Microbubble-induced increase in ablation of liver tumors by high-intensity focused ultrasound
Introduction
High-intensity focused ultrasound (HIFU) is used to cause therapeutic coagulation and necrosis [1], [2]. In preliminary clinical studies, HIFU has been shown to be safe and effective against solid tumors, including those of the prostate, liver, breast, kidney, bladder, pancreas, and bone [3], [4], [5], [6], [7]. Especially in the treatment of localized prostate cancer, HIFU is a potential alternative to conventional therapies [8], [9], [10]. HIFU's role in oncology could increase as it becomes more widely available [11], as occurred with the development of noninvasive thermal ablation [12].
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, resulting in more than 500,000 deaths per year [13]. It is usually treated by surgical resection, liver transplantation, percutaneous ethanol injection (PEI), radio-frequency ablation (RFA), or transarterial chemoembolization (TACE) [14], [15], [16]. HIFU may also have a role in treating HCC, because it is only minimally invasive. However, HIFU as it is commonly used has an important disadvantage: adequate treatment of a liver tumor requires necrosis of a 0.5–1.0 cm margin of apparently healthy tissue adjacent to the tumor, but the extent of necrosis caused by a single HIFU exposure is so small that ablating a clinically adequate volume of liver-tumor tissue would require hundreds of exposures [17]. To overcome this disadvantage, we developed a more efficient method of HIFU exposure by using microbubbles.
In ultrasound imaging of liver tumors, microbubbles are used as contrast agents. They are used, for example, to characterize and evaluate responses to treatment after TACE, RFA and HIFU [18], [19], [20], [21]. Attention has recently been drawn to the interaction between ultrasound and the dynamic behavior of microbubbles [22], [23], [24]. Theoretically, microbubbles can change the acoustic properties of tissues and can cause ultrasound energy to be deposited more efficiently. Intravenously infused microbubbles can increase the efficiency of HIFU in the kidneys or livers of healthy rabbits [25], [26] but we know of no previous study of the effects of microbubbles on HIFU-induced coagulation of liver tumors.
We induced liver tumors in rats by injecting diethylnitrosamine, and exposed the tumors (in vivo) to HIFU. Then we studied the echogenicity of the affected areas and the amount of tissue that had been coagulated.
Section snippets
Animal model of liver cancer
Male Wister rats weighing 80–100 g were purchased from Nihon-Seibutu-Zairyo (Tokyo, Japan). To induce liver carcinogenesis, dimethylnitrosamin (DEN, Nacalai Tesque Co., Kyoto, Japan) was administrated at 100 ppm through the drinking water ad libitum. Every 2 weeks, the rats were anesthetized with 40 mg/kg sodium pentobarbital (Nembutal, North Chicago, IL, USA) and their livers were examined by transcutaneous gray-scale ultrasonography (12-MHz probe, M2540A EnVisor, Philips Medical Systems,
Tumors induced by DEN
Tumors developed in all rats after 8–12 weeks of DEN administration. Macroscopically, the tumors were irregularly shaped, white nodules (Fig. 2A).
Microscopically, multifocal nodules of moderately differentiated hepatocellular carcinoma (HCC) were seen. The nuclei were abnormally large, with coarse chromatin and conspicuous nucleoli. The cells had high nuclear/cytoplasmic ratios. The cells were arranged chiefly in a trabecular manner, and a pseudo-glandular structure was occasionally observed.
Discussion
The volume of liver-tumor tissue ablated by HIFU was about 4.5 times greater in the rats that had received Levovist™ than in those that had received saline. This finding is consistent with previous reports of the effects of microbubbles on tissue coagulation by HIFU [25], [26]. HIFU has been used in combination with low-dose radiotherapy to treat rectal carcinoma, with some success [30], and injecting microbubbles before HIFU might be useful in treating HCC.
Microbubble agents may be delivered
Acknowledgement
This study was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture, and Technology of Japan.
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