Hubert Parmentier

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.

Thermal ablation produced using a surgical toroidal high-intensity focused ultrasound device is independent from hepatic inflow occlusion

In the liver, the efficacy of radiofrequency or high-intensity focused ultrasound (HIFU) ablation is impaired by blood perfusion. This can be overcome by hepatic inflow occlusion. Here we report the in vivo evaluation of ablations performed in the liver using a surgical toroidal HIFU device used during an open procedure with and without hepatic inflow occlusion. The HIFU device was composed of 256 toroidal-shaped emitters working at 3 MHz and an integrated ultrasound imaging probe working at 7.5 MHz. Using an intermittent Pringle maneuver (IPM), thermal ablations were created in three pigs with hepatic inflow occlusion (IPM group) and in three pigs with normal perfusion (NoIPM group). The ablations were studied on sonograms, macroscopically and microscopically 14 days after the treatment. In the NoIPM group, the average coagulated volume obtained after a 40 s exposure was 7.4 +/- 3.8 cm(3) (2.2-16.6). In the IPM group, the average ablated volume was 6.3 +/- 2.9 cm(3) (2.6-12.1). There was no significant difference between the two groups in terms of ablated volume (p = 0.25), diameter (p = 0.37) or depth (p = 0.61). Therefore, a toroidal-shaped HIFU device allows treatment in the liver that can be considered as independent from hepatic inflow occlusion.

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.

In vivo preclinical evaluation of the accuracy of toroidal-shaped HIFU treatments using a tumor-mimic model

The pig is an ideal animal model for preclinical evaluation of HIFU treatments, especially in the liver. However, there is no liver tumor model available for pigs. In this work, we propose to study an in vivo tumor-mimic model as a tool for evaluating if a sonographycally guided HIFU treatment, delivered by a toroidal-shaped device dedicated for the treatment of liver metastases, is correctly located in the liver. One centimeter tumor-mimics were created in liver tissues. These tumor-mimics were detectable on ultrasound imaging and on gross pathology. Two studies were carried out. First, an in vivo study of tolerance at mid-term (30 days, 10 pigs) revealed that tumor-mimics are suitable for studying HIFU treatments at a preclinical stage, since local and biological tolerances were excellent. The dimensions of the tumor-mimics were reproducible (diameter at day 0: 9.7 +/- 2.0 mm) and were the same as a function of time (p = 0.64). A second in vivo study was carried out in ten pigs. Tumor mimics were used as targets in liver tissues in order to determine if the HIFU treatment is correctly located in the liver. A procedure of extensive HIFU ablation using multiple HIFU lesions juxtaposed manually was then tested on eight tumor-mimics. In 88% of the cases (seven out of eight), tumor-mimics were treated with negative margins (>or=1 mm) in all directions. On average, negative margins measured 10.0 +/- 6.7 mm. These tumor-mimics constitute an excellent reference for studying in vivo the accuracy of HIFU therapy in the liver.

Toric HIFU Transducer for Large Thermal Ablation

A new geometry of High Intensity Focused Ultrasound (HIFU) transducer is described to enlarge the coagulated volume and decrease treatments time. Eight transducer elements and their quarter-wave plate were diced out of a single toric piezocomposite element. Each transducer operates at a frequency of 3 MHz. The focal zone is conic and located at 70 mm from the transducer. A 7.5 MHz ultrasound imaging probe is placed in the centre of the device for guiding the treatment. Optimal exposure parameters were determined from numerical simulations. This new geometry allows achieving a thermal ablation of 7.5 cm3 when each of the eight transducers has performed a 5-s ultrasound exposure alternatively and consecutively. In vivo trials have been performed on five pigs to demonstrate this new principle. 33 elementary lesions have been performed. All lesions were reproducible and homogeneous. The average diameter of an elementary lesion obtained in 40 seconds was 19.5 plusmn 3.8 mm (min 10 - max 29 mm). The coagulated volume obtained in 40 seconds was on average 9.1 plusmn 4.6 cm3 (min 1.5 - max 17.6 cm3).

A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study

To date, the efficacy of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because of the small size of these animals, the lesion produced by HIFU devices has to be small. Thus, the local and systemic effects of the treatment as encountered in humans cannot be studied. The purpose of this study was to use an in vivo tumor-mimic model to evaluate the accuracy of HIFU ablation in the liver in preclinical studies. Tumor mimics were created in in vivo porcine livers by injecting a 1-cc warm mixture of agarose, cellulose, glycerol and methylene blue, which formed 1-cm hyperechoic discrete lesions on sonograms. Three studies were carried out: (i) in vitro experiments were conducted to study the acoustical proprieties of the tumor mimics; (ii) in vivo experiments were conducted in 10 pigs to evaluate the tolerance of the tumor mimics when injected in the liver; (iii) ultrasound- guided HIFU ablation was performed in 10 pigs to demonstrate that it is possible to treat a predetermined zone accurately. It was shown that the acoustical properties of tumor mimics are visible in sonograms and do not modify the shape and dimensions of HIFU lesions. The local and biological tolerance of tumor mimics was excellent. In addition, it was demonstrated that the average difference between the predetermined location of the HIFU ablation and the actual coagulated area was 32%. Therefore, this tumor mimic can be used to teach HIFU ablation before starting clinical studies, especially if the ultrasound device is to be used manually, as the one presented in this study was.

Modèle de pseudotumeur pour guider l’ablation thermique par ultrasons focalisés : étude sur le porc

Resume Il n’existe pas de modele tumoral chez le porc pour etudier les effets des traitements localises par agents physiques des tumeurs du foie. Un modele de pseudotumeur reperable en echographie et macroscopiquement a ete etudie sur 20 porcs a moyen terme pour valider les etudes de therapie par ultrasons focalises au stade preclinique. Les pseudotumeurs ont des dimensions echographiques reproductibles (diametre : 9,6 ± 1,9 mm) et correlees a la mesure sur la piece operatoire (R 2 = 0,73). Une etude de ciblage de la therapie ultrasonore montre que ce modele permet de verifier si la destruction tissulaire observee sur la piece operatoire correspond a la zone ciblee sur l’image echographique.

Comparison of different compression methods for ultrasound elastography in order to detect HIFU ablations in the liver: preliminary in vivo results.

Guiding HIFU treatments using elastic properties of ablated tissues is gaining attention since it is non-invasive and can provide new information. Good-quality elasticity imaging requires highly controlled compressions, which are often challenging to obtain with hand-held devices. Here we report the comparison of 4 compression methods for the detection of HIFU ablations created in the liver during an open procedure. This work was performed in vivo in 4 pigs. HIFU lesions of 20 cm3 were produced in the liver during surgery using a previously validated toroidal HIFU device working at 3 MHz. Ablations were imaged with conventional ultrasound imaging and elastography. A 7.5 MHz sectorial array placed in the centre of the HIFU device was used for elastography. The probe was placed directly on the liver and compression was performed using four different methods: (i) the probe was used to manually exert a periodic pressure on the liver, (ii) the liver was compressed manually between a PVC cylindrical plate (diameter 120mm, height 7mm) and the probe, and (iii) the compression was performed by the probe fixed on a motorized arm. Seven days after the treatment, ablations were imaged again using the same methodology. The resulting images were analyzed and compared by calculating CNRe, SNRe and contrast. Dimension of ablation measured on sonograms and elastograms were compared with the dimensions measured on gross pathology. The mean elastography contrast was similar for each compression method (range: 20.9 – 21.9 dB). The quality of elastograms was also similar for all compression methods, CNRe ranged between 3.12 and 4.28, SNRe ranged between 1.12 and 1.17. The correlation between dimensions measured on elastograms and on gross pathology were higher in the case of elastography obtained by compression with the plate (r = 0.82). In the other cases the correlations were: r = 0.67 for manual compression, and r = 0.62 for motorized compression. Compared with sonograms, all elastography methods shown higher contrast and better estimation of ablation dimensions. Strains generated using hand-held compression with or without a plate produce satisfactory results. However hand-held compression may have broader possible applications.

Preclinical Evaluation of the Accuracy of HIFU Treatments Using a Tumor‐Mimic Model. Results of Animal Experiments

Presented in this paper is a tumor‐mimic model that allows the evaluation at a preclinical stage of the targeting accuracy of HIFU treatments in the liver. The tumor‐mimics were made by injecting a warm mixture of agarose, cellulose, and glycerol that polymerizes immediately in hepatic tissue and forms a 1 cm discrete lesion that is detectable by ultrasound imaging and gross pathology. Three studies were conducted: (i) in vitro experiments were conducted to study acoustical proprieties of the tumor‐mimics, (ii) animal experiments were conducted in ten pigs to evaluate the tolerance of the tumor‐mimics at mid‐term (30 days), (iii) ultrasound‐guided HIFU ablation has been performed in ten pigs with tumor‐mimics to demonstrate that it is possible to treat a predetermined zone accurately. The attenuation of tumor‐mimics was 0.39 dB.cm‐1 at 1 MHz, the ultrasound propagation velocity was 1523 m.s‐1, and the acoustic impedance was 1.8 MRayls. The pigs tolerated tumor‐mimics and treatment well over the experiment...