| High intensity focused ultrasound (HIFU), as a noninvasive technology, could focus ultrasonic energy on the target tissue through its focalization and tissular penetrability. The mechanisms of HIFU treatment were thermal and cavitation effects. During HIFU procedure, the temperature on the target rapidly rised to more than 60 ℃in a short time, and irreversible coagulative necrosis occurred. HIFU has been widely used in the treatment of liver cancer, bone tumor, breast tumor or uterine fibroids, currently. However, the HIFU treatment is time consuming. Theoretically, this problem can be solved by enhancing sound intensity or polonging treatmet time, but this may increase the incidence of adverse events (AEs). So a challenge in HIFU applications is how to improve the treatment efficiency safely. Many studies have shown that iodine oil, ultrasound contrast agent (UCA), anhydrous ethanol, liposomes or nanoparticles were effective in enhancing HIFU treatment effects.ObjectivesTo explore the time point of the enhancing treatment effects of HIFU after administration of SonoVue, the mechanism of SonoVue how to improve HIFU ablation efficiency, and the effectiveness and safety of the utilize of SonoVue.Methods1. To explore when to start HIFU can obtain the best ablation effects after administration of SonoVueAccording to the intravenous concentration of SonoVue,51 experimental rabbits were randomly assigned to a control group (HIFU alone),0.03 ml/kg group,0.05 ml/kg group, or 0.07 ml/kg group. Two areas were ablated in each rabbit liver,3 rabbits (6 areas) as a control group were treated by MRI-guided HIFU (MRgHIFU) alone; 48 were treatem using HIFU combined with SonoVue, which were pretreated with 0.03 ml/kg,0.05 ml/kg or 0.07 ml/kg SonoVue received a bolus before HIFU treatment. After 10 s,30 s,60 s,90 s,120 s,150 s,180 s,210 s,250 s,300 s of perfusion, the target was exposed to HIFU for 5 s. The power of 300 W, the depth of 20 mm was setted, each time point of experiment needed repeat at least 3 times, which means more than 30 areas were ablated in each group. Temperatures on the targets were measured by MRI during HIFU procedure, biological focal regions(BFR) were measured after HIFU, and the energy efficiency factors(EEF) were calculated. Histograms of abscissa for time to start HIFU, ordinate for temperature, BFR and EEF were made, to explore when to start HIFU can obtain the best ablation effects after administration of SonoVue. A scatter diagram of abscissa for temperatures, ordinate for necrotic volumes was made.2. To explore the optimal combination of the major factors of HIFU ablated in vivo rabbit liver with SonoVuePower, concentration of SonoVue and the depth of focus away from the surface are the main factors, which influence the treatment effects of HIFU in this experiment, L9 (34) orthogonal experimental design wsa used to explore the influence of BFR by various influence factors under different level combinationC Power:200W,250W,300W; concentration of SonoVue: 0.03ml/kg,0.05ml/kg,0.07ml/kg; irradiation depth:15mm,20mm,25mm). Based on the orthogonal design,9 rabbit liver was ablated by HIFU,the sonication time was setted as 5 s, lmin after administration of SonoVue to start HIFU treatment (obtained from experiment part one). BFRs were measured after HIFU, the largest BFR in the liver was considered as the best. The optimal combination of the sonication power, concentration of SonoVue and sonication depth were selected. The tests were repeated twice to ensure the accuracy of experiments. Histological structures and ultrastructures of target tissues were observed under light and electron microscope.3. To explore the mechanisms of SonoVue in enhancing HIFU ablation effectsUsing power of 300 W, with the same, depth of sonication at 20 mm (obtained from the experiment part two), the sonication time was 5 s,60 s after the administration of SonoVue to start HIFU ablation (obtained from the experiment part one). A passive cavitation detection (PCD) with a 5 MHZ broadband transducer was used to collect transient cavitation signal. The influence of transient cavitation signal in the process of HIFU ablation was observed without using SonoVue or different concentration of SonoVue:0.03 ml/kg,0.05 ml/kg,0.07 ml/kg, cavitation mechanism of SonoVue enhanced efficiency of HIFU was explored. The rate of gray scale changes and the values of gray scale changes were observed without using SonoVue or different SonoVue concentration.4. To explore the optimal treatment method of HIFU combined with SonoVue for uterine fibroidsFrom September 2013 to January 2015,143 patients with a solitary uterine fibroid at a single center were assigned to four groups,30 patients were treated using HIFU alone as a control group,30 patients were pretreated with SonoVue 1 min before HIFU procedure (1 min group),32 were pretreated with SonoVue 3 min before HIFU procedure (3 min group), and 38 were pretreated with SonoVue 5 min before HIFU procedure (5 min group). The rate of massive gray scale changes, the sonication time to reach massive gray-scale changes, nonperfused volume (NPV), fractional ablation, average total energy used, average sonication time, soncation time for 1 cm3 of tiusse volume, energy efficiency factor (EEF) were compared among the four groups, and the optimal treatment method of HIFU combined with SonoVue for uterine fibroids was explored.5. Safety evaluation of HIFU combined with SonoVueFrom November 2010 to December 2013,2604 patients with benign uterine diseases (1663 were uterine fibroids,941 were uterine adenomyosis) were treated with HIFU. Among them,1300 patients were exposed to an UCA, while 1304 patients were not. The intraoperative and postoperative AEs and complications were compared between the two group, and the safety of SonoVue in the process of HIFU was evaluated.Results1. Within the scope of the security, the greater the concentration of contrast agent, the greater the sonication of BFR in the same conditions.The highest temperature, maximum BFR and minimum EEF were obtained when in vivo rabbit livers were pretreated with SonoVue received a bolus 1 min before HIFU procedure. The regression equation between temperatures and necrotic volumes in 0.03ml/kg group,0.05ml/kg group and 0.07 ml/kg group were y= 2.3009x-104.41 (R2= 0.6216), y= 3.2477x-167.74 (R2=0.9113) and y= 4.927x-279.06 (R2= 0.9251), respectively. The optimal degree of fitting was 0.07 ml/kg group.2. Using power of 300 W, SonoVue of 0.07 ml/kg, sonication depth was 20 mm from skin can obtain the largest BFR in rabbit live. The role of the factors palyed:power> sonication depth> concentration of contrast agent. A clear demarcation between the target and normal liver tissue was observed. The targeted tissue was ablated thoroughly, the liver cells in the treated region were damaged, crushed, some cavities were observed in a large area of necrosis tissue under light microscopy; cavities, inflammatory cells and apoptosis bodies were observed under electron microscopy.3. Significant broadband noise were detected both in the control group and experimental group. The RMS baseline values increased with the increase of the contrast agent concentration, and RMS relative values also increased with the increase of the contrast agent concentration, significant differences were observed among the three groups (P< 0.05). When sonication power of 300 W, sonication time of 5 s, SonoVue had no effect on rate of grey-scale changes or grey values.4. The rate of massive grey-scale changes in the three experimental groups were significantly greater than that of the control group, and 1 minute group had the greatest rate(P<0.05). The sonication time to achieve massive grey-scale changes in the three experimental groups were significantly shorter than that of the control group, and 1 minute group had the shortest time (P<0.05). The soncation time for 1 cm3 of fibroid volume, EEF in the three experimental groups were significantly lower than that of the control group, and 1 minute group had the lowest result (P<0.05)5. During HIFU procedure, the incidences of leg pain, sacral/buttock pain, groin pain, treatment area pain, and the discomfort "hot" sensation on skin were higher in the patients who were exposed to SonoVue than those who were not (20.5%vs 11.7%,52.5%vs 42.3%,6.5%vs 4.5%,68.9%vs 55.4%, and 48.1%vs 42.9%, respectively). Among the incidence of postoperative AEs, the rate of lower abdominal pain was significantly higher in patients who were exposed to an UCA than those who were not (51.2%vs 39.9%, P<0.05). Two patients who were exposed to an UCA had acute renal function failure.Conclusion1. SonoVue can significantly enhance the efficiency of HIFU treatment by enhancing thermal effect; 1 min after the administration of SonoVue was the optimal time to start HIFU ablation, the highest temperature increase at the target, the largest BFR and the minimum EEF can be obtained at that time; the synergistic effects were proportional to the concentration of UCA.2. Sonication power, the concentration of UCA and the depth of sonication point can significantly affect the effect of HIFU ablation. Among them, the used power had larger effect than sonication depth, followed by the concentration of UCA. The greater the power, the greater the concentration of UCA, and cooperate with the appropriate irradiation depth can get the optimal BFR volume.3. SonoVue could also improve the efficiency of HIFU ablation by enhancing cavitation effect, the cavitation intensity was proportional to the concentration of UCA, and the cavitation effect palyed a greater contribution to synergy than heat effect.4. SonoVue could be safely used to enhance the ablation effects of HIFU, and 1 min after the administration of SonoVue is the optimal time to start HIFU ablation for benign disease.5. UCA may increase the incidences of some common HIFU-related adverse effects during HIFU treatment for benign uterine diseases, but most of which were acceptable and self-limited. After HIFU treatment, renal function should be monitored in patients with a history of hypertension or taking NSAIDs. At the same time, by hydrating and alkalizing urine to promote the harmful material discharged, and avoid the occurrence of acute renal failure. |
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