Sabrina Chesnais

Experimental evaluation of lesion prediction modelling in the presence of cavitation bubbles: Intended for high-intensity focused ultrasound prostate treatment

The accuracy of high-intensity focused ultrasound (HIFU) lesion prediction modelling was evaluated for a truncated spherical transducer designed for prostate cancer treatment. The modelling adapted the bio heat transfer equation (BHTE) to take into account the activity of cavitation bubbles generated during HIFU exposure. This modelling was used to predict the lesions produced by three different transducer geometries: fixed-focus, concentric-ring and 1.5D phased-array. Lesions were predicted for different ultrasound exposure conditions close to those used in prostate cancer treatment. Twenty-onein vitro and ninein vitro experiments were performed on pig liver to validate the accuracy of the predictions. A good match was found between the predicted and experimental lesion shapes. Lesion dimensions (maximum depth and length, area at the centre of the lesion or central surface area) were measured on experimental and predicted lesions. The central surface area was predicted by the model with a range of error of 0.15–6.5% forin vitro tests and 0.97–9%in vivo. For comparison, BHTE without bubbles had a range of error of 0.4–55.5% (in vitro) and 9–25.5% (in vivo). The model should be accurate enough to predict HIFU lesions under ultrasound exposure conditions used in prostate cancer treatment.

THERMAL ABLATION BY HIGH-INTENSITY-FOCUSED ULTRASOUND USING A TOROID TRANSDUCER INCREASES THE COAGULATED VOLUME. RESULTS OF ANIMAL EXPERIMENTS

Surgical resection is the only treatment of colorectal liver metastases that can ensure long-term survival and cure in some patients. However, only 20% of patients are suitable for surgery. As a result, many nonresectional modalities of treatment have been assessed to provide an alternative to liver resection. Several limitations have been observed when using these techniques and available evidence is limited. Here, we report that a new design of high intensity focused ultrasound transducer can significantly enlarge the coagulated volume over short periods of time and that treatment in the liver can be guided in real-time using an integrated ultrasound imaging probe. Our long-term objective is to develop a device that can be used during surgery for eventual clinical use in conjunction with resection. Eight ultrasound emitters, divided into 256 elements, were created by sectioning a single toroid piezocomposite transducer. The focal zone was conical in shape and located 70 mm from the transducer; enabling the treatment of deep-seated tumors. A single thermal lesion was created when the eight emitters performed alternative and consecutive 5-s ultrasound exposures. This article presents in vivo evidence that the coagulated volume obtained from a 40 s total exposure in the liver was 7.0 +/- 2.5 cm(3) (minimum 1.5 - maximum 20.0 cm(3)) with an average diameter of 17.5 +/- 3.8 mm (minimum 10.0 - maximum 29.0 mm). All lesions were visible with high contrast on sonograms. The correlation between the diameter of lesions observed on sonograms and during gross examination was 92%. This method also allowed the user to easily enlarge the coagulated volume by juxtaposing single lesions. This approach may have a role in treating unresectable colorectal liver metastases and may also be used in conjunction with resection to extend its limits.

Ultrasound surgery with a toric transducer allows the treatment of large volumes over short periods of time

Thermal ablation by physical agents is widely used in clinical settings, but it generally results in a small coagulated volume. Here, we report that a technologically advanced high intensity focused ultrasound transducer can significantly enlarge the coagulated volume over short periods of time. Eight ultrasound emitters were created by sectioning a single toric piezocomposite transducer. A single thermal lesion is created when the eight emitters perform alternative and consecutive 5s ultrasound exposures. This paper presents in vivo evidence that the coagulated volume obtained from a 40s total exposure in the liver was 8.6±4.8cm3.

Synergistic inhibitory effect of high-intensity focused ultrasound combined with chemotherapy on Dunning adenocarcinoma

To evaluate the therapeutic effect of high‐intensity focused ultrasound (HIFU) combined with chemotherapy (paclitaxel + estramustine) on AT2 Dunning adenocarcinoma, as no satisfactory treatment for localized prostate cancer is available for patients with a poor prognosis, e.g. stage T3, a high Gleason score, or a prostate‐specific antigen level of >15 ng/mL.

Utility of a Tumor-Mimic Model for the Evaluation of the Accuracy of HIFU Treatments. Results of In Vitro Experiments in the Liver

Presented in this article is a tumor-mimic model that allows the evaluation, before clinical trials, of the targeting accuracy of a high intensity focused ultrasound (HIFU) device for the treatment of the liver. The tumor-mimic models are made by injecting a warm solution that polymerizes in hepatic tissue and forms a 1 cm discrete lesion that is detectable by ultrasound imaging and gross pathology. First, the acoustical characteristics of the tumor-mimics model were measured in order to determine if this model could be used as a target for the evaluation of the accuracy of HIFU treatments without modifying HIFU lesions in terms of size, shape and homogeneity. On average (n = 10), the attenuation was 0.39 +/- 0.05 dB.cm(-1) at 1 MHz, the ultrasound propagation velocity was 1523 +/- 1 m.s(-1) and the acoustic impedance was 1.84 +/- 0.00 MRayls. Next, the tumor-mimic models were used in vitro in order to verify, at a preclinical stage, that lesions created by HIFU devices guided by ultrasound imaging are properly positioned in tissues. The HIFU device used in this study is a 256-element phased-array toroid transducer working at a frequency of 3 MHz with an integrated ultrasound imaging probe working at a frequency of 7.5 MHz. An initial series of in vitro experiments has shown that there is no significant difference in the dimensions of the HIFU lesions created in the liver with or without tumor-mimic models (p = 0.3049 and p = 0.8796 for the diameter and depth, respectively). A second in vitro study showed that HIFU treatments performed on five tumor-mimics with safety margins of at least 1 mm were properly positioned. The margins obtained were on average 9.3 +/- 2.7 mm (min. 3.0 - max. 20.0 mm). This article presents in vitro evidence that these tumor-mimics are identifiable by ultrasound imaging, they do not modify the geometry of HIFU lesions and, thus, they constitute a viable model of tumor-mimics indicated for HIFU therapy.

New integrated imaging high intensity focused ultrasound probe for transrectal prostate cancer treatment.

The present study proposes a new integrated imaging (II) high-intensity focused ultrasound (HIFU) probe intended as an improvement to the Ablatherm prostate cancer treatment. Because of a perforation in the center of the II probe, the expected lesion differs from the one obtained for the original Ablatherm probe. In this paper, the new geometry and the strategy followed to establish the treatment parameters are presented. The original probe has a 40-mm focal length, a 50-mm aperture and is truncated at 31 mm. The II probe has a 45-mm focal length, a 61-mm aperture, a central perforation of 25 mm and is truncated at 31 mm. Both probes operate at 3 MHz. A mathematical model for lesion prediction was used for setting the treatment parameters for the II probe. These parameters should ensure equivalence between the lesions obtained with the original and II probes. Simulation-obtained parameters were validated by in-vitro and in-vivo (on liver of 70 New Zealand rabbits) experiments. The new II probe was used clinically to treat 30 patients. The mean age was 70.9 +/- 5.3 years (SD), the mean prostate volume 26.9 +/- 7.7 mL and the mean serum prostate specific antigen (PSA) concentration before treatment was 9.2 +/- 5.5 ng/mL. Simulations showed that for the II probe acoustical power and duration when the transducer is inactive should be reduced of 14% and 1s. In-vitro and in-vivo experiments confirmed the equivalence between the lesions obtained with the two probes. The lesion volume obtained under in-vitro conditions (for a traversed tissue depth of 16 mm to the focus) was 5 +/- 0.4 cm(3) and 5.1 +/- 0.5 cm(3) for the original and II probes, respectively. Under in-vivo conditions, the lesion volume (for a traversed tissue depth of 18 mm) was 5.3 +/- 1.1 cm(3) and 5.1 +/- 1.1 cm(3) for the original and II probes, respectively. During the clinical trial, a correction of + 1s in the exposure time was required to recreate the same degree of efficacy observed with the original probe (p = 0.97): 66.7 % of negative biopsies and 75% of patients with PSA at 3 mo < or =1 ng/mL. The morbidity observed was minimal and identical to that observed with the original probe.

Feasibility study of cavitation-induced liposomal doxorubicin release in an AT2 Dunning rat tumor model.

Background: Targeted and triggered release of liposomal drug using heat or ultrasound represents a promising treatment modality able to increase the therapeutic-totoxicity ratio of encapsulated drugs. Purpose: To study the ability for high-intensity focused ultrasound to induce liposomal drug release mainly by focused inertial cavitation in vitro and in an animal model. Methods: A 1 MHz ultrasound setup has been developed for in vitro and in vivo drug release from a specific liposomal doxorubicin formulation at a target cavitation dose. Results: Controlled cavitation at 1 MHz was applied within the tumors 48 hours after liposome injection according to preliminary pharmacokinetic study. A small non-significant therapeutic effect of US-liposomal treatment was observed compared to liposomes alone suggesting no beneficial effect of ultrasound in the current setup. Conclusion: The in vitro study provided a suitable ultrasound setup for delivering a cavitation dose appropriate for safe liposomal drug release. However, when converting to an in vivo model, no therapeutic benefit was observed. This may be due to a number of reasons, one of which may be the difficulty in converting in vitro findings to an in vivo model. In light of these findings, we discuss important design features for future studies.

Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model

Abstract The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24–48 h post intravenous administration. Animals injected 6 mg kg−1 liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg−1, however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

Impedance changes in liver tissue exposed in vitro to high-energy ultrasound

The present study reports the impedance changes observed in bovine liver samples exposed in vitro to high-intensity ultrasound. The measurement frequency ranged from 80 kHz to 2 MHz. The treatment resulted in the average increase of 20% in impedance magnitude at low frequency and the average decrease of 30% at high frequency. The phase angle increased significantly by more than 15 degrees at all measurement frequencies. The slope of the log-modulus of impedance against log-frequency increased in treated tissue at frequencies above 500 kHz. This change was attributed to the alteration of the capacitive response of the tissue. The experimental observations are consistent with the known changes induced by high-energy ultrasound in liver tissue. This study confirmed that ultrasound energy produces measurable changes in a tissues impedance and that indices can be derived to distinguish between original and treated tissues. The results obtained in liver tissue need confirmation in organs treatable with therapeutic ultrasound, such as breast and prostate.

HIFU and Chemotherapy Synergistic Inhibitory Effect on Dunning AT2 Tumour‐Bearing Rats

Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty‐one Dunning AT2 tumour‐bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU‐chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control gro...