Prostate Ablation By Combining Microbubble Enhanced Ultrasound And Prothrombin

BackgroundBenign prostatic hyperplasia （BPH） is a common disease in aging men. The goldstandard for treatment of BPH is transurethral resection of prostate （TURP）, which is aneffective and also an invasive operation with associated surgical risks. Many minimallyinvasive therapeutic methods have been developed over the past decade. However, theseminimally invasive methods are inferior to TURP due to limited relief of urodynamicobstruction. So an effective and less-invasive method for BPH treatment is desirable.BPH develops mainly in the inner gland of prostate. Contrast enhanced ultrasound（CEUS） has confirmed that the contrast enhancement of the inner gland was much strongerthan that of the outer gland.Acoustic cavitation is a major physical effect of ultrasound. When bubble collapsesduring cavitation, it can produce transient intense local heating, high pressures,microstream, shock wave and light emission, etc. Previous studies have demonstrated thatmicrobubble ultrasound contrast agent is able to increase the possibility of acousticcavitation and cavitation-related vascular damage effects. At high acoustic pressureamplitude, microbubble-enhanced ultrasound （MEUS） can make severe mechanical damageto endothelium of capillaries or small vessels and result in single vessel occlusion with thehelp of intravascular injection of thrombin. Studies have showed that the microvasculatureof rat Walker-256tumor can be mechanically disrupted by MEUS at a low acousticintensity because the tumor angiogenesis is a defective and vulnerable target forintravascular acoustic cavitation. So, it is also possible to destruct the microvasculature ofBPH using MEUS.ObjectivesTo investigate the ablative ability of combining microbubble enhanced ultrasound andprothrombin （PMEUS） on canine prostate and corresponding mechanism.Materials and Methods 1. Materials①Therapeutic ultrasound device: Thedevice was connected to a weak focusedtransducer with a16cm of radius of curvature. It was operated at the frequency of831kHzwith the peak acoustic pressure of4.3MPa and a duty cycle of0.5%.②Microbubble: Zhifuxian, a lipid-coated microbubble, was used for the nucleation ofacoustic cavitation as well as the contrast agent of CEUS. They have a mean particlediameter of2um with98%of the particles less than8um and a bubble concentration of4-9×10¹⁰/mL.③D iagnostic ultrasound system: Siemens Acuson S2000operating with a9L4probeand contrast imaging function.2. MethodsAnesthesia was induced in twenty male mongrel dogs by intravenous injection of3%sodium pentobarbital at1.0ml/kg. Then the prostate of the animal was surgically exposed.Prior to treatment, CEUS was performed directly on all the exposed prostates. Then HumanProthrombin Complex at20IU/kg was intravenously infused in all animals. In the PMEUSgroup, ten prostates were directly contacted and insonated for10min using therapeuticultrasound with intravenous injection of microbubble at0.1mL/kg. The microbubbles werereplaced by10mL saline in the PTUS group. Sham ultrasound exposure was applied in theprothrombin group with10mL saline injection. After treatment, CEUS was performed onthe prostates again at post0min,30min and60min time points. CEUS quantification wasanalyzed directly in diagnostic ultrasound system. Then three animals in every group wereeuthanized and the prostates were harvested for pathological examination.Another12male mongrel dogs were divided into3groups using the same treatmentprotocols as the above. Each group divided two time points for pathological examination:immediately and48hours after treatment.Results1. Immediately after treatment, the CEUS showed that a significant non-enhanced orpoorly perfused region was formed in treated area in the PMEUS group. Then the contrastenhancement slowly filled in the area but it remained poorly enhanced all through theobservation. The peak value dropped from36.21±5.58%to27.12±6.34%（P <0.05）immediately after treatment. At post30and60min, the peak value was26.27±8.19%（P ＜0.05）and28.91±4.28%（P＜0.05）. The values of area under curve （AUC） alsodisplayed the similar decline as the peak but there were no statistical differences before andafter treatment in the PMEUS group. In the two control groups, the blood perfusion ofprostate after treatment remained homogeneous as before. In the PMEUS group,pathological examination confirmed severe microvascular hemorrhage, hematoma andthrombosis in target area while two control groups showed almost intact prostate withouthemorrhage.2. In the PMEUS group, severe microvascular hemorrhage and thrombosis werediscovered in target area immediately after treatment; Forty-eight hours after treatment, thenormal glandular structure almost disappeared in the treated area. Instead, there was patchyor flaky necrosis and significant and diffused infiltrations of inflammatory cells. But in thetwo control groups, the prostates were presented as normal with above findings.Conclusion1. PMEUS could disrupt the microvasculature of prostate and reduced the bloodperfusion of the target area.2. PMEUS can disrupt the microvasculature of prostate, resulting in partial prostaticnecrosis. This simple and presumably noninvasive therapeutic method might become a newphysical therapy for BPH.