We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate with experiments in vivo that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication.bioeffects | contrast agent | vascular disruption | radiosensitization

The aim of this study was to evaluate the immunohistochemical expression of phospho-Akt and its possible association with clinicopathological features in uveal melanoma. Thirty-four enucleated eyes from 34 patients with choroidal melanoma were included in the study. Patients were divided into two groups based on the treatment received: (1) primary enucleation (n=18); (2) radiotherapy, either external beam or brachytherapy, and enucleation (n=16). Clinicopathological data were obtained. The minimum follow-up time was 72 months. Immunohistochemistry for phospho-Akt was performed using an anti-phospho-Akt (Ser 473) rabbit antibody. The association of phospho-Akt with clinicopathological parameters was investigated in each patient group separately. Phospho-Akt immunostaining was cytoplasmic in both groups. In the primary enucleation group, 10 tumours were phospho-Akt positive (55.5%). Patients with phospho-Akt-positive tumours were older (average 70.8 years versus 59 years, P=0.01) and phospho-Akt immunoreactivity was significantly associated with a higher risk of metastatic disease (Kaplan-Meier analysis, P=0.02). In the radiotherapy and enucleation group, nine tumours were phospho-Akt positive (56.2%). The absence of phospho-Akt expression was correlated with male gender (P=0.02). The following conclusions can be drawn from this study: (1) phospho-Akt immunoexpression was detected in 55.5% of uveal melanomas treated with primary enucleation and in 56.2% of uveal melanomas treated with radiotherapy and enucleation; (2) the association of phospho-Akt immunoexpression with clinicopathological features, including prognosis, merits further study.

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