Intra-operative High-Intensity Focused Ultrasound in Patients With Colorectal Liver Metastases: A Prospective Ablate-and-Resect Study.

OBJECTIVE: High-intensity focused ultrasound (HIFU) is a recent, non-ionizing and non-invasive technology of focal destruction. Independence from the heat-sink effect of blood flow makes HIFU an interesting technique for focal ablation of liver tumors. Current available technology is based on extracorporeal treatment that limits use of HIFU for the treatment of liver tumors, as elementary ablations are small and must be juxtaposed to treat tumors, resulting in long-duration treatment. We developed an HIFU probe with toroidal technology, which increases the volume of ablation, for intra-operative use, and we assessed the feasibility and efficacy of this device in patients with colorectal liver metastasis (CLM) measuring less than 30 mm. METHODS: This study was an ablate-and-resect, prospective, single-center, phase II study. All ablations were performed in the area of liver scheduled for liver resection to avoid loss of chance of recovery. The primary objective was to ablate CLM with safety margins (>5 mm). RESULTS: Between May 2014 and July 2020, 15 patients were enrolled and 24 CLM were targeted. The HIFU ablation time was 370 s. In total, 23 of 24 CLM were successfully treated (95.8%). No damage occurred to extrahepatic tissues. HIFU ablations were oblate shaped with an average long axis of 44.3 ± 6.1 mm and an average shortest axis of 35.9 ± 6.7 mm. On pathological examination, the average diameter of the treated metastasis was 12.2 ± 4.8 mm. CONCLUSION: Intra-operative HIFU can safely and accurately produce large ablations in 6 min with real-time guidance (ClinicalTrials.gov identifier: NCT01489787).

Intraoperative HIFU Ablation of the Pancreas Using a Toroidal Transducer in a Porcine Model. The First Step towards a Clinical Treatment of Locally Advanced Pancreatic Cancer.

Apart from palliative chemotherapy, no other therapy has been proven effective for the treatment of locally advanced pancreatic tumors. In this study, an intraoperative high-intensity focused ultrasound (HIFU) device was tested in vivo to demonstrate the feasibility of treating the pancreatic parenchyma and tissues surrounding the superior mesenteric vessels prior to clinical translation of this technique. Twenty pigs were included and treated using a HIFU device equipped with a toroidal transducer and an integrated ultrasound imaging probe. Treatments were performed with energy escalation (from 30 kJ to 52 kJ). All treatments resulted in visible (macroscopically and in ultrasound images) homogeneous thermal damage, which was confirmed by histology. The dimensions of thermal lesions measured in ultrasound images and those measured macroscopically were correlated (r = 0.82, p < 0.05). No arterial spasms or occlusion were observed at the lowest energy setting. Temporary spasm of the peripancreatic artery was observed when using an energy setting greater than 30 kJ. The possibility of treating the pancreas and tissues around mesenteric vessels without vascular thrombosis holds great promise for the treatment of locally advanced pancreatic cancers. If clinically successful, chemotherapy followed by HIFU treatment could rapidly become a novel treatment option for locally advanced pancreatic cancer.

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·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-IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1-2 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.

Efficacy of high-intensity focused ultrasound-assisted hepatic resection (HIFU-AR) on blood loss reduction in patients with liver metastases requiring hepatectomy: study protocol for a randomized controlled trial.

BACKGROUND: Liver resection is the only potentially curative treatment for colorectal liver metastases (LM). It is considered a safe procedure, but is often associated with blood loss during liver transection. Blood transfusions are frequently needed, but they are associated with increased morbidity and risk of recurrence. Many surgical devices have been developed to decrease blood loss. However, none of them has proven superior to the standard crushing technique. We developed a new, powerful intra-operative high-intensity focused ultrasound (HIFU) transducer which destroys tissue by coagulative necrosis. We aim to evaluate whether HIFU-assisted liver resection (HIFU-AR) results in reduced blood loss. METHODS: This is a prospective, single-centre, randomized (1:1 ratio), comparative, open-label phase II study. Patients with LM requiring a hepatectomy for ≥ 2 segments will be included. Patients with cirrhosis or sinusoidal obstruction syndrome with portal hypertension will be excluded. The primary endpoint is normalized blood loss in millilitres per square centimetre of liver section plane. Secondary endpoints are: total blood loss, transection time, transection time per square centimetre of liver area, haemostasis time, clip density on the liver section area, rate and duration of the Pringle manœuvre, rate of patients needing a blood transfusion, length of hospital stay, morbidity, patients with positive resection margin, and local recurrence. Assuming a blood loss of 7.6 ± 3.7 mL/cm2 among controls, the study will have 85% power to detect a twofold decrease of blood loss in the experimental arm, using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 two-sided significance level. Twenty-one randomized patients per arm are required. Considering the risk of contraindications at surgery, up to eight patients may be enrolled in addition to the 42 planned, with an enrolment period of 24 months. Randomization will be stratified by surgeon. DISCUSSION: We previously demonstrated the safety and efficacy of intra-operative HIFU in patients operated on for LM. We also demonstrated the efficacy of HIFU-AR in a preclinical study. Participants in the HIFU-AR group of this randomized trial can expect to benefit from reduced blood loss and decreased ischemia of liver parenchyma. TRIAL REGISTRATION: Clinicaltrial.gov, NCT02728167 . Registered on 22 March 2016.

Thermal Ablation of the Pancreas With Intraoperative High-Intensity Focused Ultrasound: Safety and Efficacy in a Porcine Model.

OBJECTIVE: New focal destruction technologies such as high-intensity focused ultrasound (HIFU) may improve the prognosis of pancreatic ductal adenocarcinoma. Our objectives were to demonstrate the safety and efficacy of intraoperative pancreatic HIFU ablation in a porcine model. METHODS: In a porcine model (N = 12), a single HIFU ablation was performed in either the body or tail of the pancreas, distant to superior mesenteric vessels. All animals were sacrificed on the eighth day. The primary objective was to obtain an HIFU ablation measuring at least 1 cm without premature death. RESULTS: In total, 12 HIFU ablations were carried out. These ablations were performed within 160 seconds and on average measured 20 (15-27) × 16 (8-26) mm. The primary objective was fulfilled in all but 1 pig. There were no premature deaths or severe complications. High-intensity focused ultrasound treatment was associated with a transitory increase in amylase and lipase levels, and pseudocysts were observed in half of the pigs without being clinically apparent. All ablations were well delimited at both gross and histological examinations. CONCLUSIONS: Intraoperative thermal destruction of porcine pancreas with HIFU is feasible. Reproducibility and safety have to be confirmed when applied close to mesenteric vessels and in long-term preclinical studies.

First clinical experience of intra-operative high intensity focused ultrasound in patients with colorectal liver metastases: a phase I-IIa study.

BACKGROUND: Surgery is the only curative treatment in patients with colorectal liver metastases (CLM), but only 10-20% of patients are eligible. High Intensity Focused Ultrasound (HIFU) technology is of proven value in several indications, notably prostate cancer. Its intra-operative use in patients with CLM has not previously been studied. Preclinical work suggested the safety and feasibility of a new HIFU device capable of ablating volumes of up to 2cm x 2cm in a few seconds. METHODS: We conducted a prospective, single-centre phase I-IIa trial. HIFU was delivered immediately before scheduled hepatectomy. To demonstrate the safety and efficacy of rapidly ablating liver parenchyma, ablations were performed on healthy tissue within the areas scheduled for resection. RESULTS: In total, 30 ablations were carried out in 15 patients. These ablations were all generated within 40 seconds and on average measured 27.5mm x 21.0mm. The phase I study (n = 6) showed that use of the HIFU device was feasible and safe and did not damage neighbouring tissue. The phase IIa study (n = 9) showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark (used to represent a major anatomical structure) and that ablations could be undertaken deliberately to avoid such a mark. Ablations were achieved with a precision of 1-2 mm. CONCLUSION: HIFU was feasible, safe and effective in ablating areas of liver scheduled for resection. The next stage is a phase IIb study which will attempt ablation of small metastases with a 5 mm margin, again prior to planned resection. TRIAL REGISTRATION: ClinicalTrials.govNCT01489787.

Electronic beam steering used with a toroidal HIFU transducer substantially increases the coagulated volume.

Treatment with high-intensity focused ultrasound is well established but requires extended treatment time. A device composed of 256 elements arranged on a toroidal transducer was developed to increase the coagulated volume. When all the elements are working in phase for 40 s, a volume of 6-8 cm(3) can be ablated. However, the mechanical juxtaposition of single lesions is still necessary for treating one tumor with a diameter of 2 cm. The objective of this study was to combine this toroidal transducer geometry with electronic beam steering to ablate tumors with adequate normal tissue margins and without any mechanical displacement of the high-intensity focused ultrasound device. In vitro tests demonstrated that the coagulated volume obtained from 130 s of total exposure has an average diameter of 41.4 ± 4.0 mm and an average length of 53.3 ± 6.1 mm. This single lesion can be used to treat various size of metastasis, located at depths in the liver ranging 5-45 mm.