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Manuscript Number: BJR-D-08-00729

Title: Dual-Energy Contrast-Enhanced Digital Breast Tomosynthesis - A Feasibility Study

Article Type: Short Communication

Section/Category: Physics & Technology

Corresponding Author: Mrs. Ann-Katherine Carton, Ph.D.

Corresponding Author's Institution: University of Pennsylvania

First Author: Ann-Katherine Carton, Ph.D.

Order of Authors: Ann-Katherine Carton, Ph.D.; Sara C Gavenonis, MD; Jean Anne Currivan; Emily

F Conant, MD; Mitchell D Schnall, MD, Ph.D.; Andrew D Maidment, Ph.D.

Abstract: The purpose of this study is to assess the feasibility of dual-energy subtraction as a

technique for contrast-enhanced digital breast tomosynthesis (CE-DBT). CE-DBT is a novel

modality for imaging breast lesion morphology and vascularity, and a temporal subtraction CE-DBT

technique has been previously described. As CE-DBT evolves, exploration of alternate image

acquisition techniques will contribute to its optimization.

Evaluation of dual-energy CE-DBT was conducted with IRB approval from our institution and in

compliance with federal HIPAA guidelines. A 55-year old patient with a known malignancy in the

right breast underwent imaging with digital mammography, ultrasound, MRI, and CE-DBT (temporal

subtraction and dual energy techniques).

CE-DBT was performed in the medial lateral oblique view with a DBT system, modified under IRB

approval to allow high-energy (HE) image acquisition with a 0.25 mm Cu filter. Image acquisition

occurred via both temporal and dual-energy subtraction CE-DBT.

Between the precontrast and postcontrast DBT image sets, a single bolus of iodinated contrast

agent (1.0 ml/kg) was administered, followed by a 60 ml saline flush. The contrast agent and saline

were administrated manually at a rate of ~2 ml/second.

Images were reconstructed using filtered-backprojection in 1-mm increments and transmitted to a

clinical PACS workstation.

Dual-energy CE-DBT is shown to be clinically feasible. In our index case, dual-energy technique

was able to demonstrate morphology and kinetics information about the known malignancy. This

information is qualitatively concordant with that of CE-MRI. In comparison with the temporal

subtraction CE-DBT technique, dual-energy CE-DBT appears less susceptible to motion artifacts.

Suggested Reviewers: Mats Danielsson pHd

Professor, Department of Physics, Royal Institute of Technology, SE-104 05 Stockholm, Sweden

md@mi.physics.kth.se

Dr. Danielsson has experience with contrast enhanced digital breast tomosynthesis. His group has

published on this subject in SPIE proceedings.

Roberta Jong MD

Associate Scientist, Sunnybrook Health Sciences Centre, Toronto

roberta.jong@sunnybrook.ca

Dr. Jong has extensive experience with temporal subtraction mammography

John M. Lewin MD

Radiologist, Radiology, Diversified Radiology of Colorado, PC, Denver, Colorado

jlewin@divrad.com

Dr Lewin has experience with dual energy mammography.

Opposed Reviewers: Not Applicable Not Applicable

Not Applicable, Not Applicable

We do not oppose any specific reviewers.

Dual-Energy Contrast-Enhanced Digital Breast Tomosynthesis – A Feasibility Study

RUNNING TITLE: Feasibility of Dual-Energy Contrast-Enhanced Digital Breast Tomosynthesis

Category: SHORT COMMUNICATIONS

Ann-Katherine Carton, Ph.D.*Sara C. Gavenonis, M.D.*

Jean Anne Currivan*Emily F. Conant, M.D.*

Mitchell D. Schnall, M.D., Ph.D.*Andrew D.A. Maidment*

*Hospital of the University of PennsylvaniaDept. of Radiology, 1 Silverstein

3400 Spruce StreetPhiladelphia, PA 19104

This work was supported by a National Cancer Institute grant (NIH P01 CA85484-01A2)

* Title Page

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Dual-Energy Contrast-Enhanced Digital Breast Tomosynthesis – A Feasibility Study

RUNNING TITLE: Feasibility of Dual-Energy Contrast-Enhanced Digital Breast Tomosynthesis

Category: SHORT COMMUNICATIONS

* ManuscriptClick here to view linked References

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Abstract

The purpose of this study is to assess the feasibility of dual-energy subtraction as a technique for

contrast-enhanced digital breast tomosynthesis (CE-DBT). CE-DBT is a novel modality for imaging

breast lesion morphology and vascularity, and a temporal subtraction CE-DBT technique has been

previously described. As CE-DBT evolves, exploration of alternate image acquisition techniques will

contribute to its optimization.

Evaluation of dual-energy CE-DBT was conducted with IRB approval from our institution and in

compliance with federal HIPAA guidelines. A 55-year old patient with a known malignancy in the right

breast underwent imaging with digital mammography, ultrasound, MRI, and CE-DBT (temporal

subtraction and dual energy techniques).

CE-DBT was performed in the medial lateral oblique view with a DBT system, modified under

IRB approval to allow high-energy (HE) image acquisition with a 0.25 mm Cu filter. Image

acquisition occurred via both temporal and dual-energy subtraction CE-DBT.

Between the precontrast and postcontrast DBT image sets, a single bolus of iodinated contrast agent

(1.0 ml/kg) was administered, followed by a 60 ml saline flush. The contrast agent and saline were

administrated manually at a rate of ~2 ml/second.

Images were reconstructed using filtered-backprojection in 1-mm increments and transmitted to a

clinical PACS workstation.

Dual-energy CE-DBT is shown to be clinically feasible. In our index case, dual-energy technique was

able to demonstrate morphology and kinetics information about the known malignancy. This

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information is qualitatively concordant with that of CE-MRI. In comparison with the temporal

subtraction CE-DBT technique, dual-energy CE-DBT appears less susceptible to motion artifacts.

Key Words – Breast imaging, neoangiogenesis, contrast-enhanced digital breast tomosynthesis – dual energy – temporal subtraction

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IntroductionBreast tumor growth and metastasis are accompanied by the development of new blood vessels that

have an abnormally increased permeability [1]. As a result, the absorption of vascular contrast agents

is often different in malignant breast tissue than in benign and normal tissues. Today, contrast

enhanced magnetic resonance imaging (CE-MRI), which uses a gadolinium chelate as a vascular

contrast agent, is the standard for vascular imaging of breast cancers [2-7]. Breast lesion

characterization with CE-MRI relies on a combination of the analysis of the morphological features of

the lesion as well as the vascular enhancement kinetics.

Preliminary studies have demonstrated that contrast-enhanced digital breast tomosynthesis (CE-DBT)

using an iodinated vascular contrast agent has the potential to demonstrate morphology and vascular

enhancement information concordant with that of CE-MRI [8]. As the clinical uses of CE-MRI

continue to expand, investigation into a potential alternative such as CE-DBT (which is projected to be

less costly and more widely available than MRI) may also increase in importance.

A temporal subtraction CE-DBT technique has been reported, where one pre- and one or more post-

contrast tomosynthesis time-points are acquired using a spectrum predominantly above the K-edge of

iodine (32.3 keV) [9-12]. Pre- and post-contrast image series are then logarithmically subtracted

yielding iodine-enhanced images.

Another contrast-enhanced x-ray breast imaging technique that has been reported is dual-energy

subtraction. This has been reported in the context of digital mammography (DM), where post-contrast

images are acquired in pairs at energies that closely bracket the K-absorption edge of iodine [13-16].

At each time point, iodine-enhanced images are calculated by weighted logarithmic subtraction of the

low- and high-energy (LE and HE) images.

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The objective of this study is to assess the feasibility of applying a dual energy subtraction technique

to CE-DBT. In addition, we sought to compare the quality of the images obtained with a dual energy

CE-DBT technique with those obtained via temporal subtraction CE-DBT.

Materials and MethodsEligibility CriteriaIRB approval was obtained for a pilot project to assess the clinical feasibility of temporal and dual

energy subtraction CE-DBT. The CE-DBT pilot study was part of a National Cancer Institute-funded

grant (NIH P01 CA85484-01A2) evaluating multimodality breast imaging. A patient with a known

malignancy (status post ultrasound-guided core biopsy with clip placement) was imaged with both CE-

DBT techniques and with CE-MRI. We present the findings from this index patient.

Imaging ProtocolTemporal and dual energy subtraction CE-DBT imaging were performed with a General Electric

Senographe DS DBT system (GE Medical Systems, Chalfont St. Giles, U.K.). The system was

modified under IRB approval to allow HE image acquisition by adding a 0.25 mm Cu filter (Alfa Aesar,

Ward Hill, MA) to the x-ray beam path. The affected breast of each patient underwent CE-DBT using

a single breast compression in the mediolateral oblique (MLO) view, with the patient remaining seated

for the duration of the exam. The DBT prototype used in this study did not have the ability to record

compression force; light to moderate compression was applied to immobilize the breast and to reduce

the dose latitude and scatter. The timing of the DBT image sequence is shown in Figure 1. First, a

pre-contrast HE DBT projection image series was acquired. After contrast agent administration, HE

and LE DBT projection image series were acquired twice. The technical parameters for the HE and

LE image series for this patient with a breast thickness of 5 cm in compression are specified in Table

1. The technique was optimized as a compromise between iodine enhancement, the heating and

cooling capacity of the x-ray tube, the patient radiation dose and the speed of the image read-out.

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Each DBT projection series consists of seven images acquired in 6.7-degree increments over a 40-

degree arc and the tube motion is motorized from head to toe; between each image series there is a

need to reset the x-ray tube to the original start position.

The contrast agent was Visipaque-320® ( 320 mg I/ml iodixanol, Amersham, Princeton, NJ) with a

dosage of 1.0 ml/kg bodyweight. The contrast agent injection was followed by a 60 ml saline flush.

The contrast agent and saline were administrated manually at a rate of ~2 ml/second.

The total procedure time was 8 minutes. The HE pre-contrast series took approximately 0.27 minutes

to acquire. The total injection time (contrast agent + saline flush) was approximately 1 minute given

this patient’s weight (85 kg). The first post-contrast HE series was initiated 1.5 minutes after the start

of contrast agent injection, the first post-contrast LE series was initiated 2.9 minutes after the start of

the injection, the second post-contrast HE series was at 4.4 minutes after the start of the injection,

and the second post-contrast LE series, was initiated 5.85 minutes after the start of the injection. The

time delay between the post-contrast series was limited by the image read-out time of the x-ray

detector.

The total mean glandular dose (MGD) was 6.48mSv for this patient with a breast thickness of 5 cm in

compression; this is comparable to the dose of two conventional mammographic views. MGD were

calculated using a model published by Boone [17]. This model requires knowledge of the breast

entrance dose and the spectrum incident on the breast. Breast entrance doses were calculated

based on air kerma measured free-in-air measured with an air ionization chamber (Radcal MDH1515,

Radcal Corporation, Monrovia, CA). We simulated the input spectrum necessary for this calculation

using a validated extrapolation of Boone’s model for high-energy mammographic spectra [12, 18].

MGD were calculated assuming breasts with a 50% glandular – 50% adipose equivalency.

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Image processing Temporal and dual energy subtraction iodine-enhanced images were produced from the recorded

projection images; these images are corrected for detector non-uniformity; the data are linear with

detector dose. Temporal subtraction projection series were obtained at two time points (Figure 1.).

At each time point a logarithmic subtraction was performed between the HE pre-contrast series and

the respective HE post-contrast image series.

Dual energy subtraction projection series were generated at three time points (Figure 1). The second

dual energy series is a result of using the first LE image series twice, once as a LE mask for the first

dual energy timepoint, and again as the LE mask for the second dual energy timepoint. At each time

point, a weighted logarithmic subtraction was applied to the HE and LE image series. For the breast

in this case, a constant weighting factor, tw , was applied; tw was optimized for the region of the breast

with constant compressed thickness [16]. The optimal tw value was determined by varying tw in the

logarithmic subtraction from 0 to 1 in steps of 0.01 in a region with uniform compressed breast

thickness; tw = 0.21 resulted in the minimum breast tissue background variance.

Tomographic reconstructionEach subtracted projection image series was reconstructed using a custom filtered-backprojection

algorithm [19]. This reconstruction algorithm was also applied to the final LE image series to provide

a 3D image of the breast anatomy. A 20.5×20.5×T cm3 volume of interest was reconstructed in each

instance, where T is equal to the thickness of the breast as measured by the compression device and

recorded in the source image DICOM header. The images were reconstructed in planes parallel to

the detector in 1-mm increments, images were reconstructed with an in-plane voxel pitch of 220 µm.

Each reconstructed image series was written as DICOM CT object to the PACS.

Image Display

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The DBT and MRI images were displayed with Efilm (V1.5.3; Merge Healthcare, Milwaukee, WI) at full

resolution on two 21” 1200×1600 grayscale monitors (Siemens SMM-21125P, Karlsruhe, Germany) in

stack mode. Monitor luminance was calibrated to the DICOM GSDF using the AAPM TG18 protocol

[20].

ResultsThe patient in our feasibility study had undergone ultrasound-guided core biopsy with clip placement

in the right upper outer quadrant breast lesion, with pathology results of poorly differentiated invasive

ductal carcinoma. Suspicious rim enhancement was demonstrated on both CE-DBT techniques. This

enhancement was qualitatively concordant with that demonstrated on CE-MRI in the same patient

(Figure 2).

All images show consistent lesion morphology (Figures 2, 3 and 4). Using the clip from prior core

biopsy as an internal marker for motion artifact, the dual-energy images had less motion artifact than

the temporal subtraction images (Figures 3 and 4). Given less motion artifact, the internal enhancing

architecture of the tumor is sharper on the dual-energy images when compared with the temporal

subtraction images.

DiscussionMalignant breast lesions often have an altered microenvironment which results in neoangiogenesis

[1]. This feature of their biology can differentiate them on imaging from benign breast tissue via the

way in which intravenous contrast agent is handled. Currently, CE-MRI and gadolinium are used to

obtain breast lesion morphology and vascular enhancement information [2, 3, 5, 6]. Recently, CE-

DBT has been reported to be a potential alternative method of imaging malignant breast lesion

morphology and vascular enhancement patterns [8]. A temporal subtraction CE-DBT technique has

been described previously [8-11]. In this study, we report the application of a dual-energy subtraction

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CE-DBT technique.

In this feasibility study, DBT image series were obtainable via the methods described. The dual

energy CE-DBT images demonstrate gross lesion morphology as well as enhancement information.

In comparison with CE-MRI in the same patient, qualitatively concordant information was obtained

from the dual energy CE-DBT images.

Temporal subtraction CE-DBT images were also obtained in this case. When compared, less motion

artifact is present on the dual energy images. This is likely the consequence of the smaller time delay

between the respective pairs of DBT series used to generate the dual energy images relative to the

time that elapsed between the pre-contrast DBT series and each post-contrast DBT series used for

the temporal subtraction images. This is one of the theoretical advantages of dual energy subtraction

contrast-enhanced x-ray imaging of the breast [13-16].

In addition, data from an intermediate timepoint was available from the dual energy sequences, as the

first post-contrast LE set could be used with the HE data set acquired either immediately before or

after it. This extra kinetic information is not available from the temporal subtraction method, and

illustrates another theoretical advantage of a dual energy CE-DBT technique.

Future directionsIn theory, another potential advantage of dual energy CE-DBT is that the protocol would allow for a

delayed post-contrast DBT pair of the contralateral breast. With a pure temporal subtraction CE-DBT

technique, this contralateral imaging is not possible. As synchronous contralateral cancers do occur,

information about the contralateral breast can be useful clinically.

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Additional investigation into minimizing motion artifacts, either a priori or via post-processing, remains

to be done. This can be said of both dual energy and temporal subtraction CE-DBT techniques. For

example, as currently described, the dual energy CE-DBT technique is not optimized to minimize

patient motion as the time between the acquisition of the HE and LE image series at a single time-

point is 1.4 to 1.5 minutes. At this time, this delay is necessary to allow for the read-out of each

tomosynthesis series. Data series acquisition time can be reduced by developing a dedicated CE-

DBT system with rapid image read-out and whereby either interleaved LE and HE exposures are

acquired in rapid succession within one x-ray tube sweep. Decreasing the time delay between the

acquisitions in dual energy CE-DBT will not only reduce motion artifacts but also improve the temporal

resolution.

Image post-processing of the dual energy CE-DBT images also requires further optimization. With

dual energy CE-DBT, the background breast parenchyma is partially visualized even on the

subtraction images. In this case, we applied a constant tw for the compressed breast in order to

cancel background breast tissue with the goal of increasing enhancement conspicuity. A breast in

compression is not of a uniform thickness, however, and the optimal tw is breast thickness dependent

[21]. Thus, to optimally cancel background breast tissue, smaller tw values should be applied at the

periphery of the breast than in the center. Quantification of the breast thickness as a function of

position at the periphery of the breast is required to fine-tune tw . This could be obtained by

incorporating a correction for x-ray field non-uniformities caused by the heel-effect, beam hardening,

scatter, and inverse square law in the source projection images.

Furthermore, power injection instead of manual injection of contrast agent should be used. With

power injection, the rate of contrast administration could be doubled. Thus, the first post-contrast

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image series could be acquired earlier. This would potentially decrease patient motion as well as

improve temporal resolution.

ConclusionIn this study, dual-energy CE-DBT is shown to be a clinically feasible technique. In our index case,

dual-energy technique was able to demonstrate morphology and kinetics information about the known

malignancy. Though this is not a clinical study, this information was qualitatively concordant with that

of CE-MRI. In comparison with the temporal subtraction CE-DBT technique, dual-energy CE-DBT

appears less susceptible to motion artifacts. Future directions include further investigation into dual-

energy CE-DBT, and comparison or possibly fusion of this with temporal subtraction CE-DBT.

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16. Carton AK, Lindman K, Ullberg CK, Francke T. Dual-energy subtraction for contrast enhanced digital breast tomosynthesis. In: Hsieh J, Flynn MJ, editors. Physics of Medical Imaging; 2007; San Diego: SPIE; 2007.17. Boone JM. Normalized glandular dose (DgN) coefficients for arbitrary x-ray spectra in mammography: Computer-fit values of Monte Carlo derived data. Medical Physics. 2002;29(5):869-75.18. Boone JM, Fewell TR, Jennings RJ. Molybdenum, rhodium, and tungsten anode spectral models using interpolating polynomials with application to mammography. Medical Physics. 1997;24(12):1863-74.19. Wu T, Moore RH, Rafferty EA, Kopans DA. A comparison of reconstruction algorithms for breast tomosynthesis. Medical Physics. 2004;31(9):2636-47.20. Samei E, Badano A, Chakraborty D, Compton K, Cornelius C, Corrigan K, et al. Assessment of Display Performance for Medical Imaging Systems, Report of the American Association of Physicists in Medicine (AAPM) Task Group 18. Assessment of Display Performance for Medical Imaging Systems, Report of the American Association of Physicists in Medicine (AAPM) Task Group 18 April 2005 April 2005 [cited 2006 August 24]; Available from: 21. Carton A-K, Ullberg C, Lindman K, Francke T, Maidment ADA. Optimization of a dual-energy contrast-enhanced technique for a photon counting digital breast tomosynthesis system. 9th International workshop on digital mammography; 2008; Tucson (Arizona): Elsevier; 2008.

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Figure 1.Illustration of the imaging sequence and timing of acquisition. The affected breast is

compressed, then a HE pre-contrast tomosynthesis image series is acquired. After injection,

two HE/LE tomosynthesis image series are acquired. After image processing and

tomographic reconstruction temporal subtraction CE-DBT images at 2 time points (Temp1

and Temp2) and dual energy (DE) CE-DBT images at 3 time points (DE1, DE2 and DE3),

were available.

Figure 2.CE-MRI slice (A.) and DBT slice (B.) at similar planes demonstrate comparable morphologic

information about the malignant lesion (arrow).

Figure 3. Dual energy (DE) CE-DBT image at the first time point (A.), which demonstrates the

malignancy (arrow). The malignant lesion and its rim enhancement are highlighted in the

zoomed images at each of the three dual energy time points (B., C., and D.)

Figure 4. Temporal subtraction CE-DBT image at the first time point (A.), which also demonstrates the

malignancy (arrow). The malignant lesion and its rim enhancement are highlighted in the

zoomed images at each of the two temporal subtraction time points (B. and C.) Note the

motion artifacts in the temporal subtraction CE-DBT images; a clip inside the lesion shows a

displacement of approximately 2 mm.

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Table 1.Technical parameters used to acquire the high energy (HE) and low energy (LE) DBT

projection image series. The mean glandular dose (MGD) is specified for a 5 cm thick 50%

glandular – 50% adipose breast.

Figure 1Click here to download high resolution image

Figure 2Click here to download high resolution image

Figure 3Click here to download high resolution image

Figure 4Click here to download high resolution image

Table 1.Technical parameters used to acquire the high energy (HE) and low energy (LE) DBT projection

image series. The mean glandular dose (MGD) is specified for a 5 cm thick 50% glandular – 50%

adipose breast.

target filter kVp HVL [mm Al] mAs MGD [mSv]HE Rh 25 µm Rh + 0.25 mm Cu 49 3.36 160 0.58

LE Rh 25 µm Rh 30 0.44 71 2.37

Table 1

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