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      Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response

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          Abstract

          Background

          High-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth.

          Methods

          A total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature.

          Results

          Tumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited.

          Conclusions

          Our findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

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          Most cited references 45

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          High-intensity focused ultrasound in the treatment of solid tumours.

           E. Kennedy (2005)
          Traditionally, surgery has been the only cure for many solid tumours. Technological advances have catalysed a shift from open surgery towards less invasive techniques. Laparoscopic surgery and minimally invasive techniques continue to evolve, but for decades high-intensity focused ultrasound has promised to deliver the ultimate objective - truly non-invasive tumour ablation. Only now, however, with recent improvements in imaging, has this objective finally emerged as a real clinical possibility.
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            Vascular targeting agents as cancer therapeutics.

             Karen Thorpe (2004)
            Vascular targeting agents (VTAs) for the treatment of cancer are designed to cause a rapid and selective shutdown of the blood vessels of tumors. Unlike antiangiogenic drugs that inhibit the formation of new vessels, VTAs occlude the pre-existing blood vessels of tumors to cause tumor cell death from ischemia and extensive hemorrhagic necrosis. Tumor selectivity is conferred by differences in the pathophysiology of tumor versus normal tissue vessels (e.g., increased proliferation and fragility, and up-regulated proteins). VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. Preclinical studies have shown VTA-induced enhancement of the effects of conventional chemotherapeutic agents, radiation, hyperthermia, radioimmunotherapy, and antiangiogenic agents. There are broadly two types of VTAs, small molecules and ligand-based, which are grouped together, because they both cause acute vascular shutdown in tumors leading to massive necrosis. The small molecules include the microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and Oxi 4503, and the flavonoid, DMXAA. Ligand-based VTAs use antibodies, peptides, or growth factors that bind selectively to tumor versus normal vessels to target tumors with agents that occlude blood vessels. The ligand-based VTAs include fusion proteins (e.g., vascular endothelial growth factor linked to the plant toxin gelonin), immunotoxins (e.g., monoclonal antibodies to endoglin conjugated to ricin A), antibodies linked to cytokines, liposomally encapsulated drugs, and gene therapy approaches. Combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and DMXAA are undergoing clinical evaluation. Phase I monotherapy studies have shown that the agents are tolerated with some demonstration of single agent efficacy. Because efficacy is expected when the agents are used with conventional chemotherapeutic drugs or radiation, the results of Phase II combination studies are eagerly awaited.
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              Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients.

              This work evaluated the clinical feasibility of transcranial magnetic resonance imaging-guided focused ultrasound surgery. Transcranial magnetic resonance imaging-guided focused ultrasound surgery offers a potential noninvasive alternative to surgical resection. The method combines a hemispherical phased-array transducer and patient-specific treatment planning based on acoustic models with feedback control based on magnetic resonance temperature imaging to overcome the effects of the cranium and allow for controlled and precise thermal ablation in the brain. In initial trials in 3 glioblastoma patients, multiple focused ultrasound exposures were applied up to the maximum acoustic power available. Offline analysis of the magnetic resonance temperature images evaluated the temperature changes at the focus and brain surface. We found that it was possible to focus an ultrasound beam transcranially into the brain and to visualize the heating with magnetic resonance temperature imaging. Although we were limited by the device power available at the time and thus seemed to not achieve thermal coagulation, extrapolation of the temperature measurements at the focus and on the brain surface suggests that thermal ablation will be possible with this device without overheating the brain surface, with some possible limitation on the treatment envelope. Although significant hurdles remain, these findings are a major step forward in producing a completely noninvasive alternative to surgical resection for brain disorders.
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                Author and article information

                Contributors
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central
                1479-5876
                2012
                11 November 2012
                : 10
                : 221
                Affiliations
                [1 ]Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan
                [2 ]Department of Hepatogastroenterology, Chang-Gung Memorial Hospital, Taoyuan, Taiwan
                [3 ]Animal Medicine Center, National Taiwan University, Taipei, Taiwan
                Article
                1479-5876-10-221
                10.1186/1479-5876-10-221
                3543346
                23140567
                20759b72-0779-4b52-928c-bdb004b6d676
                Copyright ©2012 Liu et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research

                Medicine

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