Hong Kong Med J 2016 Aug;22(4):382–92 | Epub 6 Jul 2016
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
REVIEW ARTICLE CME
Clinical applications of high-intensity focused ultrasound
WH She, MB, BS, FRCS1; TT Cheung, MS, FRCS1; Caroline R Jenkins, MB, BS, FRCA2; Michael G Irwin, MD, FRCA2
1 Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
2 Department of Anaesthesiology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
Corresponding author: Dr TT Cheung (email@example.com)
A video clip showing clinical applications of high-intensity focused ultrasound is available at www.hkmj.org
Ultrasound has been developed for therapeutic use in addition to its diagnostic ability. The use of focused ultrasound energy can offer a non-invasive method for tissue ablation, and can therefore be used to treat various solid tumours. High-intensity focused ultrasound is being increasingly used in the treatment of both primary and metastatic tumours as these can be precisely located for ablation. It has been shown to be particularly useful in the treatment of uterine fibroids, and various solid tumours including those of the pancreas and liver. High-intensity focused ultrasound is a valid treatment option for liver tumours in patients with significant medical co-morbidity who are at high risk for surgery or who have relatively poor liver function that may preclude hepatectomy. It has also been used as a form of bridging therapy while patients awaiting cadaveric donor liver transplantation. In this article, we outline the principles of high-intensity focused ultrasound and its clinical applications, including the management protocol development in the treatment of hepatocellular carcinoma in Hong Kong by performing a search on MEDLINE (OVID), EMBASE, and PubMed. The search of these databases ranged from the date of their establishment until December 2015. The search terms used were: high-intensity focused ultrasound, ultrasound, magnetic resonance imaging, liver tumour, hepatocellular carcinoma, pancreas, renal cell carcinoma, prostate cancer, breast cancer, fibroids, bone tumour, atrial fibrillation, glaucoma, Parkinson’s disease, essential tremor, and neuropathic pain.
High-intensity focused ultrasound (HIFU) was initially used in the 1940s to treat brain pathologies such as Parkinson’s disease.1 2 3 In the 1990s, it was introduced to ophthalmology to treat raised intra-ocular pressure, traumatic capsular tears, glaucoma, retinal detachment, and vitreous haemorrhage.4 5 6 7 8 9 This technique has a unique ability to target deep-seated soft tissue tumours. Furthermore, as long as the lesions within solid organs can be clearly visualised on magnetic resonance imaging (MRI) or ultrasonography (USG)—that is, the presence of the acoustic window to allow the transmission of ultrasound energy—many lesions can be targeted such as those in the liver, kidney, pancreas and breast; and uterine fibroids, benign prostatic hypertrophy, and prostate cancer. In recent years, HIFU has been used to treat both benign and malignant lesions of various solid organs. This non-invasive modality allows treatment of tumours without surgery and offers a new treatment option for those patients who are not candidates for surgery, or who do not want surgery.
A search was performed on the following electronic databases: MEDLINE (OVID), EMBASE, and PubMed. The search of these databases ranged from the date of their establishment until December 2015. The search terms used were: high-intensity focused ultrasound, ultrasound, magnetic resonance imaging, liver tumour, hepatocellular carcinoma, pancreas, renal cell carcinoma, prostate cancer, breast cancer, fibroids, bone tumour, atrial fibrillation, glaucoma, Parkinson’s disease, essential tremor, and neuropathic pain. Only studies reported in English were included. Full papers were selected if they contained facts, data, or scientific evidence related to the treatment of HIFU. The reference lists of articles selected were screened for full-text review.
Mechanism of high-intensity focused ultrasound
High-intensity focused ultrasound incorporates multiple ultrasound beams produced by piezoelectric or piezoceramic transducers directed into a three-dimensional focal point of typically 1 to 5 mm in diameter and 10 to 50 mm in length.10 Various mechanisms have been proposed for the subsequent tissue destruction with a synergistic effect from thermal and mechanical means. This technique induces heat generation due to absorption of the acoustic energy with the temperature rising rapidly to 60°C or higher, causing coagulation necrosis in a short period of time. Focusing is an important component as only a small volume (eg 1 mm diameter and 9 mm length) is targeted by the ultrasound beam and hence HIFU induces minimal thermal damage to tissue located between the transducer and the focal point.11
A mechanical effect is produced by acoustic pulses only at higher intensities. Various phenomena are observed, including cavitation, microstreaming, and radiation forces. Cavitation is defined as the creation or motion of a gas cavity in an acoustic field due to alternating compression and expansion of tissue as an ultrasound burst propagates through it.12 There are two forms of cavitation to consider: stable and inertial.11 If the tissue expansion or rarefaction pressure is of sufficient magnitude, gas can be extracted from the tissue, resulting in bubble formation. In stable cavitation, the bubble is exposed to a low-pressure acoustic field, resulting in stable oscillation of the size of the bubble. In inertial cavitation, exposure of the bubble to the acoustic filed results in violent oscillations of the bubble and rapid growth during the rarefaction phase, eventually leading to the violent collapse and destruction of the bubble. It will produce shock waves of very high pressure (20-30 000 bars) and a high temperature (2000-5000 K) in the microenvironment.13 14 Micro-streaming is a phenomenon produced by stable cavitation in which rapid movement of fluid occurs near the bubble due to its oscillating motion. It can produce high shear forces that can cause transient damage to cell membranes and may play a role in ultrasound-enhanced drug or gene delivery when damage to the cell membrane is transient.13 15
Radiation forces are developed when a wave is either absorbed or reflected. If the reflecting or absorbing medium is tissue or other solid material, the force presses against the medium, producing a pressure termed ‘radiation pressure’. If the medium is liquid and can move under pressure, then streaming results.16
The intention of HIFU is to raise and maintain an isolated part of the volume above 60°C for more than 1 second or longer, in order to cause coagulative necrosis and immediate cell death.17 18 It aims to deliver the energy required to raise the tissue temperature to a cytotoxic level sufficiently fast that the tissue vasculature does not have a significant effect on the extent of cell killing.19 20 In a study of the application of HIFU in the liver, 2 hours of exposure resulted in a rim of glycogen-free cells of about 10 cells wide. These cells were dead 48 hours later, and showed signs of coagulative necrosis typical of thermal injury.19
Limitations of high-intensity focused ultrasound
Of all the ablative modalities, HIFU has the advantage that it does not require the introduction of an applicator in order to achieve the ablative effect and is the only non-invasive option. This makes it a very attractive choice. It has several limitations, however. This technique is essentially USG and, therefore, any artefacts, such as acoustic shadowing, reverberation, and refraction also apply to it. Superficial lesions are treated most effectively by HIFU due to the limitations of ultrasound penetrance through many tissues, but the sound wave reflected carries very high energy, and can also produce burns in tissues that lie between the target and the transducer. Many collateral injuries have been reported due to scattered and reflected high-intensity ultrasound waves, such as skin burns, peripheral nerve damage, and bowel injury.21 22 Great care also needs to be taken in areas that are subject to respiratory movement, because of a lack of precision, or the presence of sonic shadowing due to overlying bony substances.21 In such situations it may be necessary for the anaesthetist to use controlled ventilation. The amount of energy absorbed by the tissue may vary, as fibrotic, fatty, and highly vascularised tissues attenuate sound energy differently. Excessive energy absorption may result in an unpredictable distribution of cell death.23 Careful planning is therefore required to ensure adequate tumour coverage, as coagulation, desiccation, and vapour formation are detrimental to ultrasound energy propagation, as well as precise localisation of the lesion.24
The high-intensity focused ultrasound system
Both USG and MRI can be used to visualise, target, and monitor the status of tissue destruction.
This is the most common method to target and monitor the status of HIFU destruction.25 The therapeutic and diagnostic transducers can be packaged into one instrument that allows real-time monitoring of the delivery of HIFU, the outcome of the lesion, and the outcome of the peripheral tissues. Although it is cost-effective, it has relatively low spatial resolution that limits its accuracy for targeting and it is also hard to visualise the details of the structures in close proximity to the bowel because of the gas-containing portions (air conducts sound very poorly). In our unit, we use an USG-guided HIFU system.26
Magnetic resonance imaging
This offers excellent resolution and tumour detail. It locates the tumour boundary very clearly and is particularly useful in patients in whom tumours cannot be visualised with USG, for example, in obese patients.27 Magnetic resonance imaging possesses real-time thermal resolution with high spatial resolution, and provides temperature data within seconds of HIFU exposure. This allows detection of small temperature elevations before any irreversible tissue damage occurs.28 Nonetheless, MRI guidance is expensive, labour intensive, noisy, and bulky. Equipment such as that used for monitoring and anaesthesia needs to be non-ferrous and MRI-safe and treatment time is prolonged.
High-intensity focused ultrasound device
There are several devices available for the treatment of various diseases, including extracorporeal, transrectal, and interstitial devices.
Organs lying externally or those that are readily accessible—such as breasts, cutaneous tissue, limbs, abdomen, and brain—are usually treated with extracorporeal HIFU that is guided by either USG or MRI. As long as there is a suitable acoustic window on the skin that allows uninterrupted propagation of the HIFU energy beam to the target organs, one can consider the use of extracorporeal HIFU for treatment.
Ultrasonography-guided transcutaneous high-intensity focused ultrasound
We are currently using a HIFU machine produced by Haifu Technology Company (Chongqing, China) [Figs 1, 2, 3]. It has been used and shown to be effective in treatment of a variety of benign and malignant solid organ tumours, such as liver and pancreatic cancer, uterine fibroids, soft tissue tumours, breast cancer, and bladder cancer.29 30 31 This system consists of three selectable therapeutic transducers and a real-time imaging transducer. The transducers are mounted in a water reservoir with the beam axis directed upward, and the patient is positioned above the transducers in a prone or decubitus position. The HIFU exposure level is adjusted until a hyperechoic region is seen on the USG image.
Figure 1. The usual setup of the high-intensity focused ultrasound (HIFU) system
(a) Control system; (b) HIFU machine and patient lying on the treatment table; and (c) anaesthetic machine
Magnetic resonance imaging–guided high-intensity focused ultrasound
Two major clinical MRI-HIFU systems are available worldwide: InSightec (Tirat Carmel, Israel) and Philips Healthcare (Vantaa, Finland).32 33 Their HIFU transducers are similar in terms of enabling both mechanical and electronic adjustment of HIFU focus and MR thermometric temperature monitoring, but their sonication strategies are different and hence they differ in energy efficiency.34 These machines are not available in Hong Kong.
Transrectal devices were developed for the treatment of benign and malignant prostatic diseases. They aim to ablate the entire prostate. Both USG-guided probes and MRI-guided systems have been developed. The USG probes are inserted per rectum and incorporate both imaging and therapeutic transducers in one unit,35 36 37 38 39 40 41 such as Ablatherm (Edap Technomed, France) and the Sonablate (Focus Surgery Inc, US), whereas a prostate-dedicated MRI-HIFU system makes use of either the transrectal (ExAblate OR; InSightec) or transurethral (Philips Healthcare) approach.42 43
Ultrasonographic transducers with different shapes and sizes were developed in order to place the focused applicators as close as possible to the target area. Several shapes are available, including cylindrical, semi-cylindrical, cylindrical with focusing by wave reflection, plane and cylindrical array. Various applicators have been developed to facilitate access and guidance of the device, such as the flexible applicator in an endoscopically placed HIFU device for the treatment of cholangiocarcinoma44 or oesophageal tumours45; or rigid applicators for a linear approach. Probes for percutaneous and laparoscopic treatment are also being developed and it is likely that the therapeutic indications will increase.
Current clinical applications
High-intensity focused ultrasound has been used to treat various benign and malignant solid tumours. It is also used in conditions such as ablation for atrial fibrillation,46 glaucoma,47 and benign obstetric and gynaecological procedures such as fibroids.32
In general, liver resection is still the mainstay of treatment of hepatocellular carcinoma (HCC), provided the patient is surgically fit, has fair liver function with good liver remnant and resectable tumour. Liver transplantation is planned for patients whose tumour is within the transplant criteria, and a living or deceased donor is available.
Ablative therapy, such as radiofrequency ablation (RFA), is considered for patients with a relatively small tumour, preserved liver function, and favourable location, that is, away from pleural or gastrointestinal tract. For those patients whose tumours are relatively small, located at the dome of the liver, with clinical evidence of ascites or pleural effusion, HIFU would be an alternative as long as the lesion can be visualised and located by USG. For those patients with multifocal tumours that are not amenable to surgical resection or ablation, and who have reasonable liver function without evidence of ascites, transarterial chemoembolisation is the treatment of choice. Sorafenib is an effective target therapy for patients undergoing palliative care, but has significant side-effects.
High-intensity focused ultrasound is now one of the treatment modalities in our centre for HCC and has been used as bridging therapy for patients who are awaiting cadaveric donor liver transplantation. This technique can be utilised for patients who are not suitable for percutaneous RFA but have a satisfactory general condition as assessed by an anaesthesiologist. They should have intact skin over the ablative region.
High-intensity focused ultrasound treatment procedure
Before treatment, the patient undergoes USG screening to ensure that the targeted lesions are visible on the USG localisation system. An anaesthesiologist will assess the patient’s co-morbidities and suitability for general anaesthesia as many patients may be unfit for open surgery. Standard fasting and drug administration guidelines apply. Before treatment starts, the patient’s skin is cleansed with degassed water and a negative-pressure aspirator is used to degas the skin and reduce the dampening effect of ultrasonic waves.
We use the JC HIFU system (Chongqing Haifu Technology, Chongqing, China); HIFU ablation is performed under general anaesthesia by a team of surgeons and radiologists. Total intravenous anaesthesia is favoured in our centre because of its titratability, avoidance of nitrous oxide, and no need for scavenging waste anaesthetic gases that may be hazardous to the health of attendant staff.48 A dose of antibiotic (Augmentin 1.2 g; Beecham Pharmaceuticals, Brentford, UK) is given just before the procedure begins. Artificial pleural effusion of 500 mL of normal saline is introduced if the liver tumour is located at the dome, in order to facilitate better ultrasound access to this region and protect the lung. In addition, intermittent cessation of respiratory movement by the anaesthesiologist facilitates better localisation of the lesions during energy transfer. For right-sided lesions, the patient is placed in the right lateral position after tracheal intubation. For left-sided lesions, the patient is placed in the prone position. The JC HIFU system consists of a treatment unit that delivers focused ultrasound energy with a focal length of 12 cm deep. The body is immersed in a degassed water circulation unit that provides a medium for ultrasound transmission. Grey-scale changes at the ablation site are observed during the procedure, indicating the temperature change inside the targeted lesion. Oral antibiotics are given for 5 days after treatment.49
When ablating a large tumour, the ultrasound energy is focused on the deep margin of the lesion first so as to avoid prohibition of effective penetration of energy by the cavitation effect and the presence of coagulation necrosis. Meticulous planning of the focus point before the procedure, in which the ablation sequence is from the deepest layer to the most superficial layer, is required for maximal destruction of the targeted lesion. Intermittent cessations of the procedure allow recovery of the cavitation effect shown under USG monitoring, giving additional allowance for ablation of the residual lesion in the periphery.50
Although a minimally invasive approach can be employed in patients with HCC and liver cirrhosis, hepatectomy is contra-indicated in patients with decompensated cirrhosis.51 Our pilot studies suggested that HIFU is relatively safe and effective.52 53 Patients who have poor liver function can still be offered HIFU.54 Its effectiveness in treating small HCC of size <3 cm was proven to be comparable with percutaneous RFA.55 Furthermore, its application in recurrent HCC allows patients to undergo ablation, especially when the abdomen is hostile due to previous surgery, or there is inadequate liver remnant due to previous major hepatectomy.56 In the treatment of HCC in non-surgical candidates, 1- and 3-year overall survival rates of 87.7% and 62.4%, respectively were achieved in 49 patients with a median tumour size of 2.2 cm.49 In addition, our prospective study suggested that the response rate for those patients with HCC who underwent HIFU as the bridging treatment while awaiting cadaveric liver transplantation was higher than in those who underwent transarterial chemoembolisation.52 It is particularly useful in patients who also have poor liver function with clinical ascites, as ascites itself is a good acoustic media for HIFU.57
High-intensity focused ultrasound does carry certain risks in the treatment for HCC. Minor complications such as skin and subcutaneous tissue injury occur in most patients.54 At our centre, there has been a case of post-HIFU bile duct stricture requiring endoscopic retrograde cholangiography.
Inoperable locally advanced pancreatic cancer remains difficult to treat. Local ablative therapy with HIFU has been used in patients with unresectable pancreatic cancer and proven to be safe in both clinical trials and retrospective studies,31 58 59 60 with no damage to the exocrine or endocrine function.61 62 63 It has been used as a form of palliative treatment in some pilot studies with a median survival ranging from 10 to 12.6 months, either alone or combined with chemotherapy.62 63 64 65 Pain relief was also found to be effective.31 58 59 63 65 66 Unfortunately, treatment after HIFU usually lacked histomorphological examination. The survival benefit needs to be tested in further studies, and preferably confirmed by randomised controlled trials.
Transrectal HIFU is advocated as a form of minimally invasive treatment for localised prostate cancer. It is suggested primarily for patients with low- to intermediate-risk prostate cancer, according to D’Amico Risk stratification.67 68 69 70 71 72 It has also been used to treat locally recurrent prostate cancer. Patients with unifocal and multifocal prostate cancer were subjected to HIFU and had no evidence of disease on MRI at 12 months.73 Good functional outcome was achieved after the treatment, such as continence and good erectile function. Nonetheless, complications such as acute retention of urine or more severe rectal wall injury can occur. More sophisticated MRI-guided HIFU will allow more precise localisation of such lesions.74 To date, most studies have been in the form of retrospective studies or case series only with no randomised controlled trial of HIFU for the treatment of prostate cancer.
International consensus panels recommend ablative techniques in patients who are unfit for surgery, who are not considered candidates for or elect against active surveillance, and who have a small renal mass.75 76 European Association of Urology guidelines recommend the use of an ablative method only in tumours of less than 4 cm.76 In fact, HIFU has been investigated in the treatment of both primary and metastatic renal tumours.77 78 79 Results suggest that there were discrete zones of ablation in 67% of patients in the final histology and HIFU achieved stable lesions in two thirds of patients with minimal morbidity; 90% of patients had good pain control immediately after HIFU.79 There were several limitations, however, such as the degree of subcutaneous and perinephric fat and the position of the tumour in relation to the ribs.80 Higher acoustic output is needed to compensate for the energy loss due to the thickness of the perinephric fat that might in turn increase the risk of prefocal and surrounding tissue damage.81 Currently, there is no controlled study to suggest the superiority of HIFU over various ablative techniques, such as RFA or cryoablation.
High-intensity focused ultrasound was first used in the 1950s to treat Parkinson’s disease.82 83 84 It required access through the skull to the brain and, therefore, craniotomy was necessary. It subsequently became unpopular due to the concurrent development of the drug levodopa. With the advancement of MRI guidance, there has been a resurgence of interest as a non-invasive treatment for essential tremor, neuropathic pain, and Parkinson’s disease. It is safe, without major risk of infection or bleeding, but may result in transient oedema. In Parkinson’s disease, as the disease progresses, patients will eventually require levodopa that is associated with tolerance and, eventually, development of levodopa-resistant symptoms with movement fluctuations and dyskinesias. At this time surgical intervention may be considered. High-intensity focused ultrasound can allow ablation of the fibres that join the thalamus with the globus pallidus. Results of a pilot study suggested that there was improvement in terms of the functional score as rated by the Unified Parkinson’s Disease Rating Scale.85
Essential tremor is a common neurological condition usually managed conservatively, or with propranolol and primidone. For those treatment-resistant patients, surgical intervention may be considered. Usually RFA, stereotactic radiosurgery, gamma knife thalamotomy, or deep brain stimulation are used to either cause tissue destruction or to block abnormal nerve signals. High-intensity focused ultrasound has been used in a clinical trial context with promising results and marked reduction (>80%) of tremor.86 87
Neuropathic pain is a complex condition often associated with damage to or dysfunction of the nerve fibres that then send incorrect signals to the pain centres with minimal stimulation. High-intensity focused ultrasound can be directed to the part of the central lateral thalamic nucleus of those patients suffering from chronic therapy-resistant neuropathic pain. Significant pain relief has been observed with long-term follow-up in a pilot study.88
High-intensity focused ultrasound is an ideal breast-conserving therapy because it does not significantly change the patients’ breast shape and does not cause bleeding or scarring. It does not require general anaesthesia, and hence has a reduced recovery time. Both USG- and MRI-guided HIFU ablations have been used. The aim is to achieve complete tumour necrosis but results have been inconsistent with some showing complete necrosis,89 and others residual tumour of less than 10% and residual tumour between 10% and 90%.90 91 92 93 94 A negative margin is the most important basis and factor for local control of the breast cancer.95 96 Nonetheless, it is difficult to ensure a negative margin after HIFU therapy with the aid of imaging alone, hence adjuvant radiotherapy has been suggested. Currently, there is limited prospective study or randomised trial in this area. Most work has been pilot studies or feasibility studies only.
Complications include pain, skin burns, oedema, pectoralis major muscle injury,97 and rib pain.98 These are relatively minor compared with those following traditional breast surgery with its attendant potential complications of wound pain, infection, bleeding, and impaired wound healing.
Uterine fibroid is a common benign gynaecological condition in women of childbearing age. Patients usually suffer symptoms such as heavy, painful, and prolonged menstrual bleeding, mass effect with urinary urgency, and constipation.99 Conservative medical therapy with non-steroidal anti-inflammatory drugs, contraceptive steroids, and gonadotropin-releasing hormone agonists are the first-line treatment. Ablative treatment as well as surgery will be necessary for those in whom conservative management fails or in those with progressive symptoms. Treatment is by means of myomectomy or hysterectomy. In cases where the patient does not want surgery, or where the patient is planning a future pregnancy, HIFU is a good option.100 101 Extracorporeal HIFU enables ablation of various sizes and shape of fibroid. Symptoms are reduced by more than 50% in terms of pain,102 103 104 bulk-related and menstrual symptoms, comparable with the results of conventional surgery.105 After HIFU, the ablated fibroid volume is decreased, and is related to the non-perfused volume of the tumour immediately after treatment.44 106 107 Nonetheless, HIFU cannot propagate through air-filled viscera such as bowel. There is a potential risk of bowel perforation if it lies close to the fibroids.108 Most of the articles were from China, as HIFU has been used in China for treatment of fibroids. In our hospital, the following criteria are used for patient selection: (1) premenopausal women with no plans for further childbearing; (2) severe fibroid symptoms (as defined by a transformed symptom severity score of >41 on the Uterine Fibroid Symptom and Quality of Life questionnaire); (3) a clinical uterine size of less than 20 weeks’ gestation, a dominant fibroid of less than 10 cm in diameter without areas of necrosis as judged by contrast-enhanced MRI, a non-pedunculated fibroid, and a fibroid not suspicious of malignancy; (4) no evidence of known or suspected extensive pelvic adhesions such as history of acute pelvic inflammatory disease, severe pelvic endometriosis, or lower abdominal surgery; and (5) an abdominal wall thickness of less than 5 cm.109
In palliative treatment of bone tumours, therapeutic goals include pain palliation, tumour reduction, prevention of impending pathological fractures, and/or tumour decompression. Opioid analgesics and radiation therapy are widely used for pain control in patients suffering from bone metastases but this does not always provide desired relief in many patients and is associated with undesirable side-effects.110 111 112 113 114 115 Research reveals that MRI-guided HIFU is safe and effective in the treatment of painful bone tumours.116 117 118 Periosteal denervation and tumour debulking may play a significant role in symptom relief.74 116 117 Response to HIFU is rapid and good pain control has been seen within days of treatment. This greatly improves the quality of life for many patients with disseminated cancer.119 There is also evidence of a reduction in lesion viability after HIFU and a remineralisation of spongious bone.120
Tumour ablation in curative treatment aims for complete coagulation necrosis of the primary lesion. Primary bone malignancy such as osteosarcoma has been treated with HIFU. A combination of chemotherapy with HIFU seems to be as effective as limb-sparing surgery and chemotherapy for malignant bone tumours.121 This is potentially useful for patients who are not fit for surgery. Treatment complications include skin burns, procedure-related pain, and post-treatment fractures.121 122 Most of the studies were clinical trials. More studies should focus on the treatment outcome in terms of the function, quality of life, and survival.
The specific advantage of HIFU is that the energy can be focused through non-optically transparent media without uncontrolled energy absorption, thus reducing the effects on adjacent tissues. It allows a defined and adjustable tissue volume to be heated and treated at any depth or location within the eye. Intra-ocular pressure is decreased both by reducing aqueous humour production (aqueous inflow) and by facilitating the evacuation of aqueous humour from the eye (aqueous outflow).123 Prospective case series suggest there is a significant reduction in intra-ocular pressure without significant peri- or post-treatment side-effects.124
High-intensity focused ultrasound has been used to treat atrial fibrillation in cardiac surgery. This is designed to deliver pulmonary vein and posterior left atrial wall isolation on the beating heart using an encircling ‘cinch’ and create left atrial lines using a handheld wand device. It then ablates areas around the ganglionic plexi where dense collections of complex fractionated atrial electrograms are found. It has been proven to be safe and effective.125 Patients can be reverted to sinus rhythm and the results are more pronounced in patients with paroxysmal atrial fibrillation.46 126 Selected use of this technique has been suggested.127 If symptoms persist, other modalities should be considered.125
High-intensity focused ultrasound has many applications in both benign and malignant diseases. It offers an alternative to those patients for whom surgery is contra-indicated or inappropriate. The results of HIFU in the management of HCC patients in our centre are particularly promising. Further studies of the application of HIFU in various organs should be conducted for both clinical trials as well as comparative studies with other ablative modalities in the form of randomised controlled trials.
No funding was received for the study or its publication. None of the authors has any conflict of interest with regard to the study or its publication.
1. Lynn JG, Zwemer RL, Chick AJ, Miller AE. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 1942;26:179-93. CrossRef
2. Fry WJ, Fry FJ. Fundamental neurological research and human neurosurgery using intense ultrasound. IRE Trans Med Electron 1960;ME-7:166-81. CrossRef
3. Lynn JG, Putnam TJ. Histology of cerebral lesions produced by focused ultrasound. Am J Pathol 1944;20:637-49.
4. Coleman DJ, Lizzi FL, el-Mofty AA, Driller J, Franzen LA. Ultrasonically accelerated resorption of vitreous membranes. Am J Ophthalmol 1980;89:490-9. CrossRef
5. Coleman DJ, Lizzi FL, Torpey JH, et al. Treatment of experimental lens capsular tears with intense focused ultrasound. Br J Ophthalmol 1985;69:645-9. CrossRef
6. Coleman DJ, Lizzi FL, Driller J, et al. Therapeutic ultrasound in the treatment of glaucoma. II. Clinical applications. Ophthalmology 1985;92:347-53. CrossRef
7. Rosenberg RS, Purnell EW. Effects of ultrasonic radiation to the ciliary body. Am J Ophthalmol 1967;63:403-9. CrossRef
8. Silverman RH, Vogelsang B, Rondeau MJ, Coleman DJ. Therapeutic ultrasound for the treatment of glaucoma. Am J Ophthalmol 1991;111:327-37. CrossRef
9. Rosecan LR, Iwamoto T, Rosado A, Lizzi FL, Coleman DJ. Therapeutic ultrasound in the treatment of retinal detachment: clinical observations and light and electron microscopy. Retina 1985;5:115-22. CrossRef
10. Mearini L. High intensity focused ultrasound, liver disease and bridging therapy. World J Gastroenterol 2013;19:7494-9. CrossRef
11. Dubinsky TJ, Cuevas C, Dighe MK, Kolokythas O, Hwang JH. High-intensity focused ultrasound: current potential and oncologic applications. AJR Am J Roentgenol 2008;190:191-9. CrossRef
12. Yang R, Reilly CR, Rescorla FJ, et al. High-intensity focused ultrasound in the treatment of experimental liver cancer. Arch Surg 1991;126:1002-9; discussion 1009-10. CrossRef
13. Holland CK, Apfel RE. Thresholds for transient cavitation produced by pulsed ultrasound in a controlled nuclei environment. J Acoust Soc Am 1990;88:2059-69. CrossRef
14. Marmottant P, Hilgenfeldt S. Controlled vesicle deformation and lysis by single oscillating bubbles. Nature 2003;423:153-6. CrossRef
15. Pitt WG, Husseini GA, Staples BJ. Ultrasonic drug delivery—a general review. Expert Opin Drug Deliv 2004;1:37-56. CrossRef
16. Vaezy S, Shi X, Martin RW, et al. Real-time visualization of high-intensity focused ultrasound treatment using ultrasound imaging. Ultrasound Med Biol 2001;27:33-42. CrossRef
17. Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys 1984;10:787-800. CrossRef
18. Dewhirst MW, Viglianti BL, Lora-Michiels M, Hanson M, Hoopes PJ. Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int J Hyperthermia 2003;19:267-94. CrossRef
19. ter Haar GR, Robertson D. Tissue destruction with focused ultrasound in vivo. Eur Urol 1993;23 Suppl 1:8-11.
20. Wu F, Chen WZ, Bai J, et al. Pathological changes in human malignant carcinoma treated with high-intensity focused ultrasound. Ultrasound Med Biol 2001;27:1099-106. CrossRef
21. Kim YS, Rhim H, Choi MJ, Lim HK, Choi D. High-intensity focused ultrasound therapy: an overview for radiologists. Korean J Radiol 2008;9:291-302. CrossRef
22. Li JJ, Xu GL, Gu MF, et al. Complications of high intensity focused ultrasound in patients with recurrent and metastatic abdominal tumors. World J Gastroenterol 2007;13:2747-51. CrossRef
23. Sibille A, Prat F, Chapelon JY, et al. Extracorporeal ablation of liver tissue by high-intensity focused ultrasound. Oncology 1993;50:375-9. CrossRef
24. Roberts WW, Hall TL, Ives K, Wolf JS Jr, Fowlkes JB, Cain CA. Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney. J Urol 2006;175:734-8. CrossRef
25. ter Haar G. Ultrasound focal beam surgery. Ultrasound Med Biol 1995;21:1089-100. CrossRef
26. Hynynen K, Freund WR, Cline HE, et al. A clinical, noninvasive, MR imaging–monitored ultrasound surgery method. Radiographics 1996;16:185-95. CrossRef
27. Yagel S. High-intensity focused ultrasound: a revolution in non-invasive ultrasound treatment? Ultrasound Obstet Gynecol 2004;23:216-7. CrossRef
28. Hynynen K, Pomeroy O, Smith DN, et al. MR imaging–guided focused ultrasound surgery of fibroadenomas in the breast: a feasibility study. Radiology 2001;219:176-85. CrossRef
29. Dong X, Yang Z. High-intensity focused ultrasound ablation of uterine localized adenomyosis. Curr Opin Obstet Gynecol 2010;22:326-30. CrossRef
30. Jung SE, Cho SH, Jang JH, Han JY. High-intensity focused ultrasound ablation in hepatic and pancreatic cancer: complications. Abdom Imaging 2011;36:185-95. CrossRef
31. Orsi F, Zhang L, Arnone P, et al. High-intensity focused ultrasound ablation: effective and safe therapy for solid tumors in difficult locations. AJR Am J Roentgenol 2010;195:W245-52. CrossRef
32. Tempany CM, Stewart EA, McDannold N, Quade BJ, Jolesz FA, Hynynen K. MR imaging–guided focused ultrasound surgery of uterine leiomyomas: a feasibility study. Radiology 2003;226:897-905. CrossRef
33. Kim YS, Keserci B, Partanen A, et al. Volumetric MR-HIFU ablation of uterine fibroids: role of treatment cell size in the improvement of energy efficiency. Eur J Radiol 2012;81:3652-9. CrossRef
34. Kim YS. Advances in MR image–guided high-intensity focused ultrasound therapy. Int J Hyperthermia 2015;31:225-32. CrossRef
35. Sanghvi NT, Foster RS, Bihrle R, et al. Noninvasive surgery of prostate tissue by high intensity focused ultrasound: an updated report. Eur J Ultrasound 1999;9:19-29. CrossRef
36. Beerlage HP, Thüroff S, Debruyne FM, Chaussy C, de la Rosette JJ. Transrectal high-intensity focused ultrasound using the Ablatherm device in the treatment of localized prostate carcinoma. Urology 1999;54:273-7. CrossRef
37. Andreou C, Blana A, Orovan W, Hassouna M, Warner J, Woods E. Technical review: high-intensity focused ultrasound for prostate cancer. Can J Urol 2005;12:2684-5; discussion 2686.
38. Christopher T. HIFU focusing efficiency and a twin annular array source for prostate treatment. IEEE Trans Ultrason Ferroelectr Freq Control 2005;52:1523-33. CrossRef
39. Curiel L, Chavrier F, Souchon R, Birer A, Chapelon JY. 1.5-D high intensity focused ultrasound array for non-invasive prostate cancer surgery. IEEE Trans Ultrason Ferroelectr Freq Control 2002;49:231-42. CrossRef
40. Rebillard X, Gelet A, Davin JL, et al. Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer. J Endourol 2005;19:693-701. CrossRef
41. Saleh KY, Smith NB. A 63 element 1.75 dimensional ultrasound phased array for the treatment of benign prostatic hyperplasia. Biomed Eng Online 2005;4:39. CrossRef
42. Lindner U, Ghai S, Spensieri P, et al. Focal magnetic resonance guided focused ultrasound for prostate cancer: Initial North American experience. Can Urol Assoc J 2012;6:E283-6.
43. Siddiqui K, Chopra R, Vedula S, et al. MRI-guided transurethral ultrasound therapy of the prostate gland using real-time thermal mapping: initial studies. Urology 2010;76:1506-11. CrossRef
44. Lafon C, Chapelon JY, Prat F, et al. Design and preliminary results of an ultrasound applicator for interstitial thermal coagulation. Ultrasound Med Biol 1998;24:113-22. CrossRef
45. Melodelima D, Salomir R, Chapelon JY, Theillère Y, Moonen C, Cathignol D. Intraluminal high intensity ultrasound treatment in the esophagus under fast MR temperature mapping: in vivo studies. Magn Reson Med 2005;54:975-82. CrossRef
46. Reyes G, Ruyra X, Valderrama F, et al. High intensity focused ultrasound ablation for atrial fibrillation: results from the National Spanish Registry. Minerva Cardioangiol 2015 May 26. Epub ahead of print.
47. Melamed S, Goldenfeld M, Cotlear D, Skaat A, Moroz I. High-intensity focused ultrasound treatment in refractory glaucoma patients: results at 1 year of prospective clinical study. Eur J Ophthalmol 2015;25:483-9. CrossRef
48. Yao CL, Trinh T, Wong GT, Irwin MG. Anaesthesia for high intensity focused ultrasound (HIFU) therapy. Anaesthesia 2008;63:865-72. CrossRef
49. Ng KK, Poon RT, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma: a single-center experience. Ann Surg 2011;253:981-7. CrossRef
50. Cheung TT, Poon RT, Jenkins CR, et al. Survival analysis of high-intensity focused ultrasound therapy vs. transarterial chemoembolization for unresectable hepatocellular carcinomas. Liver Int 2014;34:e136-43. CrossRef
51. Cheung TT, Poon RT, Yuen WK, et al. Long-term survival analysis of pure laparoscopic versus open hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a single-center experience. Ann Surg 2013;257:506-11. CrossRef
52. Cheung TT, Fan ST, Chan SC, et al. High-intensity focused ultrasound ablation: an effective bridging therapy for hepatocellular carcinoma patients. World J Gastroenterol 2013;19:3083-9. CrossRef
53. Wu F, Wang ZB, Chen WZ, et al. Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 2005;235:659-67. CrossRef
54. Cheung TT, Chu FS, Jenkins CR, et al. Tolerance of high-intensity focused ultrasound ablation in patients with hepatocellular carcinoma. World J Surg 2012;36:2420-7. CrossRef
55. Cheung TT, Fan ST, Chu FS, et al. Survival analysis of high-intensity focused ultrasound ablation in patients with small hepatocellular carcinoma. HPB (Oxford) 2013;15:567-73. CrossRef
56. Chan AC, Cheung TT, Fan ST, et al. Survival analysis of high-intensity focused ultrasound therapy versus radiofrequency ablation in the treatment of recurrent hepatocellular carcinoma. Ann Surg 2013;257:686-92. CrossRef
57. Chok KS, Cheung TT, Lo RC, et al. Pilot study of high-intensity focused ultrasound ablation as a bridging therapy for hepatocellular carcinoma patients wait-listed for liver transplantation. Liver Transpl 2014;20:912-21. CrossRef
58. Orgera G, Krokidis M, Monfardini L, et al. High intensity focused ultrasound ablation of pancreatic neuroendocrine tumours: report of two cases. Cardiovasc Intervent Radiol 2011;34:419-23. CrossRef
59. Wang K, Zhu H, Meng Z, et al. Safety evaluation of high-intensity focused ultrasound in patients with pancreatic cancer. Onkologie 2013;36:88-92. CrossRef
60. Sung HY, Jung SE, Cho SH, et al. Long-term outcome of high-intensity focused ultrasound in advanced pancreatic cancer. Pancreas 2011;40:1080-6. CrossRef
61. Shi Y, Ying X, Hu X, et al. Influence of high intensity focused ultrasound (HIFU) treatment to the pancreatic function in pancreatic cancer patients. Pak J Pharm Sci 2015;28 Suppl:1097-100.
62. Zhao H, Yang G, Wang D, et al. Concurrent gemcitabine and high-intensity focused ultrasound therapy in patients with locally advanced pancreatic cancer. Anticancer Drugs 2010;21:447-52. CrossRef
63. Gao HF, Wang K, Meng ZQ, et al. High intensity focused ultrasound treatment for patients with local advanced pancreatic cancer. Hepatogastroenterology 2013;60:1906-10.
64. Xiong LL, Hwang JH, Huang XB, et al. Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer. JOP 2009;10:123-9.
65. Wang K, Chen Z, Meng Z, et al. Analgesic effect of high intensity focused ultrasound therapy for unresectable pancreatic cancer. Int J Hyperthermia 2011;27:101-7. CrossRef
66. Wu F, Wang ZB, Zhu H, et al. Feasibility of US-guided high-intensity focused ultrasound treatment in patients with advanced pancreatic cancer: initial experience. Radiology 2005;236:1034-40. CrossRef
67. Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. Int J Urol 2009;16:881-6. CrossRef
68. Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63:297-300. CrossRef
69. Ripert T, Azémar MD, Ménard J, et al. Six years’ experience with high-intensity focused ultrasonography for prostate cancer: oncological outcomes using the new ‘Stuttgart’ definition for biochemical failure. BJU Int 2011;107:1899-905. CrossRef
70. Crouzet S, Chapelon JY, Rouvière O, et al. Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. Eur Urol 2014;65:907-14. CrossRef
71. Mearini L, D’Urso L, Collura D, Nunzi E, Muto G, Porena M. High-intensity focused ultrasound for the treatment of prostate cancer: A prospective trial with long-term follow-up. Scand J Urol 2015;49:267-74. CrossRef
72. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent—update 2013. Eur Urol 2014;65:124-37. CrossRef
73. Ahmed HU, Hindley RG, Dickinson L, et al. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol 2012;13:622-32. CrossRef
74. Napoli A, Anzidei M, De Nunzio C, et al. Real-time magnetic resonance–guided high-intensity focused ultrasound focal therapy for localised prostate cancer: preliminary experience. Eur Urol 2013;63:395-8. CrossRef
75. Van Poppel H, Becker F, Cadeddu JA, et al. Treatment of localised renal cell carcinoma. Eur Urol 2011;60:662-72. CrossRef
76. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015;67:913-24. CrossRef
77. Illing RO, Kennedy JE, Wu F, et al. The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population. Br J Cancer 2005;93:890-5. CrossRef
78. Ritchie RW, Leslie T, Phillips R, et al. Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up. BJU Int 2010;106:1004-9. CrossRef
79. Wu F, Wang ZB, Chen WZ, Bai J, Zhu H, Qiao TY. Preliminary experience using high intensity focused ultrasound for the treatment of patients with advanced stage renal malignancy. J Urol 2003;170(6 Pt 1):2237-40. CrossRef
80. Kohrmann KU, Michel MS, Gaa J, Marlinghaus E, Alken P. High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature. J Urol 2002;167:2397-403. CrossRef
81. Ritchie R, Collin J, Coussios C, Leslie T. Attenuation and de-focusing during high-intensity focused ultrasound therapy through peri-nephric fat. Ultrasound Med Biol 2013;39:1785-93. CrossRef
82. Fry WJ, Mosberg WH Jr, Barnard JW, Fry FJ. Production of focal destructive lesions in the central nervous system with ultrasound. J Neurosurg 1954;11:471-8. CrossRef
83. Fry WJ, Barnard JW, Fry EJ, Krumins RF, Brennan JF. Ultrasonic lesions in the mammalian central nervous system. Science 1955;122:517-8. CrossRef
84. Fry FJ. Precision high intensity focusing ultrasonic machines for surgery. Am J Phys Med 1958;37:152-6. CrossRef
85. Jeanmonod D, Moser D, Magara A, et al. Study of incisionless transcranial magnetic resonance–guided focused ultrasound treatment of Parkinson’s disease: Safety, accuracy and initial clinical outcomes. Proceedings of the Current and Future Applications of Focused Ultrasound 2012, 3rd International Symposium; 2012 Oct 14-17; Washington, DC Metro Area, United States.
86. Elias WJ, Huss D, Voss T, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2013;369:640-8. CrossRef
87. Lipsman N, Schwartz ML, Huang Y, et al. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 2013;12:462-8. CrossRef
88. Jeanmonod D, Werner B, Morel A, et al. Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus 2012;32:E1. CrossRef
89. Wu F, Wang ZB, Cao YD, et al. Changes in biologic characteristics of breast cancer treated with high-intensity focused ultrasound. Ultrasound Med Biol 2003;29:1487-92. CrossRef
90. Furusawa H, Namba K, Thomsen S, et al. Magnetic resonance–guided focused ultrasound surgery of breast cancer: reliability and effectiveness. J Am Coll Surg 2006;203:54-63. CrossRef
91. Gianfelice D, Khiat A, Amara M, Belblidia A, Boulanger Y. MR imaging–guided focused US ablation of breast cancer: histopathologic assessment of effectiveness—initial experience. Radiology 2003;227:849-55. CrossRef
92. Gianfelice D, Khiat A, Amara M, Belblidia A, Boulanger Y. MR imaging–guided focused ultrasound surgery of breast cancer: correlation of dynamic contrast-enhanced MRI with histopathologic findings. Breast Cancer Res Treat 2003;82:93-101. CrossRef
93. Zippel DB, Papa MZ. The use of MR imaging guided focused ultrasound in breast cancer patients; a preliminary phase one study and review. Breast Cancer 2005;12:32-8. CrossRef
94. Khiat A, Gianfelice D, Amara M, Boulanger Y. Influence of post-treatment delay on the evaluation of the response to focused ultrasound surgery of breast cancer by dynamic contrast enhanced MRI. Br J Radiol 2006;79:308-14. CrossRef
95. Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute randomized trial. Cancer 2003;98:697-702. CrossRef
96. van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer. Eur J Cancer 1992;28A(4-5):801-5. CrossRef
97. Myers MR. Transient temperature rise due to ultrasound absorption at a bone/soft-tissue interface. J Acoust Soc Am 2004;115:2887-91. CrossRef
98. Zderic V, Foley J, Luo W, Vaezy S. Prevention of post-focal thermal damage by formation of bubbles at the focus during high intensity focused ultrasound therapy. Med Phys 2008;35:4292-9. CrossRef
99. Vollenhoven BJ, Lawrence AS, Healy DL. Uterine fibroids: a clinical review. Br J Obstet Gynaecol 1990;97:285-98. CrossRef
100. Wu F, Wang ZB, Chen WZ, et al. Extracorporeal focused ultrasound surgery for treatment of human solid carcinomas: early Chinese clinical experience. Ultrasound Med Biol 2004;30:245-60. CrossRef
101. Smart OC, Hindley JT, Regan L, Gedroyc WM. Magnetic resonance guided focused ultrasound surgery of uterine fibroids—the tissue effects of GnRH agonist pre-treatment. Eur J Radiol 2006;59:163-7. CrossRef
102. Yoon SW, Kim KA, Cha SH, et al. Successful use of magnetic resonance–guided focused ultrasound surgery to relieve symptoms in a patient with symptomatic focal adenomyosis. Fertil Steril 2008;90:2018.e13-5. CrossRef
103. Fennessy FM, Tempany CM, McDannold NJ, et al. Uterine leiomyomas: MR imaging–guided focused ultrasound surgery—results of different treatment protocols. Radiology 2007;243:885-93. CrossRef
104. Lénárd ZM, McDannold NJ, Fennessy FM, et al. Uterine leiomyomas: MR imaging–guided focused ultrasound surgery—imaging predictors of success. Radiology 2008;249:187-94. CrossRef
105. Mikami K, Murakami T, Okada A, Osuga K, Tomoda K, Nakamura H. Magnetic resonance imaging–guided focused ultrasound ablation of uterine fibroids: early clinical experience. Radiat Med 2008;26:198-205. CrossRef
106. LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: report of 80 patients. AJR Am J Roentgenol 2010;194:274-80. CrossRef
107. Zhang L, Chen WZ, Liu YJ, et al. Feasibility of magnetic resonance imaging–guided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus. Eur J Radiol 2010;73:396-403. CrossRef
108. Kennedy JE, Ter Haar GR, Cranston D. High intensity focused ultrasound: surgery of the future? Br J Radiol 2003;76:590-9. CrossRef
109. Cheung VY. Sonographically guided high-intensity focused ultrasound for the management of uterine fibroids. J Ultrasound Med 2013;32:1353-8. CrossRef
110. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007;25:1423-36. CrossRef
111. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005;97:798-804. CrossRef
112. Cleeland CS. The measurement of pain from metastatic bone disease: capturing the patient’s experience. Clin Cancer Res 2006;12(20 Pt 2):6236s-42s. CrossRef
113. van der Linden YM, Lok JJ, Steenland E, et al. Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 2004;59:528-37. CrossRef
114. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-93. CrossRef
115. Saarto T, Janes R, Tenhunen M, Kouri M. Palliative radiotherapy in the treatment of skeletal metastases. Eur J Pain 2002;6:323-30. CrossRef
116. Catane R, Beck A, Inbar Y, et al. MR-guided focused ultrasound surgery (MRgFUS) for the palliation of pain in patients with bone metastases—preliminary clinical experience. Ann Oncol 2007;18:163-7. CrossRef
117. Gianfelice D, Gupta C, Kucharczyk W, Bret P, Havill D, Clemons M. Palliative treatment of painful bone metastases with MR imaging–guided focused ultrasound. Radiology 2008;249:355-63. CrossRef
118. Liberman B, Gianfelice D, Inbar Y, et al. Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study. Ann Surg Oncol 2009;16:140-6. CrossRef
119. Zeng L, Chow E, Bedard G, et al. Quality of life after palliative radiation therapy for patients with painful bone metastases: results of an international study validating the EORTC QLQ-BM22. Int J Radiat Oncol Biol Phys 2012;84:e337-42. CrossRef
120. Napoli A, Anzidei M, Marincola BC, et al. Primary pain palliation and local tumor control in bone metastases treated with magnetic resonance–guided focused ultrasound. Invest Radiol 2013;48:351-8. CrossRef
121. Chen W, Zhu H, Zhang L, et al. Primary bone malignancy: effective treatment with high-intensity focused ultrasound ablation. Radiology 2010;255:967-78. CrossRef
122. Hurwitz MD, Ghanouni P, Kanaev SV, et al. Magnetic resonance–guided focused ultrasound for patients with painful bone metastases: phase III trial results. J Natl Cancer Inst 2014;106:dju082. CrossRef
123. Aptel F, Begle A, Razavi A, et al. Short- and long-term effects on the ciliary body and the aqueous outflow pathways of high-intensity focused ultrasound cyclocoagulation. Ultrasound Med Biol 2014;40:2096-106. CrossRef
124. Aptel F, Dupuy C, Rouland JF. Treatment of refractory open-angle glaucoma using ultrasonic circular cyclocoagulation: a prospective case series. Curr Med Res Opin 2014;30:1599-605. CrossRef
125. Davies EJ, Bazerbashi S, Asopa S, Haywood G, Dalrymple-Hay M. Long-term outcomes following high intensity focused ultrasound ablation for atrial fibrillation. J Card Surg 2014;29:101-7. CrossRef
126. Garcia R, Sacher F, Oses P, et al. Electrophysiological study 6 months after Epicor high-intensity focused ultrasound atrial fibrillation ablation. J Interv Card Electrophysiol 2014;41:245-51. CrossRef
127. Colli A, Romero-Ferrer B. It is time to revisit the theory of acute conduction block: efficacy of high-intensity focused ultrasound epicardial ablation. Eur J Cardiothorac Surg 2013;43:451-2. CrossRef