Background: High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment.

This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of distant metastases and to investigate its association with HIFU-elicited anti-tumor immunity in a murine melanoma (B16-F10) model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to differentiate the contribution of the elicited anti-tumor immunity. In mice undergoing amputation immediately after mechanical, thermal, or no HIFU treatment, metastasis rates were comparable (18.8%, 13.3% and 12.5 %). In contrast, with a 2-day delay in amputation, the corresponding metastasis rates were 6.7%, 11.8% and 40%, respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Altogether, our results suggest that HIFU treatment does not increase the risk of distant metastasis. Instead, HIFU treatment can elicit an anti-tumor immune response that may be harnessed to improve the overall effectiveness and quality of cancer therapy. KeywordsHigh intensity focused ultrasound; metastasis; anti-tumor immunity; bioluminescent imaging; melanoma High-intensity focused ultrasound (HIFU) has recently emerged as a promising treatment modality for localized solid malignancies [1]. HIFU therapy has the unique advantage of being noninvasive and easily tolerable by the patient, thus allowing for repeated treatments. Despite this, there has been a long-standing concern regarding whether HIFU-induced mechanical damage may lead to the dissemination of cancer cells into the blood circulation, and thus promoting distant metastasis. Several groups have investigated the potential risk of metastasis induced by HIFU using animal models, but the results are contradictory [2;3;4;5]. Further, a recent clinical study has demonstrated no apparent increase in the number of patients with detectable circulating tumor cells following HIFU treatment, compared to the non-HIFU group [6].In early clinical applications, HIFU therapy was aimed to produce thermal coagulative necrosis of the tumor while avoiding the induction of cavitation bubbles [7]. This is because of the Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods AnimalsC57BL/6 female mice, 5-8 weeks old, were purchased from the Jackson Laboratory (Bar Harbor, ME) and handled in accordance with the established animal care policy. All animal studies were approved by the Duke University Institutional Animal Care & Use Committee. Tumor modelMurine melanoma cell line (B16-F10-Luc-G5) with stably transduced firefly luciferase gene was pur...

Transesophageal echocardiography (TEE) is an essential diagnostic tool in patients with poor transthoracic echocardiographic windows or when detailed imaging of structures distant from the chest wall is necessary. A real-time 3D TEE probe has been fabricated in our laboratory in order to increase the amount of information available during a transesophageal procedure. The 1 cm diameter esophageal probe utilizes a 2-dimensional, 5 MHz array at its tip with a 6.3 mm diameter aperture, including 504 active channels. The array has a periodic vernier geometry with an element pitch of 0.18 mm, built onto a multilayer flexible (MLF) interconnect circuit. In order to accommodate 504 channels within the device, a 1 m long Gore MicroFlat cable was utilized for wiring the MLF to the corresponding system connectors. Pulse-echo tests in a water tank have yielded a -6 dB bandwidth of 25.3%. Fully connected to the system through 3 m of cable, the probe shows an average 50 omega insertion loss of-85 dB with a standard deviation of 4 dB, as determined through pitch-catch measurements for a sampling of 10 elements. Using the completed 3D TEE probe with the Volumetrics Medical Imaging 3D scanner, real-time volumetric images of in vivo canine cardiac anatomy have been acquired, displaying atrial views, mitral valve function and interventional catheter guidance.

Transesophageal echocardiography (TEE) is established as an essential diagnostic tool for patients that are obese or that exhibit signs of pulmonary disease. However, current techniques in transesophageal scanning of the heart are limited by the maneuverability of the esophageal probe as well as by incomplete visualization in close proximity to the transducer. A real-time 3D TEE probe has been fabricated in our laboratory in order to improve on the shortcomings of current TEE devices and increase the amount of information available during a transesophageal procedure. The 8mm diameter endoscope probe utilizes a 2-dimensional, 5MHz array at its tip with a 6.3mm diameter aperture, including 504 active channels. The array has a periodic vernier geometry with an element pitch of 0.18mm, and it was built on a multilayer flexible interconnect circuit (MLF). In order to accommodate 504 channels within the endoscope, 1m long Gore MicroFlat TM cable was utilized for wiring the MLF to the corresponding system connectors. Using the completed 3D TEE probe with the Volumetrics Medical Imaging 3D scanner, real-time volumetric images of in vivo canine cardiac anatomy have been acquired, displaying atrial views, mitral valve function, and catheter guidance.

Abstract-Laparoscopic ultrasound has seen increased use as a surgical aide in general, gynecological, and urological procedures. The application of real-time, threedimensional (RT3D) ultrasound to these laparoscopic procedures may increase information available to the surgeon and serve as an additional intraoperative guidance tool. The integration of RT3D with recent advances in robotic surgery also can increase automation and ease of use. In this study, a 1-cm diameter probe for RT3D has been used laparoscopically for in vivo imaging of a canine. The probe, which operates at 5 MHz, was used to image the spleen, liver, and gall bladder as well as to guide surgical instruments. Furthermore, the three-dimensional (3-D) measurement system of the volumetric scanner used with this probe was tested as a guidance mechanism for a robotic linear motion system in order to simulate the feasibility of RT3D/robotic surgery integration. Using images acquired with the 3-D laparoscopic ultrasound device, coordinates were acquired by the scanner and used to direct a robotically controlled needle toward desired in vitro targets as well as targets in a post-mortem canine. The rms error for these measurements was 1.34 mm using optical alignment and 0.76 mm using ultrasound alignment.