Technique, protocols and adverse reactions for contrast-enhanced spectral mammography (CESM): a systematic review

Insights into Imaging, Aug 2019

We reviewed technical parameters, acquisition protocols and adverse reactions (ARs) for contrast-enhanced spectral mammography (CESM). A systematic search in databases, including MEDLINE/EMBASE, was performed to extract publication year, country of origin, study design; patients; mammography unit/vendor, radiation dose, low-/high-energy tube voltage; contrast molecule, concentration and dose; injection modality, ARs and acquisition delay; order of views; examination time. Of 120 retrieved articles, 84 were included from 22 countries (September 2003–January 2019), totalling 14012 patients. Design was prospective in 44/84 studies (52%); in 70/84 articles (83%), a General Electric unit with factory-set kVp was used. Per-view average glandular dose, reported in 12/84 studies (14%), ranged 0.43–2.65 mGy. Contrast type/concentration was reported in 79/84 studies (94%), with Iohexol 350 mgI/mL mostly used (25/79, 32%), dose and flow rate in 72/84 (86%), with 1.5 mL/kg dose at 3 mL/s in 62/72 studies (86%). Injection was described in 69/84 articles (82%), automated in 59/69 (85%), manual in 10/69 (15%) and flush in 35/84 (42%), with 10–30 mL dose in 19/35 (54%). An examination time < 10 min was reported in 65/84 studies (77%), 120 s acquisition delay in 65/84 (77%) and order of views in 42/84 (50%) studies, beginning with the craniocaudal view of the non-suspected breast in 7/42 (17%). Thirty ARs were reported by 14/84 (17%) studies (26 mild, 3 moderate, 1 severe non-fatal) with a pooled rate of 0.82% (fixed-effect model). Only half of CESM studies were prospective; factory-set kVp, contrast 1.5 mL/kg at 3 mL/s and 120 s acquisition delay were mostly used; only 1 severe AR was reported. CESM protocol standardisation is advisable.

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Technique, protocols and adverse reactions for contrast-enhanced spectral mammography (CESM): a systematic review

Insights into Imaging December 2019, 10:76 | Cite as Technique, protocols and adverse reactions for contrast-enhanced spectral mammography (CESM): a systematic review AuthorsAuthors and affiliations Moreno ZanardoAndrea CozziRubina Manuela TrimboliOlgerta LabajCaterina Beatrice MontiSimone SchiaffinoLuca Alessandro CarbonaroFrancesco Sardanelli Open Access Critical Review First Online: 02 August 2019 252 Downloads Abstract We reviewed technical parameters, acquisition protocols and adverse reactions (ARs) for contrast-enhanced spectral mammography (CESM). A systematic search in databases, including MEDLINE/EMBASE, was performed to extract publication year, country of origin, study design; patients; mammography unit/vendor, radiation dose, low-/high-energy tube voltage; contrast molecule, concentration and dose; injection modality, ARs and acquisition delay; order of views; examination time. Of 120 retrieved articles, 84 were included from 22 countries (September 2003–January 2019), totalling 14012 patients. Design was prospective in 44/84 studies (52%); in 70/84 articles (83%), a General Electric unit with factory-set kVp was used. Per-view average glandular dose, reported in 12/84 studies (14%), ranged 0.43–2.65 mGy. Contrast type/concentration was reported in 79/84 studies (94%), with Iohexol 350 mgI/mL mostly used (25/79, 32%), dose and flow rate in 72/84 (86%), with 1.5 mL/kg dose at 3 mL/s in 62/72 studies (86%). Injection was described in 69/84 articles (82%), automated in 59/69 (85%), manual in 10/69 (15%) and flush in 35/84 (42%), with 10–30 mL dose in 19/35 (54%). An examination time < 10 min was reported in 65/84 studies (77%), 120 s acquisition delay in 65/84 (77%) and order of views in 42/84 (50%) studies, beginning with the craniocaudal view of the non-suspected breast in 7/42 (17%). Thirty ARs were reported by 14/84 (17%) studies (26 mild, 3 moderate, 1 severe non-fatal) with a pooled rate of 0.82% (fixed-effect model). Only half of CESM studies were prospective; factory-set kVp, contrast 1.5 mL/kg at 3 mL/s and 120 s acquisition delay were mostly used; only 1 severe AR was reported. CESM protocol standardisation is advisable. KeywordsBreast Contrast media Drug-related side effects and adverse reactions Mammography Radiation dosage  Abbreviations AGD Average glandular dose CC Craniocaudal CESM Contrast-enhanced spectral mammography CI Confidence interval CT Computed tomography DM Digital mammography ICA Iodinated contrast agent kVp Peak kilovoltage MLO Mediolateral oblique MRI Magnetic resonance imaging PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses Key points Eighty-four articles on CESM totalling 14012 patients were reviewed A 1.5 mL/kg contrast dose automatically injected at 3 mL/s was generally adopted Per-view average glandular dose ranged from 0.43 to 2.65 mGy Studies for contrast agent dose-finding and view acquisition ordering are lacking Adverse reaction rate (only one severe) was similar to that reported for CT Background During the 1960s and 1970s, randomised controlled trials proved that screen-film mammography for breast cancer screening yields a reduction in breast cancer mortality [1]. Since the early 2000s, screen-film mammography was progressively replaced by digital mammography (DM), which improved performance especially in women under 50 years of age and in case of dense breasts, even though providing an intrinsically inferior spatial resolution [2]. In the last two decades, digital breast tomosynthesis brought substantial further improvements [3, 4], increasing cancer detection rate and reducing the recall rate [5]. Contrast-enhanced mammography is the combination of X-ray mammography with intravenous administration of iodinated contrast agent (ICA) [6]. It was first attempted using a digital subtraction technique [7, 8, 9], but this approach was soon abandoned due to difficulties in co-registration of unenhanced and contrast-enhanced images [10, 11]. In the last two decades, contrast-enhanced spectral mammography (CESM) has been introduced, based on dual-energy breast exposure (about 26–33 kVp and 44–50 kVp) after contrast administration, so that the pre-contrast exposure was no longer needed [10, 12]. CESM allows for the visualisation of enhancing findings over the normal unenhancing breast tissue, exploiting the increased contrast uptake of malignancies [6, 10, 13]. Original studies have investigated the use of CESM in a number of settings, such as evaluation of symptomatic women [14, 15, 16, 17], screening recalls [18, 19, 20, 21, 22], local staging [23, 24, 25, 26, 27, 28, 29, 30, 31, 32], pre- and post-operative evaluations [23, 24, 33, 34, 35, 36] and neoadjuvant chemotherapy response monitoring [37, 38, 39, 40]. In 2016, a first meta-analysis on CESM described a high pooled sensitivity (98%) albeit with a relatively low specificity (58%) [41], the latter partly caused by inexperience. A more recent meta-analysis [42] reported globally satisfying data for CESM-pooled sensitivity (89%) and specificity (84%), proposing it as an alternative to contrast-enhanced magnetic resonance imaging (MRI) and even suggesting CESM as a “useful triage test for initial breast lesions assessment” [41]. A time delay between the first appearance of new imaging techniques and their implementation in diagnostic routine is expected for many reasons, including not only the definition of indications but also the reproducibility of results. The latter is strongly influenced by technique details, such as contrast agent concentration, dose and injection rate, breast compression and positioning, exposure parameters and acquisition protocol. Indeed, the fact that CESM is variably performed across different centres, without an agreed and standardised technique, does not come as a surprise: this circumstance echoes the one observed for contrast-enhanced breast MRI in the 1990s, now settled by the publication of detailed international guidelines [43, 44, 45, 46]. Therefore, the aim of this work was to review CESM studies focusing on adopted technique, contrast agent issues and acquisition workflow. This effort is crucial for future CESM investigations to be reproducible and comparable. Methods Study protocol No ethics committee approval was needed for this systematic review. The study protocol was registered on PROSPERO (protocol CRD42018118554), the international prospective register of systematic reviews [47]. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [48]. Search strategy and eligibility criteria In February 2019, a systematic search was performed on MEDLINE (PubMed, https://www.ncbi.nlm.nih.gov/pubmed/), EMBASE (Elsevier), the Cochrane Library (Cochrane Database of Systematic Reviews) and the Cochrane Central Register of Controlled Trials for articles that reported or may have reported CESM technique. A controlled vocabulary (medical subject headings in PubMed and EMBASE thesaurus keywords in EMBASE) was used. The search string was (cesm OR ‘contrast enhanced spectral mammography’/exp. OR ‘dual energy mammography’ OR ‘contrast enhanced digital mammography’/exp. OR ‘contrast-enhanced mammography’ OR ‘dual-energy subtraction mammography’ OR cedm OR cedsm OR ‘contrast enhanced spectral imaging’ OR ‘high energy and low energy digital mammography’) AND (‘procedures’/exp. OR ‘method’ OR ‘methods’ OR ‘procedure’ OR ‘procedures’ OR ‘technique’ OR ‘acquisition’/exp. OR ‘contrast medium’/exp. OR ‘contrast agent’ OR ‘contrast dye’ OR ‘contrast material’ OR ‘contrast media’ OR ‘contrast medium’ OR ‘radiocontrast medium’ OR ‘radiography contrast medium’ OR ‘roentgen contrast medium’ OR ‘image processing’/exp. OR ‘image processing’ OR ‘image processing, computer-assisted’ OR ‘processing, image’). The search was limited to original studies on humans published in English, French and Spanish on peer-reviewed journals, with an available abstract. No publication date limits were applied. First article screening was performed by two independent readers (A.C. and M.Z., with 1- and 3-year experience in breast imaging, respectively) considering only title and abstract. Eligible articles were those that reported in the title or in the abstract the use of CESM technique or that could have contained these data in the manuscript. After downloading eligible articles, the full text was read for a complete assessment. Finally, references of included articles were hand-searched to check for further eligible studies. Data extraction Data extraction was performed independently by the same two readers who performed the literature search. Disagreements were settled by consensus. For each analysed article, year of publication, institution (such as hospitals, imaging facilities, breast units including radiology sections or any other type of centre in which CESM is performed) and country origin as well as research groups, design, number of patients and demographics were retrieved. Mammography unit, vendor, radiation dose and technical features such as low- and high-energy peak kilovoltage (kVp), anode/filter combinations and exposure parameters were also extracted. Moreover, contrast agent type, dose and concentration were retrieved, as well as injection modality, if manual or automated, flow rate and additional post-contrast saline flush or “bolus chaser” if present. Furthermore, mild, moderate or severe adverse reactions to ICAs were extracted alongside strategies for their prevention. Regarding the acquisition protocol, time between contrast injection and first image acquisition and maximum examination duration were extracted. Regarding the order of views, we reported the acquisition sequence of the standard mammographic projections considering the craniocaudal (CC) and the mediolateral oblique (MLO) views, including the first side acquired. Missing data were requested to authors. Evidence synthesis To avoid risk of data duplication bias, in case of articles published by the same research group, we considered the possibility of performing subgroup analysis: therefore, before delving into further analysis of protocol description, we chose to change our viewpoint from the number of articles reporting a specific protocol to the minimum number of times a protocol was reported by a single research group. Regarding the pooled rate of adverse reactions related to ICA administration across studies, statistical analysis was performed using Comprehensive Meta-Analysis v2.2.057 (Biostat, Englewood, NJ, USA) using the meta-analysis model “Number of events and study population”. I2 statistics was first calculated to assess heterogeneity and the fixed-effect model was used to provide the rate of adverse reactions and 95% of confidence intervals (CI). The risk of publication bias was assessed by visually inspecting funnel plot and performing the Egger test [49]. Results Studies A flowchart of study selection is shown in Fig. 1. Of 120 retrieved articles, 84 (70%), published between September 2003 and January 2019, were analysed [7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101]; 40/84 (48%) being retrospective and 44/84 (52%) prospective (43/44 monocentric (98%) and 1/44 multicentric (2%); 54/84 (64%) articles investigated CESM diagnostic performance, whereas 30/84 (36%) focused on technical features. The geographic distribution of research groups is depicted in Fig. 2. Open image in new window Fig. 1 Flowchart of the study selection and exclusion for articles on contrast-enhanced spectral mammography Open image in new window Fig. 2 Geographic distribution of research groups which published results of clinical applications of contrast-enhanced spectral mammography. From very light blue to dark blue, the number of groups progressively increases from 1 to 7; grey colour means no publications Populations and settings Data synthesis is reported in Table 1. The number of patients ranged from 5 [63] to 2303 [13], for a total of 14,012 patients, with mean or median age ranging from 45 years [40] to 66 years [23]. In 29/84 studies (35%), CESM was performed on patients from comprehensive databases of heterogeneous settings, such as pre- or post-operative evaluation, adjuvant or neoadjuvant chemotherapy response monitoring and equivocal findings at conventional imaging. The remaining 55 studies (65%) were individually centred on a unique setting. Twenty-seven studies (32%) performed CESM on suspicious cases from conventional imaging and screening recalls, 11 studies (13%) in a first-line screening setting, 7 (8%) performed CESM exclusively for known cancer staging, 4 (5%) in a pre-operative setting, 4 (5%) to assess and monitor the response to adjuvant chemotherapy and 2 (2%) in a post-operative setting. Table 1 Main characteristics of the 84 analysed studies Author/year Ref. Study design Country of research group Number of patients Mean or median age (years) Contrast agent type Concentration (mgI/mL) Dose (mL/kg) Flow rate (mL/s) Delay after injection (s) Total exam time Houben 2019 [22] R The Netherlands 147 61 Iopromide 300 1.5 3 120   Barra 2018 [40] P mono Brazil 33 45 Iohexol 300 1.5 3 120 B Bicchierai 2018 [93] R Italy 40 50 Iopromide 370 1.5 3 120 B Danala 2018 [69] R USA 111   Iohexol 350 1.5 3 120 B Deng 2018 [78] R Taiwan 141 48 Iohexol 350 1.5 3 120 B Helal 2018 [25] P mono Egypt 300 54 Iohexol 300 1.5 3 120 B Kim 2018 [87] P mono South Korea 84 51 Iohexol 350 1.5 2 120 B Klang 2018 [88] R Israel 953 51 Iopamidol 370 1.5 3 120 B Łuczyńska 2018 [36] R Poland 82 57 Iopromide 370 1.5 3 120 B Moustafa 2018 [17] P mono Egypt 160   Iohexol 300 1.5 3 120 B Navarro 2018 [90] P mono Chile 465 53 Ioversol 320 1.5    B Patel 2018 (01) [38] P mono USA 65 53 Iohexol 350 1.5 3 120 A Patel 2018 (02) [34] R USA 50 57 Iohexol 350 1.5 3 120 B Patel 2018 (03) [23] R USA 30 66 Iohexol 350 1.5 3 120 B Phillips 2018 [82] R USA 45 53 Iohexol 350 1.5 3 120   Sorin 2018 [92] R Israel 611 54 Iopamidol 370 1.5 3 120 B Tohamey 2018 [51] P mono Egypt 178 46 Iohexol 300 1.5 3 120 B Travieso-Aja 2018 [24] R Spain 158 51    1.5 3 120 B Xing 2018 [84] P mono China 235 51 Iohexol 350 1.5 3 120 B Barra 2017 [39] R Brazil 11 46 Iohexol 300 1–2 3 120 B Bhimani 2017 [13] R USA 2303   Iopamidol 370 1.5 2 120 B Fallenberg 2017 [76] P multi Germany 155 53 Iobitridol 300 1.5 3 120 A Gluskin 2017 [63] R USA 5 59 Iohexol 350 1.5 3 150–180 A Helal 2017 (01) [28] P mono Egypt 98 50 Iohexol 300 1.5 3 120 B Helal 2017 (02) [99] P mono Egypt 30 47 Iohexol 300 1.5   120   Houben 2017 [58] R The Netherlands 839 60 Iopromide 300 1.5 3 120   Iotti 2017 [37] P mono Italy 54 54 Ioversol 350 1.5   120   James 2017 [56] R USA 173   Iohexol 350 1.5 3 120 A Jochelson 2017 [54] P mono USA 309 51 Iohexol 350 1.5 3 150–180 B Knogler 2017 [94] P mono Austria 11 58 Iomeprol 400 2 3.5 90   Lee-Felker 2017 [26] R USA 52 50 Iohexol 350   3 120 B Lewis 2017 [16] R USA 208   Iohexol 350 1.5 3 120 B Li 2017 [100] R USA 48 56 Iopamidol 370 1.5 1.5–2   B Mori 2017 [74] P mono Japan 72 48 Iohexol 300 1.5 3 120   Patel 2017 (01) [27] R USA 88 62 Iohexol 350 1.5 3 120 B Patel 2017 (02) [65] R USA 410   Iohexol 350 1.5 3 120 B Phillips 2017 [70] P mono USA 38 53 Iohexol 350 1.5 3 120 B Richter 2017 [62] R Germany 118 58 Iopromide 300 1.5 2–3 120   Saraya 2017 [18] P mono Egypt 34 54 Iohexol 300 1.5 4   C Savaridas 2017 [75] P mono Australia 66 54    1.5 3 120 B Sogani 2017 [80] R USA 278 51 Iohexol 350 1.5 3 150 A Ali-Mucheru 2016 [33] R USA 351 62 Iohexol 350 1.5 3 120 B Ambicka 2016 [29] R Poland 82 57 Iopromide 370 1.5 3 120 B Brandan 2016 [77] P mono Mexico 18 51 Ioversol 300   4 60 B Cheung 2016 (01) [72] R Taiwan 256 48 Iohexol 350 1.5 3 120 A Cheung 2016 (02) [98] R Taiwan 87 54 Iohexol 350 1.5 3 120 B Kamal 2016 [95] R Egypt 239 48 Iohexol 300 1.5 3 120 B Kariyappa 2016 [68] P mono India 44   Iomeprol 350 1.5 3 120 B Knogler 2016 [83] P mono Austria 15 58 Iomeprol 400 2 3.5 60–90   Lalji 2016 [21] R The Netherlands 199 58 Iopromide 300 1.5 3 120   Łuczyńska 2016 (01) [50] P mono Poland 116 55 Iopromide 370 1.5 3 120 B Łuczyńska 2016 (02) [67] P mono Poland 193 55 Iopromide 370 1.5 3 120 B Tardivel 2016 [19] R France 195 56 Iobitridol 300 1.5 3 120 B Tennant 2016 [15] R UK 99 49        Tsigginou 2016 [89] P mono Greece 216 55 Iopromide 300 1.5 2–3 120 B Wang 2016 [97] P mono China 68 53 Iohexol 350 1.5 3 120 A Yagil 2016 [71] R Israel 200 51 Iopamidol 370 1.5 3 120 B Chou 2015 [14] P mono Taiwan 185 51 Iohexol 300 1.5 2 120 B Elsaid 2015 [73] P mono Egypt 34 55 Iohexol 300 1.5 3   B Hobbs 2015 [81] P mono Australia 49 55 Iohexol 350 1.5 3 120 B Kamal 2015 [79] R Egypt 168   Iohexol 300 1.5 3 120 B Lobbes 2015 [30] R The Netherlands 87 62 Iopromide 300 1.5 3 120   Łuczyńska 2015 (01) [91] P mono Poland 174 56 Iopromide 370 1.5 3 120 B Łuczyńska 2015 (02) [53] P mono Poland 102   Iopromide 370 1.5 3 120   Badr 2014 [101] P mono France 75 54 Iohexol 300 1.5   120 B Blum 2014 [31] P mono Germany 20 57 Iopamidol 300 1.5 3 120   Cheung 2014 [86] R Taiwan 89 48 Iohexol 350 1.5 3 120–180 B Fallenberg 2014 (01) [85] P mono Germany 118 53 Iobitridol 300 1.5 3 120 B Fallenberg 2014 (02) [32] P mono Germany 80 54 Iobitridol 300 1.5 3 120 B Francescone 2014 [66] R USA 88 50        Jeukens 2014 [60] R The Netherlands 47 58 Iopromide 300 1.5 3 120   Lobbes 2014 [20] R The Netherlands 113 57 Iopromide 300 1.5 3 120   Łuczyńska 2014 [35] P mono Poland 152 56 Iopromide 370 1.5 3 120 B Mokhtar 2014 [57] P mono Egypt 60   Iohexol 300 1.5   120 A Travieso-Aja 2014 [64] R Spain 136 49    1.5 3 120 B Hill 2013 [10] R Canada 98 57 Iobitridol 300 1.5 3 120 B Jochelson 2013 [55] P mono USA 82 50 Iohexol 350 1.5 3 150–300 B Dromain 2012 [52] P mono France 110 57 Iobitridol 300 1.5 3 120 A Diekmann 2011 [61] P mono Germany 70 55 Iopromide 370 1 4 60/120/180 A Dromain 2011 [59] P mono France 120 56 Iobitridol 300 1.5 3 120 A Dromain 2006 [9] P mono France 20 63 Iohexol 300   3 30 B Diekmann 2005 [8] P mono Germany 21   Iopromide 370 1 4 60/120/180 A Jong 2003 [7] P mono Canada 22   Iohexol 300    60 B Lewin 2003 [96] P mono USA 26 51 Iohexol 350   4–5 150   R retrospective, P mono prospective monocentric, P multi prospective multicentric, A = total exam time < 5 min, B = total exam time between 5 and 10 min, C = total exam time > 10 min Timing of CESM examination with menstrual cycle was reported only in 18/84 studies (21%). In 10/18 (56%) articles, it was mentioned but not applied; in 6/18 (33%), it was applied with a feasibility window between the 5th and 14th day of menstrual cycle; in 2/18 (11%), CESM was synchronously performed with MRI in different phases of menstrual cycle to evaluate and compare background parenchymal enhancement. Technical features and parameters In 70 out of 84 studies (83%), different systems from General Electric Healthcare (Chicago, IL, USA) were used, all with a prototype or a commercial release of the SenoBright upgrade which is required to perform dual-energy contrast-enhanced imaging. Twelve out of 84 articles (14%) reported the adoption of Selenia Dimensions Mammography Unit (Hologic Inc., Marlborough, MA, USA), while the remaining 2/84 (3%) studies were conducted with a Siemens Healthineers (Erlangen, Germany) Mammography System (Mammomat or Mammomat Inspiration). The type of ICA used was not reported in five articles [15, 24, 64, 66, 75], while in the remaining 79 studies (94%), for a total of 13465 patients (96%), six different molecules were used: Iohexol was the most frequently employed, being used in 42/79 studies (53%) for a total of 5049/13465 patients (37%), followed by Iopromide (18/79 studies, 23%; 2798/13465 patients, 21%), while Iobitridol, Iomeprol, Iopamidol and Ioversol were administered in the remaining studies (19/79 studies, 24%; 5618/13465 patients, 42%). Iohexol was utilised at a concentration of 350 mg iodine/mL (25/42 studies, 60%; 3330/5049 patients, 66%) or 300 mg iodine/mL (17/42 studies, 40%; 1719/5049 patients, 34%). Iopromide was also administered at two different concentrations: 370 mg iodine/mL (10/18 studies, 56%; 1032/2798 patients, 37%) and 300 mg iodine/mL (8/18 studies, 44%; 1766/2798 patients, 63%). Of the 69 studies including a specification of the contrast injection modality, 59 (85%) utilised an automated power injector (10584/11725 patients, 90%) while manual contrast injection was carried out in the remaining 10 (15%) [7, 9, 17, 25, 28, 51, 57, 73, 95, 99] for a total of 1141/11725 patients (10%). Contrast agent dose, detailed in 77 studies, was fixed at 1.5 mL/kg in 72 (93%) of them for a total of 13559/13687 (99%) patients. Contrast agent flow rate, reported in 76/84 studies (90%), was most frequently fixed at 3 mL/s (65/76 studies, 86%); the 11 remaining articles detailed a flow rate ranging from 2 to 5 mL/s. Thirty-five out of 84 (42%) articles for a total 8734/14012 patients (62%) also mentioned the use of additional post-contrast saline flush or “bolus chaser,” 19 of them (54%, for a total 4477/8734 patients, 51%) likewise detailing a saline amount ranging from 10 to 30 mL. Of 69 studies detailing the tube voltage of both low- and high-energy acquisitions, all but one (99%) acquired low-energy images between 26 and 33.2 kVp, which is the peak kilovoltage threshold of iodine, while all 69 acquired high-energy images well above this threshold, i.e. between 44 and 50 kVp. The anode/filter combination was reported by 42/84 studies. Exposure parameters were unambiguously reported only in one study [10], whereas in 5 early studies [7, 8, 32, 59, 85], they were manually adjusted according to breast thickness and density; thirty-five other studies declared an automatic regulation of these parameters performed by the mammography unit. Regarding radiation dose, data were scarcer: even though 45/84 articles (54%) mentioned this aspect, 17/45 (31%) did it without exhibiting original information but reporting observations from previous studies, therefore restricting the number of studies with new data to 28/84 (33%). Of these 28 studies, 19 (68%) provided an average glandular dose (AGD), 3 (16%) of them calculating it per-patient and ranging 1.5–6.9 mGy [8, 9, 58], 5/19 (26%) calculating it per-breast ranging 2.19–7.15 mGy and the remaining 11 (58%) reporting a per-view AGD ranging from 0.43 [61] to 2.65 mGy [101]. A comparison with DM was mentioned in 17 studies: only 1 (6%) documented a dose reduction (− 2%) for CESM compared to DM [32], while other 16 (94%) reported an increase in AGD ranging between 6.2% [85] and 100% [77]. However, it is worth to notice that 3 studies specifically contrived to assess CESM radiation doses reported an AGD increase of 42% [56], 78% [82] and 80% [60]. Acquisition protocols Studies reporting the time interval between contrast injection and the first image acquisition were 78 out of 84 (93%), for a total 13244/14012 patients (95%) and 65 (83%) of them (12278/13244 patients, 93%) had it fixed at 120 s. Sixty-six out of 84 articles (79%, 11900/14012 patients, 85%) gave an indication of the acquisition time after contrast injection: in 12/66 (18%, 1381/11900 patients, 11.6%), the exam was completed in less than 5 min; in 52/66 (80%, for total of 10485/11900 patients, 88.1%) between 5 and 10 min, while in 1/66 (2%, 34/11900 patients, 0.3%) the duration exceeded 10 min. The outline of the image acquisition sequence remains more variable. Ten out of 84 studies (12%), accounting for 2734 patients (19%) did not clearly describe it and did not provide a reference to other protocols, while 3/84 (4%, 103/14012 patients, 1%) employed a curtailed and side-insensitive acquisition sequence. Adherence to standard but unspecified digital mammography protocols was declared by 29/84 (34%) studies, for total 3741/14012 patients (27%). The other half of the articles analysed (42/84, accounting for 7434/14012 patients, 53%) unequivocally detailed an acquisition sequence. Of these 42 studies, 14 (34%, 2048/7434 patients, 28%) adopted a projection order that was conventionally agreed upon, while the other 28 (66%, accounting for 5386/7434 patients, 72%) based their acquisition sequence on the presence of previous suspect or clearly pathologic findings. Eighty-four articles came from 38 different research groups. Subgroup analysis according to research groups showed that 17 acquisition sequences based on a conventionally agreed projection order were executed in 15 research groups. As described in Fig. 3, the most common sequence description, reported by 6/17 (35%) institutions, was MLO - MLO - CC - CC (in order of acquisition), without any further indication about the first side to be examined (right or left or side with/without suspicious lesion or already diagnosed cancer). The second most common sequence (4/17, 24%) was CC - CC - MLO - MLO with the first projection standardised on the right side (independently of pathology or with suspected pathology). Open image in new window Fig. 3 Graphical summary of conventionally agreed view acquisition orders for contrast-enhanced spectral mammography: CC craniocaudal view, MLO mediolateral oblique view, L left, R right Among the 22 acquisition sequences (coming from 20 institutions) centred on the presence of previous suspect or clearly pathologic findings, we found substantial variability between different orders of acquisition, as shown in Fig. 4. However, the most common sequence, adopted by 4/22 (19%) research groups, was 1) CC, suspected side; 2) CC, non-suspected side; 3) MLO, suspected side; and 4) MLO, non-suspected side. Open image in new window Fig. 4 Graphical summary of pathology-oriented view acquisition orders for contrast-enhanced spectral mammography: CC craniocaudal view, MLO mediolateral oblique view, S suspicious breast, NS not suspicious breast Contrast agent adverse reaction rate meta-analysis Regarding side effects from ICA administration, 48/84 studies (57%) declared a preventive anamnestic screening for previous adverse reactions or general contraindications to ICA administration. Pre-examination tests of renal function was mentioned in 39/84 studies (46%). Of note, 14/84 studies (29%) reported 30 adverse reactions out of 14012 patients, of which 26/30 (87%) were mild reactions limited to pruritus, hives, “scratchy throat” or other minor skin flushing that resolved promptly even when antihistamines or corticosteroids were not administered. In 3/30 (10%) cases [54, 58, 87], side effects were of moderate importance with nausea and vomiting, widespread urticaria resolved only after antihistamines and corticosteroids per os, and dyspnea that equally responded to oral antihistamine administration. Only 1/30 (3%) severe adverse reaction, requiring “intensive care” but resolved after short time, occurred in 14012 patients (0.007%) [61]. Therefore, the number of adverse reactions related to ICA administration ranged from 0, reported by 70 (88%) studies, to a maximum of 6 adverse reactions [14] with a total of 30 adverse reactions, showing no heterogeneity (Q = 64, degree of freedom 83, τ = 2.0972, I2 = 0%, p = 0.931). As shown in the forest plot of Fig. 5, using fixed-effect model, the pooled rate of adverse reactions across studies was 0.82%, with 0.64% and 1.05% as 95% CI. Open image in new window Fig. 5 Forest plot of the 84 analysed articles on contrast-enhanced spectral mammography. No heterogeneity was found among studies (I2 = 0%). The last row shows the pooled rate for adverse reactions arising from iodinated contrast agent administration, calculated using the fixed-effect model Visually inspecting the funnel plot in Fig. 6, risk of publication bias was found, as confirmed by the Egger test (p = 0.00028). Open image in new window Fig. 6 Funnel plot showing risk of publication bias in articles on contrast-enhanced spectral mammography, confirmed by the Egger test (p < 0.001) Discussion Our systematic review included 84 articles, accounting for 14012 patients, reporting the use of CESM in various settings. The sheer number of studies and, as depicted in Fig. 7, their increase in the last 3 years (27 studies between 2003 and December 2015, 57 from January 2016 to January 2019) points out a considerable interest in this emerging breast imaging modality. Open image in new window Fig. 7 Graphic showing the number of articles published per year regarding contrast-enhanced spectral mammography A number of narrative reviews [6, 42, 102, 103, 104, 105, 106] favourably outlined CESM future perspectives in several clinical settings (e.g. recall work-up, pre-operative staging, and monitoring the effect of neoadjuvant therapy) as a potential alternative to MRI. In the first phase of CESM development, some non-fixed parameters regarding contrast agent administration (i.e. contrast agent molecule, concentration, dose, flow rate, and injection modality) and some acquisition features (i.e. time between contrast injection and first acquisition, kVp ranges for low- and high-energy acquisitions) gained an international agreement. However, in the framework of comprehensive optimisation and standardisation of CESM, large-scale studies are undoubtedly needed to address the knowledge gap concerning the choice of technical parameters. Our data show a consensus among studies (93%) on the choice of 1.5 mL/kg contrast dose administered with a 3 mL/s flow rate (74%) and a less extensive agreement on the use of Iohexol (53% of all studies) at a concentration of 350 mg iodine/mL (30% of all studies). However, these parameters have probably been empirically adopted from CT protocols, as the first investigators plainly stated [7], without any other particular explication or justification. No dose-finding studies have been published yet. Similarly, the common use of a power contrast injector (87% of all studies, with the remaining 13% coming from a single research group) is assumed from CT and MRI protocols in which it has been demonstrated to be effective in obtaining a stable contrast inflow and bolus shape [107, 108, 109]. Moreover, the use of a power injector allows for the administration of a bolus chaser, reported only in 42% of all articles, a technical refinement that has shown good results in CT [110, 111]. Two other points need to be mentioned. The first one is the correlation between menstrual cycle phase and background parenchymal enhancement, explored in a few studies [10, 75, 80] and/or fluctuations of lesion contrast uptake. Secondly, since CESM is based on a dual X-ray exposure, of which the low-energy one has been demonstrated to be equal to standard DM [66], an increase in radiation dose is expected. However, while preliminary studies estimated a negligible [7] or curtailed AGD increase, studies specifically devised to ascertain CESM effective AGD found a substantial AGD increment ranging 42–80% [56, 60, 82]. While CESM AGDs remain under the threshold stated by European guidelines for screening mammography [112], further studies are needed to investigate CESM AGD [56, 82]. Furthermore, we remark the absence of standardised protocols. This methodological void, especially regarding the acquisition workflow, represents a threat to reproducibility and comparison of imaging results. While 98% of all studies reporting the total examination time completed the examination before 10 min from contrast administration, and while some studies presented evidence on the irrelevance of the acquisition order [55, 64], there are no studies comparing different approaches. The pooled rate of adverse reactions to ICA administration was 0.82% (0.64–1.05% 95% CI) with a total of 30 adverse reactions in 14012 patients, a rate similar to that reported for CT 0.6% [113] in 84928 adult patients or 0.7% [114] in 29508 patients (given Iopromide, which is also used for CESM). Particularly, considering only severe adverse reactions in CT, Wang et al. [113] reported 11/84928 (0.0129%) reactions, as well as Mortelé et al. [114] 4/29508 (0.0135%). These rates seem to be higher than that found in our meta-analysis 1/14012 (0.007%), a comparison to consider with caution due to the nature of rare events such as severe reactions to ICA. One aspect to consider is the different profile of patients undergoing CESM compared to those requiring contrast-enhanced CT, the former being that of basically “healthy” subjects, the latter implying the possibility of relevant disease, including also serious emergency conditions. This review has limitations. Patient data are probably shared and duplicate among some studies from the same research group. This has been shown to negatively impact on review quality [115, 116] and could only be prevented via individual patient data sharing [117]. However, for technical aspects of this systematic review, our choice to evaluate study groups rather than single articles should have mitigated this bias. Conversely, our pooled rate of adverse reactions could be underestimated. In conclusion, our review shows that CESM is unevenly performed across different centres, in terms of contrast agent type and concentration and order of view acquisition. However, most research groups performed CESM using a contrast dose of 1.5 mL/kg, factory-set kVp ranges for low- and high-energy acquisitions, beginning image acquisition after 120 s from contrast agent injection and completing the examination within 10 min. Further studies are needed to investigate the role of background parenchymal enhancement and to harvest data that can firmly back up subsequent technical guidelines and consensus statements for standardised CESM protocols. Notes Authors’ contributions Each author has participated sufficiently in this work to take public responsibility for its content. The manuscript is approved by all authors and by the responsible authorities. All authors read and approved the final manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests FS declares to have received grants from or to be member of speakers’ bureau/advisory board for Bayer, Bracco, and General Electric. All other authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Frigerio A, Sardanelli F, Podo F (2017) Radiological screening of breast cancer: evolution. In: Veronesi U, Goldhirsch A, Veronesi P, Gentilini OD, Leonardi MC (eds) Breast Cancer. Springer International Publishing, Cham, pp 171–203CrossRefGoogle Scholar 2. Pisano ED, Gatsonis C, Hendrick E et al (2005) Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 353:1773–1783PubMedCrossRefPubMedCentralGoogle Scholar 3. Gilbert FJ, Tucker L, Young KC (2016) Digital breast tomosynthesis (DBT): a review of the evidence for use as a screening tool. Clin Radiol 71:141–150PubMedCrossRefPubMedCentralGoogle Scholar 4. Pattacini P, Nitrosi A, Giorgi Rossi P et al (2018) Digital mammography versus digital mammography plus tomosynthesis for breast cancer screening: the Reggio Emilia Tomosynthesis randomized trial. Radiology 288:375–385PubMedCrossRefPubMedCentralGoogle Scholar 5. Marinovich ML, Hunter KE, Macaskill P, Houssami N (2018) Breast cancer screening using tomosynthesis or mammography: a meta-analysis of cancer detection and recall. J Natl Cancer Inst 110:942–949PubMedCrossRefPubMedCentralGoogle Scholar 6. Patel BK, Lobbes MBI, Lewin J (2018) Contrast enhanced spectral mammography: a review. Semin Ultrasound CT MRI 39:70–79PubMedCrossRefPubMedCentralGoogle Scholar 7. Jong RA, Yaffe MJ, Skarpathiotakis M et al (2003) Contrast-enhanced digital mammography: initial clinical experience. Radiology 228:842–850PubMedCrossRefPubMedCentralGoogle Scholar 8. Diekmann F, Diekmann S, Jeunehomme F, Muller S, Hamm B, Bick U (2005) Digital mammography using iodine-based contrast media. Invest Radiol 40:397–404PubMedCrossRefPubMedCentralGoogle Scholar 9. Dromain C, Balleyguier C, Muller S et al (2006) Evaluation of tumor angiogenesis of breast carcinoma using contrast-enhanced digital mammography. AJR Am J Roentgenol 187:W528–W537PubMedCrossRefPubMedCentralGoogle Scholar 10. Hill ML, Mainprize JG, Carton A-K et al (2013) Anatomical noise in contrast-enhanced digital mammography. Part II. Dual-energy imaging. Med Phys 40:081907PubMedCrossRefGoogle Scholar 11. Dromain C, Balleyguier C, Adler G, Garbay JR, Delaloge S (2009) Contrast-enhanced digital mammography. Eur J Radiol 69:34–42PubMedCrossRefGoogle Scholar 12. Skarpathiotakis M, Yaffe MJ, Bloomquist AK et al (2002) Development of contrast digital mammography. Med Phys 29:2419–2426PubMedCrossRefGoogle Scholar 13. Bhimani C, Matta D, Roth RG et al (2017) Contrast-enhanced spectral mammography. Acad Radiol 24:84–88PubMedCrossRefGoogle Scholar 14. Chou C-P, Lewin JM, Chiang C-L et al (2015) Clinical evaluation of contrast-enhanced digital mammography and contrast enhanced tomosynthesis—comparison to contrast-enhanced breast MRI. Eur J Radiol 84:2501–2508PubMedCrossRefGoogle Scholar 15. Tennant SL, James JJ, Cornford EJ et al (2016) Contrast-enhanced spectral mammography improves diagnostic accuracy in the symptomatic setting. Clin Radiol 71:1148–1155PubMedCrossRefGoogle Scholar 16. Lewis TC, Pizzitola VJ, Giurescu ME et al (2017) Contrast-enhanced digital mammography: a single-institution experience of the first 208 cases. Breast J 23:67–76PubMedCrossRefPubMedCentralGoogle Scholar 17. Moustafa AFI, Kamal EF, Hassan MM, Sakr M, Gomaa MMM (2018) The added value of contrast enhanced spectral mammography in identification of multiplicity of suspicious lesions in dense breast. Egypt J Radiol Nucl Med 49:259–264CrossRefGoogle Scholar 18. Saraya S, Adel L, Mahmoud A (2017) Indeterminate breast lesions: can contrast enhanced digital mammography change our decisions? Egypt J Radiol Nucl Med 48:547–552CrossRefGoogle Scholar 19. Tardivel A-M, Balleyguier C, Dunant A et al (2016) Added value of contrast-enhanced spectral mammography in postscreening assessment. Breast J 22:520–528PubMedCrossRefPubMedCentralGoogle Scholar 20. Lobbes MB, Lalji U, Houwers J et al (2014) Contrast-enhanced spectral mammography in patients referred from the breast cancer screening programme. Eur Radiol 24:1668–1676Google Scholar 21. Lalji UC, Houben IP, Prevos R et al (2016) Contrast-enhanced spectral mammography in recalls from the Dutch breast cancer screening program: validation of results in a large multireader, multicase study. Eur Radiol 26:4371–4379PubMedPubMedCentralCrossRefGoogle Scholar 22. Houben IP, Vanwetswinkel S, Kalia V et al (2019) Contrast-enhanced spectral mammography in the evaluation of breast suspicious calcifications: diagnostic accuracy and impact on surgical management. Acta Radiol. [Epub ahead of print]Google Scholar 23. Patel BK, Davis J, Ferraro C et al (2018) Value added of preoperative contrast-enhanced digital mammography in patients with invasive lobular carcinoma of the breast. Clin Breast Cancer 18:e1339–e1345PubMedCrossRefPubMedCentralGoogle Scholar 24. Travieso-Aja MDM, Naranjo-Santana P, Fernández-Ruiz C et al (2018) Factors affecting the precision of lesion sizing with contrast-enhanced spectral mammography. Clin Radiol 73:296–303PubMedCrossRefPubMedCentralGoogle Scholar 25. Helal MH, Mansour SM, Salaleldin LA, Alkalaawy BM, Salem DS, Mokhtar NM (2018) The impact of contrast-enhanced spectral mammogram (CESM) and three-dimensional breast ultrasound (3DUS) on the characterization of the disease extend in cancer patients. Br J Radiol 91:20170977Google Scholar 26. Lee-Felker SA, Tekchandani L, Thomas M et al (2017) Newly diagnosed breast cancer: comparison of contrast-enhanced spectral mammography and breast MR imaging in the evaluation of extent of disease. Radiology 285:389–400PubMedCrossRefPubMedCentralGoogle Scholar 27. Patel BK, Garza SA, Eversman S, Lopez-Alvarez Y, Kosiorek H, Pockaj BA (2017) Assessing tumor extent on contrast-enhanced spectral mammography versus full-field digital mammography and ultrasound. Clin Imaging 46:78–84PubMedCrossRefPubMedCentralGoogle Scholar 28. Helal MH, Mansour SM, Zaglol M, Salaleldin LA, Nada OM, Haggag MA (2017) Staging of breast cancer and the advanced applications of digital mammogram: what the physician needs to know? Br J Radiol 90:20160717PubMedPubMedCentralCrossRefGoogle Scholar 29. Ambicka A, Luczynska E, Adamczyk A, Harazin-Lechowska A, Sas-Korczynska B, Niemiec J (2016) The tumour border on contrast-enhanced spectral mammography and its relation to histological characteristics of invasive breast cancer. Pol J Pathol 3:295–299CrossRefGoogle Scholar 30. Lobbes MB, Lalji UC, Nelemans PJ et al (2015) The quality of tumor size assessment by contrast-enhanced spectral mammography and the benefit of additional breast MRI. J Cancer 6:144–150PubMedPubMedCentralCrossRefGoogle Scholar 31. Blum KS, Rubbert C, Mathys B, Antoch G, Mohrmann S, Obenauer S (2014) Use of contrast-enhanced spectral mammography for intramammary cancer staging. Acad Radiol 21:1363–1369PubMedCrossRefPubMedCentralGoogle Scholar 32. Fallenberg EM, Dromain C, Diekmann F et al (2014) Contrast-enhanced spectral mammography versus MRI: initial results in the detection of breast cancer and assessment of tumour size. Eur Radiol 24:256–264PubMedCrossRefPubMedCentralGoogle Scholar 33. Ali-Mucheru M, Pockaj B, Patel B et al (2016) Contrast-enhanced digital mammography in the surgical management of breast cancer. Ann Surg Oncol 23:649–655PubMedCrossRefPubMedCentralGoogle Scholar 34. Patel BK, Ranjbar S, Wu T et al (2018) Computer-aided diagnosis of contrast-enhanced spectral mammography: a feasibility study. Eur J Radiol 98:207–213PubMedCrossRefPubMedCentralGoogle Scholar 35. Luczyńska E, Heinze-Paluchowska S, Dyczek S, Blecharz P, Rys J, Reinfuss M (2014) Contrast-enhanced spectral mammography: comparison with conventional mammography and histopathology in 152 women. Korean J Radiol 15:689PubMedPubMedCentralCrossRefGoogle Scholar 36. Luczynska E, Niemiec J, Heinze S et al (2018) Intensity and pattern of enhancement on CESM: prognostic significance and its relation to expression of podoplanin in tumor stroma - a preliminary report. Anticancer Res 38:1085–1095PubMedGoogle Scholar 37. Iotti V, Ravaioli S, Vacondio R et al (2017) Contrast-enhanced spectral mammography in neoadjuvant chemotherapy monitoring: a comparison with breast magnetic resonance imaging. Breast Cancer Res 19:106PubMedPubMedCentralCrossRefGoogle Scholar 38. Patel BK, Hilal T, Covington M et al (2018) Contrast-enhanced spectral mammography is comparable to MRI in the assessment of residual breast cancer following neoadjuvant systemic therapy. Ann Surg Oncol 25:1350–1356PubMedCrossRefGoogle Scholar 39. Barra FR, de Souza FF, Camelo REFA, Ribeiro ACO, Farage L (2017) Accuracy of contrast-enhanced spectral mammography for estimating residual tumor size after neoadjuvant chemotherapy in patients with breast cancer: a feasibility study. Radiol Bras 50:224–230PubMedPubMedCentralCrossRefGoogle Scholar 40. Barra FR, Sobrinho AB, Barra RR et al (2018) Contrast-enhanced mammography (CEM) for detecting residual disease after neoadjuvant chemotherapy: a comparison with breast magnetic resonance imaging (MRI). Biomed Res Int 2018:1–9CrossRefGoogle Scholar 41. Tagliafico AS, Bignotti B, Rossi F et al (2016) Diagnostic performance of contrast-enhanced spectral mammography: systematic review and meta-analysis. Breast 28:13–19PubMedCrossRefPubMedCentralGoogle Scholar 42. Zhu X, Huang J-M, Zhang K et al (2018) Diagnostic value of contrast-enhanced spectral mammography for screening breast cancer: systematic review and meta-analysis. Clin Breast Cancer 18:e985–e995PubMedCrossRefPubMedCentralGoogle Scholar 43. Sardanelli F, Boetes C, Borisch B et al (2010) Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. Eur J Cancer 46:1296–1316CrossRefPubMedGoogle Scholar 44. Mann RM, Kuhl CK, Kinkel K, Boetes C (2008) Breast MRI: guidelines from the European Society of Breast Imaging. Eur Radiol 18:1307–1318PubMedPubMedCentralCrossRefGoogle Scholar 45. The American Society of Breast Surgeons. Consensus guideline on diagnostic and screening magnetic resonance imaging of the breast. https://www.breastsurgeons.org/about/statements/PDF_Statements/MRI.pdf. Accessed 30 May 2019. 46. American College of Radiology. ACR practice parameter for the performance of contrast-enhanced magnetic resonance imaging (MRI) of the breast. Available from: https://www.acr.org/-/media/ACR/Files/Practice-Parameters/mr-contrast-breast.pdf. Accessed 30 May 2019. 47. Zanardo M, Cozzi A, Trimboli RM, Carbonaro LA, Sardanelli F. Technique and diagnostic performance of contrast-enhanced spectral mammography: a systematic review. PROSPERO 2018 CRD42018118554. Available from: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018118554. Accessed 30 May 2019. 48. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med 6:e1000097PubMedPubMedCentralCrossRefGoogle Scholar 49. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedPubMedCentralCrossRefGoogle Scholar 50. Luczyńska E, Heinze S, Adamczyk A, Rys J, Mitus JW, Hendrick E (2016) Comparison of the mammography, contrast-enhanced spectral mammography and ultrasonography in a group of 116 patients. Anticancer Res 36:4359–4366PubMedPubMedCentralGoogle Scholar 51. Tohamey YM, Youssry SW, Abd El Aziz AI (2018) Interpretation of patterns of enhancement on contrast-enhanced spectral mammography: an approach to a standardized scheme. Egypt J Radiol Nucl Med 49:854–868CrossRefGoogle Scholar 52. Dromain C, Thibault F, Diekmann F et al (2012) Dual-energy contrast-enhanced digital mammography: initial clinical results of a multireader, multicase study. Breast Cancer Res 14:R94PubMedPubMedCentralCrossRefGoogle Scholar 53. Łuczyńska E, Heinze-Paluchowska S, Hendrick E et al (2015) Comparison between breast MRI and contrast-enhanced spectral mammography. Med Sci Monit 21:1358–1367PubMedPubMedCentralCrossRefGoogle Scholar 54. Jochelson MS, Pinker K, Dershaw DD et al (2017) Comparison of screening CEDM and MRI for women at increased risk for breast cancer: a pilot study. Eur J Radiol 97:37–43PubMedCrossRefPubMedCentralGoogle Scholar 55. Jochelson MS, Dershaw DD, Sung JS et al (2013) Bilateral contrast-enhanced dual-energy digital mammography: feasibility and comparison with conventional digital mammography and MR imaging in women with known breast carcinoma. Radiology 266:743–751PubMedPubMedCentralCrossRefGoogle Scholar 56. James JR, Pavlicek W, Hanson JA, Boltz TF, Patel BK (2017) Breast radiation dose with CESM compared with 2D FFDM and 3D tomosynthesis mammography. AJR Am J Roentgenol 208:362–372PubMedCrossRefPubMedCentralGoogle Scholar 57. Mokhtar O, Mahmoud S (2014) Can contrast enhanced mammography solve the problem of dense breast lesions? Egypt J Radiol Nucl Med 45:1043–1052CrossRefGoogle Scholar 58. Houben IPL, Van de Voorde P, Jeukens CRLPN et al (2017) Contrast-enhanced spectral mammography as work-up tool in patients recalled from breast cancer screening has low risks and might hold clinical benefits. Eur J Radiol 94:31–37PubMedCrossRefPubMedCentralGoogle Scholar 59. Dromain C, Thibault F, Muller S et al (2011) Dual-energy contrast-enhanced digital mammography: initial clinical results. Eur Radiol 21:565–574PubMedCrossRefPubMedCentralGoogle Scholar 60. Jeukens CRLPN, Lalji UC, Meijer E et al (2014) Radiation exposure of contrast-enhanced spectral mammography compared with full-field digital mammography. Invest Radiol 49:659–665PubMedCrossRefPubMedCentralGoogle Scholar 61. Diekmann F, Freyer M, Diekmann S et al (2011) Evaluation of contrast-enhanced digital mammography. Eur J Radiol 78:112–121PubMedCrossRefPubMedCentralGoogle Scholar 62. Richter V, Hatterman V, Preibsch H et al (2018) Contrast-enhanced spectral mammography in patients with MRI contraindications. Acta Radiol 59:798–805PubMedCrossRefPubMedCentralGoogle Scholar 63. Gluskin J, Click M, Fleischman R, Dromain C, Morris EA, Jochelson MS (2017) Contamination artifact that mimics in-situ carcinoma on contrast-enhanced digital mammography. Eur J Radiol 95:147–154PubMedCrossRefPubMedCentralGoogle Scholar 64. Travieso Aja MM, Rodríguez Rodríguez M, Alayón Hernández S, Vega Benítez V, Luzardo OP (2014) Dual-energy contrast-enhanced mammography. Radiologia 56:390–399CrossRefGoogle Scholar 65. Patel BK, Naylor ME, Kosiorek HE et al (2017) Clinical utility of contrast-enhanced spectral mammography as an adjunct for tomosynthesis-detected architectural distortion. Clin Imaging 46:44–52PubMedCrossRefPubMedCentralGoogle Scholar 66. Francescone MA, Jochelson MS, Dershaw DD et al (2014) Low energy mammogram obtained in contrast-enhanced digital mammography (CEDM) is comparable to routine full-field digital mammography (FFDM). Eur J Radiol 83:1350–1355PubMedCrossRefPubMedCentralGoogle Scholar 67. Łuczyńska E, Niemiec J, Hendrick E et al (2016) Degree of enhancement on contrast enhanced spectral mammography (CESM) and lesion type on mammography (MG): comparison based on histological results. Med Sci Monit 22:3886–3893PubMedPubMedCentralCrossRefGoogle Scholar 68. Kariyappa KD, Gnanaprakasam F, Anand S, Krishnaswami M, Ramachandran M (2016) Contrast enhanced dual energy spectral mammogram, an emerging addendum in breast imaging. Br J Radiol 89:20150609PubMedPubMedCentralCrossRefGoogle Scholar 69. Danala G, Patel B, Aghaei F et al (2018) Classification of breast masses using a computer-aided diagnosis scheme of contrast enhanced digital mammograms. Ann Biomed Eng 46:1419–1431PubMedCrossRefPubMedCentralGoogle Scholar 70. Phillips J, Miller MM, Mehta TS et al (2017) Contrast-enhanced spectral mammography (CESM) versus MRI in the high-risk screening setting: patient preferences and attitudes. Clin Imaging 42:193–197PubMedCrossRefPubMedCentralGoogle Scholar 71. Yagil Y, Shalmon A, Rundstein A et al (2016) Challenges in contrast-enhanced spectral mammography interpretation: artefacts lexicon. Clin Radiol 71:450–457PubMedCrossRefPubMedCentralGoogle Scholar 72. Cheung Y-C, Tsai H-P, Lo Y-F, Ueng S-H, Huang P-C, Chen S-C (2016) Clinical utility of dual-energy contrast-enhanced spectral mammography for breast microcalcifications without associated mass: a preliminary analysis. Eur Radiol 26:1082–1089PubMedCrossRefPubMedCentralGoogle Scholar 73. ElSaid NAE, Farouk S, Shetat OMM, Khalifa NM, Nada OM (2015) Contrast enhanced digital mammography: is it useful in detecting lesions in edematous breast? Egypt J Radiol Nucl Med 46:811–819CrossRefGoogle Scholar 74. Mori M, Akashi-Tanaka S, Suzuki S et al (2017) Diagnostic accuracy of contrast-enhanced spectral mammography in comparison to conventional full-field digital mammography in a population of women with dense breasts. Breast Cancer 24:104–110PubMedCrossRefPubMedCentralGoogle Scholar 75. Savaridas SL, Taylor DB, Gunawardana D, Phillips M (2017) Could parenchymal enhancement on contrast-enhanced spectral mammography (CESM) represent a new breast cancer risk factor? Correlation with known radiology risk factors. Clin Radiol 72:1085.e1–1085.e9CrossRefGoogle Scholar 76. Fallenberg EM, Schmitzberger FF, Amer H et al (2017) Contrast-enhanced spectral mammography vs. mammography and MRI – clinical performance in a multi-reader evaluation. Eur Radiol 27:2752–2764PubMedCrossRefPubMedCentralGoogle Scholar 77. Brandan M-E, Cruz-Bastida JP, Rosado-Méndez IM et al (2016) Clinical study of contrast-enhanced digital mammography and the evaluation of blood and lymphatic microvessel density. Br J Radiol 89:20160232PubMedPubMedCentralCrossRefGoogle Scholar 78. Deng C-Y, Juan Y-H, Cheung Y-C et al (2018) Quantitative analysis of enhanced malignant and benign lesions on contrast-enhanced spectral mammography. Br J Radiol 91:20170605Google Scholar 79. Mohamed Kamal R, Hussien Helal M, Wessam R, Mahmoud Mansour S, Godda I, Alieldin N (2015) Contrast-enhanced spectral mammography: impact of the qualitative morphology descriptors on the diagnosis of breast lesions. Eur J Radiol 84:1049–1055PubMedCrossRefPubMedCentralGoogle Scholar 80. Sogani J, Morris EA, Kaplan JB et al (2017) Comparison of background parenchymal enhancement at contrast-enhanced spectral mammography and breast MR imaging. Radiology 282:63–73PubMedCrossRefPubMedCentralGoogle Scholar 81. Hobbs MM, Taylor DB, Buzynski S, Peake RE (2015) Contrast-enhanced spectral mammography (CESM) and contrast enhanced MRI (CEMRI): patient preferences and tolerance. J Med Imaging Radiat Oncol 59:300–305PubMedCrossRefPubMedCentralGoogle Scholar 82. Phillips J, Mihai G, Hassonjee SE et al (2018) Comparative dose of contrast-enhanced spectral mammography (CESM), digital mammography, and digital breast tomosynthesis. AJR Am J Roentgenol 211:839–846PubMedCrossRefPubMedCentralGoogle Scholar 83. Knogler T, Homolka P, Hörnig M et al (2016) Contrast-enhanced dual energy mammography with a novel anode/filter combination and artifact reduction: a feasibility study. Eur Radiol 26:1575–1581PubMedCrossRefPubMedCentralGoogle Scholar 84. Xing D, Lv Y, Sun B et al (2018) Diagnostic value of contrast-enhanced spectral mammography in comparison to magnetic resonance imaging in breast lesions. J Comput Assist Tomogr 43:245–251PubMedCrossRefPubMedCentralGoogle Scholar 85. Fallenberg EM, Dromain C, Diekmann F et al (2014) Contrast-enhanced spectral mammography: does mammography provide additional clinical benefits or can some radiation exposure be avoided? Breast Cancer Res Treat 146:371–381PubMedCrossRefPubMedCentralGoogle Scholar 86. Cheung Y-C, Lin Y-C, Wan Y-L et al (2014) Diagnostic performance of dual-energy contrast-enhanced subtracted mammography in dense breasts compared to mammography alone: interobserver blind-reading analysis. Eur Radiol 24:2394–2403PubMedCrossRefPubMedCentralGoogle Scholar 87. Kim EY, Youn I, Lee KH et al (2018) Diagnostic value of contrast-enhanced digital mammography versus contrast-enhanced magnetic resonance imaging for the preoperative evaluation of breast cancer. J Breast Cancer 21:453PubMedPubMedCentralCrossRefGoogle Scholar 88. Klang E, Krosser A, Amitai MM et al (2018) Utility of routine use of breast ultrasound following contrast-enhanced spectral mammography. Clin Radiol 73:908.e11–908.e16PubMedCrossRefPubMedCentralGoogle Scholar 89. Tsigginou A, Gkali C, Chalazonitis A et al (2016) Adding the power of iodinated contrast media to the credibility of mammography in breast cancer diagnosis. Br J Radiol 89:20160397PubMedPubMedCentralCrossRefGoogle Scholar 90. Navarro ME, Razmilic D, Araos I, Rodrigo A, Andia ME (2018) Contrast-enhanced spectral mammography. Experience in 465 examinations. Rev Med Chil 146:141–149Google Scholar 91. Luczynska E, Niemiec J, Ambicka A et al (2015) Correlation between blood and lymphatic vessel density and results of contrast-enhanced spectral mammography. Pol J Pathol 3:310–322CrossRefGoogle Scholar 92. Sorin V, Yagil Y, Yosepovich A et al (2018) Contrast-enhanced spectral mammography in women with intermediate breast cancer risk and dense breasts. AJR Am J Roentgenol 211:W267–W274PubMedCrossRefGoogle Scholar 93. Bicchierai G, Nori J, De Benedetto D et al (2018) Role of contrast-enhanced spectral mammography in the post biopsy management of B3 lesions: preliminary results. Tumori J. [Epub ahead of print]Google Scholar 94. Knogler T, Homolka P, Hoernig M et al (2017) Application of BI-RADS descriptors in contrast-enhanced dual-energy mammography: comparison with MRI. Breast Care (Basel) 12:212–216PubMedPubMedCentralCrossRefGoogle Scholar 95. Kamal RM, Helal MH, Mansour SM et al (2016) Can we apply the MRI BI-RADS lexicon morphology descriptors on contrast-enhanced spectral mammography? Br J Radiol 89:20160157PubMedPubMedCentralCrossRefGoogle Scholar 96. Lewin JM, Isaacs PK, Vance V, Larke FJ (2003) Dual-energy contrast-enhanced digital subtraction mammography: feasibility. Radiology 229:261–268PubMedCrossRefGoogle Scholar 97. Wang Q, Li K, Wang L, Zhang J, Zhou Z, Feng Y (2016) Preclinical study of diagnostic performances of contrast-enhanced spectral mammography versus MRI for breast diseases in China. Springerplus 5:763PubMedPubMedCentralCrossRefGoogle Scholar 98. Cheung Y-C, Juan Y-H, Lin Y-C et al (2016) Dual-energy contrast-enhanced spectral mammography: enhancement analysis on BI-RADS 4 non-mass microcalcifications in screened women. PLoS One 11:e0162740PubMedPubMedCentralCrossRefGoogle Scholar 99. Helal M, Abu Samra MF, Ibraheem MA, Salama A, Hassan EE, Hassan NE-H (2017) Accuracy of CESM versus conventional mammography and ultrasound in evaluation of BI-RADS 3 and 4 breast lesions with pathological correlation. Egypt J Radiol Nucl Med 48:741–750CrossRefGoogle Scholar 100. Li L, Roth R, Germaine P et al (2017) Contrast-enhanced spectral mammography (CESM) versus breast magnetic resonance imaging (MRI): a retrospective comparison in 66 breast lesions. Diagn Interv Imaging 98:113–123PubMedCrossRefPubMedCentralGoogle Scholar 101. Badr S, Laurent N, Régis C, Boulanger L, Lemaille S, Poncelet E (2014) Dual-energy contrast-enhanced digital mammography in routine clinical practice in 2013. Diagn Interv Imaging 95:245–258PubMedCrossRefPubMedCentralGoogle Scholar 102. Covington MF, Pizzitola VJ, Lorans R et al (2018) The future of contrast-enhanced mammography. AJR Am J Roentgenol 210:292–300PubMedCrossRefPubMedCentralGoogle Scholar 103. Lancaster RB, Gulla S, De Los Santos J, Umphrey HR (2018) Contrast-enhanced spectral mammography in breast imaging. Semin Roentgenol 53:294–300PubMedCrossRefPubMedCentralGoogle Scholar 104. James JJ, Tennant SL (2018) Contrast-enhanced spectral mammography (CESM). Clin Radiol 73:715–723PubMedCrossRefPubMedCentralGoogle Scholar 105. Patel BK, Gray RJ, Pockaj BA (2017) Potential cost Savings of Contrast-Enhanced Digital Mammography. AJR Am J Roentgenol 208:W231–W237PubMedCrossRefPubMedCentralGoogle Scholar 106. Lewin J (2018) Comparison of contrast-enhanced mammography and contrast-enhanced breast MR imaging. Magn Reson Imaging Clin N Am 26:259–263PubMedCrossRefPubMedCentralGoogle Scholar 107. Minsinger KD, Kassis HM, Block CA, Sidhu M, Brown JR (2014) Meta-analysis of the effect of automated contrast injection devices versus manual injection and contrast volume on risk of contrast-induced nephropathy. Am J Cardiol 113:49–53PubMedCrossRefPubMedCentralGoogle Scholar 108. Endrikat J, Barbati R, Scarpa M, Jost G, Ned Uber AE 3rd (2018) Accuracy and repeatability of automated injector versus manual administration of an MRI contrast agent—results of a laboratory study. Invest Radiol 53:1–5PubMedCrossRefPubMedCentralGoogle Scholar 109. Jost G, Endrikat J, Pietsch H (2017) The impact of injector-based contrast agent administration on bolus shape and magnetic resonance angiography image quality. Magn Reson Insights 10:1178623X1770589CrossRefGoogle Scholar 110. Auler MA, Heagy T, Aganovic L, Brothers R, Costello P, Schoepf UJ (2006) Saline chasing technique with dual-syringe injector systems for multi-detector row computed tomographic angiography: rationale, indications, and protocols. Curr Probl Diagn Radiol 35:1–11PubMedCrossRefPubMedCentralGoogle Scholar 111. Kidoh M, Nakaura T, Awai K et al (2013) Novel connecting tube for saline chaser in contrast-enhanced CT: the effect of spiral flow of saline on contrast enhancement. Eur Radiol 23:3213–3218PubMedCrossRefPubMedCentralGoogle Scholar 112. Perry N, Broeders M, de Wolf C, Tornberg S, Holland R, von Karsa L (2007) European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition--summary document. Ann Oncol 19:614–622PubMedCrossRefPubMedCentralGoogle Scholar 113. Wang CL, Cohan RH, Ellis JH, Caoili EM, Wang G, Francis IR (2008) Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions. AJR Am J Roentgenol 191:409–415PubMedCrossRefPubMedCentralGoogle Scholar 114. Mortelé KJ, Oliva M-R, Ondategui S, Ros PR, Silverman SG (2005) Universal use of nonionic iodinated contrast medium for CT: evaluation of safety in a large urban teaching hospital. AJR Am J Roentgenol 184:31–34PubMedCrossRefPubMedCentralGoogle Scholar 115. Huston P, Moher D (1996) Redundancy, disaggregation, and the integrity of medical research. Lancet 347:1024–1026CrossRefGoogle Scholar 116. Murphy L, Wyllie A (2009) Duplicate patient data in a meta-analysis: a threat to validity. J Crit Care 24:466–467PubMedCrossRefPubMedCentralGoogle Scholar 117. Sardanelli F, Alì M, Hunink MG, Houssami N, Sconfienza LM, Di Leo G (2018) To share or not to share? Expected pros and cons of data sharing in radiological research. Eur Radiol 28:2328–2335PubMedCrossRefPubMedCentralGoogle Scholar Copyright information © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Authors and Affiliations Moreno Zanardo1Andrea Cozzi1Email authorRubina Manuela Trimboli1Olgerta Labaj2Caterina Beatrice Monti1Simone Schiaffino3Luca Alessandro Carbonaro3Francesco Sardanelli131.Department of Biomedical Sciences for HealthUniversità degli Studi di MilanoMilanItaly2.Department of Morphology, Surgery and Experimental Medicine, Section of RadiologyUniversity of FerraraFerraraItaly3.Unit of RadiologyIRCCS Policlinico San DonatoSan Donato MilaneseItaly


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Moreno Zanardo, Andrea Cozzi, Rubina Manuela Trimboli, Olgerta Labaj, Caterina Beatrice Monti, Simone Schiaffino, Luca Alessandro Carbonaro, Francesco Sardanelli. Technique, protocols and adverse reactions for contrast-enhanced spectral mammography (CESM): a systematic review, Insights into Imaging, 2019, 76, DOI: 10.1186/s13244-019-0756-0