algorithm and measured relevant outcomes; 2) all patients with positive blood culture results admitted to the Vanderbilt NICU 2006-2012 - we tested the correlation between CRP and WBC results within 7 days of blood culture phlebotomy; 3) 1,000 randomly selected patients out of the 7,062 patients admitted to the NICU 2006-2012 - we correlated time-associated CRP values and absolute neutrophil counts. RESULTS: Of 636 VLBW infants in cohort 1), 569 (89%) received empiric antibiotics for suspected early-onset sepsis. In 409 infants (72%) the CDS algorithm was followed; antibiotics were discontinued ≤48 hours in 311 (55%) with normal serial CRPs and continued in 98 (17%) with positive CRPs, resulting in significant reduction in antibiotic exposure (p<0.001) without increase in complications or subsequent infections. One hundred sixty (28%) were considered non-compliant because antibiotics were continued beyond 48 hours despite negative serial CRPs and blood cultures. Serial CRPs remained negative in 38 (12%) of 308 blood culture-positive infants from cohort 2, but only 4 patients had clinically probable sepsis with single organisms and no immunodeficiency besides extreme prematurity. Leukopenia of any cell type was not linked with CRPs in cohorts 2 and 3. CONCLUSIONS: CDS/CRP-guided antibiotic use is safe and effective in culture-negative VLBW infants. CRP results are not affected by low WBC indices.

Anatomical noise in contrast-enhanced digital mammography. Part II. Dual-energy imaging.

PURPOSE: Dual-energy (DE) contrast-enhanced digital mammography (CEDM) uses an iodinated contrast agent in combination with digital mammography (DM) to evaluate lesions on the basis of tumor angiogenesis. In DE imaging, low-energy (LE) and high-energy (HE) images are acquired after contrast administration and their logarithms are subtracted to cancel the appearance of normal breast tissue. Often there is incomplete signal cancellation in the subtracted images, creating a background "clutter" that can impair lesion detection. This is the second component of a two-part report on anatomical noise in CEDM. In Part I the authors characterized the anatomical noise for single-energy (SE) temporal subtraction CEDM by a power law, with model parameters α and ß. In this work the authors quantify the anatomical noise in DE CEDM clinical images and compare this with the noise in SE CEDM. The influence on the anatomical noise of the presence of iodine in the breast, the timing of imaging postcontrast administration, and the x-ray energy used for acquisition are each evaluated. METHODS: The power law parameters, α and ß, were measured from unprocessed LE and HE images and from DE subtracted images to quantify the anatomical noise. A total of 98 DE CEDM cases acquired in a previous clinical pilot study were assessed. Conventional DM images from 75 of the women were evaluated for comparison with DE CEDM. The influence of the imaging technique on anatomical noise was determined from an analysis of differences between the power law parameters as measured in DM, LE, HE, and DE subtracted images for each subject. RESULTS: In DE CEDM, weighted image subtraction lowers ß to about 1.1 from 3.2 and 3.1 in LE and HE unprocessed images, respectively. The presence of iodine has a small but significant effect in LE images, reducing ß by about 0.07 compared to DM, with α unchanged. Increasing the x-ray energy, from that typical in DM to a HE beam, significantly decreases α by about 2×10(-5) mm2, and lowers ß by about 0.14 compared to LE images. A comparison of SE and DE CEDM at 4 min postcontrast shows equivalent power law parameters in unprocessed images, and lower α and ß by about 3×10(-5) mm2 and 0.50, respectively, in DE versus SE subtracted images. CONCLUSIONS: Image subtraction in both SE and DE CEDM reduces ß by over a factor of 2, while maintaining α below that in DM. Given the equivalent α between SE and DE unprocessed CEDM images, and the smaller anatomical noise in the DE subtracted images, the DE approach may have an advantage over SE CEDM. It will be necessary to test this potential advantage in future lesion detectability experiments, which account for realistic lesion signals. The authors' results suggest that LE images could be used in place of DM images in CEDM exam interpretation.

In vitro assessment of poly-iodinated triglyceride reconstituted low-density lipoprotein: initial steps toward CT molecular imaging.

RATIONALE AND OBJECTIVES: Targeted molecular probes offer the potential for greater specificity in cancer imaging with contrast-enhanced computed tomography (CT). We investigate a low-density lipoprotein (LDL) nanoparticle loaded with poly-iodinated triglyceride (ITG) in a proof of concept study of targeted x-ray imaging. LDLs are targeted to the LDL cell surface receptor (LDLR), which is overexpressed in several tumor types. The LDL-LDLR pathway presents a high-capacity and self-renewing transport system for molecular imaging in CT. MATERIALS AND METHODS: ITG was synthesized and loaded into the core of LDL particles to form a reconstituted nanoparticle, hereafter referred to as (rITG)LDL. Particle size was measured by dynamic light scattering. The x-ray attenuation of the (rITG)LDL solution was measured with CT imaging and signal enhancement was calibrated for equivalent iodine concentration. Cultured human hepatoblastoma G2 (HepG2) cells, which overexpress LDLR, were incubated with (rITG)LDL with or without native LDL. The cells were imaged with CT to characterize particle sequestration. RESULTS: Reconstitution of LDL with ITG was successful and did not compromise the targeting function of the particle. Measurement of the x-ray attenuation properties of the (rITG)LDL solution revealed an effective iodine concentration of 0.78 mg/mL. In vitro studies of HepG2 cells demonstrated a significant increase in CT image intensity over control cells when incubated with (rITG)LDL. CONCLUSION: The in vitro results of this study suggest that (rITG)LDL can provide adequate image enhancement for CT molecular imaging. Potential applications include breast imaging and small animal imaging at low x-ray energies. In vivo experiments will be required to verify that tumor uptake of (rITG)LDL is sufficient for enhanced detection. Use at higher x-ray energies, as used in conventional CT, will require a further increase in iodine loading.