Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66

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Nuclear Instruments and Methods in

Physics Research A
journal homepage: www.elsevier.com/locate/nima

Combined SPECT/CT and PET/CT for breast imaging

Paolo Russo a,b, Michele Larobina c, Francesca Di Lillo a,b, Silvana Del Vecchio d,
Giovanni Mettivier a,b,n
a
Università di Napoli Federico II, Dipartimento di Fisica, Via Cintia, Naples I-80126, Italy
b
INFN Sezione di Napoli, Via Cintia, Naples I-80126, Italy
c
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Via Tommaso De Amicis, 95, Naples I-80145, Italy
d
Università di Napoli Federico II, Dipartimento di Scienze Biomediche Avanzate, Via Pansini, 5, Naples I-80131, Italy

art ic l e i nf o a b s t r a c t

Available online 24 October 2015 In the field of nuclear medicine imaging, breast imaging for cancer diagnosis is still mainly based on 2D
Keywords: imaging techniques. Three-dimensional tomographic imaging with whole-body PET or SPECT scanners,
Breast imaging when used for imaging the breast, has performance limits in terms of spatial resolution and sensitivity,
SPECT/CT which can be overcome only with a dedicated instrumentation. However, only few hybrid imaging
PET/CT systems for PET/CT or SPECT/CT dedicated to the breast have been developed in the last decade, pro-
viding complementary functional and anatomical information on normal breast tissue and lesions. These
systems are still under development and clinical trials on just few patients have been reported; no
commercial dedicated breast PET/CT or SPECT/CT is available. This paper reviews combined dedicated
breast PET/CT and SPECT/CT scanners described in the recent literature, with focus on their technological
aspects.
& 2015 Elsevier B.V. All rights reserved.

1. Introduction
Dual-modality imaging with hybrid tomographic scanners
provides combined anatomical and functional 3D imaging data for
diagnosis, disease staging and follow up, with improved diagnostic
performance than obtained by separate imaging procedures, via
more accurate assessment of tissue lesions (see, e.g., [1,2]).
In the case of breast cancer diagnosis, the partial volume effect
and the limited spatial resolution of most whole-body scanners
(approximately 5 mm FWHM for positron emission tomography,
PET, systems) limit precise imaging and quantification of primary
tumors. For this purpose, dedicated scanners for emission tomo-
graphy coupled to X-ray computed tomography (CT) have been
assembled, thus providing combined images of the breast also
useful in radiation therapy planning and in monitoring the
response to therapies. Dedicated hybrid scanners have potential
advantages since they may provide higher resolution and higher
sensitivities with a more accurate quantification of primary breast
tumor, particularly for small-size tumors (about 1 cm or less in
diameter). This occurs thanks to the use of small pixel size
detectors and of the reduced distance from the tumor to the
n In this work the authors review hybrid breast PET/CT and
Corresponding author at: Università di Napoli Federico II, Dipartimento di
Fisica, Via Cintia, Naples I-80126, Italy. Tel.: þ39 081 676137.
E-mail address: mettivier@na.infn.it (G. Mettivier).
detector, which make such hybrid systems useful in particular for
early disease detection [3–5].
The addition of an X-ray contrast agent for contrast-enhanced
CT may improve the detection of malignant breast lesions [6].
Chemotherapy administered to patients with large size tumor
before surgery or radiation – to reduce tumor burden and systemic
spreading of the disease (neoadjuvant chemotherapy, NAC) –
might also benefit from the use of such dedicated dual-modality
scans for tumor response assessment [7].
Although a few high-resolution, high-sensitivity CT, PET and
SPECT scanners have been developed in the last decade, tomo-
graphic breast imaging is still an active area of research and
development. The integration of functional and anatomical ima-
ging permitted the distinction between malignant and benign
lesions, but open critical points still remain in this field. These
include the detection of very small lesions and of lesions located
near the chest wall, the reduction of the dose delivered to the
patient, and the detection of microcalcifications. The inclusions of
all these points in the realization of high image quality, highly
sensitive PET/CT and SPECT/CT hybrid scanners dedicated to the
breast, is still a technological challenge; as a consequence, the
process of introducing such devices in the clinical routine is slow.
breast SPECT/CT systems described in extenso in publications in
the last decade, though not covering exhaustively the large variety

http://dx.doi.org/10.1016/j.nima.2015.10.071
0168-9002/& 2015 Elsevier B.V. All rights reserved.
 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66
of techniques, technologies and devices developed so far. The
rationale for dedicated PET and SPECT breast imaging is also
briefly summarized, and breast PET (non hybrid) systems available
commercially are described.
2. Background and clinical context
Functional imaging studies of breast lesions by planar scinti-
graphy or Single Photon Emission Computed Tomography (SPECT)
using 99mTc-Sestamibi was initially developed as an adjunct to
diagnostic mammography and extensively investigated over the
past years, showing a sensitivity of 83% and a specificity of 85% [8].
However, tumor size was early recognized as one of the major
factors affecting sensitivity, since non-palpable lesions were
detected with a lower sensitivity (59%) than palpable lesions
(87%). Similarly, the reported sensitivity of 18F-fluorodeoxyglucose
(FDG-PET) or PET/CT for detection of breast tumors was 83–89%
[9,10]; this value decreased to less than 50% for detection of sub-
centimeter tumors, low-grade invasive cancers or ductal carci-
noma in situ (DCIS) [11]. Therefore, the limited spatial resolution
of both gamma camera and PET scanners prevented their wide
clinical use in the management of breast cancer patients, including
early detection of breast cancer, staging, follow-up and therapy
monitoring. The availability of dedicated breast imaging systems
with improved spatial resolution may result in a larger clinical use
of functional imaging in breast cancer patients for several appli-
cations including preoperative evaluation, monitoring of tumor
response and evaluation of dense breasts [12].
Since the detection of additional sites of malignancy in the
same or contralateral breast can alter the subsequent surgical
treatment, an accurate preoperative evaluation of both breasts is
mandatory. Dynamic contrast-enhanced breast Magnetic Reso-
nance Imaging (MRI) is currently used for surgical planning since
it is able to detect additional tumor sites in 20% of patients [13].
However, specificity of MRI is limited and the occurrence of false
positive may require additional biopsies and delay surgery. Dedi-
cated breast imaging with its high sensitivity and specificity may
be more accurate than MRI in the presurgical evaluation of breast
cancer patients. Previous studies [14,15] showed indeed that both
breast-specific gamma-ray imaging with 99mTc radiotracers [16]
and Positron Emission Mammography (PEM) [17] with FDG, have a
sensitivity comparable to that of MRI but a higher specificity in the
detection of additional malignancy.
Functional imaging with whole-body FDG-PET or PET/CT
scanners is currently used for monitoring tumor response to NAC
that is administrated to breast cancer patients before surgery to
reduce tumor size resulting in a more conservative surgical
treatment. The need of a dedicated imaging system with high
spatial resolution in this clinical setting derives from the fact that
very small residual tumors after NAC may not be detected by
whole-body FDG-PET or PET/CT. Dedicated breast PET scanners
may be able to identify even minimal residual disease after NAC
[18]. Even more important, there is the clinical need for dedicated
breast imaging systems in the evaluation of dense breast in
asymptomatic women. Screening mammography is the standard
imaging technique for the early diagnosis of breast cancer in
asymptomatic women; mammography showed effective in redu-
cing breast cancer mortality, though overdiagnosis may be present
[19,20] and there is still active debate on this topic [21,22]. How-
ever, sensitivity of mammography is limited in women with
radiologically dense breast, and additional screening examinations
such as ultrasounds and MRI may be required in these patients. In
this context, dedicated breast imaging systems may contribute to
the accurate evaluation of dense breast [23] although their
implementation in the screening setting may be limited by the
59
increased radiation exposure from a systemically administered
radiotracer.
Different PET tracers for the biological characterization of
breast tumor lesions have been proposed and are approaching
clinical use with present PET and PET/CT whole-body scanners,
including 18F-Fluorothymidine for imaging of proliferation,18F-
Fluoroestradiol for characterization of estrogen receptor status
and 89Zr-trastuzumab for detection of HER2 expression [24]. These
biological characteristics are prognostic and predictive biomarkers
of the clinical outcome and guide therapeutic options in individual
breast cancer patients. Dedicated breast PET scanners may take
advantage of these specific PET imaging tracers, as dedicated
clinical tools for precisely targeted medicine.
In the clinical context, another key issue associated with
nuclear breast imaging is the radiation dose administered. The
dose to the breast gland from a CT scan with dedicated (cone
beam) setups is typically kept in the limit of the maximum mean
glandular dose (3 mGy, for a “standard” breast in the USA reg-
ulations, for one view), i.e. less than 6 mGy for two-view mam-
mography, this being equivalent to an effective dose of 0.72 mSv
for a CT scan of one breast. For all breast sizes, the body effective
dose for a screening mammogram is in the range 0.7–1.0 mSv [25].
In nuclear breast imaging with administration of 740 MBq 99mTc-
Sestamibi, the (whole-body) effective dose is approximately
5.9 mSv [12]. For FDG-PET, a whole-body effective dose of 6.2–
7.1 mSv for administration of 370 MBq 18F-FDG has been reported
[26], and for FDG-PET dedicated to the breast, a body effective
dose of 3.5 mSv has been estimated [27] for administration of
185 MBq FDG (effective dose of 0.019 mSv/MBq from calculations
based on ICRP 106 data [28]). These figures indicate that dose
reduction is an issue in hybrid breast imaging, since the (body)
effective dose of the nuclear scan can be comparable or higher
than that of the X-ray CT scan. Hence, with the availability of
higher sensitivity detectors for dedicated breast SPECT/CT and PET/
CT imaging, there is potential for a reduction of the radiation dose
burden, compared to breast imaging with whole-body SPECT/CT or
PET/CT scanners.
3. Dedicated scanners for breast imaging
3.1. Single photon imaging
Nuclear medicine tomographic imaging benefits from the
technological advances in detectors and DAQ systems to achieve
high spatial resolution and sensitivity [12,29]. Small gamma
cameras in mammographic configuration for planar imaging have
been developed in the last two decades for breast imaging,
employing either arrays of small scintillator crystals (CsI, NaI,
LaBr3) [16,30] or semiconductor pixel detectors on CdTe or CdZnTe
(CZT) substrates [16,31,32]. Breast specific semiconductor-based,
double-head compact gamma cameras showed an overall sensi-
tivity of 90% and a sensitivity of 82% for lesions less than 10 mm in
size, in patients with suspected breast cancer [16]. Typically, single
photon gamma-ray imaging dedicated to the breast is performed
with the FDA-approved 99mTc-Sestamibi as radiopharmaceutical,
with typical injected activity of 740–1100 MBq [33].
3.2. PET imaging
The increased spatial resolution and photon detection sensi-
tivity improves the detectability of sub-centimeter lesions, this
being one of the major limitation of clinical whole-body PET
scanners [34–36]. Indeed, the spatial resolution of whole-body PET
scanners is approximately 5 mm FWHM; for example, a FWHM
resolution in the axial plane of 4.4 mm, 4.9–5.2 mm in the
60 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66
transverse radial direction and 4.7 mm in the transverse tangential
direction at 10 mm radial distance from center field of view (FOV)
has been reported for a last-generation PET/CT scanner, in non-
time of flight reconstruction [37]. On the other hand, the (max-
imum) FWHM spatial resolution of dedicated breast PET scanners
can be as high as: a) 1.6 mm, 1.8 mm and 1.9 mm (axial, radial and
tangential directions, respectively), coupled to a maximum sensi-
tivity (according to NEMA NU 4-2008 standard) as high as 20% at
the center of FOV in the energy range of 250–750 keV [38]; b)
2.0 mm, 1.6 mm and 1.7 mm (axial, radial, tangential, filtered
backprojection reconstruction) with 11.2% maximum sensitivity
[39].
Dedicated breast PET setups take advantage also of the reduced
distance between detectors as the FOV needed to image the breast
is much smaller than that a whole-body scanner. In PET, the
reduced detector distances mitigate the blur due to the acolli-
nearity of the two annihilation photons, so that these systems can
reach higher spatial resolution (ranging between 1 and 3 mm),
analogously to what occurs with scanners dedicated to small
animal imaging [40]. Indeed, for a detector ring of radius R (mm),
the angular uncertainty in the direction of the two back-to-back
annihilation quanta when an in-flight positron annihilation occurs,
determines a Gaussian blur whose FWHM is 0.0044R [41]: for a
dedicated PET system with, e.g., 25-cm diameter, this corresponds
to a FWHM of 0.55 mm, whereas for a whole-body PET scanner
this value increases up to a factor 3. On the other hand, there is a
specific influence of the parallax error on the spatial resolution of
such small-diameter PET systems; indeed, the breast occupies a
small fraction of the center FOV in large-diameter whole-body PET
scanners, while PET scanners dedicated to the breast have a FOV
diameter of less than 25 cm, typically. The use of long scintillator
crystals (for obtaining high detection efficiency for 511 keV pho-
tons), placed close to the organ, produces an additional contribu-
tion to the parallax error, so that such dedicated PET scanners
include depth-of-interaction (DOI) encoding capabilities, since, for
a given crystal configuration, the detection performance (and then
the overall imaging performance) is dependent on the depth at
which the gamma-ray interaction occurs in the scintillator crystal.
For example, in the University of California at Davis prototype
dedicated to breast PET, the intrinsic spatial resolution at the edge
of the FOV improved from 6 to 1.7 mm after DOI information
implementation [42].
Some of the developed systems require breast compression
[43] (as in PEM, where acquisition times can be as long as 10–
20 min per breast) while other systems work with the patient in
the prone position and the breast hanging within the FOV
[38,44,45], with a setup similar to that used in MRI. One group
developed both O-shaped and C-shaped PET scanners, in this last
case with the patient leaning forward [46].
The prone position may be more comfortable for the patient
and more compatible with the long acquisition time of radiotracer
imaging. However, there are limitations on the detectability of
lesions located near the chest wall. The limitations arise from the
prone position of the patient, from the scanner type (fixed or
rotational), from dead areas around the detector assembly, from
the vertical position of the detector heads/rings. Thus, the top part
of the axial FOV including the chest wall and breast axillary tail
may not be adequately covered and be shorter than the corre-
sponding axial FOV of the CT scanner in dedicated hybrid systems
[44]. In the first-generation University of California at Davis’
scanner (DbPET/CT), there is a 20-mm difference in field coverage
at chest wall of the PET image with respect to CT image; moreover,
in one patient, that team measured a distance of 8 mm between
top of PET axial FOV and anterior aspect of pectoralis muscles [44].
On the other hand, the prone position determines a significantly
larger distance (19 mm on the average) of the tumor-to-thoracic-
wall than in the supine position (8 mm on the average), as eval-
uated with whole-body PET/CT scanning on 40 patients with
suspected recurrent breast cancer [47]. This finding – indicating an
additional advantage of adopting the prone position of the patient
in dedicated breast scanners–highlights the critical issue of
incomplete field coverage at the thoracic wall of dedicated breast
PET scanners, since the average axial position of breast tumors
might be at the border or outside the PET FOV. Lesions outside the
FOV of dedicated scanners can lower the lesion-based sensitivities
with respect to that of whole-body PET/CT (from 92% of lesions
detected with the conventional scanner to 82–83% of the dedi-
cated lesions with O-ring and C-ring scanners) [46].
The vast majority of dedicated PET scanners adopts scintillation
crystals readout by position sensitive PMTs but arrays of semi-
conductor detectors have been proposed as well, for direct-
detection gamma-ray imaging. The team at University of Stan-
ford investigated a dual-panel PET camera dedicated to breast
cancer imaging, based on 4-cm thick 12  15 cm2 CZT panel
detectors equipped with cross-strip electrodes for readout [48].
Simulations indicated a maximum photon sensitivity of 32% for a
point source at the center of the FOV, and capability for the
visualization of 2-mm diameter spheres with a 5:1 activity con-
centration ratio within about 7 min acquisition time [48].
3.3. CT imaging
In X-ray imaging, flat-panel-based cone-beam CT with dedi-
cated scanners has been investigated and recognized as a potential
modality for breast imaging, including patient screening [49–52]:
a review of this field has been published recently [53]. In cone-
beam breast CT the goal is to perform a CT scan of the uncom-
pressed breast with a mean glandular dose comparable to that of
two-view mammography for the same compressed breast [49]. In
January 2015, the dedicated breast cone-beam CT scanner manu-
factured by Koning Corporation (West Henrietta, NY, USA) received
the FDA approval in U.S.A. In the United States, a spinoff company
from Duke University (ZumaTek Inc.) has developed a dedicated
breast CT scanner using a flat-panel detector (see also Section 5.1);
in Europe, a spinoff from the Medical Physics Institute at Friedrich-
Alexander University Erlangen-Nürnberg (Germany) [54] has
presented in 2014a high-resolution, dedicated breast CT spiral
scanner, which employs a photon-counting, high-resolution, CdTe
semiconductor detector [55]. The emerging limited-angle tomo-
graphic technique of Digital Breast Tomosynthesis (DBT) [56,57]
also received in the last years an increasing interest, and today at
least five different stand-alone commercially available X-ray
mammography systems offer the DBT acquisition (GE, Hologic,
IMS, Planmed and Siemens).
3.4. Commercial breast PET systems
Commercially available PET systems dedicated to the breast
include three systems: a) The Oncovision (Valencia, Spain)
MAMMI Breast PET [38], a scanner for a patient in prone position
which uses a full ring of detectors (17 cm transaxial FOV, 4 cm
axial FOV, spatial resolution: 1.6, 1.8, and 1.9 mm in the axial,
radial, and tangential directions, respectively) and no breast
compression; and b) the Naviscan (San Diego, CA, USA) PEM Flex
Solo II [58] which comprises two 6-cm-thick 6  16.4 cm2 planar
detector heads mounted inside compression paddles: the detec-
tors scan in unison the compressed breast along a direction par-
allel to the chest wall (24  16.4 cm2 imaging FOV, 2.4 mm in-
plane spatial resolution); c) the Shimadzu Corp. (Kyoto, Japan)
ELMAMMO, consisting of 36 LGSO detector blocks organized in
3 rings (155.5 mm axial FOV, 183 mm transaxial FOV, spatial
resolution: 2.0, 1.6, and 1.7 mm in the axial, radial, and tangential
 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66 61

directions, respectively), designed for scanning the uncompressed

breast of the patient in prone position [39,59].
In clinical trials with FDG injected (median activity of
444 MBq), the PEM Flex camera showed a sensitivity for detecting
breast cancer of 90% and a specificity of 86% [60]. In a first clinical
trial, both MAMMI PET and conventional PET/CT visualized the
primary tumor in 97% of stage II and III breast cancer patients, and
the standardized uptake quantification assessed with MAMMI PET
produced values consistently higher than with PET/CT in all
patients [61]. In addition, the evaluation of heterogeneity of
uptake in primary tumor with 18F-FDG produced scores higher on
MAMMI PET than on PET/CT in 31% of patients [62].

3.5. Commercial breast SPECT systems

Requirements for breast-dedicated SPECT scanners include a

superior performance in terms of spatial resolution and sensitivity,
than either planar systems or tomographic general-purpose SPECT
systems [5]. In the authors' knowledge, there is no commercially
available breast-specific SPECT scanner, while several commercial
planar imaging systems are available differing mainly for the
detector configuration (stationary double vs. single head) and for
the type of detector material used (scintillator or semiconductor)
(for review, see e.g. [30,33]). Some of these systems adopt CZT for
the detector substrate, a compound, zinc-alloyed CdTe semi-
conductor material with favorable characteristics (high spatial and
energy resolution, and excellent detection efficiency, for the
energy range of SPECT radiotracers and given the few-mm thick-
ness of available CZT substrates) [63,64].

4. Dedicated breast PET/CT systems

The integration of PET and CT in whole-body scanners (avail-

able only as hybrid systems since a decade ago) represented a
significant step forward, especially for oncology studies, and con-
tributed greatly to improving the diagnostic accuracy [1,65].
Similarly, the integration of (multidetector) CT with SPECT (since
2004) permitted to improve sensitivity and specificity in a wide
number of clinical applications [66], so whole-body hybrid scan-
ners have their well recognized role in the clinical practice.
Few groups are assembling PET/CT systems dedicated to the
breast. Two technological approaches were followed, which pro-
duce a limited-angle, focal-plane tomographic (tomosynthesis) or
a fully tomographic view of the breast, respectively. In the first
type of devices, which were largely investigated in the last two
decades also in patient studies, two stationary planar or curved
detector heads are adopted above and below the mild-compressed
breast (PEM); this implies a partial angular coverage of the breast
producing non-isotropic spatial resolution [58,67–70]. In the sec-
ond type of devices, the use of two detector heads rotating around
the breast, or of a (partial or complete) circular array of fixed
detectors, allows to perform fully tomographic imaging [3,38,71–
73]; this technique (also termed bPET) is relatively more recent
and less investigated in the clinic. Two research groups developed
PET/CT breast dedicated systems with full tomographic capability,
as described in the following sub-sections.

4.1. University of California at Davis

The project at the University of California at Davis evolved
through the realization of three prototypes of the PET scanner
(DbPET, DbPET 2.0, DbPET 2.1). In its initial configuration, the
system featured a PET scanner (Davis bPET, DbPET) with two
rotating heads each one composed of a pixelated LSO with
3  3  20 mm3 crystals size coupled to PSPMTs to cover an area of
Fig. 1. (a) PET/CT prototype at the University of California at Davis (courtesy of R. D.
Badawi). 1: CT flat panel detector, 2: X-ray tube and rotating filter wheel, 3: PET
heads. (b) PET/CT prototype at the University of West Virginia, comprising a robotic
needle biopsy system (courtesy of R. R. Raylman). 1: CT X-ray detector, 2: X-ray
tube, 3: PET heads, 4: Robotic needle for biopsy. (c) PET/X prototype at the Uni-
versity of Washington (courtesy of L. R. MacDonald, P. Kinahan). 1: X-ray detector,
2: X-ray tube, 3: PET heads.
62 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66

12  12 cm2 [44,72] (Fig. 1a). For scanning, the patient is posi- proposed by the team at Lawrence Berkeley National Laboratory
tioned prone with a single breast hanging into the FOV through an [81]. The PET scanner consists of two 20  15 cm2 and two
aperture in the table. In addition to rotation in step-and-shoot 10  15 cm2 detectors positioned to form a rectangular gantry.
mode, the two planar head PET detectors can be translated verti- Each detector module consists of monolithic continuous LSO
cally (to position them as close as possible to the chest wall) as crystal subunits coupled to multi-anode position sensitive PMTs
well as horizontally (to modify the heads separation to accom- [79]. The separation between the two main detectors can be set to
modate breasts of different size). The CT system is one of the 4 cm or 8 cm corresponding to two possible breast compression
dedicated cone-beam CT setups developed by the team of Prof. thicknesses [80]. A preliminary evaluation with the first patients is
Boone at the same institution [74–76] and comprises a planned for the end of 2015.
30  40 cm2 a-Si/CsI:Tl-based flat-panel detector with 0.194-mm
pixel pitch and a 0.6-mm thick scintillator. Up to 500 projections
are acquired in about 17 seconds for 360° coverage, at 80 kVp and 5. Dedicated breast SPECT/CT systems
with a mean glandular dose per breast comparable to that of two-
view mammography. Results from a preliminary clinical trial using SPECT/CT systems dedicated to the breast developed at Duke
this system (termed DbPET/CT) [72] have been reported [44]. This University and at University of Naples are described in the fol-
system has a transaxial FOV of 11.9 cm (less than the average lowing sections.
diameter of the pendant breast at the chest wall). The last proto-
type (DbPET2.1) is an upgrade of the previous 2.0 version PET
5.1. Duke University
scanner; the improvements regarded the scintillation detector and
the readout electronics [3]. In this new prototype, the detection
The team at Duke University has developed an integrated
system comprises 1.27  1.27  20 mm3 LYSO scintillator crystals
SPECT/CT scanner prototype with full tomographic capability of
arranged in modules consisting of 16  16 crystals spanning an
the pendant, uncompressed breast [64,82] (Fig. 2). The SPECT part
angular range of 90° in an incomplete ring. Each head employs 16
is composed of a single head of 16  20 cm2 CZT detector array of
(2  8) modules to cover a FOV of 17.5 cm in transaxial and 5.0 cm
2.3  2.3  5 mm3 crystals with a pixel pitch of 2.5 mm (LumaGEM
in the axial direction. With respect to the original setup DbPET
3200S, Gamma Medica, Inc.).
[72], the head-to-head distance is fixed to 24.7 cm, and the system
The energy resolution at 140 keV is 6.7% FWHM and the colli-
exhibits a higher spatial resolution (3.3 mm and 1.6 mm at the
mator sensitivity is 37.9 cps/MBq [83,84]. Resolution tests with
center of the FOV using filtered back-projection for DbPET and 99m
Tc-pertechnetate and a rod phantom showed that the size of
DbPET 2.1, respectively).
detectable rods was 3.4–5.2 mm for an activity concentration ratio
of 10:1 or 2.5:1 (detail/background), respectively, with 370 kBq/mL
4.2. University of West Virginia
in the rods [32]. A relevant feature of this scanner prototype is the
possibility to move the detector head by means of precision
The project developed at the University of West Virginia has a
PET scanner with four rotating detector heads. Each head uses a positioning equipment with three degree of freedom on a trajec-
2  2  15 mm3 LYSO crystal matrix (pitch ¼2.1 mm) coupled to tory that can follow the breast contour. The non-conventional
PSPMTs for an area of 20  15 cm2[45,77]. Recently, the team orbit of the gamma-ray detector, usually circular in conventional
assembled an optimized version of the early-developed PET sys- setups, maximizes the imaged breast volume including the area
tem, employing a new DAQ electronics and optical coupling near the chest wall [85,86]. A parallel-hole collimator is adopted,
scheme; in addition, a cone-beam CT subsystem was included [77]. with hexagonal holes of 1.2 mm aperture, 0.2-mm septa and
In this new PET/CT prototype (Fig. 1b) the X-ray source and 25.4 mm height.
detector pair replaced one pair of PET detectors. The two PET The CT part includes a low dose cone-beam X-ray system which
detectors are separated by 27.8 cm. The scan time of the PET sys- incorporates a quasi-monochromatic X-ray source (allowing high
tem is 3 min per breast; the overall tomographic spatial resolution quality imaging with low radiation doses, comparable to that of
is ffi2 mm FWHM [77]. Specifically, compared to the previous two-view mammography) and a 20  25 cm2 CsI:Tl digital detector
version of the scanner, the optimization of the scanner led to a
gain of 15% in spatial resolution (1.55 mm, 1.52 mm, 1.51 mm
spatial resolution in the radial, tangential, and axial direction,
respectively, at 5 mm from the center of the FOV using OSEM
reconstruction) [78]. The CT uses a pulsed X-ray source capable of
operating at potentials ranging from 50 to 120 kV paired with a
30  40 cm2 X-ray a-Si/CsI:Tl flat panel detector. PET and CT scans
are acquired sequentially with the patient in prone position. The
system also includes a commercial biopsy system provided by Bard
Inc. (http://www.bardbiopsy.com/). In an initial clinical study with
five patients, they reported good quality PET images of 18F-FDG-
avid cells also in small volumes like 3-mm diameter mammary
lymph nodes, not visible in X-ray mammography or whole-body
FDG PET [77].

4.3. Other systems

Another project (PET/X scanner) is ongoing at the University of

Washington [43,79,80]. Here, the team devised a stationary four-
head PET scanner as add-on to a conventional mammography
device. Hence, the X-ray counterpart is a conventional mammo-
graphy unit (Fig. 1c); the four-head detector box is similar to that
Fig. 2. SPET/CT prototype at Duke University (courtesy of M. P. Tornai). The X-ray
tube is on the right, facing the flat panel detector, and the CZT gamma camera head
is mounted on the motorized goniometric cradle at the center of the rotating
gantry. The hole in the patient bed is on the top in the image.
 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66 63

(Paxscan 2520, Varian Medical Systems, Inc.) with 0.127-mm

pixels [83]. The quasi-monochromatic X-ray beam with a mean
energy of 34–36 keV at 60 kVp is produced by a Ce filtered,
tungsten-anode, 0.4/0.8 mm focal spot size X-ray tube (RAD-94,
Varian Medical Systems, Inc.). In a recently updated setup, a RAD-
70B X-ray tube and a Paxscan 3030 flat panel were adopted [87].
The SPECT subsystem is placed orthogonally with respect to the X-
ray source detector axis. The CT orbit can also follow complex
trajectories. The patient is in prone position with the uncom-
pressed breast hanging within the field of view through an aper-
ture in the table. The SPECT and CT acquisitions can be either
sequential or simultaneous, the sequential acquisition being the
most often operated scan type [88], in step-and shoot mode [82].
Reportedly, a typical scan comprises 128 SPECT projections (5 s
each) and 240 cone-beam CT projections, for a total of 12 min
(SPECT) þ8 min (CT) scan time with 99mTc-Sestamibi; attenuation
correction, decay time correction and scatter correction are per-
formed [82]. Here, the authors report that 99mTc-Sestamibi uptake
(in a pilot study with seven patients) was similar in adipose and in
glandular breast tissue, with average concentration of
0.10 70.16 μCi/mL. Removal of scatter radiation contamination
from cardiac and liver uptake, in OSEM reconstructed phantom
breast images, has been shown by this group [88,90]: this is a
feature of interest for the specific SPECT setup of the Duke Uni-
versity scanner, which permits non-traditional (tilted) scan tra-
jectories [85] for which classical scatter subtraction techniques of
circular orbit SPECT scanners might not applicable in a
straightforward way.

5.2. University of Naples

The team at Naples University developed a laboratory scanner

dedicated to CT imaging of the breast combined with a single-
head, small-FOV SPECT system [52,53]. The CT part, previously
featuring a 40-W X-ray tube with a 40-μm focal spot [91], has
been updated to include a microfocus X-ray tube with a variable
focal spot size (7, 20 or 50 μm, at 10, 30 and 75 W, respectively), in
addition to a 50-μm pitch CMOS CsI:Tl flat panel detector (Fig. 3).
Imaging with a partially coherent X-ray source and a high-
resolution detector permits attenuation-based imaging as well as
phase-contrast planar and tomographic imaging (for a review of
medical phase contrast imaging see, e.g., [92]). Imaging tests with
breast phantoms produced high-resolution CT images, at dose
levels comparable to two-view mammography [93]; scan times in
the order of 2 min are planned for future in vivo imaging, by using
patient-specific breast holders to remove body motion artefacts.
The geometry of the system permits the acquisition in various
geometries: contact mammography, variable-magnification phase-
contrast X-ray CT as well as X-ray digital tomosynthesis with
complete isocentric motion geometry. Attenuation based CT is
Fig. 3. Laboratory CT/SPECT system dedicated to breast imaging, developed at
University of Naples (1-Microfocus X-ray tube; 2-CMOS flat panel detector;
3-pinhole CdTe compact gamma camera; 4-PMMA breast phantom).
Fig. 4. Dual-modality breast tomosynthesis prototype at University of Virginia
(courtesy of M. B. Williams).
performed with the cone-beam filtered backprojection algorithm.
Phase-retrieval (i.e., the derivation of the spatial map of the phase
delay of the X-ray wavefield in traversing the material) is per-
formed on the projections on the assumption of uniform phase
properties of the sample: then, the projection phase map were
input to the filtered backprojection algorithm for CT recon-
struction.
The SPECT part is based on a pinhole compact gamma camera
(MediProbe) featuring a CdTe semiconductor pixel detector (1-mm
thick) hybridized with a Medipix2 photon counting readout
microelectronic circuit developed by the Medipix2 Collaboration
[94,95]; this SPECT system employed the same high-resolution
detector (256  256 pixels, 55 μm pitch) of the MediSPECT small
animal SPECT imaging system described in previous works by the
same group [96,97]. The MediProbe camera was also tested for
sentinel lymph node preoperative imaging in melanoma and
breast cancer therapy [98].
The use of a pinhole minification factor m, determined by the
small sensitive area of the detector (14  14 mm2), reduces the
collimator resolution to (1 þ1/m) times the pinhole effective dia-
meter [98]: for an imaging FOV at isocenter of 70  70 mm2, this
determines a spatial resolution of 7.2 mm FWHM for a 1.2 mm
aperture pinhole, and 12.6 mm for a 2.1 mm pinhole.
 64
P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66
Table 1
Main characteristics of the imaging systems described in this work. Also three commercial PET (non hybrid) systems have been included (columns 1–3 from the left), for the purpose of performance comparison. nAccording to
NEMA NU 4-2008.

MAMMI Breast PET PEM FLEX SOLO II ELMAMMO (Shimadzu) DbPET (UC Davis) DbPET 2.1 (UC Davis) PEM/PET (University of Duke University University of Naples
(Oncovision) (Naviscan) West Virginia)

Type PET PET PET PET/CT PET/CT PET/CT SPECT/CT SPECT/CT

Detector Monolithic LYSO 2  2  13 mm3 pixe- 1.4  1.4  4.5 mm3 LGSO 3  3  20 mm3 pixe- 1.27  1.27  20 mm3 pixe- 2  2  15 mm3 LYSO 160  200  5 mm3 CZT 14  14  1 mm3 CdTe
10 mm thickness 12 lated LYSO two non 12 detector modules  3 lated polished LSO lated polished LYSO two two planar heads array with a parallel-(hex- pinhole compact
detector modules, rotating heads rings two rotating heads rotating heads agonal) hole collimator gamma camera
polygon geometry
FOV 170 mm transaxial 240  164 mm2 183 mm transaxial 119 mm transaxial 175 mm transaxial 150  150  150 mm3 160  200 mm2 70  70 mm2
40 mm axial 155.5 mm axial 119 mm axial 50 mm axial @ 50 mm distance
Spatial Resolu- 1.9 tangential 2.4 in-plane image 1.7 tangential 2.77 tangential 3.28 1.6 2.6 radial 3.5 12.6 (w/2.1 mm
tion (mm radial pinhole)
FWHM)
1.8 radial 8 cross-planes 1.6 radial 2.5 tangential @50 mm 7.2 (w/1.2 mm
pinhole)
1.6 axial 2.0 axial 3.46 axial
@ 5 mm from the center-
of-rotation
Sensitivity 20% @ (250–750) – 11.2% 1.64% 0.5% 1.36% 37.9 cps/MBq E30 cps/MBq (w/
keV n 2.1 mm pinhole)
@ (350-650) keV @ (350-850) keV E 10 cps/MBq (w/
1.2 mm pinhole)
Energy 18% – 16.9% 25% 15.7% 17% 6.7% –
Resolution
@ 511 keV @ 511 keV @ 511 keV @ 511 keV @ 511 keV @ 140 keV
References [38] [58,60] [39,46] [44,72] [3] [45,77,78] [64,82–90] [52,53,91–98]
 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66
6. Combined X-ray and Emission Tomosynthesis
As alternative to systems combining SPECT and CT, a research
group at the University of Virginia proposed a dedicated breast
scanner with the integration of an X-ray tomosynthesis and a
limited-angle SPECT (also called gamma emission breast tomo-
synthesis) [99,100]. In tomosynthesis the X-ray tube rotates on a
limited angular range (typical values in the interval 10°–60°) to
collect different projections of the breast. The number of projec-
tions ranges from 9 to 25 with an angular increment typically from
1° to 3°, while some systems adopt non-equally spaced angular
steps to cover the angle scan. Projections are then reconstructed to
provide a pseudo-3D volume map. In a similar set-up, limited
angle SPECT can be achieved with a high-resolution gamma
camera that rotates around the breast to collect a limited number
of views.
In the prototype developed at the University of Virginia (Fig. 4),
the SPECT scan is performed sequentially to the X-ray scan by
acquiring five projections of 2 min acquisition time [101]. The
gamma camera was developed by the team at Thomas Jefferson
National Accelerator Facility and is a pixelated NaI:Tl detector
(2.2 mm crystal pitch) coupled to PSPMTs for an imaging area of
15  20 cm2. The camera uses a lead-foil parallel-hole collimator
and has an overall sensitivity of 617 counts/min/μCi. Transmission
and emission scans are acquired sequentially using mild breast
compression.
Other research groups are working on limited angle SPECT with
a variable angle slant-hole collimator. This configuration features
projection acquisition without moving the gamma camera, with
the additional advantage of reducing the object-to-detector dis-
tance [102,103]. Similarly, for the X-ray tomosynthesis other
groups are working on the realization of scanners able to acquire
multiple projections without the movement of the gantry, holding
the X-ray tube and the detector (stationary breast tomosynthesis
systems) [104,105]. The technique is limited by the incomplete
angular sampling that may lead to artifacts on reconstructed
images, for which specific reconstruction algorithms have been
developed.
A comparison of main performance parameters for the systems
described above is presented in Table 1.
7. Discussion and conclusions
We have described PET/CT and SPECT/CT laboratory and clinical
scanners developed in the last several years, with results pub-
lished in the last decade, as well as commercially available PET and
SPECT scanners dedicated to the breast. This research activity
capitalizes the expertize and the efforts of the various groups in
the previous several years in the development of planar imaging
systems dedicated to the breast, for PEM and gamma camera
imaging, as well as for dedicated cone-beam CT imaging. Most
tomographic hybrid systems have been assembled only in the last
6–7 years, and clinical trials with these devices are scarce and only
a very set of a few tens of patients have been studied.
Among the most advanced hybrid systems developed, there are
the latest generation of the breast PET/CT system of the University
of California Davis group, the PET system developed at University
of West Virginia, and the breast SPECT/CT system of the Duke
University group. Their transaxial FOV is able to cover breast sizes
up to the largest diameters at chest wall (which may span a range
between 8 cm and 18 cm, as determined by measuring the cir-
cumference of the pendant breast close to the chest wall and
deriving the equivalent diameter [106]). These figures from the
experimental prototypes compare well with those of commercial
dedicated breast PET (non hybrid) scanners [38,39,46] (see e.g.
65
first three columns in Table 1). The axial FOV of the DbPET2.1
system has a field coverage not exceeding 50 mm, against the 150-
mm axial scanner of the University of West Virginia's prototype
and the 155.5-mm axial FOV of the Shimadzu (non hybrid) breast
PET scanner [39,46]. These experimental high complexity, high
performance hybrid scanners show remarkably good spatial
resolution (in the order of 2–3 mm for the PET scanners, and
3.5 mm for the SPECT scanner, respectively) and sensitivity in the
order of 1% for PET systems at the center of the FOV, and 37.9 cps/
MBq for 99mTC for the Duke University SPECT scanner (columns 5,
6, 7 in Table 1). These three systems show high potential for
effective clinical use: they have been developed since the begin-
ning as breast-specific tomographic devices with state-of-the-art
detector technology, for imaging the uncompressed pendant
breast of the patient in prone position. The University of Naples'
CT/SPECT system is a laboratory device embodying a microCT
high-resolution scanner [53] and a pinhole SPECT head whose
performance is limited by the use of a pinhole aperture which
limits the practical FOV, sensitivity and spatial resolution.
Increasing of axial FOV and of sensitivity are important technolo-
gical development tasks in hybrid PET/CT scanners, since peak
sensitivity above 11% have been reported for breast PET (non
hybrid) systems (columns 1, 3 in Table 1). In the authors' opinion,
the main investigative goal remains, however, the clinical valida-
tion of such systems in extensive trials: only a few tens of patients
have been examined so far with such PET/CT and SPECT/CT scan-
ners (at UC Davis, Duke University and University of West Virgi-
nia), though showing preliminary excellent results (see, e.g., the
impressive hybrid PET/CT images in Ref. [44]). Only via extensive
clinical investigations with these experimental hybrid devices, still
underway for the latest setups, the full advantages of PET/CT and
SPECT/CT dedicated to the breast will be demonstrated, so vali-
dating the highly effective laboratory tests and the initial clinical
trials.
References
[1] D.W. Townsend, Journal of Nuclear Medicine 49 (2008) 938.
[2] E.C. Ford, et al., Journal of Nuclear Medicine 50 (2009) 1655.
[3] A. Ferrero, et al., Biomedical Physics & Engineering Express 1 (2015) 015202.
[4] B.B. Koolen, et al., Journal of Oncology 2012 (2012) 438647.
[5] S.D. Mann et al. Lecture notes in computer science, in: A.D.A. Maidment, P.R.
Bakic, S. Gavenonis (Eds.), Proceedings of IWDM 2012, 7361, Springer-Verlag,
Berlin, 2012, p. 402.
[6] N.D. Prionas, et al., Radiology 256 (2010) 714.
[7] D. Groheux, et al., European Journal of Nuclear Medicine and Molecular
Imaging 38 (2011) 419.
[8] X.B. Xu, et al., Nuclear Medicine Communications 32 (2011) 980.
[9] J.W. Fletcher, et al., Journal of Nuclear Medicine 49 (2008) 480.
[10] D. Groheux, et al., Radiology 266 (2013) 388.
[11] R. Kumar, et al., Breast Cancer Research and Treatment 98 (2006) 267.
[12] C.B. Hruska, M.K. O'Connor, Medical Physics 40 (2013) 050901.
[13] M.N. Plana, et al., European Radiology 22 (2012) 26.
[14] B.S. Kim, Annals of Nuclear Medicine 26 (2012) 131.
[15] W.A. Berg, et al., Radiology 258 (2011) 59.
[16] M. O’Connor, D. Rhodes, C. Hruska, Expert Review of Anticancer Therapy 9
(2009) 1073.
[17] C.J. Thompson, et al., Medical Physics 21 (1994) 529.
[18] H.S. Lee, et al., Breast Cancer Research and Treatment 145 (2014) 91.
[19] M. Broeders, Journal of Medical Screening 19 (2012) 14.
[20] M.G. Marmot, et al., Lancet 380 (2012) 1778 , Independent UK Panel on
Breast Cancer Screening.
[21] A.B. Miller, et al., British Medical Journal 348 (2014) G366.
[22] P.C. Gøtzsche, K.J. Jørgensen, Cochrane Database of Systematic Reviews, Issue
6, Art. no.: Cd001877, 2013.
[23] C.B. Hruska, et al., American Journal of Roentgenology 204 (2015) 1345.
[24] H.M. Linden, F. Dehdashti, Seminars in Nuclear Medicine 43 (2013) 324.
[25] D.J. Rhodes, et al., Radiology 258 (2011) 106.
[26] R.E. Hendrick, Radiology 257 (2010) 246.
[27] M. Hosono, et al., Annals of Nuclear Medicine 28 (2014) 597.
[28] ICRP Publication 106, Annals of the ICRP 38 (2008).
[29] S. Surti, Seminars in Nuclear Medicine 43 (2013) 271.
66 P. Russo et al. / Nuclear Instruments and Methods in Physics Research A 809 (2016) 58–66

[30] F. Garibaldi, et al., Nuclear Instruments and Methods in Physics Research A [68] M.C. Abreu, et al., IEEE Transactions on Nuclear Science NS53 (2006) 71.
617 (2010) 227. [69] K. Murthy, Journal of Nuclear Medicine 41 (2000) 1851.
[31] R.M. Moadel, Seminars in Nuclear Medicine 41 (2011) 229. [70] E.A. Levine, et al., The Annals of Surgical Oncology 10 (2003) 86.
[32] S.J. Cutler, et al., Physics in Medicine and Biology 55 (2010) 1903. [71] B. Ravindranath, et al., Society of Nuclear Medicine 53 (2012) 1217.
[33] A.M. Fowler, et al., Journal of Nuclear Medicine 55 (2014) 177. [72] Y. Wu, et al., Physics in Medicine and Biology 54 (2009) 4273.
[34] N. Avril, et al., Journal of Clinical Oncology 18 (2000) 3495. [73] A. Karimian, et al., Nuclear Instruments and Methods in Physics Research A
[35] H. Bagahei, W.-H. Wong, H. Li, in: E.E. Kim, M.-C. Lee, T. Inoue, W.-H. Wong 545 (2005) 427.
(Eds.), Clinical PET and PET/CT Principles and Applications, Springer-Verlag, [74] J. Santos, et al., Physica Medica 30 (2014) 713.
Berlin, 2013, p. 18. [75] A.L.C. Kwan, et al., Medical Physics 34 (2007) 275.
[36] R. Freifelder, J.S. Karp, Physics in Medicine and Biology 42 (1997) 2463. [76] K.K. Lindfors, et al., Radiology 246 (2008) 725.
[37] B.W. Jakoby, et al., Physics in Medicine and Biology 56 (2011) 2375. [77] R.R. Raylman, et al., Journal of Medical Imaging and Radiation Oncology 55
[38] L. Moliner, et al., Medical Physics 39 (2012) 5393. (2011) 58.
[39] K.K. Miyake, et al., Journal of Nuclear Medicine 55 (2014) 1198. [78] R.R. Raylman, Personal Communication, 2015.
[40] A. Del Guerra, N. Belcari, Nuclear Instruments and Methods in Physics [79] L.A. Pierce, et al., Physics in Medicine and Biology 59 (2014) 5347.
Research A 583 (2007) 119. [80] L.R. MacDonald, et al., IEEE Transactions on Nuclear Science NS60 (2013)
[41] W.W. Moses, Nuclear Instruments and Methods in Physics Research A 648 3242.
(2011) S236. [81] G.C. Wang, et al., IEEE Transactions on Nuclear Science NS53 (2006) 1129.
[42] F. Godinez, et al., Physics in Medicine and Biology 57 (2012) 3435. [82] S.D. Mann, et al., Journal of Oncology 2012 (2012) 146943.
[43] P.E. Kinahan, et al., Journal of Nuclear Medicine 53 (2012) (abstract presented [83] R.L. McKinley, et al., IEEE Transactions on Nuclear Science NS52 (2005) 1243.
at 2012 SNM meeting). [84] P. Madhav, et al., Physics in Medicine and Biology 54 (2009) 3659.
[44] S.L. Bowen, et al., Journal of Nuclear Medicine 50 (2009) 1401. [85] M.P. Tornai, et al., Nuclear Instruments and Methods in Physics Research A
[45] R.R. Raylman, et al., Physics in Medicine and Biology 53 (2008) 637. 497 (2003) 157.
[46] M. Iima, et al., Journal of Nuclear Medicine 53 (2012) 1. [86] C.N. Brzymialkiewicz, et al., IEEE Transactions on Medical Imaging 24 (2005)
[47] T.-A. Heusner, et al., The British Journal of Radiology 81 (2008) 743. 868.
[48] H. Peng, C.S. Levin, Physics in Medicine and Biology 55 (2010) 2761. [87] J.P. Shah, et al., Medical Physics 42 (2015) 4497.
[49] J.M. Boone, et al., Journal of Mammary Gland Biology and Neoplasia 11 [88] M.P. Tornai, Personal Communication, 2015.
(2006) 103. [89] K.L. Perez, et al., Physics in Medicine and Biology 55 (2010) 4721.
[50] R.L. McKinley et al. in: A.D.A. Maidment, P.R. Bakic, S. Gavenonis (Eds.), [90] S.D. Mann, J.P. Shah, M.P. Tornai, Lecture notes in computer science, in: H.
Proceedings of Breast Imaging, Lecture Notes in Computer Science, 7361, Fujita, T. Hara, C. Muramatsu (Eds.), Proceedings of IWDM 2014, 8539,
Springer-Verlag, Berlin, 2012, p. 424. Springer-Verlag, Berlin, 2014, p. 501.
[51] A. O'Connell, et al., American Journal of Roentgenology 195 (2010) 496. [91] P. Russo, et al., IEEE Transactions on Nuclear Science NS57 (2010) 160.
[52] G. Mettivier, et al., Nuclear Instruments and Methods in Physics Research A [92] A. Bravin, P. Coan, P. Suortti, Physics in Medicine and Biology 58 (2013) R1.
629 (2011) 350. [93] G. Mettivier, et al., Medical Physics 39 (2012) 2805.
[53] A. Sarno, G. Mettivier, P. Russo, Medical Physics 42 (2015) 2786. [94] M. Chmeissani, et al., IEEE Transactions on Nuclear Science NS51 (2004)
[54] W.A. Kalender, European Radiology 22 (2012) 1. 2379.
[55] 〈http://www.ct-imaging.de/en/〉. [95] M.G. Bisogni, et al., IEEE Transactions on Nuclear Science NS51 (2004) 3081.
[56] J.A. Baker, J.Y. Lo, Academic Radiology 18 (2011) 1298. [96] R. Accorsi, et al., Nuclear Instruments and Methods in Physics Research A 571
[57] I. Sechopoulos, Medical Physics 40 (2013) 014301. (2007) 44.
[58] L. MacDonald, et al., Journal of Nuclear Medicine 50 (2009) 1666. [97] R. Accorsi, et al., Nuclear Instruments and Methods in Physics Research A 571
[59] 〈http://www.shimadzu.com/about/csr/k25cur0000002bbz-att/ (2007) 415.
k25cur0000003ao8.pdf〉. [98] P. Russo, et al., Medical Physics 38 (2011) 1547.
[60] W.A. Berg, et al., The Breast Journal 12 (2006) 309. [99] M.J. More, et al., IEEE Transactions on Nuclear Science NS54 (2007) 504.
[61] B.B. Koolen, et al., The Quarterly Journal of Nuclear Medicine and Molecular [100] M.B. Williams, Scanner for Integrated X-Ray Breast Tomosynthesis and
Imaging 57 (2013) 92. Molecular Breast Imaging Tomosynthesis, in: J. Martì et al. (Eds.), Proceed-
[62] B.B. Koolen, et al., Nuclear Medicine Communications 35 (2014) 446. ings of IWDM 2010, LNCS 6136, p. 444.
[63] M.E. Myronakis, M. Zvelebil, D.G. Darambara, IEEE Nuclear Science Sympo- [101] Z. Gong, et al., Medical Physics 39 (2012) 7580.
sium and Medical Imaging Conference (2012) 2756. [102] O. Gopan, et al., IEEE Transactions on Nuclear Science NS61 (2014) 1143.
[64] P. Madhav, et al., IEEE Nuclear Science Symposium and Medical Imaging [103] R. Pellegrini, et al., Journal of Instrumentation 10 (2015) C03003.
Conference 4 (2006) 2382. [104] J. Zhang, et al., Applied Physics Letters 86 (2005) 184104.
[65] P. Shreve, D.W. Townsend (Eds.), Clinical PET-CT in Radiology, Springer, New [105] X. Qian, et al., Medical Physics 36 (2009) 4389.
York Dordrecht Heidelberg London, 2011. [106] J.M. Boone, et al., Medical Physics 31 (2004) 226.
[66] G. Mariani, et al., European Journal of Nuclear Medicine and Molecular
Imaging 37 (2010) 1959.
[67] E.L. Rosen, et al., Radiology 234 (2005) 237.