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Simple Summary  The incidence of hepatocellular carcinoma (HCC) has consistently increased over the last two decades. Although surgical resection is the preferred treatment for HCC, approximately 80% of the patients are not suited for surgery because the tumors are in advanced stage of the disease and unresectable. Locoregional therapies like anti-vascular ultrasound (AVUS) provide a unique alternative for treatment. In this study we evaluate the use of repeated subsequent AVUS therapy as an approach to optimize the therapeutic efficacy by targeting tumor vasculature at different times. This approach can overcome the heterogeneity in tumor vasculature structure and functionality often observed at time of therapy. For this purpose, we evaluated two regiments of subsequent AVUS treatments with a predetermined time interval between the treatments. The results showed that AVUS when applied subsequently in a shorter duration, boosts the therapy effects showing more than 75% reduction in tumor perfusion post therapy. However, this improvement was lost for a longer duration between subsequent therapies. These findings demonstrate the significance of the viability of tumors for maximizing the therapeutic effects of tumor vasculature targeting therapies.    Abstract  The response of hepatocellular carcinoma (HCC) to anti-vascular ultrasound therapy (AVUS) can be affected by the inherent differences in tumor vascular structure, and the functionality of tumor vessels at the time of treatment. In this study, we evaluate the hypothesis that repeated subsequent AVUS therapies are a possible approach to overcome these factors and improve the therapeutic efficacy of AVUS. HCC was induced in 30 Wistar rats by oral ingestion of diethylnitrosamine (DEN) for 12 weeks. A total of 24 rats received treatment with low intensity, 2.8 MHz ultrasound with an intravenous injection of microbubbles. Treated rats were divided into three groups: single therapy group (ST), 2-days subsequent therapy group (2DST), and 7-days subsequent therapy group (7DST). A sham control group did not receive ultrasound therapy. Tumor perfusion was measured by quantitative contrast-enhanced ultrasound (CEUS) nonlinear and power-Doppler imaging. Tumors were harvested for histologic evaluation of ultrasound-induced vascular changes. ANOVA was used to compare the percent change of perfusion parameters between the four treatment arms. HCC tumors treated with 2DST showed the largest reduction in tumor perfusion, with 75.3% reduction on average for all perfusion parameters. The ST group showed an average decrease in perfusion of 54.3%. The difference between the two groups was significant  p  < 0.001. The 7DST group showed a reduction in tumor perfusion of 45.3%, which was significant compared to the 2DST group ( p  < 0.001) but not different from the ST group ( p  = 0.2). The use of subsequent targeted AVUS therapies applied shortly (two days) after the first treatment enhanced the anti-vascular effect of ultrasound. This gain, however, was lost for a longer interval (1 week) between the therapies, possibly due to tumor necrosis and loss of tumor viability. These findings suggest that complex interplay between neovascularization and tumor viability plays a critical role in treatment and, therefore, must be actively monitored following treatment by CEUS for optimizing sequential treatment.

Subsequent Ultrasound Vascular Targeting Therapy of Hepatocellular Carcinoma Improves the Treatment Efficacy