Non-invasive treatment of uterine fibroid by feeding vessel occlusion using HIFU sonication.

本研究的最终目的是利用高强度聚焦超声（HIFU）建立一种无创的血管闭塞治疗子宫肌瘤的方法。为了实现这一目标，我们进行了以下基础研究。1)子宫肌瘤血流量测定；应用微泡溶液Levovist^R治疗子宫肌瘤。通过脉冲间隔时间（0.5、1、3、5秒）测量组织信号强度的增加，并计算血流指数。比较子宫肌瘤与子宫肌层的组织血流指标。结果显示子宫肌瘤的组织血流量低于子宫肌层。2)动脉闭塞动物实验；采用超声对大鼠股深动脉行HIFU。超声持续时间为5秒。通过4300 W/cm^2的HIFU超声实现血流阻断，但在530、1080和2750 W/cm^2的强度下血流得以保留。超声动脉收缩期血流速度在1080和2750 W/cm^2时增加，并与HIFU强度相关。组织学研究表明，暴露于2750和4300 W/cm^2的HIFU下的血管中膜出现空泡变性。注射超声造影剂（Levovist^R）降低了动脉闭塞所需的HIFU强度，因为超声作用下微泡被破坏，对血管内皮产生空化作用，使血管受损。3)阻断肿瘤供血动脉，将皮肤鳞状癌细胞VX2植入日本大白兔右侧股肌内。3周后给予动物HIFU对供血动脉超声（峰值强度4kW/cm^2）。对照组肿瘤体积较超声前明显增大。另一方面，在研究组中，肿瘤体积有增大的趋势，但没有认识到其意义。HE染色显示动脉中膜空泡变性和肿瘤退行性坏死。4)人子宫肌瘤供血动脉闭塞；本研究共纳入6例预定行子宫切除术的子宫肌瘤患者。剖腹手术后应用HIFU。峰值强度分别为2 （n=4）和4 (n=5) kW/cm^2。在HIFU以2 kW/cm^2照射的肌瘤动脉中，HE染色显示动脉中膜有空泡变性，但血流没有停止。4 kW/cm^2的HIFU能成功阻断子宫肌瘤动脉。在这些病例中，HE染色显示中膜和塌陷腔内有强烈的空泡变性。我们的研究已经证明HIFU超声可以实现深动脉闭塞。除此之外，子宫肌瘤的低组织血流量也支持HIFU阻断肿瘤供血可能是子宫肌瘤无创治疗的一种选择。少

The final goal of our study is to develop the non-invasive therapy for uterine fibroid by feeding vessels occlusion using high intensity focused ultrasound (HIFU). As a step for the goal, following basic studies have been conducted.1) Measurement of blood flow to uterine fibroid; A micro bubble solution, Levovist^R, was administrated to the patient of uterine fibroid. Increases in the intensity of signal from the tissue were measured by pulsing interval times (0.5, 1, 3, 5 seconds) and blood flow indices were calculated. The indices of tissue blood flow of uterine fibroids were compared with those of the myometrium. The result showed lower tissue blood flow to uterine fibroid than myometrium.2) Animal experiments for artery occlusion; HIFU was sonicated to deep femoral arteries of Sprague Dawley rats. Duration of sonication was 5seconds. Blood flow occlusion was accomplished by HIFU sonication at 4300 W/cm^2, but the flow was preserved with intensities at 530, 1080 and 2750 W/cm^2. Pea … More k systolic velocity of blood flow increased in sonicated arteries with HIFU at 1080 and 2750 W/cm^2 and correlated with HIFU intensity. Histological studies have demonstrated vacuolar degeneration in tunica media of the vessels exposed to HIFU at 2750 and 4300 W/cm^2. Injecting ultrasound contrast agents (Levovist^R) decreased the HIFU intensity required for arterial occlusion, because microbubbles were destroyed under ultrasound sonication and exerted a cavitation effect on the vessel endothelium, which would damage blood vessels.3)Reducing effect of tumor by occlusion of the tumor feeding artery, VX2 (dermatological squamous cancer cell) was implanted in the right femoral muscles of Japanese White rabbits. After 3 weeks, animals were provided to experiment of HIFU sonication to feeding arteries (Peak intensity; 4kW/cm^2). In the control group, the tumor volume increased significantly in comparison with before HIFU sonication. On the other hand, in the study group, the tumor volume showed a tendency to increase, but the significance was not recognized. HE staining revealed vacuolar degeneration in the tunica media of the artery and degenerative necrosis in the tumor.4) Occlusion of the human uterine fibroid feeding artery; A total of 6 patients with uterine fibroids, who had been scheduled for hysterectomy were enrolled in this study. HIFU was applied after laparotomy. Peak intensities were 2 (n=4) and 4 (n=5) kW/cm^2. In those fibroid arteries to which HIFU had been applied at 2 kW/cm^2, the HE stain revealed a vacuolar degeneration in the tunica media of the artery, although cessation of blood flow was not accomplished. The uterine fibroids artery could be successfully occluded by HIFU at 4 kW/cm^2 in two cases out of five. In these cases, the HE stain revealed strong vacuolar degeneration in the tunica media and collapsed cavity. It has been demonstrated by our study that HIFU sonication can achieve the occlusion of deep arteries. Additionally to this fact, low tissue blood flow to uterine fibroid also support that, occlusion of tumors' feeding by HIFU may be an option for non-invasive therapy for uterine fibroid. Less