Contrast-Enhanced Ultrasound and Canine Prostates: Comparison
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Ultrasonography is the best imaging technique for real-time assessment of the reproductive organs and pregnancy in both human and veterinary medicine. Among the most advanced ultrasound techniques developed, in recent years, CEUScontrast-enhanced ultrasound (CEUS) is widely applied in reproductive imaging of humans and small animals. CEUS is based on intravenous injection of gas-filled microbubbles that allow real-time ultrasound tracking of the perfusion of tissues by following contrast circulation into the vascular bed. It has been used for the evaluation of canine prostate as an animal model for human medicine, as well as in veterinary medicine. In human medicine studies, it proved useful in assessing prostatic physiological and pathological conditions, like individuation of tumors, and in monitoring the effects of thermal therapy for prostatic carcinoma. In veterinary medicine, CEUS findings weren't specific for the different types of prostatic diseases (e.g., prostatitis vs benign prostatic hyperplasia), except for adenocarcinoma, whilst it worked well in the evaluation of prostatic blood flow. 

  • CEUS
  • contrast-enhanced ultrasound
  • diagnostic imaging
  • reproduction
  • dog
  • prostate

1. Contrast-EUSnhanced Ultrasound in Canine Prostates as an Animal Model

In human medicine, several papers and reviews have been published on the clinical application of contrast-enhanced ultrasound (CEUS) in the discovery, localization, and assessment of treatment for prostate cancer [3,59,60,61,62,63,64,65,66,67][1][2][3][4][5][6][7][8][9][10].
Forsberg et al. [68][11] evaluated transrectal CEUS in a canine prostate cancer model, by implanting canine-transmissible venereal sarcoma (CTVS) cells into the prostate of 24 dogs and then evaluating them by ultrasound at different times (15, 18, 21, 24, and 28 days after tumoral cell inoculation). The protocol for CEUS required IV administration at 1 mL/s of 2–5 injections of a 1% solution of Sonazoid, in dosages of 0.00625 to 0.20 μL of microbubble/kg, at intervals of 10–15 min between injections. Characterization of the prostatic lesions (number, size, location) was determined by transrectal ultrasonography (TRUS) and CEUS. Finally, the dogs were euthanized, and gross histologic examination of the prostate and local lymph nodes was performed. CEUS enabled the individuation of tumors inside the parenchyma and outside the capsule of the prostate, in the rectal wall and close lymph nodes; also, Sonazoid allowed a better visualization of the vascularity of prostatic tumor and delineation of the size and shape of the mass. Indeed, tumors were characterized by tortuous intra-tumoral vessels, with avascular central regions associated with necrosis. Histopathologic examination confirmed the ultrasonographic findings. CEUS was more accurate than conventional TRUS in diagnosing prostate tumors in dogs and allowed the reliable identification of 5-mm tumors. Contrast-enhanced power Doppler TRUS could be useful in showing focal prostatic abnormalities, in providing additional biopsy guidance, and in allowing higher cancer detection rates [68][11]. In any case, the authors did not report any quantitative analysis but only the results of the qualitative evaluation of images through a comparison of CEUS and B-mode images.
In many studies, CEUS for canine prostates was used for monitoring prostatic thermal therapy of prostatic carcinoma in a canine animal model [22,69,70,71,72,73][12][13][14][15][16][17]. It consists in applying high temperatures to neoplastic tissues, which denature and coagulate structural proteins and blood supply, hence determining the death of cells. Tissues can be heated by local application of microwave antennas, radiofrequency ablation (RFA) electrodes, laser fiber optic probes, or high-intensity focused ultrasound transducers [70][14].
Among these techniques, prostate RFA is considered a feasible treatment for prostate cancer [69,72,73][13][16][17]. CEUS has been used as guidance to monitor and control the procedure [22][12], to analyze feasibility and possible ways to improve the technique [69[13][15],71], and to evaluate the outcome of RFA of canine prostate lesions [73][17]. In all these cases, CEUS confirmed its efficacy. Even a comparation between B-mode US, CEUS, and MRI for the study of RFA lesions showed similar results between CEUS and MRI; however, the former has the advantage of being more economical and using more convenient equipment and faster scanning, thus representing the best choice [72][16].
In 2006, CEUS was used as guidance to monitor and control radio frequency (RF) ablation of a canine prostate in an animal model [22][12], with a protocol of a preoperative bolus injection of Sonazoid® (0.04 mL/kg) followed by a 5 mL saline flush, a continuous infusion (0.015 μL/kg at 11 mL/min) during the RF ablation procedure, and then other bolus injections after completing each RF ablation and at the end of the entire ablation procedure. Pulse inversed harmonic (PIHI) CEUS and Doppler CEUS were performed with a transrectal approach. CEUS enabled the visualization of both the normal prostate and the thermal lesions created. PIHI CEUS better differentiated thermal lesions, while power Doppler CEUS showed blooming artifacts that covered thermal lesion areas, hindering their vision. Measurements obtained from contrast-enhanced PIHI had good agreement and good linear correlation with pathological findings. CEUS also allowed the direct visualization of the urethra and neurovascular bundles, minimizing the possibility of damaging these areas [22][12].
In a similar study, Liu et al. [69][13] performed CEUS-guided RFA of a canine prostate with application of urethral and neurovascular bundle (NVB) cooling. Study groups received trans-urethral infusion of cold saline solution, control groups did not. During ablation, transrectal PIHI CEUS was performed, after an intravenous bolus injection (0.04 mL/kg) and infusion (0.015 L/kg/min) of Sonazoid®. PIHI CEUS allowed visualization and monitoring of urethral and NVB blood flow during the ablation. Contrast-enhanced US could successfully guide RF ablation of the entire prostate. In control groups, US and pathology showed damage to the urethra and the NVB, confirming the efficacy of cold in protecting these tissues during this procedure [69][13].
In another animal model, CEUS was used in association with MRI for monitoring prostate microwave focal thermal therapy [70][14]. Seven beagle dogs underwent CEUS and MRI scans before, during, and after microwave heating of the prostate. CEUS was performed by an injection in bolus of Definity® (0.3 mL, then 10 mL saline flush). These exams aimed to accurately evaluate the thermal lesion and to individuate areas of vascular compromission inside the lesion, by comparison with the surrounding normal tissue. The authors found that these techniques may possibly provide indication of damage during and right after the procedure, within 2 h. However, the injury was evident over time after therapy, starting with a peripheric hyperemic rim, which can become necrotic and is therefore a better predictor of damage [70][14].
Hu et al. [71][15] used RFA on healthy canine prostates to create one lesion in each lobe. An amount equal to 2.4 mL of SonoVue boluses were infused, followed by 5 mL of physiologic saline, thus imaging was suddenly performed; immediately after the procedure, all dogs were euthanized to remove the prostate and compare the gross pathology and the histopathology. CEUS was able to detect thermal lesions as areas without vascularization, hypoechoic to surrounding normal parenchyma, with a more precise demarcation than B mode US [71][15].
Feng et al. [72][16] performed CEUS using a bolus of 2.4 mL of the same medium contrast, followed by a 5 mL saline flush to evaluate RFA lesions at different periods of time (7, 30, 90, and 180 days) after the RFA procedure and comparing pathologic results after the dogs’ euthanasia [72][16] Finally, Jia et al. [73][17] used the same technique to create thermal lesion in healthy canine prostates, then they performed B-mode US and CEUS immediately after, 1 week after, and 1 month after [73][17]. The medium contrast (SonoVue) was injected using a 2.4 mL bolus in the forelimb vein, followed by a 5 mL flush of saline solution. After each evaluation, the dogs were euthanized to compare pathologic results. In the three cases, the authors showed a correspondence between the study of lesions by CEUS and the pathologic results, due to the possibility to follow the dynamic process of the range of lesions and the vascularization changes induced by RFA [71,72,73][15][16][17].

2. Contrast-EUSnhanced Ultrasound (CEUS) in Canine Prostatic Evaluation in Veterinary Medicine

A study of prostatic vascularization through the CEUS technique in veterinary medicine was first published in 2001 by Krüger Hagen et al. [74][18] using perfluorobutane microbubbles of Sonazoid® (GE HealthCare), a first-generation contrast agent. The contrast medium was infused through an 18-G angiocatheter placed in a forelimb vein [74][18]. The first dog received doses ranging from 0.0125 to 0.0375 mL microbubbles/kg, and the other dogs received mainly doses of 0.00625 mL micro-bubbles/kg. All dogs received, on average, six injections of Sonazoid. Every injection of Sonazoid was followed by a 10 mL flush of saline solution [74][18]. The authors evaluated prostatic blood flow in five mongrels under general anesthesia. This study compared 3D and 4D ultrasound before and after contrast agent injection, obtaining a better visualization of prostatic blood flow [74][18].
In 2009, Russo et al. [75][19] used a second-generation contrast agent (SonoVue, Bracco Imaging, Milan, Italy) to study the blood flow of normal canine prostates in five anesthetized dogs. After injection (a bolus of 0.03 mL/kg of SonoVue®, followed by a bolus of 5 mL of saline solution), prostatic artery branches were visible in 10–15 s, then the contrast agent spread into the prostatic parenchyma from the dorsolateral surface with a homogeneous enhancement and wash-out phase. Moreover, after SonoVue injection, a stronger Doppler signal compared to the pre-contrast evaluation was evidenced [75][19]. In 2011, Vignoli et al. [32][20] compared perfusion peak intensity (PPI) and time to peak (TTP) values between normal and pathological prostates in dogs. SonoVue® was infused into the cephalic vein at a dose of 0.03 mL/kg, followed by a rapid bolus of 5 mL of saline solution. Through the study of different pathologies (successively confirmed by histological examination), the authors found three different range of values: normal prostate for the dogs with benign prostatic hyperplasia and mixed benign lesions; lower values in dogs with prostatitis and leiomyosarcoma; higher values in dogs with adenocarcinoma. Therefore, the authors concluded that it was not possible to distinguish the different types of prostatic diseases using only the CEUS technique, except for adenocarcinoma [32][20]. Similar results were obtained by Russo et al. (2012) [40][21]. Both studies were conducted in dogs under total anesthesia, differently from the study of Troisi et al. (2015) [30][22], who used contrast agent (a bolus of 0.03 mL/kg of SonoVue® followed by a rapid bolus of 5 mL of saline solution) in non-anesthetized animals [30][22]. Based on their results, benign prostatic hyperplasia can be clinically recognized by a chaotic vascular pattern during the wash-in phase, probably due to simultaneous blood vessel enhancement and the presence of circular avascular areas characterizing prostatic cavitation [30][22]. Similar findings were reported in dogs with prostatitis: in addition to the chaotic vascular pattern during the wash-in phase, there was a significative enhancement during the wash-out phase of the vessels encircling the urethra compared to the surrounding parenchyma [30][22]. Concerning specific vascular patterns of prostatic tumors, adenocarcinoma showed large arteries with a chaotic appearance instead of the normal subcapsular pattern and a general hypoechoic, nodular vascular pattern of the tumors compared to the parenchyma. Lymphoma showed an increased enhancement during the early wash-in phases and a heterogeneous hypoechoic appearance with fine echo pollution of the microcirculation during the wash-out phase [30][22].
A similar study was conducted by Bigliardi and Ferrari, in 2010 [76][23], using a different contrast medium (Levovist, injected by a bolus in the cephalic vein through an 18G catheter at a dose 300 mg/mL, followed by a 15 mL saline flush) [76][23]. All dogs were premedicated with atropine sulfate and acepromazine, then anesthetized by isoflurane administered through a face mask. The authors classified prostatic vascularization as poor, moderate, and good depending on visualized vessels: only prostatic arteries on the dorsolateral surface, capsular vessels under prostatic capsule in close proximity to it, intraprostatic arteries, the small vessels of the parenchyma, and periurethral vessels, respectively [76][23]. In this study, CEUS allowed for the significant improvement of the visualization of prostatic blood flow. Moreover, in prostatic arteries, mean systolic and peak velocity were 38.5 m/s and 15.7 m/s, respectively; mean end-diastolic velocity was 5.9 m/s; the resistive index and pulsatility index values were 0.83 and 2.3, respectively. In capsular arteries, mean systolic and peak velocity were 12.05 m/s and 9.2 m/s, respectively; mean end-diastolic velocity was 4.2 m/s; the resistive index and pulsatility index values were 0.7 and 1.31, respectively [76][23].
Other studies focused the use of CEUS on the prostate of castrated dogs. In 2020, Yoon et al. [77][24] compared the use of ultrasound and CT contrast agent (dose of 0.125 mL/kg via the cephalic vein using a 3-way stopcock and 20-gauge catheter, followed by a bolus of 5 mL of saline) in dogs with normal prostates against those with benign hypertrophic prostates and castrated dogs. The results of normal and hypertrophic prostates were in line with previously described works [30,32,58,76][20][22][23][25]. In castrated dogs, the authors found similar enhancement patterns 15 and 30 days after castration and slower wash-in and wash-out phases associated with a marked peak intensity, leading to a significantly reduced peak intensity 60 days after surgery [77][24]. Another study focused on the follow-up of prostatic blood flow in castrated dogs for at least 6 months, using a bolus of 0.03 mL/kg of SonoVue® followed by a rapid bolus of 5 mL of saline solution [78][26]. In contrast to the previous work [77][24], the authors found a significantly higher PPI in castrated dogs than in intact dogs and a similar TTP [78][26].

References

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