This work was partly funded by the LYriCAN (INCa-DGOS-Inserm_12563). The authors acknowledge the Claude Bernard University Lyon 1 for the award of the Antonin Poncet prize for work related to this study. The authors gratefully acknowledge the willing participation of the patients involved, EDAP-TMS, the role of the Steering committee (Dominique Elias, Olivier Rouviere, Alain Sezeur, Fr&#233;d&#233;ric Marchal), which consisted of responsibility for deciding on the continuation of the study after an interim analysis, as well as Jean-Yves Scoazec for pathological examination.

The protocol was reviewed and validated by a national ethics committee according to French and European directives, with written consent from the patients.
1. Inclusion
<ol>
	<li>Include patients with resectable CLM and a good clinical condition (Eastern Cooperative Oncology Group ECOG/World Health Organization WHO performance status 0-1) who are at least 18 years old. Obtain written consent from the patients.</li>
	<li>Exclude patients with previous liver, biliary, or major abdominal surgery, pregnancy, or an inability to be followed for the duration of the study.</li>
</ol>
2. HIFU Treatment
<ol>
	<li>Perform the anesthesia of the patient with an induction composed of propofol (2 to 3 mg/kg), sufentanil (0.2 to 0.3 &#181;g/kg), cisatracurium (0.15 mg/kg) and ketamine (0.15 mg/kg).</li>
	<li>Maintain anesthesia with sevoflurane to target a bispectral index between 40 and 60.</li>
	<li>Perform tracheal intubation, with the lungs mechanically ventilated with inspired oxygen fraction of 80%.</li>
	<li>Prepare the HIFU device in the operating room by covering the sterilized HIFU probe with the dedicated sterile envelope containing a sterile ultrasound coupling liquid (Figure 1). 
	NOTE: The HIFU probe was sterilized using a low-temperature gas plasma sterilizer.</li>
	<li>Perform laparotomy using a monopolar knife after classic surgical asepsis.</li>
	<li>Place the retractors under the rib cage and between the edges of the surgical incision.</li>
	<li>Confirm liver resection by exploring the liver using intraoperative diagnostic ultrasound images with a 7.5 MHz T-type transducer and palpation to confirm that no additional metastasis compromising the resection was missed with preoperative imaging22.</li>
	<li>Free the liver from its peritoneal and vascular attachments with scissors.</li>
	<li>Place a protective abdominal gauze sponge (20 x 20 cm2) with X-ray detectable threads under the targeted area to inhibit ultrasound propagation and unintended HIFU damage to adjacent organs.</li>
	<li>Bring the HIFU probe in contact with the liver surface (Figure 2).</li>
	<li>Move the HIFU probe on the surface of the liver until the position of the expected HIFU ablation (represented by the white cone superimposed on the sonogram) is at the right location according to the objectives of the different phases (Figure 3a).</li>
	<li>Activate the HIFU exposure by activating each emitter with the same phase for 40 s. Apply an acoustic power of 70 W (free-field acoustic power) for superficial ablations and 90 W (free-field acoustic power) for in-depth lesions.
	<ol>
		<li>Ultrasound images were not synchronized with HIFU exposures and, therefore, interferences were visible in sonograms during ablations. Observe that boiling is created in liver tissues treated during HIFU single exposures. Note that a cloud of ebullition appears momentarily for 1 min at the location of the lesion (Figure 3b). 
		NOTE: The single lesion appears on the sonogram as a hyperechoic zone at its center and a hypoechoic zone at its boundaries (Figure 4a).</li>
	</ol>
	</li>
	<li>Mark the position of the HIFU probe, mainly the acoustic axis at the surface of the liver, using a surgical marker, to know where to cut the liver for gross examination (Figure 2).</li>
	<li>Measure the dimensions of the HIFU ablations along two orthogonal planes after each HIFU exposure, using the integrated ultrasound imaging probe.</li>
	<li>Move the HIFU probe on the liver surface to confirm that all eight liver segments can be covered, irrespective of their conformation in the individual patient.</li>
</ol>
3. Macroscopical and Histological Evaluation of HIFU Lesions
<ol>
	<li>Perform the planned liver resection using a Kelly clamp to crush the liver parenchyma and a scissor to cut the liver. Perform hemostasis with titanium clips and/or irrigating bipolar forceps.</li>
	<li>Close the aponeurosis with monofilament, long-lasting absorbable N&#176; 0 or N&#176; 1 suture material.</li>
	<li>Close the skin with uncolored, short-term absorbable N&#176; 3/0 suture material.</li>
	<li>Give the patient oral acetaminophen (1 g every 6 h). 
	NOTE: Nausea and vomiting were treated with 4 mg of intravenous ondansetron. Oral fluids and feeding were started on the day after surgery. Morphine was given to obtain a pain visual analogic scale under 30/100.</li>
	<li>Separate the HIFU ablations and areas of CLM with a scalpel.</li>
	<li>Cut the ablations along the exposure axis with a scalpel.</li>
	<li>Take pictures of the HIFU ablations.</li>
	<li>Measure the dimensions of the ablated area macroscopically with a ruler and on a photograph, using appropriate image analysis software.</li>
	<li>Slice each ablation into 5 mm sections to assess macroscopic homogeneity.</li>
	<li>Fix the ablated areas in 10% phosphate-buffered formalin (pH = 7), embed them in paraffin, and stain them with hematoxylin and eosin.</li>
	<li>Histologically examine the ablated and surrounding tissues.</li>
</ol>
4. Follow-up
<ol>
	<li>Follow the patients for one month according to the institution&#8217;s guidelines for patients resected for CLM.</li>
	<li>Summarize data regarding demographic characteristics, vital signs (baseline and 5 min after HIFU), and safety observations and measurements regarding the HIFU lesions.</li>
	<li>Use Spearman&#8217;s rank correlation coefficient to test the association between variables.</li>
</ol>

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The authors have nothing to disclose.

The aim of this study was to confirm the feasibility, safety, and efficacy of a new intraoperative HIFU device. As this was its first use in humans, an ablate-and-resect study was designed in order to verify the ability of the device to create complete ablation and accurate targeting without compromising the chance of potentially curative therapy for patients. In total, 30 HIFU ablations were safely created in 15 patients, each within 40 s. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2. There was no secondary lesion in neighboring organs. Importantly, the shape of the HIFU ablations was not altered by the major blood vessels (up to 5 mm in diameter). This is of particular importance since it has been reported that blood flow plays a pivotal role in thermal ablation by limiting the ablation size and altering ablation shape23. Another important advantage of this intraoperative HIFU device when compared with ablations performed using radiofrequency or microwaves is that there is no need to insert a probe in the liver parenchyma.
The choice of developing a HIFU device dedicated to intraoperative use was supported by oncological necessities and technological challenges that remain unmet in HIFU technology. Extracorporeal HIFU treatments have been proved to be clinically feasible. However, the liver volume accessible to an extracorporeal HIFU treatment is about 30% unless a partial rib resection is performed24. In addition, when using HIFU extracorporeally for treating liver tumors, skin burns and gastric lesions can be created25,26. The intraoperative approach was selected to avoid these potentially important complications.More importantly, intraoperative ablations are widely employed in the management of CLM, whether they are associated with surgery or not. Despite improvements in imaging, new liver metastasis are found in approximately 15% of patients22, and new findings, such as peritoneal carcinomatosis, may preclude the need for liver-directed therapy. For this first use in humans of the intraoperative HIFU device, ablations were created close to metastases and only in areas planned for resection. This first step was regarded as essential to demonstrate the accuracy and the safety of this new HIFU device before considering its routine use to treat CLM.
The size of the HIFU probe (10 cm in diameter) does not limit its ease of use since it was possible to place the probe as such that it allowed a targeting of approximately 90% of the entire liver. This was possible even through a limited midline laparotomy. HIFU ablations were easily identified by ultrasound imaging, allowing a reliable monitoring of the treatment, which is a major advantage over other ablative techniques. The slight difference between ablation dimensions measured on ultrasound images and those measured on macroscopic examination was due to the difficulty to cut fresh liver exactly along the imaging plane.
Although this study confirmed the theoretical advantages of HIFU for liver ablation (i.e., no need for an intraparenchymal introduction of a probe and real-time monitoring, and independence from the heat-sink effect), the efficacy of intraoperative HIFU should be demonstrated on liver metastases. If the ability to target liver metastases is confirmed during phase IIb, the next step will be to design a multicenter prospective cohort of patients treated with curative-intent with intraoperative HIFU.

Colorectal liver metastases (CLMs) represent a major public health issue. When resection and/or ablation of CLM can be achieved, a cure is possible, and five-year survival rates of up to 51% have been reported1. Despite progress in surgery (complex surgical techniques)2 and downsizing obtained with chemotherapy3, only a minority of patients are eligible for surgery (less than 20%). When metastases are confined to the liver, surgery is precluded by the size and/or location of metastases, their number, or because the necessary resection will leave an insufficient volume of functional liver4.
Radiofrequency ablation (RFA) and microwave ablation (MWA) have been widely used in association with surgery to increase the number of patients treated with a curative intent. However, these techniques require the intraparenchymal introduction of a probe. Moreover, these techniques are inadequate due to the heat-sink effect of blood flow, and real-time monitoring is not possible with these techniques.
Medical ultrasound is mainly known as a diagnostic imaging technique. However, ultrasound can be used as a modality to deliberately cause tissue damage. The energy of the HIFU beam is several orders of magnitude greater than those of a standard diagnostic ultrasound beam. The high energy levels carried in a HIFU beam are magnified further by focusing the beam deep in tissues with precision to a small volume while sparing surrounding tissues. The tissue temperature at the focal point quickly rises to 70&#8211;90 &#176;C, resulting in an irreversible destruction by coagulative necrosis5. HIFU has been proven effective in a wide range of clinical applications, especially prostate cancer6,7. Current medical devices using HIFU are based on an extracorporeal approach, and the single ablation achieved is small and ellipsoidal. The dimensions of every single lesion vary according to the transducer characteristics but are typically 1&#8211;3 mm (transverse) and 8&#8211;15 mm (along the beam axis)8. To treat tumors, hundreds of lesions must be placed systematically side by side to ablate the target tumor and some of the surrounding normal tissue margin. The placement of small lesions side by side requires precision that is difficult to ensure in moving organs and results in long-lasting treatments (in the order of 1&#8211;2 h). Whereas numerous publications have reported about MWA and RFA for the treatment of CLM9,10,11,12,13, few studies have been published about HIFU for CLM14,15. HIFU treatment presents several potential advantages when compared to MWA or RFA as follows: there is no need to puncture the parenchyma, the treatment is independent of perfusion8, and real-time monitoring is possible. Extracorporeal treatment of the liver is difficult because the focusing effect is altered by the respiratory motion of the liver and the presence of the ribcage, which may stop the propagation of ultrasound waves.
As focal destruction is often associated with open liver surgery in the management of patients with CLM, we aimed to design a new and powerful HIFU. Such a device would be able to perform large ablations in a short amount of time. Thus, we developed a new technology based on toroidal transducers16 with encouraging results in preliminary in vitro and preclinical work17,18,19. We previously demonstrated in a porcine model that this HIFU device can create reproducible ablations in 40 s20. The average volume of these ablations was 7 cm3, corresponding to an average diameter of 20 mm and an average long axis of 25 mm. These ablations were created by activating each emitter with the same phase and by applying an acoustic power of 70 W (free-field acoustic power) for 40 s18. To confirm these results, this HIFU device was used in a controlled trial in patients undergoing hepatectomy for CLM. The objective of the study was to assess the safety and the feasibility of the procedure. Data regarding the efficacy and the accuracy of the procedure were also collected. This HIFU device was not developed to replace the resection part of surgery. The long-term objective is to provide a complementary tool to surgeons in order to expand the number of patients treated with a curative intent by treating otherwise unresectable patients, using HIFU.
The study participants could not expect any personal benefit from their participation, and the priority was to avoid any loss of chance, which is why an ablate-and-resect study was designed. The surgical procedure had to be identical to the one patients would have undergone if not included in the study. For this first use of the HIFU device in humans, ablations were created on the part of the liver scheduled for resection, in order to protect participating patients from any adverse effects related to the use of this new device.
Study Design:
The protocol was a prospective, single-center phase I/II study designed to assess specific objectives in three different phases (I, IIa, and IIb). In phases I and IIa, the HIFU treatment was performed in parts of the liver planned for resection but at a distance from metastases. Liver metastases were targeted during phase IIb. Data of phase IIb are not presented as this part of the protocol is still ongoing.
The primary objectives of phase I were to evaluate the safety, feasibility, and tolerability of HIFU ablation for patients with CLM. The safety and feasibility were assessed by the ability to use the HIFU device in aseptic conditions. The ability to perform two HIFU ablations without injuring organs adjacent to the liver was also assessed. In all patients, one HIFU lesion was superficial and one was created with the focal zone placed at least 1 cm deeper. Vital signs were monitored during and for 5 min after the HIFU ablations in order to assess the tolerability of the procedure.
Secondary objectives were to determine the reliability of the ultrasound images and the ease of use of the device. The reliability of the ultrasound images was assessed by using the imaging probe integrated with the HIFU device to visualize and target the region to be treated. Ease of use was assessed by the ability to place the HIFU device such that ablations could be performed in at least 80% of the whole liver. The entire HIFU procedure has to be performed in less than 30 min.
This two-step phase was designed following Lee&#39;s sequential criteria21, allowing an early termination of enrollment in the case of an unacceptable global failure rate. The definition of failure was a period longer than 30 min to perform the HIFU procedure, the inability to place the focal zone at least 1 cm from Glisson&#39;s capsule, asepsis failure when using the device, HIFU lesions in adjacent organs, changes in vital signs superior to 10% from the baseline. The enrollment was considered to be closed if a failure was observed in at least 2/2 patients (first step) and 3/6 patients (second step).
In phase IIa, a major anatomical structure was mimicked by a metallic marker with a diameter of 5 mm, implanted in the liver parenchyma. The primary objective of phase IIa was to assess the accuracy of the HIFU device. In step 1, the ability to target the metallic marker with safety margins was assessed. In step 2, the ability to ablate the liver at a predetermined distance from the metallic marker was assessed. The ideal distance between the metallic marker and the closest ablation boundary was fixed at 7.5 mm, with a tolerated range of 1&#8211;15 mm. The secondary objective was to assess the safety of the procedure by creating HIFU lesions in the liver without injury to adjacent organs. The feasibility to image HIFU ablations using the integrated ultrasound imaging probe was a common secondary endpoint with phase I. Three to six patients were included in both steps of phase IIa. Binomial probabilities in 3 and 6 patients were used. If a failure occurred in at least 54% and 32% of the patients, respectively, there was a 90% probability of observing that failure.

<table><tbody><tr><td>MFOCUS</td><td></td><td>N/A</td><td>The transducer has a toroidal geometry and is divided into eight radial ultrasound emitters of 4.16 cm&lt;sup&gt;2&lt;/sup&gt; each. The working frequency of the transducer is 3 MHz. Each of the eight emitters is divided into 32 individual transducers of equal surface (13 mm&lt;sup&gt;2&lt;/sup&gt;). The radius of curvature of the transducer was 7 cm and the diameter was 7 cm. A curved array ultrasound imaging probe working at a frequency of 7.5 MHz (Vermon, Tours, France) was placed in the center of the device and connected to an ultrasound imaging scanner. The imaging transducer is composed of 128 elements with a 63% bandwidth. The ultrasound imaging plane was aligned with the HIFU acoustic axis in order to position the region to be treated and visualize the ablation with the same device. Due to the geometrical characteristics of a torus, the ultrasound beams coming from each of the eight emitters intersect beyond the principal focal ring and form a secondary focal zone, which contributes to reinforce the homogeneity of the lesion at its center. The location of the focal zones could be changed by electronic focusing or by adjusting the quantity of liquid between the device and the tissue.</td></tr><tr><td>Curved array ultrasound imaging probe working at a frequency of 7.5 MHz</td><td>Vermon</td><td>6,5/R11,5/192</td><td></td></tr><tr><td>Ultrasound imaging scanner BK HAWK</td><td>B-K Medical</td><td>2102 EXL</td><td></td></tr><tr><td>Metallic marker</td><td>BIP GmbH</td><td>O-twist-marker</td><td></td></tr><tr><td>ImageJ Image analysis software</td><td>Wayne Rasband</td><td></td><td></td></tr><tr><td>Sterile envelope</td><td>CIVCO</td><td>CIV-Flex Transducer Cover</td><td></td></tr><tr><td>Ultrasound coupling liquid</td><td>EDAP-TMS</td><td>Liv-kit</td><td></td></tr></tbody></table>

evaluation of the feasibility, safety, and accuracy of an intraoperative high-intensity focused ultrasound device for treating liver metastases

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm3&#183;min-1) higher than any other treatment and is independent of perfusion.
The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique.
Fifteen patients were included in phase I&#8211;IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1&#8211;2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2, corresponding to a volume of approximately 7.5 cm3. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.

Fifteen patients were included between March 2010 and November 2011. Six patients were included in phase I. Six patients were included in step 1 of phase IIa. Three patients were included in step 2 of phase IIa. A right or extended right hepatectomy was performed in all patients.Phase IIb is currently ongoing, and results are not described. Complete results of phases I and IIa have been previously published14.
Phase I:
In total, twelve HIFU ablations were successfully created in the six phase-I patients (Figure 5). One superficial HIFU ablation and one deep HIFU ablation were created in each of the 6 patients. Deep HIFU lesions were placed at a mean depth of 12 &#177; 2 (10&#8211;20) mm corresponding to a focal distance of 22 &#177; 2 (20&#8211;40) mm (Figure 3a). The resulting mean distance between Glisson&#39;s capsule and the HIFU ablation was, on average, 7 &#177; 4 (2&#8211;13) mm. Asepsis was not comprised in all patients during the preparation and utilization of the device. There was no lesion in neighboring tissues after HIFU ablation. There were no any substantial changes in respiratory and hemodynamic parameters. The duration of the HIFU procedure was, on average, 15 &#177; 7 (9&#8211;27) min. The ultrasound imaging probe integrated with the HIFU device allows visualizing, on average, 88% (95% CI: 67 to 100%) of the 15 predefined areas.
Phase IIa:
For the first three patients of step 1, the metallic mark had not been included in the HIFU lesions in one of six ablations. After reviewing the record of the procedure, it was established that a Glissonian pedicle was confused with the metallic marker (Figure 6). As required by the study design, three more patients were included, and all six additional HIFU lesions were correctly created around all six metallic markers. Since the primary objective of step 1 was achieved, the steering committee approved the continuation of the study.
The aim of step 2 was to achieve ablations distant from a metallic marker by 7.5 mm. Six ablations with a distance of 7.0 &#177; 2.3 (4.3&#8211;9.8) mm were achieved, demonstrating that it was possible to preserve an area from damage. The procedure was safe, asepsis was not compromised, and there was no lesion in the neighboring organs and no rupture of Glisson&#39;s capsule.
Common Secondary Objectives of Phases I and IIa:
All 30 HIFU ablations created in 15 patients were slightly cone-shaped. The average length of the HIFU ablations was 27.5 &#177; 6 mm. The average superior width of the HIFU ablations was 21 &#177; 3.9 mm. In ultrasound images, the average length of HIFU ablations was 28.9 &#177; 4.6 mm and the average superior width was 23.9 &#177; 3.8 mm. Figure 4b shows the rank correlation coefficient (r = 0.88; p &#60; 0.001; 95% CI, 0.82 to 0.91) between macroscopic measurements and measurements performed using ultrasound images.
Figure 7 shows the capability of the imaging system to visualize metastases. Figure 7a and 7c show examples of two metastases imaged using the ultrasound imaging probe integrated with the HIFU device. Figure 7b and 7d show the corresponding metastases observed on gross pathology after surgery. The HIFU focal region was superimposed on the sonogram and displayed in the user interface, making it possible to place the location of the ablation with precision (Figure 7a).
As illustrated in Figure 8, the delimitation between treated and untreated liver is very sharp (about 200 &#181;m). There was a halo of congestive tissues around all HIFU ablations. The microscopic examination confirmed homogeneous necrosis with all HIFU ablations. Since there were only 1 to 2 h between HIFU ablation and hepatectomy, it was not possible to observe evidence of apoptosis. However, pronounced alterations in hepatocytes were observed in all HIFU ablations. The microscopic analysis confirmed homogeneous ablations with all cases, notably around vessels (Figure 8).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57964/57964fig1.jpg" /> 
Figure 1: Preparation of the HIFU device. The HIFU device was prepared by covering the sterilized HIFU probe with a sterile envelope containing an ultrasound coupling liquid. (a) This panel shows the HIFU transducer covered with a sterile envelope. (b) This panel shows the tube for the cooling circuit. (c) This panel shows the connector for the electrical power. (d) This panel shows the connector for the ultrasound imaging probe. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/57964/57964fig2.jpg" /> 
Figure 2: Use of the HIFU probe. The HIFU probe was held by hand and brought into contact with the liver surface. (a) This panel shows the HIFU probe. (b) The position of the HIFU probe at the time of ablation was marked on the liver. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/57964/57964fig3.jpg" /> 
Figure 3: Targeting process. (a) The user interface displayed the position of the HIFU focal region superimposed on the sonogram, making it possible to place the location of the ablation in the tissues. (b) Immediately after the HIFU exposure, a cloud of ebullition appeared momentarily (for approximately 1 min) at the location of the lesion. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/57964/57964fig4.jpg" /> 
Figure 4: Monitoring. After boiling, the single lesion appeared on the sonogram as a hyperechoic zone at its center and a hypoechoic zone at its boundaries. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/57964/57964fig5.jpg" /> 
Figure 5: Macroscopic visualization of two HIFU ablations. HIFU ablations were clearly visible by gross pathology. (a) This panel shows a typical HIFU ablation. (b) This panel shows an example of a HIFU lesion created during step 1 of phase IIa. The aim was to target the metallic marker. The shape and homogeneity of the ablation were not altered by the presence of hepatic veins. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/57964/57964fig6.jpg" /> 
Figure 6: Macroscopic visualization of a HIFU ablation created in phase IIa. In one case, the metallic marker had not been included in the HIFU. After reviewing the record of the procedure, it was established that a Glissonian pedicle was confused with the metallic marker. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/57964/57964fig7.jpg" /> 
Figure 7: Visualization of metastases using the integrated ultrasound imaging probe. Panels (a) and (c) show examples of two metastases imaged using the ultrasound imaging probe integrated with the HIFU device. Panels (b) and (d) show the corresponding metastases observed by gross pathology after surgery. (a) The user interface displayed the position of the HIFU focal region superimposed on the sonogram, making it possible to place the location of the ablation in the tissues and to visualize if the metastasis will be treated with safety margins. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig7large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/57964/57964fig8.jpg" /> 
Figure 8: Histopathological examination after HIFU ablation. This panel shows a representative liver examination using H&#38;E staining. There was a sharp demarcation between treated and untreated liver with pronounced alterations in hepatocytes. Here, the magnification is 200x. <a href="https://www.jove.com/files/ftp_upload/57964/57964fig8large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases at JoVE.com

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Here, we present an ablate-and-resect prospective study to evaluate the feasibility, safety, and accuracy of intraoperative high-intensity focused ultrasound ablation in patients undergoing hepatectomy for liver metastases.

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% ...

evaluation-feasibility-safety-accuracy-an-intraoperative-high

Research

JoVE Journal

Cancer Research

7.8K Views.  Centre Léon Bérard. Dit medische apparaat, dat gerichte echografie gebruikt, kan een nieuwe therapeutische optie bieden voor patiënten met onreseceerbare levermetastasen. Het belangrijkste voordeel van deze techniek is dat het snel, veilig, breed getolereerde grote leverablaties kan bereiken met een punctie en de beschikbare echografiebegeleiding. Het aantonen van de voorbereiding van het HIFU-apparaat zal Marie Jo zijn, een gespecialiseerde verpleegkundige uit de operatiekamer.Na het ontsmetten van de i...

Video: Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters.  Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation.  Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Insonation of microbubbles is a promising strategy for tumor ablation at reduced time-averaged acoustic powers, as well as for the targeted delivery of therapeutics. The purpose of the present study is to develop low duty cycle ultrasound pulsing strategies and nanocarriers to maximize non-thermal microvascular ablation and payload delivery to subcutaneous C6 gliomas.

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the ...

Bioengineering

Thermal Ablation for the Treatment of Abdominal Tumors

Percutaneous thermal ablation is an emerging treatment option for many tumors of the abdomen not amenable to conventional treatments. During a thermal ablation procedure, a thin applicator is guided into the target tumor under imaging guidance. Energy is then applied to the tissue until temperatures rise to cytotoxic levels (50-60 &deg;C). Various energy sources are available to heat biological tissues, including radiofrequency (RF) electrical current, microwaves, laser light and ultrasonic waves. Of these, RF and microwave ablation are most commonly used worldwide.
During RF ablation, alternating electrical current (~500 kHz) produces resistive heating around the interstitial electrode. Skin surface electrodes (ground pads) are used to complete the electrical circuit. RF ablation has been in use for nearly 20 years, with good results for local tumor control, extended survival and low complication rates1,2. Recent studies suggest RF ablation may be a first-line treatment option for small hepatocellular carcinoma and renal-cell carcinoma3-5. However, RF heating is hampered by local blood flow and high electrical impedance tissues (eg, lung, bone, desiccated or charred tissue)6,7. Microwaves may alleviate some of these problems by producing faster, volumetric heating8-10. To create larger or conformal ablations, multiple microwave antennas can be used simultaneously while RF electrodes require sequential operation, which limits their efficiency. Early experiences with microwave systems suggest efficacy and safety similar to, or better than RF devices11-13.
Alternatively, cryoablation freezes the target tissues to lethal levels (-20 to -40 &deg;C). Percutaneous cryoablation has been shown to be effective against RCC and many metastatic tumors, particularly colorectal cancer, in the liver14-16. Cryoablation may also be associated with less post-procedure pain and faster recovery for some indications17. Cryoablation is often contraindicated for primary liver cancer due to underlying coagulopathy and associated bleeding risks frequently seen in cirrhotic patients. In addition, sudden release of tumor cellular contents when the frozen tissue thaws can lead to a potentially serious condition known as cryoshock 16.
Thermal tumor ablation can be performed at open surgery, laparoscopy or using a percutaneous approach. When performed percutaneously, the ablation procedure relies on imaging for diagnosis, planning, applicator guidance, treatment monitoring and follow-up. Ultrasound is the most popular modality for guidance and treatment monitoring worldwide, but computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used as well. Contrast-enhanced CT or MRI are typically employed for diagnosis and follow-up imaging.

A thermal tumor ablation procedure is described. The entire procedure is detailed, including pretreatment planning and imaging studies, anesthesia, adjuvant techniques to facilitate a percutaneous approach, imaging guidance of the ablation device to the tumor, thermal treatment, post-treatment care and follow-up.

Percutaneous thermal ablation is an emerging treatment option for many tumors of the abdomen not amenable to conventional treatments. During a thermal ...

Medicine

Real-time Monitoring of High Intensity Focused Ultrasound (HIFU) Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU)

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An oscillatory motion is generated at the focus of a 93-element and 4.5 MHz center frequency HIFU transducer by applying a 25 Hz amplitude-modulated signal using a function generator. A 64-element and 2.5 MHz imaging transducer with 68kPa peak pressure is confocally placed at the center of the HIFU transducer to acquire the radio-frequency (RF) channel data. In this protocol, real-time monitoring of thermal ablation using HIFU with an acoustic power of 7 W on canine livers in vitro is described. HIFU treatment is applied on the tissue during 2 min and the ablated region is imaged in real-time using diverging or plane wave imaging up to 1,000 frames/second. The matrix of RF channel data is multiplied by a sparse matrix for image reconstruction. The reconstructed field of view is of 90&#176; for diverging wave and 20 mm for plane wave imaging and the data are sampled at 80 MHz. The reconstruction is performed on a Graphical Processing Unit (GPU) in order to image in real-time at a 4.5 display frame rate. 1-D normalized cross-correlation of the reconstructed RF data is used to estimate axial displacements in the focal region. The magnitude of the peak-to-peak displacement at the focal depth decreases during the thermal ablation which denotes stiffening of the tissue due to the formation of a lesion. The displacement signal-to-noise ratio (SNRd) at the focal area for plane wave was 1.4 times higher than for diverging wave showing that plane wave imaging appears to produce better displacement maps quality for HMIFU than diverging wave imaging.

Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU

This article describes real-time monitoring of HIFU ablation in canine liver with high frame rate ultrasound imaging using diverging and plane wave imaging. Harmonic Motion Imaging for Focused Ultrasound is used to image the decrease of acoustic radiation force induced displacement in the ablated region.

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An ...

Generation and Quantitative Analysis of Pulsed Low Frequency Ultrasound to Determine the Sonic Sensitivity of Untreated and Treated Neoplastic Cells

Low frequency ultrasound in the 20 to 60 kHz range is a novel physical modality by which to induce selective cell lysis and death in neoplastic cells. In addition, this method can be used in combination with specialized agents known as sonosensitizers to increase the extent of preferential damage exerted by ultrasound against neoplastic cells, an approach referred to as sonodynamic therapy (SDT). The methodology for generating and applying low frequency ultrasound in a preclinical in vitro setting is presented to demonstrate that reproducible cell destruction can be attained in order to examine and compare the effects of sonication on neoplastic and normal cells. This offers a means by which to reliably sonicate neoplastic cells at a level of consistency required for preclinical therapeutic assessment. In addition, the effects of cholesterol-depleting and cytoskeletal-directed agents on potentiating ultrasonic sensitivity in neoplastic cells are discussed in order to elaborate on mechanisms of action conducive to sonochemotherapeutic approaches.

Selective damage of human leukemia cells can be achieved through a novel approach of applying low frequency ultrasound both with and without chemotherapeutic pretreatment of leukemic and normal hematopoietic cells.

Low frequency ultrasound in the 20 to 60 kHz range is a novel physical modality by which to induce selective cell lysis and death in neoplastic cells. In ...

Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For inoperable patients, local ablation therapies, such as stereotactic body radiotherapy (SBRT), can provide effective local tumor control with minimal toxicity. Because of its high precision and accuracy, SBRT delivers a higher radiation dose per fraction, is more effective, and targets smaller irradiation volumes than does conventional radiotherapy. In addition, steep dose gradients from target lesions to surrounding normal tissues are achieved using SBRT; thus, SBRT provides more effective tumor control and exhibits fewer side effects than conventional radiotherapy. The use of SBRT is prevalent for treating intracranial lesions (known as stereotactic radiosurgery); however, it is now also used for treating spinal and adrenal metastases. Because of advancements in image-guided assistance and respiratory motion management, several studies have investigated the use of SBRT for treating lung or liver tumors, which move as a patient breathes. The results of these studies have suggested that SBRT favorably controls tumors in the case of moving lesions.
Four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) is clinically convenient for effective respiratory motion management. Because this method is noninvasive and allows free breathing, its use reduces complications. Furthermore, patients consider this method convenient. Moreover, it is considered more efficient than other methods of respiratory motion management by physicians and therapists. The use of 4D-CT with an AC for treating pulmonary lesions has also been widely investigated, and the technique is gaining acceptance for treating hepatic lesions. However, the protocols for using 4D-CT with an AC for treating hepatic lesions are different from those used for treating pulmonary lesions. In this article, we describe a new protocol for SBRT with 4D-CT and an AC for treating liver metastases.

Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For ...

Real-Time Magnetic Resonance Guided Focused Ultrasound for Painful Bone Metastases

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with opioids is the standard treatment for painful bone metastases. This treatment achieves effective pain control in 60&#8722;74% of patients, but limited treatment choices with limited benefits are available for recurrent or residual painful bone metastases after radiotherapy. More than 40% of patients still experience moderate to severe bone pain after reirradiation. Magnetic resonance-guided focused ultrasound (MRgFUS) combines high-intensity focused ultrasound, which achieves thermal ablation of bone metastases and subsequent pain reduction, with real-time magnetic resonance (MR) thermometry to monitor the temperature of anatomic MR images, with an accuracy of 1 &#176;C, spatial resolution of 1 mm, and temporal resolution within 3 s. As well as being increasingly used clinically for controlling metastatic bone pain, the use of MRgFUS for other diseases has also been tested. However, the use of MR software as a thermometer is the only technique available to verify the accuracy of the software and assure energy delivery. Here, we describe an efficient method of quality assurance we developed for thermal detection and energy delivery before each MRgFUS treatment and also propose a modified workflow to expedite the treatment course as well as to reduce patients&#39; pain during the procedure.

Magnetic resonance could offer real-time monitoring of the position and temperature of focused ultrasound in thermal ablation for painful bone metastases, regardless of cancer type or previous local treatments. Our innovative method of quality assurance could facilitate the application of this effective and safe treatment.

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with ...

Application of Laparoscopic Hepatectomy Combined with Intraoperative Microwave Ablation in Colorectal Cancer Liver Metastasis

Laparoscopic hepatectomy is a common treatment for colorectal cancer liver metastasis. Previously, a sufficient number of functional liver masses had to be maintained during laparoscopic hepatectomy, with a residual liver volume of &gt;40% in cirrhotic patients and &gt;30% in non-cirrhotic patients. The high incidence of complications such as bleeding, bile leakage, or liver failure due to the exposure and difficulty of the resection of specific liver segments such as S2 and S7 reduces the success rate of liver resection. At present, microwave ablation is mainly applied in the treatment of liver metastasis using a percutaneous approach, which makes it difficult to identify hidden parts or small lesions. For some liver segments, the percutaneous puncture of liver segment 7 (S7) is likely to pass through the thoracic cavity, and the percutaneous puncture of liver segment 2 (S2) adjacent to the diaphragm is likely to injure the diaphragm and heart; these issues restrict the application of percutaneous ablation in colorectal cancer liver metastasis. Considering multiple lesions, laparoscopic microwave ablation combined with hepatectomy was performed in this study. The location of the lesions was determined by contrast-enhanced ultrasound under laparoscopy, and small lesions that were difficult to detect before the operation were identified. For the scattered lesions, which had diameters less than 3 cm and were difficult to resect, ablation was adopted to substitute hepatectomy. This technique helped to more explicitly locate the tumors, simplified the operation procedures, reduced the risk of complications such as bleeding and bile leakage, shortened the operation time, accelerated the postoperative recovery, significantly improved the success rate of operation, and enhanced the clinical prognosis of colorectal cancer liver metastasis by surgical resection.

This protocol describes the laparoscopic resection of colorectal cancer liver metastases combined with ultrasound-guided microwave ablation. This technique can safely, effectively, and accurately treat refractory liver metastases &lt;3 cm, reduce postoperative complications, and accelerate the postoperative rehabilitation of patients.

Laparoscopic hepatectomy is a common treatment for colorectal cancer liver metastasis. Previously, a sufficient number of functional liver masses had to ...

Modified Laparoscopic Anatomic Hepatectomy: Two-Surgeon Technique Combined with the Simple Extracorporeal Pringle Maneuver

Laparoscopic anatomic hepatectomy (LAH) has become increasingly prevalent worldwide in recent years. However, LAH remains a challenging procedure due to the anatomical characteristics of the liver, with intraoperative hemorrhage being a primary concern. Intraoperative blood loss is the leading cause of conversion to open surgery; therefore, effective management of bleeding and hemostasis is crucial for a successful LAH.
The two-surgeon technique is proposed as an alternative to the traditional single-surgeon approach, with potential benefits in reducing intraoperative bleeding during laparoscopic hepatectomy. However, there remains a lack of evidence to determine which mode of the two-surgeon technique yields superior patient outcomes. Besides, to our knowledge, the LAH technique, which involves the use of a cavitron ultrasonic surgical aspirator (CUSA) by the primary surgeon while an ultrasonic dissector by the second surgeon, has been rarely reported before.
Herein, we present a modified, two-surgeon LAH technique, wherein one surgeon employs a CUSA while the other uses an ultrasonic dissector. This technique is combined with a simple extracorporeal Pringle maneuver and low central venous pressure (CVP) approach. In this modified technique, the primary and secondary surgeons utilize a laparoscopic CUSA and an ultrasonic dissectorconcurrently to achieve precise and expeditious hepatectomy. A simple extracorporeal Pringle maneuver, combined with the maintenance of low CVP, is employed to regulate the hepatic inflow and outflow in order to minimize intraoperative bleeding. This approach facilitates the attainment of a dry and clean operative field, which allows for the precise ligation and dissection of blood vessels and bile ducts. The modified LAH procedure is simpler and safer due to its effective control over bleeding as well as the seamless transition between the roles of primary and secondary surgeons. It holds great promise for future clinical applications.

Here, we present a protocol to perform a modified laparoscopic anatomic hepatectomy using improved techniques and instruments.

Laparoscopic anatomic hepatectomy (LAH) has become increasingly prevalent worldwide in recent years. However, LAH remains a challenging procedure due to ...

Application of Laparoscopic Ultrasonography in Primary Choledochal Suture during Combined Two-lens Surgery

Gallstones combined with common bile duct stones are a common clinical disease. The minimally invasive treatments include laparoscopic cholecystectomy + laparoscopic common bile duct exploration (LC+LCBDE) and endoscopic retrograde cholangiopancreatography + laparoscopic cholecystectomy (ERCP+LC). LCBDE can resolve two issues in a single procedure, whereas ERCP+LC requires a two-step approach. As more studies have shown, common bile duct exploration with stone extraction followed by primary closure may lead to faster recovery and improved quality of life for patients.
Anatomical variations in bile ducts and vessels are well-known to be common. Laparoscopic ultrasound (LUS) is instrumental in clarifying the hepatic portal area's anatomical structures, determining biliary duct orientation, identifying spatial relationships between biliary ducts, hepatic arteries, and portal veins, and minimizing the risk of biliary injury.
The procedure is illustrated here through a detailed case description. After administering general anesthesia, a laparoscopic approach was routinely established to inspect the abdominal cavity and assess lesions. Laparoscopic ultrasound was employed to evaluate the gallbladder triangle within the hepatic portal region, including the anatomy of bile ducts and vessels. The gallbladder triangle was dissected, followed by a 5-0 needle incision of the bile duct wall. Choledochoscopy was performed for stone extraction, with confirmation of normal duodenal papillary function. Continuous suturing of the bile duct wall was achieved using 5-0 polydioxanone monofilament suture material. Concurrently, laparoscopic ultrasound verified complete stone clearance and assessed suture integrity.

Here, we develop and present a T-tube and intrabiliary stent-free technique utilizing dual-lens visualization (via laparoscope and choledochoscope) combined with laparoscopic ultrasonography (LUS) to perform primary choledochal suture.

Gallstones combined with common bile duct stones are a common clinical disease. The minimally invasive treatments include laparoscopic cholecystectomy + ...

Laparoscopic S7 Hepatectomy with Positive Fluorescence Staining

Laparoscopic liver resection for tumors located in the S7 segment of the liver typically adopts a traditional surgical approach. The main goal of this procedure is to accurately dissect the liver pedicle of the S7 segment. Dissecting the hepatic pedicle of the S7 segment along the hepatic hilum requires a relatively long path within the liver, which increases the risk of losing orientation and potentially injuring the adjacent hepatic pedicle of the S5 and S6 segments, thereby compromising the liver resection plane. A positive staining method was used to directly puncture the corresponding portal vein under ultrasound guidance (commonly for S7 and S8 segments) to specifically color the target liver segment, thereby avoiding extensive resection of the liver parenchyma, and reducing damage to the surrounding healthy liver tissue. However, the positive staining method requires a specific foundation in intraoperative procedures, which can be challenging for surgeons and has a certain learning curve. Currently, technologies such as three-dimensional reconstruction territory analysis, intraoperative ultrasound, and indocyanine green fluorescence imaging are popular and commonly used in laparoscopic liver resection. In this protocol, under laparoscopic ultrasound guidance, the tumor basin was punctured through the visceral and diaphragmatic surfaces of the liver to stain segment S7. Laparoscopic resection of segment S7 within the portal territory anatomic liver was successfully performed, further confirming the feasibility and advantages of positive fluorescence staining in laparoscopic liver resection at this stage.

The protocol demonstrates that, under laparoscopic ultrasound guidance, the S7 segment of the liver can be successfully stained by puncturing the visceral and diaphragmatic branches of the tumor, facilitating an anatomical hepatectomy of the S7 segment.

Laparoscopic liver resection for tumors located in the S7 segment of the liver typically adopts a traditional surgical approach. The main goal of this ...

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

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