Background
The advent of novel therapies targeting tumor angiogenesis and vascularity has highlighted the need for accurate and reproduci-ble quantitative techniques to assess early changes in tumor vascularity [560]. However, as these therapies are predominantly cytostatic, current response assessment, which is based on inter-val einter-valuation of the tumor size using the Response Einter-valuation Criteria In Solid Tumors (RECIST) [561] is inadequate as it reflects only late changes and is unable to identify non-responders at an early time-point [562].
Study procedure
Dynamic contrast-enhanced US (DCE-US) can be performed using two different approaches with different results [563]:
Bolus injection of a UCA with TIC analysis
Single plane imaging is usually performed at 10– 20 frames per second for the duration of the enhancement. The average intensi-ty within a region of interest (ROI) can be displayed as a function of time, i. e., a TIC which describes the wash-in and washout of the UCA in the ROI [564]. In addition, a second ROI can be placed in a reference tissue for comparison purposes [565]. The majority of clinical studies to date are based on this method.
Intravenous infusion of a UCA with disruption-replenishment analysis
The UCA is administered over 5 to 20 minutes. UCA is first imaged without being disrupted at a low MI, then the MI is increased for a few frames, causing microbubble disruption. Immediately after that, the MI is returned to the non-disrupting level to observe the replenishment of the microbubbles into the ROI. Various models describe the echo-signal dynamics during the UCA-replenishment phase, which can be used for flow analysis [566]. Initially, moni-toring for tumor response with UCAs relied on qualitative analyses [567], but new methodologies have been developed to produce more robust and semi-quantitative indices. Analyses of the TIC, including wash-in and washout times, can be performed with curve fitting to determine functional indices [568]. The main indi-ces include: peak intensity (PI); area under the curve (AUC); area under the wash-in (AUWI); area under the washout (AUWO; all corresponding to blood volume); time to peak intensity (TPI);
slope of the wash-in (SWI; both corresponding to blood flow);
and mean transit time (MTT). No permeability information can be obtained because of the pure blood pool nature of microbub-bles.
Clinical application
Early clinical trials employed qualitative analysis in the assessment of the response of different tumors such as gastrointestinal stromal tumor (GIST) or renal cell carcinoma [569– 572]. More recently, there have been studies using semi-quantitative tech-niques with UCA bolus injection in renal cell carcinoma, hepato-cellular carcinoma (HCC) and GIST [573– 575]. Studies showed that two indices representing blood volume correlated with the RECIST response; one study on renal cell carcinoma demonstrated a correlation of such indices with Progression Free Survival and Overall Survival [573]. The results could not be reproduced in a study testing the disruption-replenishment technique versus Progression Free Survival assessed by the RECIST method [566].
A multicenter study of various types of tumors treated with anti-angiogenic therapies, such as metastatic renal cell carcino-ma, GIST, colon cancer, melanocarcino-ma, breast cancer and HCC, with approximately half of the tumors being located outside the liver, is currently being conducted in 539 patients with more than 2000 DCE-US scans. A quality score was proposed in a standardized acquisition [576], with AUC being the best parameter. A decrease of 40 % at one month was significantly correlated with Freedom From Progression (FFP) and also with Overall Survival which is the best end-point for the validation of a biomarker [577]. There is now emerging evidence that DCE-US may be used with appropri-ate tools to differentiappropri-ate between responders and non-responders at an earlier stage than conventional methods and this potentially allows tailoring of the treatment regimen, particularly changing treatment for non-responders. DCE-US has been endorsed by the European Medical Oncology Society to assess response under biological therapy for GIST [578].
R ECO M M E N DAT I O N 7 4
Dynamic CEUS can be utilized to assess response to biologic therapy in metastatic GIST and in other tumors (LoE 1b, GoR A). Strong Consensus (15/0/4, 100 %)
Conflict of Interest
Fabrizio Calliada: Congress participation support, Toshiba, Guerbet, Bayer, Hitachi, Mindray
Vito Cantisani: Congress participation support, Toshiba, Guerbet, Bayer, Hitachi, Mindray
Dirk Clevert: Speaker honoraria for Siemens, Philips, Samsung Falk, Bracco; Advisory Board Member Siemens, Philips, Samsung, Bracco;
Research grants, Siemens, Philips, Samsung, Bracco
David Cosgrove: Speaker honoraria, Bracco, Toshiba, SuperSonic, BK Medical, Carestream; Advisory Board Member, Toshiba, Carestream;
Research grant, Carestream; Congress participation support, Bracco, Toshiba
Annamarie Dagenello: Speaker honoraria, Bracco
Christoph F Dietrich: Speaker honoraria, Bracco, Hitachi, GE, Mindray, Supersonic, Pentax, Olympus, Fuji, Covidien, Boston Scientific, AbbVie, MSD, Falk Foundation, Novartis, Roche; Advisory Board Member, Hitachi and Mindray; Research grant, Bracco, Hitachi, GE, Siemens, Mindray, SuperSonic; Congress participation support, IPSEN
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Odd Helge Gilja: Speaker honoraria, GE Healthcare Takeda AS and Meda AS
Christian Jenssen: Speaker honoraria, Bracco, Hitachi, Toshiba, Falk Foundation, Covidien; Research grant, Novartis
Nathalie Lassau: Speaker honoraria, Bracco, Toshiba; Congress partici-pation support, Bracco, Toshiba
Edward Leen: Research equipment support, Philips Healthcare & Super-Sonic Imaging
Maria Franca Meloni: Speaker honoraria, Bracco
Christian Pállson Nolsøe: Speaker honoraria and congress participation support, GE Healthcare and Neovitalis
Mirko D’Onofrio: Speaker honoraria, Bracco, Siemens; Advisor Board Member, Bracco, Siemens, Congress participation support, Bracco Fabio Piscaglia: Speaker honoraria Bracco, Bayer; Advisory Board Mem-ber, Bayer; Research support, Esaote
Maija Radzina: Speaker honoaria, Bayer, Covidien; Congress participation support, Bayer
Adrian Saftiou: Speaker honoraria, Pentax Medical Singapore Ltd; Con-sulting/Advisory board, Mediglobe Corporation Gmbh; Congress parti-cipation support, Hitachi Medical Systems UK
Paul Sidhu: Speaker honoraria, Siemens, Bracco, Hitachi, Philips and GE Hans-Peter Weskott: Speaker honoraria for Bracco, Samsung and GE The following members declared no conflicts of interest: Eva Bartels, Michele Bertolotto, Francesca Drudi, Simon Freeman, Christopher Har-vey, Ernst Michael Jung, Andrea Klauser, Carlos Nicolau, Francesco Prada, Luca Savelli, Hessel Wijkstra
Acknowledgements
The authors thank the EFSUMB’s Lynne Rudd for her continuing support of the guidelines.
We also thank the following companies for funding a consensus meeting of the authors held in London in July 2016, at which we agreed on recommendations: bk/Ultrasound, Echosens, Esaote SpA, GE Health-care, Hitachi Medical Systems, Philips HealthHealth-care, Shenzhen Mindray Bio-medical Electronics Co., Ltd, Siemens Heathineers, Supersonic, Toshiba Medical and Bracco SpA.
Representatives of these companies were in attendance at this meeting to assist with technical product information but did not take part in the writing of this manuscript or the recommendations.
References
[1] Albrecht T, Blomley MJK, Bolondi L et al. Guidelines for the use of contrast agents in ultrasound. Ultraschall in Med 2004; 25: 249– 256 [2] Claudon M, Cosgrove D, Albrecht T et al. Guidelines and Good Clinical
Practice Recommendations for Contrast Enhanced Ultrasound (CEUS)– Update 2008. Ultraschall in Medizin 2008; 29: 28– 44
[3] Claudon M, Dietrich CF, Choi BI et al. Guidelines and good clinical prac-tice recommendations for contrast enhanced ultrasound (CEUS) in the liver– update 2012. Ultraschall in Med 2013; 34: 11 – 29
[4] Piscaglia F, Nolsoe C, Dietrich CF et al. The EFSUMB guidelines and re-commendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall in Med 2012; 32: 33– 59
[5] Sidhu PS, Cantisani V, Deganello A et al. Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: An EFSUMB position statement.
Ultraschall in Med 2017; 38: 33– 43
[6] Sidhu PS, Choi BI, Bachmann Nielsen M. The EFSUMB guidelines and re-commendations on the clinical practice of contrast enhanced ultrasound (CEUS): a new dawn for the escalating use of this ubiquitous technique.
Ultraschall in Med 2012; 32: 5– 7
[7] Food & Drug Administration. MARCH 2016– APPROVED DRUG PROD-UCT LIST. 2016 http://www.fda.gov/downloads/drugs/developmentap-provalprocess/ucm071120.pdf
[8] Bracco. Lumason Prescribing Information. 2016 http://imaging.bracco.
com/sites/braccoimaging.com/files/technica_sheet_pdf/US-20160330-LUMASON-PI_0.pdf
[9] Seitz K, Strobel D. A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA. Ultraschall in Med 2016; 37:
229– 232
[10] Education and Practical Standards Committee E. Minimal Training recommendations for the practice of medical ultrasound. Ultraschall in Med 2006; 27: 79– 95
[11] Education and Practical Standards Committee E. Minimum Training Re-quirements for the Practice of Medical Ultrasound in Europe. Appendix 14: (CEUS) Contrast Enhanced Ultrasound. Ultraschall in Med 2010; 31:
426– 427
[12] Quaia E, Alaimo V, Baratella E et al. Effect of Observer Experience in the Differentiation Between Benign and Malignant Liver Tumors After Ultra-sound Contrast Agent Injection. J UltraUltra-sound Med 2010; 29: 25– 36 [13] Greis C. Technical aspects of contrast-enhanced ultrasound (CEUS)
examinations: tips and tricks. Clin Hemorheol Microcirc 2014; 58: 89– 95 [14] Blomley MJK, Sidhu PS, Cosgrove DO et al. Do different types of liver le-sions differ in their uptake of the microbubble contrast agent SH U 508A in the late liver phase? Early experience. Radiology 2001; 220: 661– 667 [15] Bryant TH, Blomley MJK, Albrecht T et al. Liver phase uptake of a liver
specific microbubble improves characterization of liver lesions: a pro-spective multi-center study. Radiology 2004; 232: 392– 399
[16] Edey AJ, Ryan SM, Beese RC et al. Ultrasound imaging of liver metastases in the delayed parenchymal phase following administration of Sona-zoid™ using a destructive mode technique (Agent Detection Imaging™).
Clin Radiol 2008; 63: 1112– 1120
[17] Piscaglia F, Bolondi L. The safety of SonoVue in abdominal applications:
retrospective analysis of 23188 investigations. Ultrasound Med Biol 2006; 32: 1369– 1375
[18] Main ML. Ultrasound contrast agent safety: from anecdote to evidence.
JACC Cardiovasc Imaging 2009; 2: 1057– 1059
[19] Main ML, Goldman JH, Grayburn PA. Thinking Outside the box:The Ul-trasound Contrast Controversy. J Am Coll Cardiol 2007; 50: 2434– 2437 [20] Tang C, Fang K, Guo Y et al. Safety of Sulfur Hexafluoride Microbubbles
in Sonography of Abdominal and Superficial Organs: Retrospective Analysis of 30222 Cases. J Ultrasound Med 2017; 36: 531– 538 [21] Wilson SR, Burns PN. Microbubble-enhanced US in body imaging: What
role? Radiology 2010; 257: 24– 39
[22] Kitzman DW, Goldman ME, Gilliam LD et al. Efficacy and safety of the novel ultrasound contrast agent perflutren (Definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol 2000; 86: 669– 674
[23] Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV ad-ministration of contrast media. Am J Roentgenol 2001; 176: 1385– 1388 [24] Hunt CH, Hartman RP, Hesley GK. Frequency and Severity of Adverse
Effects of Iodinated and Gadolinium Contrast Materials: Retrospective Review of 456930 Doses. Am J Roentgenol 2009; 193: 1124– 1127 [25] Committee for Medicinal Products for Human Use (CHMP). Assessment
report EMA/84084/2014. SonoVue. international non-properietary name: sulfur hexafluoride, Procedure No. EMEA/H/C/000303/II/0025.
2014
[26] Darge K, Papadopoulu F, Ntoulia A et al. Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS). Pediatr Radiol 2013; 43: 1063– 1073
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
[27] Harvey CJ, Alsafi A, Kuzmich S et al. Role of US contrast agents in the assessment of indeterminate solid and cystic lesions in native and trans-plant kidneys. Radiographics 2015; 35: 1419– 1430
[28] Barr RG, Peterson C, Hindi A. Evaluation of indeterminate renal massess with contrast-enhanced US: a diagnostic performance study. Radiology 2014; 271: 133– 142
[29] Harkanyi Z. Potential applications of contrast-enhanced ultrasound in pediatric patients. Ultrasound Clin North Am 2013; 8: 403– 422 [30] Sellars ME, Deganello A, Sidhu PS. Paediatric contrast-enhanced
ultra-sound (CEUS); a technique that requires co-operation for rapid imple-mentation into clinical practice. Ultraschall in Med 2014; 35: 203– 206 [31] Caruso G, Salvaggio G, Campisi A et al. Bladder Tumor Staging:
Com-parison of Contrast-Enhanced and Gray-Scale Ultrasound. Am J Roent-genol 2010; 194: 151– 156
[32] Drudi FM, Di Leo N, Maghella F et al. CEUS in the study of bladder, method, administration and evaluation, a technical note. J Ultrasound 2014; 17: 57– 63
[33] Drudi FM, Cantisani V, Liberatore M et al. Role of Low-Mechanical Index CEUS in the Differentiation between Low and High Grade Bladder Carci-noma: a Pilot Study. Ultraschall in Med 2010; 31: 589– 595
[34] Wang XH, Wang YJ, Lei CG. Evaluating the perfusion of occupying lesions of kidney and bladder with contrast-enhanced ultrasound. Clin Imaging 2011; 35: 447– 451
[35] Nicolau C, Bunesch L, Sebastia C et al. Diagnosis of bladder cancer:
contrast-enhanced ultrasound. Abdom Imaging 2010; 35: 494– 503 [36] Nicolau C, Bunesch L, Peri L et al. Accuracy of contrast-enhanced
ultra-sound in the detection of bladder cancer. Br J Radiol 2011; 84: 1091–
1099
[37] Correas JM, Claudon M, Tranquart F et al. The kidney: imaging with microbubble contrast agents. Ultrasound Q 2006; 22: 53– 66 [38] Tsuruoka K, Yasuda T, Koitabashi K et al. Evaluation of Renal
Microcircu-lation by Contrast-Enhanced Ultrasound With SonazoidTMas a Contrast Agent Comparison Between Normal Subjects and Patients With Chronic Kidney Disease. Int Heart J 2010; 51: 176– 182
[39] Ma F, Cang Y, Zhao B et al. Contrast-enhanced ultrasound with SonoVue could accurately assess the renal microvascular perfusion in diabetic kidney damage. Nephrol Dial Transplant 2012; 27: 2891– 2898 [40] Bertolotto M, Martegani A, Aiani L et al. Value of contrast-enhanced
ul-trasonography for detecting renal infarcts proven by contrast enhanced CT. A feasibility study. Eur Radiol 2008; 18: 376– 383
[41] Yusuf GT, Sellars ME, Huang DY et al. Cortical Necrosis Secondary to Trauma in a Child: Contrast-enhanced ultrasound comparable to Mag-netic Resonance Imaging. Pediatr Radiol 2014; 44: 484– 487 [42] Mazziotti S, Zimbaro F, Pandolfo A et al. Usefulness of
contrast-en-hanced ultrasonography in the diagnosis of renal pseudotumors. Abdom Imaging 2010; 35: 241– 245
[43] Quaia E, Bertolotto M, Cioffi V et al. Comparison of contrast-enhanced sonography with unenhanced sonography and contrast-enhanced CT in the diagnosis of malignancy in complex renal masses. Am J Roentgenol 2008; 191: 1239– 1249
[44] Clevert DA, Minaifar N, Weckbach S et al. Multislice computed tomog-raphy versus contrast-enhanced ultrasound in evaluation of complex cystic renal masses using the Bosniak classification system. Clin Hemor-heol Microcirc 2008; 39: 171– 178
[45] Park BK, Kim B, Kim SH et al. Assessment of cystic renal masses based on Bosniak classification: comparison of CT and contrast-enhanced US. Eur J Radiol 2007; 61: 310– 314
[46] Ascenti G, Mazziotti S, Zimbaro G et al. Complex Cystic Renal Masses:
Characterization with Contrast-enhanced US. Radiology 2007; 243:
158– 165
[47] Bertolotto M, Cicero C, Perrone R et al. Renal masses with equivocal en-hamcement at CT: characterization with contrast-enhanced ultrasound.
Am J Roentgenol 2015; 205: W557– W565
[48] Fontanilla T, Minaya J, Cortes C et al. Acute complicated pyelonephritis:
contrast-enhanced ultrasound. Abdominal Imaging 2012; 37: 639– 646 [49] Ignee A, Straub B, Brix D et al. The value of contrast enhanced ultrasound
(CEUS) in the characterisation of patients with renal masses. Clin He-morheol Microcirc 2010; 46: 275– 290
[50] Papadopoulou F, Ntoulia A, Siomou E et al. Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux: pro-spective evaluation of contrast safety in 1010 children. Pediatr Radiol 2014; 44: 719– 728
[51] Darge K. Voiding urosonography with US contrast agents for the diag-nosis of vesicureteric reflux in children. I. Procedure. Pediatr Radiol 2008; 38: 40– 53
[52] Darge K. Voiding urosonography with US contrast agents for the diag-nosis of vesicureteric reflux in children. II. Comparison with radiological examinations. Pediatr Radiol 2008; 38: 54– 63
[53] Ascenti G, Zimbaro G, Mazziotti S et al. Harmonic US imaging of vesi-coureteric reflux in children: usefulness of a second generation US con-trast agent. Pediatr Radiol 2004; 34: 481– 487
[54] Wong LS, Tse KS, Fan TW et al. Voiding urosonography with second-generation ultrasound contrast versus micturating cystourethrography in the diagnosis of vesicoureteric reflux. Eur J Pediatr 2014; 173: 1095– 1101
[55] Duran C, Riego J, Riera L et al. Voiding urosonography including ure-throsonography: high-quality examinations with an optimised proce-dure using a second-generation US contrast agent. Pediatr Radiol 2012;
42: 660– 667
[56] Kis E, Nyitrai A, Varkonyi I et al. Voiding urosonography with second-generation contrast agent versus voiding cystourethrography. Pediatr Nephrol 2010; 25: 2289– 2293
[57] Papadopoulou F, Anthopoulou A, Siomou E et al. Harmonic voiding uro-sonography with a second-generation contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol 2009; 39: 239– 244
[58] Darge K. Voiding urosonography with US contrast agent for the diagno-sis of vesicoureteric reflux in children: an update. Pediatr Radiol 2010;
40: 956– 962
[59] Giordano M, Marzolla R, Puteo F et al. Voiding urosonography as first step in the diagnosis of vesicoureteral reflux in children: a clinical ex-perience. Pediatr Radiol 2007; 37: 674–677
[60] Duran C, Valera A, Alguersuari A et al. Voiding urosonography: the study of the urethra is no longer a limitation of the technique. Pediatr Radiol 2009; 39: 124– 131
[61] Lebowitz RL, Olbing H, Parkkulainen KV et al. International system of radiographic grading of vesicourteric reflux. Internationa Reflux Study in Children. Pediatr Radiol 1985; 15: 105– 109
[62] Fernaíndez-Ibieta M, Parrondo-Muiros C, Fernaíndez-Masaguer LC et al.
Urosonografi¡a miccional con contraste de segunda generaci+¦n como herramienta primaria en el estudio de la vi¡a urinaria superior e inferior en pediatri¡a. Estudio Piloto. Actas Urolgicas Espaolas 2016; 40: 183–
189
[63] Wozniak MM, Wieczorek AP, Pawelec A et al. Two-dimensional (2D), three-dimensional static (3D) and real-time (4D) contrast enhanced voiding urosonography (ceVUS) versus voiding cystourethrography (VCUG) in children with vesicoureteral reflux. Eur J Radiol 2016; 85:
1238– 1245
[64] Duran C, Riego J, Riere L. Serial voiding urosonography: a safe technique for the study of the entire urinary tract in children. Radiologia 2013; 55:
160– 166
[65] Kmetec A, Bren AF, Kandus A et al. Contrast-enhanced ultrasound void-ing cystography as a screenvoid-ing examination for vesicoureteral reflux in
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
the follow-up of renal transplant recipient: a new approach. Nephrol Dial Transplant 2001; 16: 120– 123
[66] Valentini AL, De Gaetano AM, Minordi LM et al. Contrast-enhanced Voiding US for Grading of Reflux in Adult Patients Prior to Antireflux Ureteral Implantation. Radiology 2004; 233: 35– 39
[67] Kenda RB, Kenig A, Novijan G et al. Cyclic voiding urosonography for detecting vesicoureteric reflux in renal transplant recipients. Nephrol Dial Transplant 2001; 16: 2229– 2231
[68] Jaffer OS, Sidhu PS. Contrast-enhanced ultrasonography of the testes.
Ultrasound Clin North Am 2013; 8: 509– 523
[69] Albrecht T, Lotzof K, Hussain HK et al. Power Doppler US of the normal prepubertal testis: does it live up to its promises? Radiology 1997; 203:
227– 231
[70] Moschouris H, Stamatiou K, Lampropoulou E et al. Imaging of the acute scrotum; is there a place for contrast-enhanced ultrasonography? Int Braz J Urol 2009; 35: 702– 705
[71] Yusuf T, Sellars ME, Kooiman GG et al. Global testicular infarction in the presence of epididymitis. Clinical features, appearances on grayscale, color Doppler, and contrat-enhanced sonography, and histologic corre-lation. J Ultrasound Med 2013; 32: 175– 180
[72] Bilagi P, Sriprasad S, Clarke JL et al. Clinical and ultrasound features of segmental testicular infarction: Six-year experience from a single centre.
Eur Radiol 2007; 17: 2810– 2818
[73] Fernandez-Perez GC, Tardaguila FM, Velasco M et al. Radiologic Findings of Segmental Testicular Infarction. Am J Roentgenol 2005; 184: 1587–
1593
[74] Sriprasad SI, Kooiman GG, Muir GH et al. Acute sgmental testicular in-farction: differentiation from tumour using high frequency colour Doppler ultrasound. Br J Radiol 2001; 74: 965– 967
[75] Bertolotto M, Derchi LE, Sidhu PS et al. Acute segmental testicular in-farction at contrast-enhanced ultrasound: early features and changes during follow-up. Am J Roentgenol 2011; 196: 834– 841
[76] Lung PF, Jaffer OS, Sellars ME et al. Contrast enhanced ultrasound (CEUS) in the evaluation of focal testicular complications secondary to epidiy-mitis. Am J Roentgenol 2012; 199: W345– W354
[77] Patel K, Huang DY, Sidhu PS. Metachronous Bilateral Segmental Testi-cular Infarction: Multi-parametric Ultrasound imaging with Grey-scale Ultrasound, Doppler Ultrasound, Contrast Enhanced Ultrasound (CEUS) and Real-time Tissue Elastography (RTE). J Ultrasound 2014; 17: 233– 238
[78] Bhatt S, Dogra VS. Role of US in testicular and scrotal trauma. Radio-graphics 2008; 28: 1617– 1629
[79] Valentino M, Bertolotto M, Derchi L et al. Role of contrast enhanced ultrasound in acute scrotal diseases. Eur Radiol 2011; 21: 1831– 1840 [80] Lobianco R, Regine R, De Siero M et al. Contrast-enhanced sonography in
blunt scrotal trauma. J Ultrasound 2011; 14: 188– 195
[81] Hedayati V, Sellars ME, Sharma DM et al. Contrast-enhanced ultrasound in testicular trauma: role in directing exploration, debridement and organ salvage. Br J Radiol 2012; 85: e65– e68
[82] Yusuf GT, Konstantatou E, Sellars ME et al. Multiparametric sonography of testicular hematomas. Features on grayscale, color Doppler, and contrast-enhanced sonography and strain elastography. J Ultrasound Med 2015; 34: 1319– 1328
[83] Rafailidis V, Robbie H, Konstantatou E et al. Sonographic imaging of ex-tra-testicular focal lesions: comparison of grey-scale, colour Doppler and contrast-enhanced ultrasound. Ultrasound 2016; 24: 23– 33
[84] Horstman WG, Melson GL, Middleton WD et al. Testicular tumours:
Findings with color Doppler US. Radiology 1992; 185: 733– 737 [85] Bhatt S, Rubens DJ, Dogra VS. Sonography of benign intrascrotal lesions.
Ultrasound Q 2006; 22: 121– 136
[86] Winter TC. There is a mass in the scrotum– what does it mean? Evalua-tion of the scrotal mass. Ultrasound Q 2009; 25: 195– 205
[87] Patel K, Sellars ME, Clarke JL et al. Features of testicular epidermoid cysts on contrast enhanced ultrasound and real time elastography. J Ultra-sound Med 2012; 31: 1115– 1122
[88] Huang DY, Sidhu PS. Focal testicular lesions: colour Doppler ultrasound, contrast-enhanced ultrasound and tissue elastography as adjuvants to the diagnosis. Br J Radiol 2012; 85: S41– S53
[89] Lock G, Schmidt C, Helmich F et al. Early experience with contrast enhanced ultrasound in the diagnosis of testicular masses; a feasibility study. Urology 2011; 77: 1049– 1053
[90] Isidori AM, Pozza C, Gianfrilli D et al. Differential diagnosis of nonpalp-able testicular lesions: qualitative and quantitave contrast-enhanced US
[90] Isidori AM, Pozza C, Gianfrilli D et al. Differential diagnosis of nonpalp-able testicular lesions: qualitative and quantitave contrast-enhanced US