High Intensity Focused Ultrasound

Number: 0766

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Aetna considers high intensity focused ultrasound (HIFU) medically necessary for radio-recurrent prostate cancer in the absence of metastatic disease.

Aetna considers HIFU experimental and investigational for the following indications because of insufficient evidnece of its effectiveness (not an all-inclusive list):

  • Abdominal wall endometriosis
  • Adenomyosis-related symptoms
  • Alzheimer’s disease
  • Benign prostatic hypertrophy (see CPB 0079 - Benign Prostatic Hyperplasia)
  • Breast cancer
  • Breast fibroadenoma
  • Breast fibromatosis
  • Central nervous system diseases/disorders (e.g., brain cancer and stroke)
  • Cesarean scar pregnancy
  • Desmoid tumors
  • Epilepsy
  • Extra-abdominal desmoid tumors,
  • Fractures
  • Glaucoma
  • Gliomas
  • Graves’ disease
  • Gynecological tumors within the pelvis
  • Hepatocellular carcinoma
  • Hyper-pigmentation (pigmentary skin disorder)
  • Liver metastasis from colon and stomach cancer
  • Low-flow vascular malformations
  • Melanoma
  • Melasma
  • Metastatic bone pain
  • Migraines
  • Malignant biliary obstruction
  • Movement disorders (e.g., Parkinson's disease) other than essential tremor (see CPB 0153 - Thalamotomy)
  • Neuropathy/neuropathic pain  
  • Obsessive compulsive disorder
  • Open-angle glaucoma
  • Osteoarthritis
  • Osteoid osteoma
  • Osteosarcoma/bone tumors 
  • Pancreatic cancer
  • Placenta accreta
  • Primary hyperparathyroidism
  • Primary liver cancer
  • Renal cancer
  • Renal sympathetic denervation in the treatment of resistant hypertension
  • Thyroid nodules
  • Twin-twin transfusion syndrome/ twin reversed arterial perfusion (TRAP) sequence
  • Uterine arterio-venous malformation
  • Uterine leiomyomas and adenomyosis
  • Vulvar dystrophy.

For MRI-guided ultrasound ablation of uterine fibroids, see CPB 0304 - Fibroid Treatment.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered when selection criteria are met:

55880 Ablation of malignant prostate tissue, transrectal, with high intensity-focused ultrasound (HIFU), including ultrasound guidance

CPT codes not covered for indications listed in the CPB:

0398T Magnetic resonance image guided high intensity focused ultrasound (MRgFUS), stereotactic ablation lesion, intracranial for movement disorder including stereotactic navigation and frame placement when performed

HCPCS codes not covered for indications listed in the CPB:

C9734 Focused ultrasound ablation/therapeutic intervention, other than uterine leiomyomata, with magnetic resonance (MR) guidance

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate [radio-recurrent prostate cancer]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

B02.22 Postherpetic trigeminal neuralgia
B02.23 Postherpetic polyneuropathy
B02.29 Other postherpetic nervous system involvement
C16.0 - C16.9 Malignant neoplasm of stomach [liver metastasis from stomach cancer]
C18.0 - C18.9 Malignant neoplasm of colon [liver metastasis from colon]
C22.0, C22.2 - C22.8 Malignant neoplasm of liver, primary [hepatocellular]
C24.0 - C24.9 Malignant neoplasm of other and unspecified parts of biliary tract
C25.0 - C25.9 Malignant neoplasm of pancreas
C40.00 - C41.9 Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C43.0 - C43.9 Malignant melanoma of skin
C50.011 - C50.929 Malignant neoplasm of breast
C53.0 - C53.9 Malignant neoplasm of cervix uteri
C56.1 - C56.9 Malignant neoplasm of ovary
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis
C71.0 - C71.9 Malignant neoplasm of brain [central nervous system diseases/disorders]
C76.3 Malignant neoplasm of pelvis
C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct [liver metastasis from colon and stomach cancer]
C79.60 - C79.63 Secondary malignant neoplasm of ovary
C79.82 Secondary malignant neoplasm of genital organs
C79.89 Secondary malignant neoplasm of other specified sites
D03.0 - D03.9 Melanoma in situ
D06.0 - D06.9 Carcinoma in situ of cervix uteri
D07.39 Carcinoma in situ of other female genital organs
D07.5 Carcinoma in situ of prostate
D09.8 Carcinoma in situ of other specified sites
D16.00 - D16.9 Benign neoplasm of bone and articular cartilage [osteoid osteoma]
D21.9 Benign neoplasm of connective and other soft tissue, unspecified [extra-abdominal desmoid]
D24.1 - D24.9 Benign neoplasm of breast
D25.0 - D25.9 Leiomyoma of uterus
D26.0 - D26.9 Other benign neoplasms of uterus
D27.0 - D27.9 Benign neoplasm of ovary
D39.0 - D39.9 Neoplasm of uncertain behavior of female genital organs
D48.1 Neoplasm of uncertain behavior of connective and other soft tissue [desmoid tumors] [extra-abdominal desmoid]
D48.7 Neoplasm of uncertain behavior of other specified sites
D49.59 Neoplasm of unspecified behavior of other genitourinary organ
E04.1 - E04.9 Nontoxic nodular goiter
E05.00 - E05.31 Thyrotoxicosis with toxic nodular goiter
E08.41 Diabetes mellitus due to underlying condition with diabetic mononeuropathy
E09.41 Drug or chemical induced diabetes mellitus with neurological complications with diabetic mononeuropathy
E10.41, E11.41, E13.41 Type 1, Type2 and other specified diabetes mellitus with diabetic mononeuropathy
E21.0 Primary hyperparathyroidism
F42.2 - F42.9 Obsessive-compulsive disorder
G00.0 - G99.8 Diseases of the nervous system [central nervous system diseases/disorders]
G43.001 - G43.919 Migraine
G45.0 - G45.2
G45.8 - G46.8
Transient cerebral ischemic attacks and vascular syndromes of brain [central nervous system diseases/disorders]
G50.0 Trigeminal neuralgia
G54.4 Neuralgic amyotrophy
G58.0 Intercostal neuropathy
G58.8 - G58.9 Other specified and unspecified mononeuropathies
G89.3 Neoplasm related pain (acute)(chronic) [metastatic bone pain]
G97.31 - G97.32 Intraoperative hemorrhage and hematoma of a nervous system organ or structure complicating a procedure [central nervous system diseases/disorders]
H40.001 - H42 Glaucoma
H40.10x0 - H40.159 Open-angle glaucoma
I10 - I16.2 Hypertensive diseases [renal sympathetic denervation in the treatment of resistant hypertension]
I60.00 - I66.9
I67.1 - I67.2
I67.4 - I69.998
Cerebrovascular diseases [central nervous system diseases/disorders]
I97.810 - I97.821 Intraoperative and postprocedural infarction
L81.0 - L81.9 Other disorders of pigmentation
M15.0 - M19.93 Osteoarthritis
M08.1, M25.78, M43.6, M43.20 - M43.28
M45.0 - M46.1
M46.40 - M48.38
M48.8x1 - M53.1
M53.2x7 - M53.2x8
M53.3 - M54.09
M54.11 - M54.17
M54.2 - M54.9
Dorsopathies [central nervous system diseases/disorders]
M79.2 Neuralgia and neuritis, unspecified [neuropathic pain]
M84.750+ - M84.759+ Atypical femoral fracture
N40.0 - N40.3 Enlarged prostate [benign prostatic hypertrophy]
N60.21 - N60.29 Fibroadenosis of breast [breast fibromatosis]
N80.00 - N80.D9 Endometriosis of uterus
N80.8 Other endometriosis [abdominal wall endometriosis]
N80.9 Endometriosis, unspecified [abdominal wall endometriosis]
N85.A Isthmocele
N90.0 - N90.1
Dysplasia of vulva
O00.80 - O00.81 Other ectopic pregnancy [cesarean scar pregnancy]
O30.021 - O30.029 Conjoined twin pregnancy [twin reversed arterial perfusion (TRAP)]
O43.211 - O43.219 Placenta accrete
P02.3 Newborn (suspected to be) affected by placental transfusion syndrome [twin-twin transfusion syndrome]
Q27.0 - Q27.9 Other congenital malformations of peripheral vascular system [low-flow vascular malformations]
Q27.39 Arteriovenous malformation, other site [uterine arterio-venous malformation]
Q89.4 Conjoined twins [twin reversed arterial perfusion (TRAP)]
S02.0xx+ - S02.92x+
S12.000+ - S12.9xx+
S22.000+ - S22.9xx+
S32.000+ - S32.9xx+
S42.001+ - S42.92x+
S52.001+ - S52.92x+
S62.001+ - S62.92x+
S72.001+ - S72.92x+
S82.001+ - S82.92x+
S92.001+ - S92.919+


High-intensity focused ultrasound is a method that focuses ultrasound to heat/ablate target tissues without injuring surrounding structures.  

Prostate Cancer

Prostate cancer, accounting for 33 % of all male cancers, is the 2nd leading cause of cancer death in men, exceeded only by lung cancer.  The disease is histologically evident in as many as 34 % of men during their 5th decade of life and in up to 70 % of men aged 80 years old and older. 

Staging of prostate cancer entails the size of the tumor, if lymph nodes are affected, if the tumor has metastasized, and the appropriate course of treatment.

Table: Staging of Prostate Cancer
Stage Effects of Cancer

Stage I (A)

Prostate cancer can not be felt by digital rectal examination, causes no symptoms, and is only in the prostate, usually found incidentally in a prostatectomy specimen when surgery is done for benign prostatic hyperplasia

Stage II (B)

Cancer confined to the prostate gland found by needle biopsy done for an elevated prostate-specific antigen (PSA) level or after rectal examination reveals a mass in the prostate

Stage III (C)

Cancer cells have spread outside the capsule of the prostate to tissues around the prostate (e.g., seminal vesicles)
Stage IV (D) Cancer cells have metastasized to lymph nodes or to organs and tissues (e.g., the bone, liver, or lungs)

Another staging system for prostate cancer is known as the TNM system, which separately evaluates the tumor (T), lymph nodes (N) and metastases (M).

Table: T (Tumor) Staging:
Stage Effects of Tumor
T1 The tumor is too small to be seen on scans or felt during examination of the prostate (it has been discovered by needle biopsy)
T2 The tumor is completely inside the prostate gland
T3 The tumor has broken through the capsule of the prostate gland
T4 The tumor has spread into other body organs
Table: N (Lymph Node) Staging:
Stage Effects of Lymph Node
N0 No cancer cells found in any lymph nodes
N1 One positive lymph node smaller than 2 cm across
N2 More than 1 positive lymph node; or one that is between 2 cm and 5 cm across
N3 Any positive lymph node that is bigger than 5 cm across
Table: M (Metastases) Staging:
Stage Effects of Metastases
M0 No cancer spread outside the pelvis
M1 Cancer has spread outside the pelvis

The American Urological Association (AUA)'s Prostate Cancer Clinical Guideline Update Panel (Thompson et al, 2007) stated that standard options for the management of clinically localized prostate cancer include watchful waiting and active surveillance, interstitial prostate brachytherapy, external beam radio-therapy (EBRT), radical prostatectomy, as well as primary hormonal therapy.  Other treatment modalities entailed cryotherapy, high-intensity focused ultrasound (HIFU), and combinations of treatments (e.g., EBRT and interstitial prostate bracytherapy).  However, the Panel did not include the other treatment options in the analysis and recommendations because of a combination of factors (e.g., limited published experience and short-term follow-up).

High-intensity focused ultrasound (HIFU) is the delivery of targeted high-intensity ultrasound that rapidly elevates the temperature in a precise focal zone. The increased tissue temperature is suggested to kill excess prostate tissue.

Dubinsky and co-workers (2008) noted that although a great deal about HIFU physics is understood, its clinical applications are currently limited, and multiple trials are underway worldwide to determine its effectiveness.  In this regard, HIFU has been studied for the treatment of patients with prostate cancer.  This non-invasive approach destroys malignant cells by creating intense heat of 80 to 100° C with highly focused transrectal ultrasonic beams.  Gardner and Koch (2005) stated that continued technological advances combined with well-designed clinical trials could allow HIFU to become part of the armamentarium against prostate cancer.  Konstantinos (2005), in a review on prostate cancer in the elderly, noted that other treatment options under development include cryotherapy and HIFU.
Pickles et al (2005) performed an evidence-based review of published papers in the English language on the use of HIFU for prostate cancer.  Only case series have been published; there were no randomized studies.  These investigators stated that the quality of evidence was poor, with no reports having longer follow-up than a mean of 2 years, with median follow-ups substantially shorter.  Effectiveness outcomes were thus premature and preclude assessment.  Toxicity varied substantially with impotence rates 44 % to 61 %, grade 2 to 3 incontinence 0 % to 14 %, and rectal fistulae 0.7 % to 3.2 %.  There were limited data on the use of HIFU as salvage therapy after radiation failure.  There were no data on the toxicity of subsequent standard curative therapies after HIFU.  The authors concluded that in view of the lack of effectiveness outcomes, and in the presence of significant toxicity, HIFU should only be offered within a research setting.
Uchida et al (2006) assessed the biochemical disease-free survival (DFS) rates, predictors of clinical outcome and morbidity in patients with localized prostate cancer treated with HIFU.  A total of 181 consecutive patients underwent HIFU with the use of Sonablate (Focus Surgery, Indianapolis, IN).  Biochemical recurrence was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel.  The median age and pre-treatment PSA level were 70 years (range of 44 to 88) and 9.76 ng/ml (range of 3.39 to 89.60).  A total of 95 patients (52 %) were treated with neoadjuvant hormones.  The median follow-up period for all patients was 18.0 months (range of 4 to 68).  The biochemical DFS rates at 1, 3 and 5 years in all patients were 84 %, 80 % and 78 %, respectively.  The biochemical DFS rates at 3 years for patients with pre-treatment PSA less than 10 ng/ml, 10.01 to 20.0 ng/ml and more than 20.0 ng/ml were 94 %, 75 % and 35 %, respectively (p < 0.0001).  Multi-variate analysis identified pre-treatment PSA (p < 0.0001) as an independent predictor of relapse.  The authors concluded that HIFU therapy appeared to be a safe and effective minimally invasive therapy for patients with localized prostate cancer, especially those with a pre-treatment PSA level less than 20 ng/ml.
Eggener et al (2007) explained the rationale for and concerns about focal therapy for low-risk prostate cancer, and reviewed potential methods of delivery.  The authors concluded that early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance.  Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity.  The authors encouraged the investigation of focal therapy in select men with low-risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.
In a phase I/II clinical trial, Koch et al (2007) examined the safety and potential effectiveness of transrectally delivered HIFU for the full gland ablation of previously untreated localized prostate cancer.  A total of 20 patients underwent 1 to 3 HIFU treatments of the prostate.  The primary outcome was safety and the secondary outcomes were PSA, prostate biopsy and quality of life (QOL) measures.  A total of 19 patients had complete follow-up.  Serious adverse events related to treatment were limited, with the most common adverse event being transient urinary retention of more than 30 days in only 10 % of patients.  Rectal injury occurred in 1 patient.  With 1 to 3 treatments, 42 % of the patients achieved PSA less than 0.5 ng/ml and a negative prostate biopsy.  The authors concluded that HIFU in patients with previously untreated prostate cancer is generally well-tolerated and has the potential to completely ablate the prostate gland.  With further refinement of the optimal treatment dose and technique, this technology has the potential to be an effective form of therapy for localized prostate cancer.
Illing and Chapman (2007) noted that transrectal HIFU for prostate cancer is a promising technique with medium-term oncological results broadly comparable to standard therapies.  It is the only form of therapy which is non-invasive and does not utilize ionizing radiation.  This is an exciting field undergoing rapid developments, both in the technology and the way in which prostate cancer is managed.  Lynch and Loeb (2007) stated that HIFU has emerged in the past decade as a new addition to the arsenal of therapeutic options for prostate cancer.  Clinical studies have investigated its use as a treatment for clinically localized disease and as salvage therapy in the setting of failure after EBRT.  The authors stated that additional studies with long-term follow-up are needed to further evaluate cancer control and QOL outcomes of this new modality.

Huang and associates (2007) noted that for patients with biopsy-proven recurrent cancer confined to the prostate, local salvage therapy may be a potentially curative treatment option.  Most men, however, do not undergo local salvage therapy owing to difficulties in diagnosis as well as concerns over treatment-related complications in the salvage setting.  Recently, improvements in technique and technology have substantially reduced the morbidity associated with locally ablative therapies, resulting in an increased interest in the use of minimally invasive therapies such as brachytherapy, cryotherapy, and HIFU in the salvage setting.  Although these treatments are well-tolerated, concerns remain over incomplete and inadequate treatment with locally ablative therapies.  The authors stated that more studies are needed to appropriately select candidates for salvage ablative therapies and to determine the long-term oncological effectiveness of these treatments.
Marberger (2007) stated that energy-based ablative techniques are of growing interest for today's heterogeneous spectrum of prostate cancer.  At present, primary HIFU appears to be a valid alternative to active surveillance protocols in low-risk cancers; and to standard therapy in older patients.  Morbidity is low, although post-operative impotence occurs frequently.  Cryoablation has higher morbidity, even with third-generation conformal technology.  With radio-recurrent cancer the potential radiation damage of the rectal wall renders transrectal HIFU more hazardous.  Third-generation cryoablation seems to give better cancer control with lower morbidity in this situation.  Unfortunately, long-term outcome data from controlled trials are not available.  The author concluded that these minimally invasive techniques are not magic bullets, and patients must be informed accordingly.  Focal ablation of the prostate segment with the index cancer would minimize morbidity and therefore appears highly appealing.  Its success depends on correct localization of the lesion.  Until this is achieved with sufficient reliability by appropriate biopsy or imaging techniques, focal ablation for the treatment of prostate cancer remains strictly experimental.

Lledo García et al (2007) assessed the current state of HIFU as therapeutical option of prostate cancer.  These investigators noted that this technique is usually being indicated in Europe as treatment of many cases of either primary or relapsed prostate cancer following radiotherapy.  Although some reports suggested that HIFU is very effective as treatment for low and medium risk localized prostate cancer, no randomized series comparing this technique with conventional therapies have been presented yet.  They also found vast disparity in criteria to define DFS rendering interpretation of results difficult.  The authors concluded that experience of some groups in HIFU is highly promising.  Local tumor destruction is evident both in primary and relapsed cases of prostate cancer.  However, randomized controlled studies with long-term follow-up are necessary to measure benefits in global survival and QOL.  Comparisons must also be made with conventional techniques, and a uniform definition of DFS is necessary.

Barqawi and Crawford (2008) stated that the use of HIFU as a method for ablation of a localized tumor growth is not new.  Several attempts have been made to apply the principles of HIFU to the treatment of pelvic, brain, and gastrointestinal tumors.  However, only in the past decade has the understanding of the basic principles of HIFU allowed researchers to further exploit its application as a radical and truly non-invasive, intent-to-treat, ablative method for treating organ-confined prostate cancer.  The authors stated that HIFU may play a crucial role in the search for a safe and effective primary treatment for localized prostate cancer.  Its non-invasive and unlimited repeatability potential is appealing and unique; however, long-term results from controlled studies are needed.  In addition, a better understanding of HIFU's clinical limitations is vital before this treatment modality can be recommended to patients who are not involved in well-designed clinical studies.
Rebillard et al (2008) discussed the safety and effectiveness of HIFU in patients with prostate cancer.  These investigators searched Medline and Embase for clinical studies evaluating the safety and effectiveness of HIFU in prostate cancer (July 2007).  In addition, abstracts presented at the 2005 to 2007 annual meetings of the European Association of Urology and AUA were screened.  In all, 37 articles and abstracts were selected.  As the data on HIFU as salvage therapy were limited, the authors focused on HIFU as primary therapy.  Studies consisted of case series only.  Included patients were approximately 70 years old with T1-T2 N0M0 disease, Gleason Score less than or equal to 7, a PSA level of less than or equal to 28 ng/ml and a prostate volume of less than or equal to 40 ml.  Negative biopsy rates with the Ablatherm device were 64 % to 93 %, and a PSA nadir of less than or equal to 0.5 ng/ml was achieved in 55 % to 84 % of patients.  The 5-year actuarial DFS rates were 60 % to 70 %.  The most common complications were stress urinary incontinence, urinary tract infection, urethral/bladder neck stenosis or strictures, and erectile dysfunction.  For the Ablatherm device, the rate of complications has been significantly reduced over the years, due to technical improvements in the device as well as the use of transurethral resection of the prostate before HIFU.  The authors concluded that HIFU as primary therapy for prostate cancer is indicated in older patients (greater than or equal to 70 years) with T1-T2 N0M0 disease, a Gleason score of less than 7, a PSA level of less than 15 ng/ml and a prostate volume of less than 40 ml.  In these patients HIFU achieved short-term cancer control, as shown by a high percentage of negative biopsies and significantly reduced PSA levels.  The median-term survival data also appeared promising, but long-term follow-up studies are needed to further evaluate cancer-specific and overall survival rates before the indications for primary therapy can be expanded.
Thuroff and Chaussy (2008) stated that reports describing results of HIFU for prostate cancer are mainly based on single-center, prospective, clinical trials.  The latest published results suggest that HIFU is a valuable option for well-differentiated and moderately-differentiated tumors, as well as for local recurrence after EBRT.  The authors noted that HIFU in locally recurrent cancer after surgery, as well as adjuvant HIFU for local debulking in locally advanced or metastatic disease, shows promising results for reducing local disease-induced morbidity and for delay of progression.

Poissonnier and colleagues (2008) ascertained the effectiveness and adverse effects of HIFU for the treatment of local recurrence of prostate cancer after exclusive EBRT.  A total of 72 patients with histologically and biologically documented local recurrence after radiotherapy were treated by HIFU.  The mean age was 68.27 +/- 5.93 years, and mean PSA was 6.64 +/- 7.26 ng/ml.  A total of 30 patients were treated according to standard parameters and 42 according to specific parameters.  The 2005 ASTRO criteria, specific for salvage therapy (Phoenix consensus), were used to define recurrence.  Progression-free survival (PFS) was calculated by the Kaplan-Meier method.  Mean follow-up was 39 +/- 28 months.  The rate of negative biopsy was 80 % and the median nadir PSA was 0.10 ng/ml.  Specific survival was 94 % at 3 years and 90 % at 5 years, and PFS was 50 % at 3 years and 44 % at 5 years.  The rate of urinary incontinence was 44 % (grade 1: 12 %, grade 2/3: 32 %) and the rate of urethral stricture or bladder neck stenosis was 30 %.  The use of specific parameters reduced the incidence of severe incontinence (19 % versus 50 %, p = 0.005) and stenosis (24 % versus 40 %).  The authors concluded that treatment with HIFU achieved a 5-year PFS of 44 %, but patients must be clearly informed about the high rate of adverse effects.

Muto et al (2008) evaluated the feasibility and effectivenerss of HIFU for localized prostate cancer.  A total of 70 patients received HIFU using Sonablate(R) 500 were included in this study.  In patients whose cancer was confined to only one lobe by multi-regional biopsies, total peripheral zone and a half portion of transitional zone were ablated (focal therapy).  Otherwise, patients received whole organ ablation (whole therapy).  Scheduled biopsies were performed at 6 and 12 months after treatment.  Pre- and post-HIFU serum testosterone levels were measured.  The 2-year biochemical DFS rates in patients at low-, intermediate- and high-risk were 85.9 %, 50.9 % and 0 %, respectively, (p = 0.0028).  After 12 months, 81.6 % (40/49) of patients were biopsy negative; 84.4 % in patients who received whole therapy, whereas 76.5 % in those with focal therapy.  The 2-year biochemical DFS rates for the patients at low- and intermediate-risk was 90.9 % and 49.9 %, respectively, in patients with whole therapy, whereas 83.3 % and 53.6 % in patients with focal therapy.  In patients without neoadjuvant androgen deprivation, serum testosterone levels continuously decreased after whole therapy, whereas no changes were observed in those with focal therapy.  Patients whose follow-up biopsies were positive tended to have significantly higher changes in PSA levels than biopsy-negative patients.  The authors concluded that in patients with low-risk prostate cancer, HIFU monotherapy resulted in comparable immediate cancer control with other modalities.  In particular, focal therapy might offer a feasible minimally invasive therapeutic option, which maintained serum testosterone level.  To the authors' knowledge, this is the first report that whole, but not focal, therapy affects the serum testosterone level.

Zacharakis et al (2008) examined the use of HIFU as a salvage therapy in men with localized prostate cancer recurrence following EBRT.  A review of 31 cases treated using the Sonablate(R) 500 HIFU device was carried out.  All men had presumed organ-confined, histologically confirmed recurrent prostate cancer following EBRT.  The mean (range) age was 65 (57 to 80) years with a mean pre-operative PSA level of 7.73 (0.20 to 20) ng/ml.  Patients were followed for a mean (range) of 7.4 (3 to 24) months.  Side effects included stricture or intervention for necrotic tissue in 11 of the 31 patients (36 %), urinary tract infection or dysuria syndrome in 8 (26 %), and urinary incontinence in 2 (7 %).  Recto-urethral fistula occurred in 2 men, although 1 was due to patient movement as a consequence of inadequate anesthesia, so the "true" rate was 3 %.  Half of the patients had PSA levels of less than 0.2 ng/ml at the last follow-up.  Three patients had metastatic disease while another 2 had only local, histologically confirmed, failure.  A further 4 patients had evidence of biochemical failure only.  Overall, 71 % had no evidence of disease following salvage HIFU.  The authors concluded that salvage HIFU is a minimally invasive day-case procedure that can achieve low PSA nadirs and good cancer control in the short-term, with comparable morbidity to other forms of salvage treatment.  However, the issue of accurate staging at the time of recurrence is still problematic, as a proportion of these men will harbor microscopic metastases undetected by conventional staging investigations.

Sumitomo et al (2008) examined if combining short-term neoadjuvant androgen deprivation therapy (NADT) with HIFU had a significant benefit in a large population of men with non-metastatic prostate cancer.  These researchers evaluated the records of 530 patients whose PSA level at diagnosis was 30 ng/ml or less and whose follow-up period was not less than 12 months, at 7 investigational sites.  A total of 270 patients had received NADT (within 6 months), and 260 had not.  The primary outcome measure was DFS according to the combined criteria satisfying the Phoenix definition (less than nadir + 2), negative prostate biopsy, and no findings of distant metastasis after the last HIFU treatment.  The significance of the differences of values or the distributions of each parameter between two groups was evaluated with a Mann-Whitney U test, unpaired t test, or chi-square test, and a multi-variate Cox proportional hazards model was used to evaluate the prognostic relevance of pre-operative parameters.  Statistical analyses showed that the NADT group had worse disease (higher PSA and risk group) than the HIFU-only group.  Variables shown by multi-variate analyses to be significant prognostic parameters were pre-treatment PSA level, clinical stage, and no use of NADT.   Short-term NADT significantly improved the 3-year DFS rate of patients with intermediate-risk and high-risk prostate cancer.  During follow-up the frequencies of complications did not differ significantly with or without NADT.  The authors concluded that these findings suggested that combining short-term NADT with HIFU treatment is of significant clinical benefit to intermediate-risk and high-risk prostate cancer patients without increasing the likelihood of complications.

Misrai et al (2008) assessed the long-term oncological results of HIFU as a primary and single treatment for clinically localized prostate cancer.  A total of 119 patients underwent HIFU as first-line treatment and were retrospectively reviewed.  They were stratified according to risk groups proposed by D'Amico.  No patient had undergone previous hormonal therapy.  Patients' PSA level was monitored at 3, 6, 12, 18, 24 months and then yearly.  According to the latest ASTRO criteria, failure was defined by a PSA rise of 2 ng/ml or more above the PSA nadir.  The biochemical-free survival rate (BFSR) was calculated.  Mean patient age was 68 +/- 7.8 years (46 to 83).  Mean follow-up was 3.9 years (1 to 6.8).  Overall, 52 patients (43.7 %) experienced a biochemical recurrence which included 26, 23 and 3 patients in the low-, intermediate- and high-risk groups, respectively.  In uni-variate and multi-variate analyses, there was a statistical association between pre-operative PSA value greater than 10, a nadir PSA value greater than 1 and the risk of biochemical recurrence (p < 0.05).  The 5-year BFSR rate was 30 % with no statistical difference between low- and intermediate-risk patients.  None of the 119 patients died of prostate cancer.  The authors concluded that HIFU therapy provides efficient oncological control only in patients with low-risk prostate cancer.  However, these findings could be used to improve the selection of patients who are potential candidates for HIFU therapy.

Blana and colleagues (2008) evaluated the long-term effectiveness of HIFU therapy for patients with localized prostate cancer.  Patients included in this multi-center analysis had T1-T2 N0M0 prostate cancer, a PSA of less than 15 ng/ml, and a Gleason score of less than or equal to 7, and were treated with prototypes or first-generation Ablatherm HIFU devices.  The Phoenix definition of biochemical failure was used (PSA nadir + 2).  Treatment failure was defined as: biochemical failure or positive biopsy.  A total of 140 patients with a mean (standard deviation [SD]) age 69.1 years (6.6) were included.  Mean (SD) follow-up was 6.4 years (1.1).  Control prostate biopsies were negative in 86.4 % of patients.  Median PSA nadir of 0.16 ng/ml (range of 0.0 to 9.1) was achieved at a mean (SD) of 4.9 months (5.2).  A PSA nadir of less than or equal to 0.5 ng/ml was recorded in 68.4 % of patients.  The actuarial biochemical failure-free survival rates (SR) at 5 and 7 years were 77 % and 69 %, respectively.  The actuarial disease-free SR at 5 and 7 years were 66 % and 59 %, respectively.  The authors concluded that these findings demonstrated the effective long-term cancer control achieved with HIFU in patients with low- or intermediate-risk localized prostate cancer.

The American College of Radiology Expert Panel on Radiation Oncology-Prostate Work Group's guideline on locally advanced (high-risk) prostate cancer (Lee et al, 2006) did not mention the use of HIFU in the list of treatment options.  Furthermore, National Comprehensive Cancer Network's guideline on prostate cancer does not include HIFU among the therapeutic options for localized prostate cancer (NCCN, 2008).  The Agency for Healthcare Research and Quality's guideline on treatments for clinically localized prostate cancer (Wilt et al, 2008) does not cover some newer treatments (e.g., cryotherapy, HIFU, and laparoscopic or robotic-assisted prostatectomy) for which there is little research about comparative effectiveness.  The American Urological Association lists active surveillance, radiotherapy as well as radical prostatectomy as options for the management of patients with clinically localized prostate cancer.  It does not mention the use of HIFU (Dahm et al, 2008).  Guidelines on management of prostate cancer from the National Institute for Health and Clinical Excellence (NICE, 2008) state that HIFU for prostate cancer is "not recommended other than in the context of clinical trials."  Guidelines on treatment of prostate cancer from the Spanish National Health Service (2008) conclude that HIFU is an experimental treatment for prostate cancer. Other systematic evidence reviews have reached similar conclusions about the experimental status of HIFU for prostate cancer (Pichon-Riviere et al, 2008; Dussault, 2008).  Furthermore, HIFU for prostate cancer has not been approved for use in the United States.

Cordeiro et al (2012) provided an up-to-date review of the available literature on HIFU as a definitive treatment of prostate cancer.  A systematic literature search was conducted using MEDLINE and EMBASE via Ovid databases (January 2000 to December 2011) to identify studies on HIFU for treatment of prostate cancer.  Only English-language and human-based full manuscripts that reported on case series studies with more than 50 participants, patient characteristics, efficacy and safety data were included.  No randomized controlled trials (RCTs) were identified by the literature search.  These investigators identified 31 uncontrolled studies that examined the efficacy of HIFU as primary treatment and 2 studies that examined the efficacy of HIFU as salvage treatment.  Most treated patients had localised prostate cancer (stage T1-T2); Gleason scores of 2 to 10 and mean prostate specific antigen (PSA) values of 4.6 to 12.7 ng/ml.  The mean age range of the patients was 64.1 to 72 years.  The mean follow-up ranged from 6.4 to 76.8 months.  Negative biopsy rates ranged from 35 to 95 %; PSA nadirs ranged from 0.04 to 1.8 ng/ml.  The 5-year DFS rates ranged from 61.2 to 95 %; 7- and 8-year DFS rates ranged from 69 to 84 %.  The most common complications associated with the HIFU procedure as the primary treatment included: urinary retention (less than 1 to 20 %); urinary tract infections (1.8 to 47.9 %); stress or urinary incontinence (less than 1 to 34.3 %); and erectile dysfunction (20 to 81.6 %).  Recto-urethral fistula was reported in  less than 2 % of patients.  Treatment-related morbidity appeared to be reduced by the combination of transurethral resection (TURP) of the prostate and HIFU.  The authors concluded that novel therapeutic methods have emerged in recent years as "focal" treatment alternatives, in which cancer foci could be eradicated by greatly reducing the associated side-effects of radical treatment.  High-intensity focused ultrasound seems to result in short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies.  However, longer-term follow-up studies are needed to evaluate cancer-specific and overall survival.  If available promising results on HIFU for definitive treatment of prostate cancer are confirmed in future prospective trials, focal therapy could start to challenge the current standard of care.

In a retrospective single-center study, Pfeiffer and colleagues (2012) reported cancer control results after a single application of HIFU in patients with localized prostate cancer (PCa), stratified by tumor recurrence risk according to D'Amico risk classification.  These investigators analyzed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device.  Transurethral resection of the prostate or adenomectomy were performed before HIFU to down-size large prostate glands.  Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis.  Biochemical relapse was defined as a PSA nadir +1.2 ng/ml (Stuttgart definition), or as a rise in PSA level to greater than or equal to 0.5 ng/ml if PSA doubling time was less than or equal to 6 months.  Kaplan-Meier analysis was performed for survival estimates.  A total of 191 consecutive patients were included in the study.  The median (range) patient age was 69.7 (51 to 82) years, and 38, 34 and 28 % of these patients were in the low-, intermediate- and high-risk groups, respectively.  The median (range) follow-up was 52.8 (0.2 to 79.8) months.  At 5 years, overall and cancer-specific survival rates were 86.3 % and 98.4 %, respectively.  Stratified by risk group, negative biopsy rates were 84.2 %, 63.6 %, and 67.5 % (p = 0.032), 5-year biochemical-free survival rates were 84.8 %, 64.9 % and 54.9 % (p < 0.01), and 5-year DFS rates were 81.7 %, 53.2 % and 51.2 % (p < 0.01), respectively.  The authors concluded that single-session HIFU is recommended as a curative approach in elderly patients with low-risk PCa.  Patients at higher risk of tumor progression should be counseled regarding the likely need for salvage therapy, including repeat HIFU.

Komura et al (2012) evaluated the oncologic results of HIFU as treatment for clinically PCa.  A total of 180 patients with clinically PCa underwent HIFU and were retrospectively reviewed.  Of those 171 patients primarily treated with HIFU were included in the analysis.  They were stratified by prostatic volume, neoadjuvant hormonal ablation (NHA), and post-treatment PSA nadir; PSA level was monitored every month during the first 6 months after the treatment and every 3 months thereafter.  According to the latest Phoenix criteria, biochemical failure was defined by a PSA rise of 2 ng/ml or more above the PSA nadir.  Seventy-six (44.4 %) patients were offered pre-operative NHA in median duration of 3 months (inter-quartile range [IQR]: 3 to 5.75).  Pre-operative TURP was performed in 56 (32.7 %) patients having the calcification within the prostate.  Mean patient age was 68.3 +/- 7.0.  The median follow-up time was 43 months (IQR: 30 to 55).  According to D'amico risk groups 52 (30.4 %) patients were identified with low-risk, 47 (27.5 %) patients with intermediate-risk, and 72 (42.1 %) with high-risk.  The overall and cancer-specific survival rates at 5 years were 98.8 % and 100 %, respectively.  The metastasis-free survival rate at 5 years was 99.4 %.  No significant differences were seen in biochemical failure-free survival when stratified according to pre-operative prostatic volume and administration of pre-operative NHA (p = 0.931 and p = 0.712, respectively).  Regardless of NHA administration, patients with smaller PSA nadir (0.2 ng/ml) achieved better biochemical failure-free survival ratio.  The authors concluded that HIFU therapy provided sufficient oncologic control only in patients with low-risk prostate cancer.  However, these data could be used to improve the selection of patients who are potential candidates for HIFU therapy.

Uddin et al (2012) described the use of the Sonablate 500 HIFU system in the salvage setting of PCa recurrence after EBRT.  An evaluation was performed of a consecutive group of men with biochemical failure after EBRT with histologically proven local recurrence and bone-scan and pelvic magnetic resonance imaging (MRI) to exclude macroscopic metastases, and who chose to have whole-gland salvage HIFU (Sonablate 500) at 2 centers (3 expert HIFU surgeons at each center).  The modified Clavien system was used to categorize adverse events and validated questionnaires for functional outcomes.  Progression following HIFU treatment was defined as ASTRO-Phoenix criteria (PSA greater than nadir+2 ng/ml) and/or a positive biopsy and/or start of hormone therapy.  A total of 84 men underwent whole-gland salvage HIFU (2004 to 2009).  Median age, pre-treatment serum PSA, and biopsy Gleason score was 68 years (range of 64 to 72 years), 4.3 ng/ml (range of 1.9 to 7.9 ng/ml), and 7 (range of 6 to 7), respectively.  Mean follow-up was 19.8 months (range of 3.0 to 35.1 months).  After salvage HIFU, 62 % of the men were pad-free and leak-free.  Mean International Index of Erectile Function-5 point score fell from 8.8 to 4.7 (p < .001).  International Prostate Symptoms Score and RAND-SF36 scores were not affected.  Two men developed recto-urethral fistulae after 1 salvage procedure.  A further 2 fistulae occurred in the 6 men undergoing a second salvage HIFU.  Intervention for bladder outlet obstruction was needed in 20 % (17 of 84 patients).  If PSA non-responders were included, 1- and 2-year PFS rates were 59 % (50 of 84 patients) and 43 % (36 of 84 patients), respectively.  If PSA non-responders were excluded, 1- and 2-year PFS rates were 62 % (48 of 77 patients) and 48 % (37 of 77 patients), respectively.  The authors concluded that salvage whole-gland HIFU is a high-risk procedure.  Although its use in early cancer control is promising, strategies to better identify metastatic disease prior to salvage therapy and reduce local toxicity are needed to improve on this.

In a pilot study, Asimakopoulos et al (2012) examined HIFU as salvage first-line treatment for palpable, TRUS-evidenced, biopsy-proven locally recurrent prostate cancer (CaP) after radical prostatectomy (RP).  A total of 19 patients with palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP after RP, unwilling to undergo salvage radiotherapy (SRT), underwent HIFU as a single-session procedure.  Pre-, intra-, and post-operative data including early and late complications, and oncologic outcomes (PSA nadir, biochemical recurrence (BCR)-free survival, and need of secondary adjuvant treatment) were prospectively evaluated.  Success was defined as PSA nadir less than or equal to 0.1 ng/ml obtained within 3 months from HIFU.  In case of PSA nadir greater than 0.1 ng/ml or PSA increase greater than or equal to 1 ng/ml above the PSA nadir, a biopsy of the treated lesion was performed, and if negative, maximum androgen blockade (MAB) was adopted.  In case of positive biopsy, RT was performed.  Failure was defined as use of secondary adjuvant treatment (MAB or RT).  Median follow-up was 48 months.  All cases were performed as overnight procedure.  No case of urethra-rectal fistula or anastomotic stricture was observed.  Two cases of acute urinary retention were resolved with prolonged urethral catheterization.  Four cases of stress urinary incontinence were observed; 2 (mild incontinence) were resolved after pelvic floor exercises within 6 months, while 2 cases of severe incontinence required surgical minimally invasive treatment; 17/19 patients (89.5 %) were classified as success.  Two patients failed to show a PSA nadir of less than 0.1 ng/ml.  During follow-up, 8/17 patients (47 %) were classified as failure, with consequent total rate of failures 10/19 (52.6 %).  A statistically significant difference was observed in pre-HIFU median PSA (2 versus 5.45 ng/ml, respectively, p = 0.013) and Gleason score of the RP specimen (p = 0.01) between the success and failure group.  The authors concluded that salvage first-line HIFU for palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP is a feasible, minimally invasive day-case procedure, with an acceptable morbidity profile.  It seems to have a good cancer control in the short- and mid-term.  Patients with lower pre-HIFU PSA level and favorable pathologic Gleason score presented better oncologic outcomes.  They stated that a prospective randomized trial with an adequate recruitment and follow-up is necessary to confirm these preliminary oncologic results.

Dickinson et al (2013) described the study design of an investigator-led United Kingdom multi-center, single-arm trial using HIFU to deliver focal therapy for men with localized prostate cancer.  A total of 140 men with histologically proven localized low or intermediate risk prostate cancer (PSA less than 15, Gleason less than or equal to 7, less than or equal to T2cN0M0) will undergo precise characterization of the prostate using a combination of multi-parametric MRI (mpMRI) and trans-perineal template prostate mapping (TPM) biopsies.  Unilateral dominant tumors, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of “clinically significant” disease (as defined by Gleason greater than or equal to 7 or maximum cancer core length greater than or equal to 4 mm).  Patients will receive focal therapy using HIFU (Sonablate 500®).  Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36 months.  Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies.  Secondary outcomes address
  1. genito-urinary function using validated patient questionnaires (IPSS, IPSS-QoL, International Index of Erectile Function (IIEF)-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D),
  2. the predictive validity of imaging, and
  3. risk factors for treatment failure.
The authors concluded that INDEX will be the first multi-center, medium-term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localized prostate cancer using the TPM-ablate-TPM strategy.

An UpToDate review on “Initial approach to low-risk clinically localized prostate cancer” (Klein, 2013) states that “The role of ablation with cryotherapy or HIFU as an alternative to radical prostatectomy or RT remains uncertain.  Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure.  As such, these procedures are associated with minimal blood loss and pain.  There is also a more rapid posttreatment convalescence.  Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain however.  Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities”.

The National Institute for Health and Care Excellence’s clinical practice guideline on “Prostate cancer: Diagnosis and treatment” (NUCE, 2014) listed HIFU and cryotherapy (as part of clinical trials) as therapeutic options for the prostate cancer.

In a systematic review, Ramsay et al (2015) determined the relative clinical effectiveness and cost-effectiveness of ablative therapies compared with RP, EBRT and active surveillance (AS) for primary treatment of localized prostate cancer, and compared with RP for salvage treatment of localized prostate cancer which has recurred after initial treatment with EBRT. MEDLINE (1946 to week 3 of March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 29, 2013), EMBASE (1974 to week 13 of 2013), Bioscience Information Service (BIOSIS) (1956 to April 1, 2013), Science Citation Index (1970 to April 1, 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2013), Cochrane Database of Systematic Reviews (CDSR) (issue 3, 2013), Database of Abstracts of Reviews of Effects (DARE) (inception to March 2013) and Health Technology Assessment (HTA) (inception to March 2013) databases were searched. Costs were obtained from NHS sources. Evidence was drawn from RCTs and non-RCTs; and from case series for the ablative procedures only, in people with localized prostate cancer. For primary therapy, the ablative therapies were cryotherapy, HIFU, brachytherapy and other ablative therapies. The comparators were AS, RP and EBRT. For salvage therapy, the ablative therapies were cryotherapy and HIFU. The comparator was RP. Outcomes were cancer related, adverse effects (functional and procedural) and quality of life. Two reviewers extracted data and carried out quality assessment. Meta-analysis used a Bayesian indirect mixed-treatment comparison. Data were incorporated into an individual simulation Markov model to estimate cost-effectiveness. The searches identified 121 studies for inclusion in the review of patients undergoing primary treatment and 9 studies for the review of salvage treatment. Cryotherapy [3,995 patients; 14 case series, 1 RCT and 4 non-randomized comparative studies (NRCSs)], HIFU (4,000 patients; 20 case series, 1 NRCS) and brachytherapy (26,129 patients; 2 RCTs, 38 NRCSs) studies provided limited data for meta-analyses. All studies were considered at high risk of bias. There was no robust evidence that mortality (4-year survival 93 % for cryotherapy, 99 % for HIFU, 91 % for EBRT) or other cancer-specific outcomes differed between treatments. For functional and quality-of-life outcomes, the paucity of data prevented any definitive conclusions from being made, although data on incontinence rates and erectile dysfunction for all ablative procedures were generally numerically lower than for non-ablative procedures. The safety profiles were comparable with existing treatments. Studies reporting the use of focal cryotherapy suggested that incontinence rates may be better than for whole-gland treatment. Data on AS, salvage treatment and other ablative therapies were too limited. The cost-effectiveness analysis confirmed the uncertainty from the clinical review and that there is no technology which appears superior, on the basis of current evidence, in terms of average cost-effectiveness. The probabilistic sensitivity analyses suggest that a number of ablative techniques are worthy of further research. The authors concluded that these findings indicated that there is insufficient evidence to form any clear recommendations on the use of ablative therapies in order to influence current clinical practice. They stated that research efforts in the use of ablative therapies in the management of prostate cancer should now be concentrated on the performance of RCTs and the generation of standardized outcomes.

In an assessment for the Belgian Health Care Knowledge Centre (KCE), Veereman et al (2015) systematically evaluated the evidence on the efficacy and side effects of HIFU in the primary treatment of localized prostate cancer.  The authors performed a critical review and appraisal of Medline (Ovid), PreMedline, Embase, and Cochrane Database of Systematic Reviews publications on HIFU up to May 2013.  One systematic review and 18 primary studies, all case series, were eligible.  Outcomes were summarized and evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology.  Low-quality evidence suggested an OS rate after Ablatherm HIFU ranging from 80 % to 89 % for greater than 5 years.  The prostate cancer survival rate ranges from 97 % to 99 % for greater than 5 years. The effect of HIFU on quality of life remains undetermined.  Erectile dysfunction was the most frequent adverse event reported from zero but up to 74 % of patients.  Adverse events affecting the urinary tract occurred in 0.7 % to 31 % of patients, bladder outlet obstruction in 4 % to 51.5 %, and they were more frequent in patients who had transurethral resection of the prostate the same day or within 2 days of HIFU.  Outcomes vary for low- and high-risk categories.  The asssessment concluded that good quality evidence on the efficacy of HIFU treatment for localised prostate cancer is lacking.  The authors concluded that the quality of the evidence was very low because the information is based on a series of patients who received HIFU treatment with no comparison with active surveillance or radical treatment.  Case series suggested an overall survival rate up to 89 % and a prostate cancer survival rate up to 99 % after 5 years, but these numbers vary according to the patient's risk category.  Longer term and effects on quality of life are unknown.

Golan et al (2017) conducted a systematic review of HIFU for prostate cancer following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using a combination of MeSH terms, free text search and examination of relevant bibliographies using MEDLINE and Embase from the inception of each database through October 10, 2016. The authors excluded studies describing exclusively whole gland ablation, case reports and series where treatment was followed by immediate resection. A total of 13 studies that enrolled 543 patients were included. Of the studies 11 were performed in the primary setting and 2 in the salvage setting. Median followup ranged from 6 months to 10.6 years. Rates of posttreatment erectile dysfunction and urinary incontinence ranged from 0% to 48% and 0% to 50%, respectively, with definitions varying by study. Overall there were 254 reported complications. Marked heterogeneity between studies limited the ability to pool results regarding functional and oncologic outcomes. A total of 76 patients (14%) subsequently received further oncologic treatment. The authors concluded that early evidence suggests that partial gland ablation is a safe treatment option for men with localized disease. Longer term data are needed to evaluate oncologic efficacy and functional outcomes, and will aid in identifying the optimal candidates for therapy. Standardization of outcomes definitions will allow for better comparison between studies and among treatment modalities.

Abreu et al (2020) reported short-term outcomes of hemi-gland HIFU ablation as primary treatment for localized PCa in the U.S.  A total of 100 consecutive men underwent hemi-gland HIFU (December 2015 to December 2019).  Primary endpoint was treatment failure, defined as grade Group 2 or greater on follow-up prostate biopsy, radical treatment, systemic therapy, metastases or PCa specific mortality.  IIEF, IPSS and 90-day complications were also reported.  At study entry patients had very low (8 %), low (20 %), intermediate favorable (50 %), intermediate unfavorable (17 %) and high (5 %) risk PCa.  Median follow-up was 20 months.  The 2-year survival free from treatment failure, grade Group 2 or greater recurrence, repeat focal HIFU and radical treatment was 73 %, 76 %, 90 % and 91 %, respectively.  Bilateral PCa at diagnosis was the sole predictor for grade Group 2 or greater recurrence (p = 0.03).  Of men who underwent post-treatment biopsy (n = 58), 10 had in-field and 8 out-of-field grade Group 2 or greater positive biopsy.  Continence (0 pad) was maintained in 100 % of patients.  Median IIEF-5 and IPSS scores before versus after hemi-gland HIFU were 22 versus 21 (p = 0.99) and 9 versus 6 (p = 0.005), respectively.  Minor and major complications occurred in 13 % and 0 % of patients.  No patient had rectal fistula or died.  The authors concluded that short-term results of focal HIFU indicated safety, excellent potency and continence preservation, and adequate short-term PCa control.  Radical treatment was avoided in 91 % of men at 2 years.  Men with bilateral PCa at diagnosis have increased risk for grade Group 2 or greater recurrence.  To the authors’ knowledge, this was the initial and largest U.S. series of focal HIFU as primary treatment for PCa.

Radio-Recurrent Prostate Cancer

Ingrosso et al (2020) noted that different non-surgical therapeutic strategies can be adopted for intra-prostatic relapse of PCa after primary RT, including re-irradiation (with brachytherapy [BT] or EBRT), HIFU, and cryotherapy.  The main issues to consider when choosing non-surgical salvage local therapies are local tumor control and significant genito-urinary toxicity.  These researchers conducted a systematic review and meta-analysis on the role of non-surgical salvage modalities in patients with radio-recurrent PCa and associated clinical outcomes and toxicity profiles.  They performed a critical review of the Medline, Scopus, and ClinicalKey databases from January 1, 2000 through February 1, 2018 according to the Preferred Reporting Items and Meta-Analyses (PRISMA) statement.  To assess the overall quality of the literature reviewed, these investigators used a modified Delphi tool for case-series studies.  A total of 64 case-series studies were included, corresponding to a cohort of 5,585 patients.  The modified Delphi checklist evidenced high methodological quality overall (mean quality score of 80.6 %).  Biochemical control rates were lowest for patients treated with HIFU (58 %, 95 % CI: 47 % to 68 %) and highest for patients treated with BT (69 %, 95 % CI: 62 % to 76 %) and EBRT (69 %, 95 % CI: 53 % to 83 %).  The lowest prevalence of incontinence was for patients treated with BT (3 %, 95 % CI: 0 % to -6 %; I2 = 63.4 %) and the highest was among patients treated with HIFU (28 %, 95 % CI: 19 % to 38 %; I2 = 89.7 %).  The authors concluded that non-surgical therapeutic options, especially BT, showed good outcomes in terms of biochemical control and tolerability in the local recurrence setting.

In a prospective, cohort, multi-center study, Schmid et al (2020) examined focal therapy using HIFU for the treatment of localized PCa; they analyzed the safety and complications of this procedure.  This trial included patients who suffered from low-to-intermediate risk localized PCa with no prior treatment.  After tumor identification on multi-parametric MRI and in prostate biopsy, the lesions were treated with HIFU observing a safety margin of 8 to 10 mm; AEs after 30 and 90 days, as well as the required interventions were assessed and stratified for treatment localizations.  Of the 98 men included in the study in 2 European centers, 35 (35.7 %) experienced AEs in the first 30 days after HIFU intervention with Clavien-Dindo grade of less than or equal to II: 15 pts (15.3 %) had a post-operative urinary tract infection and 26 patients (26.5 %) a urinary retention; 4 patients (4.1 %) underwent subsequent intervention (Clavien-Dindo grade IIIa/b).  The number of late post-operative complications occurring between 30 and 90 days after intervention was low (2.0 %).  The highest complication rate was associated with tumors located at the anterior base (50.0 %).  The inclusion of the urethra in the ablation zone led to AEs in 20 out of 41 cases (48.8 %) and represented a significant risk factor for complications within 30 days (OR = 2.53; 95 % CI: 1.08 to 5.96; p = 0.033).  The authors concluded that focal therapy of PCa lesions with a robotic HIFU-probe was safe and rendered an acceptable rate of minor early AEs.  The inclusion of the urethra in the ablation zone led to an increase in early complications and should be avoided whenever possible.

In a multi-center study (2005 to 2016), Lovegrove et al (2020) examined change in functional outcomes after 2nd focal-HIFU compared to 1 focal-HIFU treatment.  A total of 821 men underwent focal-HIFU for localized non-metastatic PCa.  PROMS on IPSS, pad usage and erectile function (EF-score) were prospectively collected for up to 3 years.  Inclusion criteria were men who had completed at least 1 follow-up questionnaire.  The primary outcome was comparison of change in functional outcomes between baseline and follow-up after 1 focal-HIFU or 2nd focal-HIFU using IPSS, EPIC and IIEF questionnaires.  Of 821 men, 654 had 1 focal-HIFU and 167 had a 2nd focal-HIFU; 355 (54.3 %) men undergoing 1 focal-HIFU and 65 (38.9 %) having 2nd focal-HIFU returned follow-up questionnaires, respectively.  Mean age and PSA were 66.4 and 65.6 years, and 7.9 and 8.4 ng/ml, respectively.  After 1 focal-HIFU, mean change in IPSS was -0.03 (p = 0.02) and IIEF (EF-score) -0.4 (p = 0.02) at 1-2 years with no subsequent decline.  Absolute rates of erectile dysfunction increased from 9.9 % to 20.8 % (p = 0.08), leak-free continence decreased from 77.9 % to 72.8 % (p = 0.06) and pad-free continence from 98.6 % to 94.8 % (p = 0.07) at 1 to 2 years, respectively.  IPSS prior to 2nd focal-HIFU compared to baseline IPSS prior to 1st focal-HIFU was lower by -1.3 (p = 0.02), but mean IPSS change was +1.4 at 1 to 2 years (p = 0.03) and +1.2 at 2-3 years (p = 0.003) after 2nd focal-HIFU.  Mean change in EF-score after 2nd focal-HIFU was -0.2 at 1 to 2 years (p = 0.60) and -0.5 at 2 to 3 years (p = 0.10) with 17.8 % and 6.2 % new erectile dysfunction.  New pad use was 1.8 % at 1 to 2 years and 2.6 % at 2 to 3 years.  The authors concluded that a 2nd focal-HIFU procedure caused minor detrimental effects in urinary and erectile function.  Data can be used to counsel patients with non-metastatic PCa prior to considering HIFU therapy.

Dosanjh et al (2021) stated that HIFU is a novel therapy for PCa.  Owing to a lack of long-term data, HIFU is recommended for use only in the context of research.  These researchers examined the trend for HIFU use nationally and rates of strictures and fistulae.  Patients undergoing HIFU for PCa between April 2007 and March 2018 were studied in an English national database (Hospital Episode Statistics).  Data on complications were included for patients with a minimum of 1-year follow-up.  Analysis of complications was controlled for other interventions.  Descriptive analyses of HIFU rates and the incidence of strictures and fistulae were carried out.  Cox and logistic regression models were built for urethral stricture incidence.  A total of 2,320 HIFU treatments among 1,990 patients were identified.  The median age was 67 years (IQR 61 to 72).  Some 1,742 patients met the criteria for follow-up analysis.  The highest-volume center performed 1,513 HIFU procedures, followed by 194 at the second highest.  The number of HIFU procedures increased annually, rising from 196 to 283 per year.  There were 208 patients (11.9 %) who went on to have radiotherapy and 102 (5.9%) radical prostatectomy after HIFU.  Following HIFU, stricture developed in 133/1,290 patients (10.3 %) and urinary fistula in 16/1,240 (1.3 %) before any further intervention.  More recent years for HIFU were associated with a lower likelihood of stricture formation (2016/2017 versus 2007/2008: hazard ratio [HR] 0.30, 95 % CI: 0.11 to 0.79; p = 0.015).  Limitations included the lack of staging information and unknown rates of HIFU outside of publicly funded health care.  The authors concluded that HIFU was performed at a large number of low-volume centers and complication rates did not differ from those for established therapies.

National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 4.2019) states that “At this time, the panel recommends only cryosurgery and high-intensity focused ultrasound as options for radiation therapy recurrence in the absence of metastatic diseases”.  (2A Recommendation)

Central Nervous System Diseases / Disorders

Jagannathan and associates (2009) noted that the field of magnetic resonance imaging-guided HIFU surgery (MRgFUS) is a rapidly evolving one, with many potential applications in neurosurgery.  These researchers discussed the historical development of the technology and its potential applications in modern neurosurgery.  The evolution of MRgFUS has occurred in parallel with modern neurological surgery, and the two seemingly distinct disciplines share many of the same pioneering figures.  Early studies on focused ultrasound treatment in the 1940s and 1950s demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile.  However, the need for a craniotomy, as well as the lack of sophisticated imaging technology, resulted in limited growth of HIFU for neurosurgery.  More recently, technological advances have permitted the combination of HIFU along with magnetic resonance imaging guidance to provide an opportunity to effectively treat a variety of central nervous system disorders.  Although challenges remain, HIFU-mediated neurosurgery may offer the ability to target and treat central nervous system conditions that were previously extremely difficult to address.

Essential tremor is a common, usually hereditary or familial, disorder of movement characterized by uncontrolled trembling of the hands and often involuntary nodding of the head and tremulousness of the voice, is exacerbated by anxiety and by activity, is not associated with Parkinson's disease or any other known disease and responds to treatment with propranolol.

In a proof-of-concept study, Lipsman et al (2013) examined the effectiveness of MR-guided focused ultrasound for the management of essential tremor (ET).  This study was done in Toronto, Canada, between May, 2012, and January, 2013.  A total of 4 patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus.  Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery.  Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events.  Patients showed immediate and sustained improvements in tremor in the dominant hand.  Mean reduction in tremor score of the treated hand was 89.4 % at 1 month and 81.3 % at 3 months.  This reduction was accompanied by functional benefits and improvements in writing and motor tasks.  One patient had post-operative paraesthesia that persisted at 3 months.  Another patient developed a deep vein thrombosis, potentially related to the length of the procedure.  The authors concluded that MR-guided focused ultrasound might be a safe and effective approach to generation of focal intra-cranial lesions for the management of disabling, medication-resistant essential tremor.  They stated that if larger trials validate the safety and ascertain the effectiveness and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated.

In an open-label, uncontrolled, pilot study, Elias et al (2013) investigated the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor.  From February 2011 through December 2011, these researchers used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor.  They recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor.  These investigators assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100 %, with higher scores indicating greater perceived disability).  Thermal ablation of the thalamic target occurred in all patients.  Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesia in 4 patients.  Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (p = 0.001).  Total tremor scores improved from 54.9 to 24.3 (p = 0.001).  Disability scores improved from 18.2 to 2.8 (p = 0.001).  Quality-of-life scores improved from 37 % to 11 % (p = 0.001).  The authors concluded that in this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy.  They stated that large, RCTs are needed to assess the procedure's safety and effectiveness.

In a randomized controlled clinical study, Elias et al (2016) enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). The investigators included 67 patients in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort) as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.

An editorial accompanying the study by Elias et al (2016) stated that the results are promising, particularly since this procedure, unlike traditional thalamotomy, does not require entering the cranium with a probe (Louis, 2016). The editorialist noted, however, that there are several important concerns about this study. The first is the limited follow-up period, which was 12 months. The sustained benefit at 2 years, 3 years, and 5 or more years is not known. The editorialist stated that studies with longer follow-up intervals are needed to address this issue, noting that this is particularly important because of tachyphylaxis, which is the second concern. The primary outcome measure was the score for hand tremor (on a scale ranging from 0 to 32, with higher scores indicating more severe tremor) at 3 months. The tremor score in the group that underwent focused ultrasound thalamotomy increased from 8.84 (at 1 month) to 9.55 (at 3 months) to 10.13 (at 6 months) to 10.89 (at 12 months). The increase from months 1 to 12 was 23%. Secondary outcome measures showed similar or greater increases during the 12-month follow-up period (e.g., the Clinical Rating Scale for Tremor score increased from 23.38 at 1 month to 32.38 at 12 months, which is a 38% increase). The editorialist stated that it is not clear whether this loss of efficacy, which is also seen to some extent with deep-brain stimulation, is due to disease progression or tolerance, although typical estimates of the rate of disease progression in essential tremor make the former possibility less likely. Third, the procedure did not achieve large improvements in everyone; the percentage change in tremor was less than 20% in 9 of 56 patients.

The editorialist also noted several important caveats (Louis, 2016). The first is that the procedure is a thalamotomy. Hence, it creates a fixed brain lesion. With deep-brain stimulation, there is the potential to adjust stimulator settings in order to obtain further therapeutic gains, but there is no such potential with thalamotomy. Second, the procedure is not suitable for all patients; in particular, skull thickness presents a problem in some cases. Third, the most common side effect involved altered sensation, and this deficit remained permanent in 14% of patients. The editorialist suggested a head-to-head comparison with deep-brain stimulation to facilitate the direct comparison of the two approaches.

Kim et al (2017) stated that MRgFUS is an emerging technique to treat refractory ET.  These investigators presented MRgFUS as an alternative to radiofrequency (RF) thalamotomy or deep brain stimulation (DBS) for ET treatment.  They retrospectively analyzed 59 patients who underwent unilateral surgery for drug-resistant ET.  Treatments included RF thalamotomy (n = 17), DBS (n = 19), and MRgFUS (n = 23).  The outcomes measured were tremor severity and treatment-related complications.  At 1 month post-operatively, 100 % of RF thalamotomy patients, 89.5 % of DBS patients, and 91.3 % of MRgFUS patients exhibited absent/mild tremor (successful treatment); other patients exhibited partial relief.  At 12 months post-operatively, treatment success for each procedure was observed in 70.6, 84.2, and 78.3 % of patients, respectively.  At 1 month post-operatively, treatment-related complications had occurred in 58.8, 5.3, and 13.0 % of patients, respectively.  At 12 months post-operatively, side effects persisted in 11.8, 21.1, and 4.4 % of patients, respectively.  No statistical differences in treatment success were observed between treatments or over time.  Complication rates differed between treatment modalities (p < 0.01) and were lowest in the MRgFUS group.  The authors concluded that patients with drug-resistant ET received equivalent results from RF thalamotomy, DBS, and MRgFUS; DBS and MRgFUS resulted in fewer treatment-related complications.  Moreover, they stated that further study of MRgFUS is needed to generalize the results of this study.  This was a small study (n = 23 for the MRgFUS group) with short-term follow-up (12 months).  (It should be noted that Chan JW (see below)  is a co-author of this study).

The authors stated that this study had several drawbacks.  Regarding the study design, the present work was a retrospective review of medical records over time and it was therefore limited by sample availability and the type of information collected.  One of the biggest shortcomings of this study was timeline bias.  These researchers could not rule out the possibility of error from their experience and technical advances, because there was a gap of over 10 years between RF thalamotomy and MRgFUS.  However, to the best of their knowledge, as of early 2017 there was no ongoing or planned prospectively designed clinical trial for RF thalamotomy according to the clinical trial inventory.  Despite the presence of a well-designed, noteworthy study that compared the efficacy of RF thalamotomy and DBS, these investigators needed to re-evaluate the value of lesioning procedures and compare their clinical outcomes with the advent of a new technology, namely MRgFUS.

Chang et al (2018) stated that MRgFUS has recently been investigated as a new treatment modality for ET, but the durability of the procedure has not yet been evaluated.  This study reported results at a 2-year follow-up after MRgFUS thalamotomy for ET.  A total of 76 patients with moderate-to-severe ET, who had not responded to at least 2 trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor; 67 of the patients continued in the open-label extension phase of the study with monitoring for 2 years; 9 patients were excluded by 2 years, for example, because of alternative therapy such as DBS (n = 3) or inadequate thermal lesioning (n = 1).  However, all patients in each follow-up period were analyzed.  Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55 % at 6 months (8.6 ± 4.5; 75 patients).  The improvement in tremor score from baseline was durable at 1 year (53 %; 8.9 ± 4.8; 70 patients) and at 2 years (56 %; 8.8 ± 5.0; 67 patients).  Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64 % at 6 months (5.4 ± 4.7; 75 patients).  This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients).  Paresthesias and gait disturbances were the most common adverse effects at 1 year -- each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects.  None of the adverse events (AEs) worsened over the period of follow-up, and 2 of these resolved.  There were no new delayed complications at 2 years.  The authors concluded that tremor suppression after MRgFUS thalamotomy for ET was stably maintained at 2 years.  Latent or delayed complications did not develop after treatment.

The authors stated that this study had several drawbacks.  First, the number of reported patients was different; 56 subjects in the previous report were compared to the 20 sham-treated patients, but in this study, the authors  analyzed all 76 patients.  Second, the follow-up was versus 2 years here versus 1 year previously.  Third, as is characteristic with increasing duration of follow-up, there were patients who dropped-out of the study by 2 years.  In total, 9 patients, many of whom had unsuccessful treatment or sub-optimal benefit, crossed-over to an alternative treatment or dropped-out or were lost to follow-up at 2 years.  The exclusion of non-responders from the analysis introduced a bias and an over-estimate of the benefit in those patients that remained in the study.  Nonetheless, these findings showed that for the majority of patients, the benefits of MRgFUS were immediate and that they endured for at least 2 years.  The authors stated that additional follow-up are needed to determine the incidence of recurrence and the efficacy of MRgFUS over the long-term.  (It should be noted that this study was supported by InSightec (Haifa, Israel), the Focused Ultrasound Foundation (Charlottesville, VA) and the Binational Industrial Research and Development (BIRD) Foundation (Israel)).

Fishman et al (2018) determined the safety profile of MRgFUS unilateral thalamotomy for ET, including frequency, and severity of AEs, including serious AEs (SAEs).  Analysis of safety data for MRgFUS thalamotomy (186 patients, 5 studies).  Procedure-related SAEs were very infrequent (1.6 %), without intra-cerebral hemorrhages or infections; AEs were usually transient and were commonly rated as mild (79 %) and rarely severe (1 %).  As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related AEs.  The authors concluded that the overall safety profile of MRgFUS thalamotomy supported its role as a new option for patients with medically refractory ET.

Guidance from the National Institute for Health and Care Excellence (NICE, 2018) concluded: "The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research." The guidance stated that "Further research, which could include randomised controlled trials, should address patient selection, report on functional improvement and quality of life, and provide long-term follow-up data."

Gallay et al (2019) noted that since the first clinical application of the incisionless MRgFUS technology only small series of patients have been reported, and thus only extrapolations of the procedure-related risks could be offered.  In this study, these investigators analyzed side-effects and targeting accuracy in 180 consecutive treatments with MRgFUS for chronic therapy-resistant idiopathic Parkinson's disease (PD), ET (n = 33), cerebellar tremor (CT), and neuropathic pain (NP), all performed in their dedicated center.  A total of 180 treatments with MRgFUS for chronic therapy-resistant idiopathic PD, ET, CT, and NP were prospectively assessed for side-effects and targeting accuracy.  Monitoring for later side-effects was continued for at least 3 months after the procedure in all but 1 case (0.6 %); in that single case, the patient was lost to follow-up after an uneventful early post-operative course.  The surgical targets were the pallido-thalamic tract (pallido-thalamic tractotomy, n = 105), the cerebello-thalamic tract (cerebello-thalamic tractotomy, n = 50), the central lateral nucleus (central lateral thalamotomy, n = 84), the centrum medianum (centrum medianum thalamotomy, n = 12), and the globus pallidus (pallidotomy, n = 2).  Cognitive testing was performed before, 1 to 2 days after, and 1 year after the procedure.  The Mini-Mental State Examination (MMSE) was used for the first 29 cases and was then replaced by the Montreal Cognitive Assessment (MoCA).  Lesion reconstruction and measurement of targeting accuracy were done on 2-day post-treatment MR images for each performed target.  To determine targeting accuracy measurement, 234 out of the 253 lesions depicted in the 2-day post-operative MR examination could be 3D-reconstructed.  The mean MoCA score was slightly improved 2 days post-operatively (p = 0.002) and remained stable at 1-year follow-up (p = 0.03).  The mean MMSE score was also slightly improved 2 days post-operatively and at 1-year follow-up, but the improvement was not statistically significant (p = 0.06 and p = 0.2, respectively).  The mean (± SD) accuracy was 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for the mediolateral, anteroposterior, and dorso-ventral dimensions, respectively.  The mean 3D accuracy was 0.73 ± 0.39 mm.  As to side-effects, 14 events over 180 treatments were documented.  They were classified into procedure-related (n = 4, 2.2% ), effect on neighboring structures (n = 3, 1.7 %), and disease-related (n = 7, 3.9 %).  There was no bleeding.  The authors concluded that the incisionless transcranial MRgFUS technology demonstrated a higher targeting accuracy and a lower side-effect profile than techniques requiring cerebral penetration.  In the absence of penetration brain shift, this technique avoided the placement of a thermos-lesion away from the chosen target, thus suppressing the need for reversible therapeutic energy application.  With the use of proper physiopathology-based targets, definitive therapeutic effects could be coupled with sparing of sensory, motor, and para-limbic/multi-modal thalamo-cortical functions.  Clinical efficacy, not analyzed in this investigation, will ultimately rest in proper target selection and optimized thermos-lesional coverage of the target.  This study had 33 patients with ET with short-term follow-up (1 year).  More importantly, clinical efficacy was not addressed in this analysis.

Guidance from the National Institute for Health and Care Excellence (NICE, 2018) concluded: "Current evidence on the safety and efficacy of unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research." The guidance stated that "Further research, which could include randomised controlled trials, should address patient selection and report on long-term follow-up." 

Park et al (2019) noted that following the emergence of magnetic resonance-guided focused ultrasound (MRgFUS) as a promising tool for movement disorder surgery, thalamotomy for essential tremor using this technique has become a useful tool based on its efficacy and lack of adverse effects.  These researchers summarized the 4-year results of previous reports focusing on the durability of effectiveness of MRgFUS thalamotomy for essential tremor (ET).  From October 2013 to August 2014, a total of 15 patients with intractable ET were enrolled; 12 of them completed clinical assessment through 4 years of post-operative follow-up.  Tremor severity, task performance, and disability were measured using the Clinical Rating Scale of Tremor.  The mean age of the 12 patients was 61.7 ± 8.1 years.  Maximally delivered energy was 15,552.4 ± 6,574.1 joules.  The mean number of sonications was 17.3 ± 1.6.  The mean post-operative lesion volume was 82.6 ± 29.023 mm3 and in 1 year was a mean of 9.667 ± 8.573 mm3 .  Four years post-operatively, improvement of the hand tremor score was 56 %, that of the disability score was 63 %, that of the postural score was 70 %, and that of the action score was 63 % compared with baseline; all improvements were significant and sustained over the 4-year period after thalamotomy.  There was no permanent adverse effect throughout the 4-year follow-up period.  The authors concluded that MRgFUS thalamotomy exhibited sustained clinical efficacy 4 years following the treatment of intractable ET; AEs were generally transient.  These researchers stated that a large cohort of patients who have undergone MRgFUS thalamotomy with longer follow-up is needed to confirm these findings.

Liver Cancer (Primary or Metastatic)

Park et al (2009) ascertained the safety and effectiveness of HIFU in the treatment of liver metastasis from colon and stomach cancer.  A total of 10 patients with liver metastasis from colon cancer and 3 from stomach cancer underwent HIFU under general anesthesia.  Treatment was performed using an extra-corporeal, ultrasound-guided focused system.  Complications during the study, extent of coagulative necrosis at 2-week follow-up, and evidence of tumor on further follow-up were analyzed.  Patients were divided into 4 categories:
  1. complete ablation with no evidence of recurrence on follow-up;
  2. apparent complete ablation of target mass with new foci of disease in the target organ or distant malignancy and no local tumor progression;
  3. local tumor progression after apparent complete ablation; and
  4. partial ablation.
Mean follow-up period was 22 weeks in the colon cancer group and 58 weeks in the stomach cancer group.  The sum of total lesion size was between 1.8 cm and 21.4 cm (mean of 8.4 cm +/- 6.7 cm) for the colon cancer group and between 1.7 and 16.3 cm (mean of 8.8 cm +/- 7.3 cm) for the stomach cancer group.  In the colon cancer group, 1 patient was categorized as category (i), 1 as category (ii), 3 as category (iii), and the remaining 5 as category (iv). The stomach cancer group showed 2 patients as category (i) and 1 as category (ii). The authors concluded that for treating liver metastasis from colon and stomach cancer, HIFU seems safe but its effectiveness is questionable.  They stated that more research is needed.

An assessment of the evidence for HIFU for liver cancer from the Catalan Agency for Health Technology Assessment and Research (CAHTA) concluded: "Based on the scientific evidence available, there is not enough information on efficacy/effectiveness, safety and cost-effectiveness of HIFU treatment in patients with liver cancer (primary or metastatic).  In fact, the design and scarcity of published studies hinder a correct assessment of HIFU treatment.  Thus, interventions using high intensity focused ultrasound for liver cancer treatment should be tested in randomised clinical trials, of a sufficient sample size and adequate design" (Navarro, 2008).

Ng et al (2011) evaluated the outcome of patients with hepato-cellular carcinoma (HCC) treated by HIFU in a single tertiary referral center.  From October 2006 to December 2008, a total of 49 patients received HIFU for unresectable HCC.  Each patient underwent a single session of HIFU with a curative intent.  Treatment efficacy and survival outcome were evaluated.  Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by uni-variate analysis.  The median size of the treated tumors was 2.2 cm (range of 0.9 to 8 cm).  The majority of patients had single tumors (n = 41, 83.6 %).  Thirty-one patients (63.2 %) had artificial right pleural effusion during HIFU treatment to reduce damage to the lung and diaphragm.  The hospital mortality rate was 2 % (n = 1) and the complication rate was 8.1 % (n = 4).  The primary technique effectiveness rate was 79.5 % (39 of 49 patients).  It increased from 66.6 % in the initial series to 89.2 % in the last 28 patients.  Tumor size (greater than or equal to 3.0 cm) was the significant risk factor affecting the complete ablation rate.  The 1- and 3-year overall survival rates were 87.7 % and 62. 4%, respectively.  Child-Pugh liver function grading was the significant prognostic factor influencing the overall survival rate.  The authors concluded that HIFU is an effective treatment modality for unresectable HCC with a high technique effectiveness rate and favorable survival outcome.  The drawbacks of this study were its retrospective nature, short follow-up and small sample size.  The authors stated that further studies are needed to compare the effectiveness of HIFU with other ablation modalities.

Chan and associates (2013) reported their preliminary experience of HIFU for the treatment of recurrent hepato-cellular carcinoma (HCC).  Clinico-pathological data of 27 patients who received HIFU ablation and 76 patients who received radiofrequency ablation (RFA) for recurrent HCC from October 2006 to October 2009 were reviewed.  Survival outcomes between the 2 groups were compared using the log-rank test.  A value of p < 0.05 was considered significant.  The median follow-up was 27.9 months.  There was no difference in tumor size (HIFU, 1.7 cm; RFA, 1.8 cm; p = 0.28) between the 2 groups.  Procedure-related morbidity rate was 7.4 % in the HIFU group and 6.5 % in the RFA group (p = 1.00).  Skin burn and pleural effusion were the 2 morbidities associated with HIFU.  There was no hospital mortality in the HIFU group, whereas 2 deaths occurred in the RFA group.  The 1-, 2-, and 3-year DFS rates were 37.0 %, 25.9 %, and 18.5 %, respectively, for the HIFU group, and 48.6 %, 32.1 %, and 26.5 %, respectively for the RFA group (p = 0.61).  The 1-, 2-, and 3-year overall survival rates were 96.3 %, 81.5 %, and 69.8 %, respectively, for the HIFU group, and 92.1 %, 76.1 %, and 64.2 %, respectively, for the RFA group (p = 0.19).  The authors concluded that their preliminary experience in using HIFU for recurrent HCC is promising.  They stated that further studies are needed to explore its treatment value for primary HCC.

Also, the NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 2.2013) does not mention HIFU as a therapeutic option.

In a systematic review and meta-analysis, Hu et al (2022) examined the safety and effectiveness of HIFU combined with trans-arterial chemoembolization (TACE) for the treatment of liver cancer.  The Chinese National Knowledge Infrastructure (CNKI), China Biomedical Literature Database, Cochrane Library, Medline, and Embase databases were searched using the terms "randomized controlled trial (RCT)", "liver cancer", "transarterial chemoembolization", "TACE", "high intensity focused ultrasound", "HIFU", "HIFU combined with TACE", and "efficacy analysis".  Studies were included in accordance with the PICOS principle, and risk of bias was assessed in RCTs in accordance with the Cochrane Manual for Systematic Evaluation of Interventions.  Rev Man 5.3 and Stata 13 were used for meta-analysis.  A total of 6 RCTs (488 patients) were included in this study.  Of these studies, 5 described a random allocation (RA) method, 4 described allocation sequence concealment, and 4 used a blind method for the allocation of study subjects.  The results of the meta-analysis showed that the 1-year [OR =3.13, 95 % CI: 1.92 to 5.11, p < 0.00001], 2-year (OR =3.38, 95 % CI: 1.71 to 6.66, p = 0.0004), and 5-year (OR =2.15, 95 % CI: 1.02 to 4.55, p = 0.04) survival rates (SRs) of patients treated with HIFU + TACE were significantly better than those of patients treated with TACE alone.  The total effective rate (TER) of patients treated with HIFU + TACE (OR = 3.61, 95 % CI: 2.14 to 6.08, p < 0.00001) was significantly better than that of patients treated with TACE alone.  Compared with TACE alone, HIFU combined with TACE significantly reduced the incidence of post-operative AEs (OR = 0.57, 95 % CI: 0.34 to 9.96, p = 0.03).  The authors concluded that compared with TACE alone, HIFU combined with TACE in the treatment of LC had better effectiveness, higher prognosis and survival rate, and lower incidence of AEs.  However, due to the limited sample size of the study, there was some risk of bias in the findings.  These investigators stated that further research is needed to confirm the findings of this study.  These researchers stated that a major drawback of this study was that some of the articles showed heterogeneity, which might have affected the results.

Osteosarcoma / Bone Tumors

Li and co-workers (2009) prospectively evaluated the use of ultrasonographically guided HIFU in the salvage of limbs in patients with osteosarcoma.  A total of 7 patients underwent HIFU ablation.  Laboratory and radiological examinations were performed after intervention.  Changes in symptoms and survival time were noted at follow-up.  No severe complications were observed, and pre-existing severe pain disappeared in patients treated with HIFU.  Alkaline phosphatase did not show statistically significant changes before and after HIFU treatment, although alkaline phosphatase did change 1 month and 2 months after HIFU.  Complete response of the tumor was achieved in 3 patients with osteosarcoma.  Partial response was achieved in another 3 patients treated with HIFU.  Pulmonary metastasis was noted in only 1 patient 5 months after HIFU.  The median survival time was 68 months.  All patients were alive 3 years after HIFU treatment.  Five patients were alive at follow-up visits after 5 years.  One patient died from cachexia and infection after 4 years, another patient died of cardiac arrest attack after 4 years.  Three patients died of lung dysfunction from pulmonary metastases after 5 years.  The 5-year survival rate was 71.4 %.  The authors concluded that HIFU ablation was a safe and feasible method of treatment of osteosarcoma which salvages the limb, but they stated that large-scale randomized clinical trials are needed for confirmation.

Chen et al (2010) evaluated the long-term follow-up results of ultrasonographically (US)-guided HIFU ablation in patients with primary bone malignancy.  A total of 80 patients with a primary bone malignancy -- 60 with stage IIb disease and 20 with stage III disease (Enneking staging system) -- were treated with US-guided HIFU ablation.  High-intensity focused ultrasound ablation combined with chemotherapy was performed in 62 patients with osteosarcoma, 1 patient with periosteal osteosarcoma, and 3 patients with Ewing sarcoma.  The remaining 14 patients had chondrosarcoma, giant cell bone cancer, periosteal sarcoma, or an unknown malignancy and were treated with HIFU ablation only.  Magnetic resonance imaging (MRI) or computed tomography (CT), and single photon emission computed tomography (SPECT) were used to assess tumor response.  Cumulative survival rates were calculated by using the Kaplan-Meier method.  Adverse effects were recorded.  High-intensity focused ultrasound ablation guided by real-time US was performed.  Follow-up images demonstrated completely ablated malignant bone tumors in 69 patients and greater than 50 % tumor ablation in the remaining 11 patients.  Overall survival rates at 1, 2, 3, 4, and 5 years were 89.8 %, 72.3 %, 60.5 %, 50.5 %, and 50.5 %, respectively.  Survival rates at 1, 2, 3, 4, and 5 years were 93.3 %, 82.4 %, 75.0 %, 63.7 %, and 63.7 %, respectively, in the patients with stage IIb cancer and 79.2 %, 42.2 %, 21.1 %, 15.8 %, and 15.8 %, respectively, in those with stage III disease.  Among the patients with stage IIb disease, long-term survival rates were substantially improved in the 30 patients who received the full treatment -- namely, complete HIFU and full cycles of chemotherapy -- compared with the survival rates for the 24 patients who did not finish the chemotherapy cycles and the 6 patients who underwent partial ablation only.  Only 5 (7 %) of the 69 patients who underwent complete ablation had local cancer recurrence during the follow-up period.  A total of 40 adverse events were recorded, with 14 patients requiring surgical intervention.  The authors concluded that US-guided HIFU ablation of malignant bone tumors is feasible and effective and eventually may be a component of limb-sparing techniques for patients with these cancers.

Li et al (2010) evaluate 25 patients with malignant bone tumors before and after HIFU treatment.  High-intensity focused ultrasound resulted in significant improvement in biochemical markers, and no severe complications were observed.  Following HIFU treatment, 21 (87.5 %) patients were completely relieved of pain, and 24 (100 %) experienced significant relief.  On the basis of MRI or PET-CT, HIFU was effective: For patients with primary bone tumors, 6 (46.2 %) had a complete response, 5 (38.4 %) had a partial response, 1 (7.8 %) had a moderate response, and 1 suffered progressive disease; the response rate was 84.6 %.  For patients with metastatic bone tumors, 5 (41.7 %) had complete response, 4 (33.3 %) had partial response, 1 (8.3 %) had a moderate response, 1 (8.3 %) had stable disease, and 1 suffered progressive disease; the response rate was 75.0 %.  The 1-, 2-, 3-, and 5-year survival rates were 100.0 %, 84.6 %, 69.2 %, and 38.5 %, respectively, for patients with primary bone tumors and 83.3 %, 16.7 %, 0 %, and 0 %, respectively, for patients with metastatic bone tumors.  The survival rates for patients with primary bone tumors were significantly better than for those with metastatic tumors.  The authors concluded that HIFU safely and non-invasively ablated malignant bone tumors and relieved pain.  They stated that HIFU ablation should be further investigated in larger number of patients, as it appears to be successful in the treatment of primary malignant bone tumors.

In an editorial that accompanied the afore-mentioned study by Li et al (2010), Konski (2010) stated that caution needs to be exercised in interpreting these findings because the response rates were classified by MRI or PET-CT and not pathologically.  Well-designed studies comparing HIFU to cryotherapy, radiofrequency ablation, and/or external beam radiotherapy are needed to ascertain the effectiveness of HIFU in the treatment of bone metastases.  The editorialist noted that HIFU may provide another treatment option for patients with primary bone tumors who are not surgical candidates or who refuse surgery, but these data need to be confirmed.

Renal Cancer

In a phase I clinical study, Klinger et al (2008) evaluated the feasibility of HIFU ablation of small renal tumours under laparoscopic control.  A total of 10 kidneys with solitary renal tumors were treated with a newly developed 4.0 MHz laparoscopic HIFU probe.  In the first 2 patients with 9-cm tumors, a defined marker lesion was placed before laparoscopic radical nephrectomy.  In 8 patients with a mean tumor size of 22 mm (range of 11 to 40), the tumor was completely ablated as in curative intent, followed by laparoscopic partial nephrectomy in 7 tumors.  One patient had post-HIFU biopsies and was followed radiologically.  Specimens were studied by detailed and whole-mount histology, including NADH stains.  Mean HIFU insonication time was 19 mins (range of 8 to 42), with a mean targeted volume of 10.2 cm3 (range of 9 to 23).  At histological evaluation both marker lesions showed irreversible and homogeneous thermal damage within the targeted site.  Of the 7 tumors treated and removed after HIFU, 4 showed complete ablation of the entire tumor.  Two had a 1- to 3-mm rim of viable tissue immediately adjacent to where the HIFU probe was approximated, and 1 tumor showed a central area with about 20 % vital tissue.  There were no intra- or post-operative complications related to HIFU.  The authors concluded that the morbidity of laparoscopic partial nephrectomy mainly comes from the need to incise highly vascularized parenchyma.  Targeted laparoscopic HIFU ablation may render this unnecessary, but further studies are needed to refine the technique.

Klatte and Marberger (2009) reviewed the current status of HIFU for the treatment of renal tumors.  Application of extra-corporeal HIFU for renal tumors is well-tolerated with no serious peri-operative complications.  However, the techniques available do not permit sufficient tumor destruction that can be considered as an alternative to surgical extirpation.  Laparoscopic HIFU avoids problems with respiratory movement and interphases and may achieve a greater rate of tumor destruction.  The authors concluded that at the current time, HIFU of renal tumors has to be considered an experimental treatment approach; and prospective evaluation of laparoscopic HIFU is needed to assess its oncologic effectiveness.

Hernández Fernández et al (2009) reviewed the mechanisms of action of HIFU as well as both experimental and clinical work related to renal tumor treatment.  While most currently available experience in urological tumors with HIFU has been obtained with prostate cancer, an increasing number of studies support the efficacy and safety of this procedure for renal tumor destruction.  Together with cryotherapy and radiofrequency, HIFU completes the spectrum of minimally invasive surgery in renal cancer, intended to decrease surgical morbidity while achieving similar oncological control rates.  The authors concluded that it is still early to recommend this procedure for daily clinical practice.  They stated that while its safety and few side effects are known, many ongoing studies intended to confirm its mid-term and long-term oncological efficacy should be completed.

Caballero et al (2010) reviewed the development, physical principles, and current status of HIFU in the treatment of renal tumors.  These investigators concluded that HIFU appears to be a new option among non-invasive therapies for renal cancer in selected cases.  They stated that a low complication rate has been noted, but much longer follow-up times are needed for assessment of oncological results.

The European Association of Urology’s guidelines on “Renal cell carcinoma” (Ljungberg et al, 2013) stated that other image-guided percutaneous and minimally invasive techniques (e.g., microwave ablation, laser ablation, and HIFU ablation) are experimental and are recommended only in studies.

Pancreatic Cancer

In a phase II clinical trial, Zhao et al (2010) evaluated the safety and effectiveness of concurrent gemcitabine and HIFU therapy in patients with locally advanced pancreatic cancer.  Patients with localized unresectable pancreatic adenocarcinoma in the head or body of the pancreas received gemcitabine (1,000 mg/m) intravenously over 30 mins on days 1, 8, and 15, and concurrent HIFU therapy on days 1, 3, and 5.  The treatment was given every 28 days.  A total of 37 (94.9 %) of the 39 patients were assessable for response, and 2 cases of complete response and 15 cases of partial response were confirmed, giving an overall response rate of 43.6 % [95 % confidence interval (CI): 28.0 to 59.2 %].  The median follow-up period was 16.5 months (range of 8.0 to 28.5 months).  The median time to progression and overall survival for all patients were 8.4 months (95 % CI: 5.4 to 11.2 months) and 12.6 months (95 % CI: 10.2 to 15.0 months), respectively.  The estimates of overall survival at 12 and 24 months were 50.6 % (95 % CI: 36.7 to 64.5 %) and 17.1 % (95 % CI: 5.9 to 28.3 %), respectively.  A total of 16.2 % of patients experienced grade 3/4 neutropenia.  Grade 3 thrombocytopaenia was documented in 2 (5.4 %) patients.  Grade 3 nausea/vomiting and diarrhea were observed in 3 (8.1 %), and 2 (5.4 %) patients, respectively.  Grade 1 or 2 fever was detected in 70.3 % of patients.  Twenty-eight patients (71.8 %) complained of abdominal pain consistent with tumor-related pain before HIFU therapy.  Pain was relieved in 22 patients (78.6 %).  The authors concluded that concurrent gemcitabine and HIFU is a tolerated treatment modality with promising activity in patients with previously untreated locally advanced pancreatic cancer.  Further investigation is needed to ascertain the role of HIFU in the treatment of pancreatic cancer.

Li and colleagues (2014) examined the safety and effectiveness of HIFU combined with other physical therapies for the treatment of pancreatic cancer. PubMed, EMbase, the Cochrane Library (Issue 11, 2013), CBM, CNKI, and WanFang databases were systematically searched up to November 2013; RCTs and clinical controlled trials about the treatment of HIFU were included. According to the inclusion and exclusion criteria, 2 reviewers independently screened the studies, exacted the data, and assessed the quality. The meta-analysis was performed by using the RevMan 5.0 software. A total of 23 studies including 19 RCTs and 4 clinical controlled trials were included; of which 14 studies reported the safety. Results of meta-analyses showed that the survival rate at 6 months and 12 months, overall efficacy, and clinical benefit rate in HIFU plus radiation and chemotherapy group were significantly higher than those in groups treated with 3-D conformal radiation therapy (p < 0.05), gemcitabine (p < 0.05), gemcitabine plus cisplatin (p < 0.05), and gemcitabine plus 5-fluorouracil (p < 0.05). The adverse effect caused by HIFU plus other therapy was equal to those in the control group. The major HIFU-related adverse effect was skin damage and fever. The authors concluded that the current evidence suggested that the effectiveness of HIFU for pancreatic cancer was superior to other therapies. However, the poor quality of trails may reduce the reliability of outcome to some extent. They stated that the current evidence suggested that the effectiveness of HIFU for pancreatic cancer was superior to other therapies, but with poor quality. Therefore, a standard and unified criterion for the diagnosis and outcome measures of pancreatic cancer is needed, and the quality of study design and implementation should be bettered to improve the high quality of evidence for its clinical application.

In a meta-analysis, Dababou and colleagues (2017) evaluated the role of HIFU in pain palliation of advanced unresectable pancreatic adenocarcinoma.  An electronic search was performed in PubMed Medline database up to the end of July 2016, for unresectable pancreatic cancer pain palliation with HIFU.  Pertinent studies were identified through the PubMed search engine using the following keywords: HIFU, pancreas, pancreatic cancer, pain and palliation.  Additional studies were included after manual search of the selected bibliographies.  Pain palliation results reported in each study were analyzed using a logit-transformed random-effects model using the inverse variance method, with the DerSimonian-Laird estimator for τ2, and Cochran's Q test for heterogeneity among studies.  The I2 was calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects.  A rank correlation test of funnel plot asymmetry was done to assess possible publication bias.  The meta-analysis included a total number of 23 studies with 865 patients, 729 with pancreatic cancer.  The population enrolled ranged from 3 patients in the smallest series, up to 61 in the largest study; τ2 (variance among studies) was 0.195, and I2 (percentage of variation among studies) was 40 % (95 % CI: 1 to 64 %); the Q test p-value was 0.026, indicating significant heterogeneity among studies.  Among 639 patients treated with HIFU, 567 complained of pancreatic pain before the treatment and 459 patients experienced partial or complete pain relief after treatment.  The random effects estimate of the proportion of patients with pain reduction was 0.81 (95 % CI: 0.76 to 86).  The authors concluded HIFU appeared to be an effective tool for pain palliation in advanced pancreatic cancer.  Studies assessing treatment in patients with pancreatic adenocarcinoma were limited by factors such as small sample sizes and heterogeneity in clinical definitions and assessments.  They stated that prospective randomized and standardized studies are needed to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival.

Stanislavova et al (2021) carried out a systematic review on the resection rate after HIFU ablation in patients with borderline resectable pancreatic cancer (BRPC) and examined the impact of this technique over the oncological results.  The PubMed and Wanfang databases were searched using keywords: pancreatic cancer, HIFU ablation and high-intensity focused ultrasound.  All found articles were reviewed.  The systematic review was carried out according to the PRISMA guidelines.  The English database search showed 109 papers, of which 3 met the inclusion criteria.  The Wanfang database resulted in 110 papers; however, none met the inclusion criteria of the review.  From the included studies 97 patients underwent neoadjuvant HIFU ablation ± chemotherapy; 34 patients reached resection (35.1 %).  In 2 patients, residual tumor (R) classification was not reported.  R0 resection rate in all reported patients was 30.5 % (29/95); and R1 resection rate was 3.2 % (3/95).  The authors concluded that HIFU was safe and feasible in locally advanced and metastatic pancreatic cancer with proven down-staging and down-sizing effects.  Moreover, these researchers stated that further research on the role of HIFU ablation as a neoadjuvant treatment for borderline resectable pancreatic cancer is needed.

Vulvar Dystrophy

Ruan et al (2010) evaluated the effectiveness of HIFU in the treatment of patients with non-neoplastic epithelial disorders of the vulva.  These researchers reviewed 41 cases of lichen sclerosus, 38 cases of squamous cell hyperplasia, and 17 mixed cases.  Biopsy specimens were assessed with light microscopy before and after treatment.  Pruritus and signs of vulvar lesions were dramatically improved after HIFU treatment, without severe complications, and 90.2 % of the patients were cured or had their symptoms improved 6 months after treatment.  On light microscopy, pigmentation and epithelial structures were recovered and dermal lymphocytic infiltration was reduced.  The response rates were lower and complication rates higher among lichen sclerosus than among squamous cell hyperplasia cases (p < 0.05 for both).  The authors concluded that treatment with HIFU may be safe and effective in cases of vulvar dystrophy.  The findings of this trial need to be validated by well-desgined studies with larger number of patients and longer follow-up periods.

Thyroid Nodules

In an open, single-center, feasibility study, Esnault et al (2011) hypothesized that an optimized HIFU device could be safe and effective for ablating benign thyroid nodules without affecting neighboring structures.  A total of 25 patients were treated with HIFU with real-time ultrasound imaging 2 weeks before a scheduled thyroidectomy for multi-nodular goiter.  Thyroid ultrasonography imaging, thyroid function, were evaluated before and after treatment.  Adverse events were carefully recorded.  Each patient received HIFU for 1 thyroid nodule, solid or mixed, with mean diameter greater than or equal to 8 mm, and no suspicion of malignancy.  The HIFU device was progressively adjusted with stepwise testing.  One pathologist examined all removed thyroids.  Three patients discontinued treatment due to pain or skin microblister.  Among the remaining 22 patients, 16 showed significant changes by ultrasound.  Macroscopic and histological examinations showed that all lesions were confined to the targeted nodule without affecting neighboring structures.  At pathological analysis, the extent of nodule destruction ranged from 2 % to 80 %.  Five out of 22 patients had over 20 % pathological lesions unmistakably attributed to HIFU.  Seventeen cases had putative lesions including non-specific necrosis, hemorrhage, nodule detachment, cavitations, and cysts.  Among these 17 cases, 12 had both ultrasound changes and cavitation at histology that may be expected for an HIFU effect.  In the last 3 patients ablated at the highest energy level, significant ultrasound changes and complete coagulative necrosis were observed in 80 %, 78 %, and 58 % of the targeted area, respectively.  There were no major complications of ablation.  The authors concluded that these findings showed the potential efficacy of HIFU for human thyroid nodule ablation.  Lesions were clearly visible by histology and ultrasound after high energy treatments, and safety and tolerability were good.  The authors identified a power threshold for optimal necrosis of the target thyroid tissue.  They stated that further studies are ongoing to assess nodule changes at longer follow-up times.

Cheong et al (2022) stated that currently there are 2 systematic reviews, as well as 1 systematic review and meta-analysis on the use of HIFU for the treatment of benign thyroid nodules.  In this systematic review and meta-analysis, these investigators examined the safety and effectiveness of HIFU in the treatment of benign thyroid nodules.  PubMed, Embase and Cochrane databases were searched for relevant studies from 1990 to 2021.  A total of 9 studies were included in the systematic review and 6 in the meta-analysis.  Pooled volume reduction rates (VRRs) at 3, 6 and 24 months after HIFU were examined.  This systematic review and meta-analysis showed that pooled VRRs at 3, 6, and 24 months after HIFU were 42.14 (95 % CI: 28.66 to 55.62, I2 = 91 %), 53.51 (95 % CI: 36.78 to 70.25, I2 = 97 %) and 46.89 (95 % CI: 18.87 to 74.92, I2 = 99%), respectively.  There was significant heterogeneity in the pooled VRRs at 3, 6 and 24 months after HIFU.  No studies recorded complete disappearance of the nodules.  Common side effects included pain, skin changes and edema.  There were no major complications except for transient vocal cord paralysis and voice hoarseness (0.014 %) and transient Horner syndrome (0.5 %).  The authors concluded that HIFU may be a safe and effective alternative treatment for benign thyroid nodules.  Moreover, these researchers stated that larger clinical trials with longer follow-up are needed to examine the effectiveness of HIFU in the treatment of benign thyroid nodules.

The authors stated that this study had several drawbacks.  First, this study may be limited by publication bias as results that suggested a benefit of HIFU were more likely to be published than those that did not.  Second, the small number of studies and small sample sizes precluded the ability to adequately analyze subgroups and identify potentially important co-variates.  A further meta-analysis that considers the factors that cause heterogeneity may be needed when sufficient papers have been published in the future.  Moreover, different studies had different follow-up durations; therefore, direct comparisons could not be drawn.  Third, many studies reported medians and their ranges only.  These researchers converted those values to means and standard deviations, which may have affected the accuracy of the values.  Fourth, these investigators were unable to analyze the absolute difference in nodule volumes before and after HIFU due to the heterogeneity of the baseline mean target nodule volume.  Fifth, there were insufficient studies (less than 10) to evaluate funnel plot asymmetry based on Cochrane recommendations.  These researchers included articles in English or were translated to English, which may have resulted in an over-estimation or under-estimation of results, given the selection bias towards populations whose studies were conducted in English.


In a Cochrane review, Griffin et al (2012) evaluated the effects of HIFU, low-intensity ultrasound (LIUS), and extra-corporeal shockwave therapies (ECSW) as part of the treatment of acute fractures in adults.  These investigators searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (December 2011), the Cochrane Central Register of Controlled Trials (in The Cochrane Library 2011, Issue 4), MEDLINE (1950 to November week 3, 2011), EMBASE (1980 to 2011 week 49), trial registers and reference lists of articles.  Randomized controlled trials evaluating ultrasound treatment in the management of acute fractures in adults were selected.  Studies including participants over 18 years of age with acute fractures, reporting functional outcomes, time to union, non-union, secondary procedures such as for fixation or delayed or non-union, adverse effects, pain, costs or patient adherence were included.  Two authors independently extracted data from the included studies.  Treatment effects were assessed using mean differences or risk ratios and, where there was substantial heterogeneity, pooled using a random-effects model.  Results from "worst case" analyses, which gave more conservative estimates of treatment effects for time to fracture union, are reported in preference to those from "as reported" analyses.  A total of 12 studies, involving 622 participants with 648 fractures, were included.  Eight studies were randomized placebo-controlled trials, 2 studies were RCTs without placebo controls, 1 study was a quasi-randomised placebo controlled trial and the remaining study was a quasi-RCT without placebo control.  Eleven trials tested LIUS and 1 trial tested ECSW.  Four trials included participants with conservatively treated upper limb complete fractures and 6 trials included participants with lower limb complete fractures; these were surgically fixed in 4 trials.  The remaining 2 trials reported results for conservatively treated tibial stress fractures.  Very limited data from 2 complete fracture studies showed no difference between ultrasound and placebo control in functional outcome.  Pooled estimates from 2 studies found LIUS did not significantly affect the time to return to training or duty in soldiers or midshipmen with stress fractures (mean difference -8.55 days, 95 % CI: -22.71 to 5.61).  Based on a "worst case" analysis, which adjusted for incomplete data, pooled results from 8 heterogeneous studies showed no statistically significant reduction in time to union of complete fractures treated with LIPUS (standardised mean difference -0.47, 95 % CI: -1.14 to 0.20).  This result could include a clinically important benefit or harm, and should be seen in the context of the highly significant statistical heterogeneity (I² = 90 %).  This heterogeneity was not explained by the a priori subgroup analyses (upper limb versus lower limb fracture, smoking status).  An additional subgroup analysis comparing conservatively and operatively treated fractures raised the possibility that LIUS may be effective in reducing healing time in conservatively managed fractures, but the test for subgroup differences did not confirm a significant difference between the subgroups.  Pooled results from 8 trials reporting proportion of delayed union or non-union showed no significant difference between LIUS and control.  Adverse effects directly associated with LIUS and associated devices were found to be few and minor, and compliance with treatment was generally good.  One study reporting on pain scores found no difference between groups at 8 weeks.  One quasi-randomized study (59 fractures) found no significant difference between ECSW and no-placebo control groups in non-union at 12 months (risk ratio 0.56, 95 % CI: 0.15 to 2.01).  There was a clinically small but statistically significant difference in the visual analog scores for pain in favor of ECSW at 3-month follow-up.  The only reported complication was infection, with no significant difference between the 2 groups.  The authors concluded that while a potential benefit of ultrasound for the treatment of acute fractures in adults can not be ruled out, the currently available evidence from a set of clinically heterogeneous trials is insufficient to support the routine use of this intervention in clinical practice.  They stated that future trials should record functional outcomes and follow-up all trial participants.

Breast Cancer

Yonetsuji and associates (2013) noted that HIFU is a promising technique for cancer treatment owing to its minimal invasiveness and safety. However, skin burn, long treatment time and incomplete ablation are main shortcomings of this method. These investigators presented a novel HIFU robotic system for breast cancer treatment. The robot has 4 rotational degrees of freedom with the workspace located in a water tank for HIFU beam imaging and ablation treatment. The HIFU transducer combined with a diagnostic 2D linear ultrasound probe was mounted on the robot end-effector, which was rotated around the HIFU focus when ablating the tumor. High intensity focused ultrasound beams were visualized by the 2D probe using beam imaging. Skin burn can be prevented or alleviated by avoiding long time insonification towards the same skin area. The time cost could be significantly reduced, as there is no need to interrupt the ablation procedure for cooling the skin. In addition, the authors stated that their proposed robot control strategies can avoid incomplete ablation. Experiments were carried out and the results showed the effectiveness of the proposed system. These preliminary findings need to be validated by well-designed studies.

In a systematic review, Peek et al (2015a) evaluated the clinical effectiveness of non-invasive HIFU ablation in the treatment of breast cancer. Medline/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least 1 clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. A total of 9 studies fulfilled the inclusion criteria. The absence of tumor or residual tumor after treatment was reported for 95.8 % of patients (160 of 167). No residual tumor was found in 46.2 % (55 of 119; range of 17 to 100 %), less than 10 % residual tumor in 29.4 % (35 of 119; range of 0 to 53 %), and between 10 and 90 % residual tumor in 22.7 % (27 of 119; range of 0 to 60 %). The most common complication associated with HIFU ablation was pain (40.1 %) and less frequently edema (16.8 %), skin burn (4.2 %) and pectoralis major injury (3.6 %). Magnetic resonance imaging showed an absence of contrast enhancement after treatment in 82 % of patients (31 of 38; range of 50 to 100 %), indicative of coagulative necrosis. Correlation of contrast enhancement on pre-treatment and post-treatment MRI successfully predicted the presence of residual disease. The authors concluded that HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. They stated that consistent tumor and margin necrosis with reliable follow-up imaging are needed before HIFU ablation can be evaluated within large, prospective clinical trials.

Breast Fibroadenoma

In a multi-center study, Kovatcheva et al (2015) assessed the clinical outcome and safety of US-guided HIFU in patients with breast fibroadenoma (FA). From May 2011 to February 2013, a total of 42 women with 51 FA in 1 or both breasts were selected for treatment with US-guided HIFU; 8 of 51 FA were treated twice. Patients' age ranged from 16 to 52 years (mean of 32). All patients with FA underwent core needle biopsy with histological confirmation. High-intensity focused ultrasound treatment was performed as an out-patient procedure under conscious sedation. Exclusion criteria were pregnant or lactating women, micro-calcifications within the lesion at mammogram, history of breast cancer, previous laser or radiation therapy, and breast implant in the same breast. All patients signed written informed consent. After the treatment, follow-up US with volume evaluations were performed at 2, 6, and 12 months. The FA mean baseline volume was 3.89 ml (0.34 to 19.66). At 2-month follow-up, the mean volume reduction was 33.2 % ± 19.1 % and achieved significance at 6-month (59.2 % ± 18.2 %, p < 0.001) and 12-month (72.5 % ± 16.7 %, p < 0.001) follow-up. Related side effects as superficial skin burn with blister-like aspect in 3 patients and hyper-pigmentation over the treated area in 1 patient were transient and resolved spontaneously. In 1 patient, asymptomatic subcutaneous induration persisted at the end of the study. The authors concluded that US-guided HIFU treatment is an effective non-invasive method for the treatment of breast FA and well-tolerated by the patients. They stated that these preliminary results are encouraging and showed that HIFU could be an alternative to surgery for breast FA.

Peek et al (2015b) stated that breast FA are the most common benign lesions in women. For palpable lesions, there are currently 3 standard treatment options:
  1. reassurance (with or without follow-up),
  2. vacuum-assisted mammotomy (VAM) or
  3. surgical excision.
High-intensity focused ultrasound ablation has been used in the treatment of FA. The drawback of HIFU is its prolonged treatment duration. The aim of this trial is to evaluate circumferential HIFU treatment for the effective ablation of FA with a reduced treatment time. A total of 50 patients (age greater than or equal to 18 years) with symptomatic FA, visible on ultrasound (US, grade U2 benign) will be recruited. In patients greater than or equal to 25 years, cytology or histology will be performed to confirm the diagnosis of a FA. These patients will receive HIFU treatment using the US-guided Echopulse device (Theraclion Ltd., Malakoff, France) under local anesthesia. An additional 50 patients will be recruited and contacted 6 months after discharge from the breast clinic. These patients will be offered an US scan to determine the change in size of their FA. This natural change in size will be compared to the decrease in size after HIFU treatment. Secondary outcome measures include post-treatment complications, patient recorded outcome measures, mean treatment time and cost-analysis. The current trial is registered as ISRCTN76622747.

Guillez and colleagues (2018) examined the benefits and adverse effects of HIFU for the treatment for fibro-adenomas (FA).  These investigators searched Medline from inception to May 2017, without any restriction.  Of 20 identified abstracts, 5 primary studies met inclusion criteria.  All studies reported a reduction in the size of FA treated with an increasing effect over time.  Pain tolerance was most often assessed as moderate.  Adverse effects of HIFU were not severe in all studies.  The authors concluded that HIFU appeared to be a promising technique in the treatment of FA with a volume decrease of approximately 50 % at 6 months of therapy.

Desmoid Tumors

Avedian et al (2016) examined the potential use of HIFU in the treatment of extremity desmoid tumors. They evaluated if MR-guided HIFU can accurately ablate a pre-determined target volume within a human cadaver extremity and if MR-guided HIFU can stop progression and/or cause regression of extremity desmoid tumors? Simulated tumor volumes in 4 human cadavers, created by using plastic markers, were ablated using a commercially available focused ultrasound system. Accuracy was determined in accordance with the International Organization of Standards location error by measuring the farthest distance between the ablated tissue and the plane corresponding to the target. Between 2012 and 2014, these researchers treated 9 patients with desmoid tumors using focused ultrasound ablation. Indications for this were tumor-related symptoms or failure of conventional treatment. Of those, 5 of them were available for MRI follow-up at 12 months or longer (mean of18.2 months; range of 12 to 23). The radiographic and clinical outcomes of 5 patients who had desmoid tumors treated with focused ultrasound were prospectively recorded. Patients were assessed pre-operatively with MRI and followed at routine intervals after treatment with MRI scans and clinical examination. The ablation accuracy for the 4 cadaver extremities was 5 mm, 3 mm, 8 mm, and 8 mm. Four patients' tumors became smaller after treatment and 1 patient has slight progression at the time of last follow-up. The mean decrease in tumor size determined by MRI measurements was 36 % (95 % CI: 7 % to 66 %). No patient has received additional adjuvant systemic or local treatment. Treatment-related adverse events included first- and second-degree skin burns occurring in 4 patients, which were managed successfully without further surgery. The authors concluded that this preliminary investigation provided some evidence that MR-guided HIFU may be a feasible treatment for desmoid tumors. It may also be of use for other soft tissue neoplasms in situations in which there are limited traditional treatment options such as recurrent sarcomas. They stated that further investigation is needed to better define the indications, effectiveness, role, and long-term oncologic outcomes of focused ultrasound treatment.

Also, an UpToDate review on “Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy” (Ravi et al, 2015) lists surgery, radiation therapy and neoadjuvant systemic therapy as therapeutic options; it does not mention HIFU.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcoma” (Version 1.2015) states that “RT is generally only recommended for desmoid tumors that are in the extremity, superficial trunk, or head and neck”.  It does not mention HIFU as a therapeutic option.

Hyper-Pigmentation (Pigmentary Skin Disorder)

Choi et al (2016) macroscopically and histopathologically investigated dermatological changes after HIFU at different exposure doses in a UVB-induced guinea pig model of hyper-pigmentation. These researchers applied HIFU irradiation at 0.1 and 0.2 J/cm2 to UVB-induced spotty hyper-pigmentation in guinea pig skin. The therapeutic effects of HIFU were judged based on gross appearance using photography, dermoscopy, and chromametry during a period of 3 weeks after HIFU irradiation. Histological assessments were performed using Fontana-Masson staining 1 day before and 3 weeks after HIFU irradiation. Macroscopically, UVB-induced hyper-pigmentation was significantly reduced 2 weeks after HIFU with 0.2 J/cm2 , and 3 weeks after HIFU with 0.1 J/cm2 . Histopathologically, the heavy deposition of melanin in the epidermis induced by UVB exposure was reduced 3 weeks after HIFU irradiation. The authors confirmed that HIFU has a positive effect on UVB-induced hyper-pigmentation as well as mechanical destructive activity. They suggested that HIFU may be useful as an alternative modality for human patients suffering from skin pigmentary conditions

Metastatic Bone Pain

In an observational cohort study, Huisman et al (2014) described the first experience with volumetric MR-HIFU for palliative treatment of painful bone metastases and evaluated the technique on 3 levels:
  1. technical feasibility,
  2. safety, and
  3. initial effectiveness.
A total of 11 consecutive patients (7 males and 4 females; median age of 60 years; age range of 53 to 86) underwent 13 treatments for 12 bone metastases. All patients exhibited persistent metastatic bone pain refractory to the standard of care. Patients were asked to rate their worst pain on an 11-point pain scale before treatment, 3 days after treatment, and 1 month after treatment. Complications were monitored. All data were prospectively recorded in the context of routine clinical care. Response was defined as a greater than or equal to2-point decrease in pain at the treated site without increase in analgesic intake. Baseline pain scores were compared to pain scores at 3 days and 1 month using the Wilcoxon signed-rank test. For reporting, the STROBE guidelines were followed. No treatment-related major adverse events were observed. At 3 days after volumetric MR-HIFU ablation, pain scores decreased significantly (p = 0.045) and response was observed in a 6/11 (55 %) patients. At 1-month follow-up, which was available for 9 patients, pain scores decreased significantly compared to baseline (p = 0.028) and 6/9 patients obtained pain response (overall response rate 67 % (95 % CI: 35 % to 88 %)). The authors concluded that this was the first study reporting on the volumetric MR-HIFU ablation for painful bone metastases. No major treatment-related adverse events were observed during follow-up. The results of this study showed that volumetric MR-HIFU ablation for painful bone metastases is technically feasible and can induce pain relief in patients with metastatic bone pain refractory to the standard of care. They stated that future research should be aimed at standardization of the treatment procedures and treatment of larger numbers of patients to assess treatment effectiveness and comparison to the standard of care.

Hurwitz et al (2014) reported on a phase III trial to assess the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS) for palliation of pain due to bone metastases. Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher’s exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. The investigators enrolled 147 subjects, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day.

An assessment of magnetic resonance-guided focused ultrasound surgery for palliation of pain due to bone metastases (McIntosh, et al., 2015) reached the following conclusions:
  1. there are no published studies comparing magnetic resonance guided focused ultrasound surgery (MRgFUS) with radiotherapy or other treatment alternatives for painful bone metastases;
  2.  one randomized controlled trial has compared MRgFUS with a sham control procedure in patients where radiotherapy was unsuccessful, contraindicated or declined; the trial concluded that MRgFUS was safe and effective;
  3.  there is limited published evidence on the safety of MRgFUS from small uncontrolled case series; procedure related pain is the most commonly reported adverse effect;
  4.  two ongoing randomised controlled trials comparing MRgFUS with radiotherapy were identified;
  5.  there are no published evaluations on the cost effectiveness of MRgFUS compared with radiotherapy or other treatment alternatives for painful bone metastases.

Placenta Accreta

Bay et al (2015) evaluated the safety and effectiveness of the HIFU in the treatment of placenta accreta after vaginal delivery. From September 2011 to September 2013, a total of 12 patients diagnosed with placenta accreta with stable vital signs were enrolled in this study. All patients had vaginal delivery and were treated using an ultrasound-guided HIFU treatment system. Decreased vascular index on color Doppler scanning, reduced degree of enhancement on MRI and avoided hysterectomy following treatment indicated the effectiveness of the treatment. Side effects, hemorrhage, infection, sex steroids levels, return of menses and subsequent pregnancy were also recorded to assess the safety of HIFU treatment. All patients received HIFU treatment with an average post-partum length of stay of 6.8 days and an average period of residual placenta involution of 36.9 days. These results demonstrated that HIFU treatment did not increase risk of infection and hemorrhage and no patient required hysterectomy. All patients had return of menstruation with an average delay of 80.3 days, and sex steroid levels during the middle luteal phase of the second menstrual cycle were normal. Two patients were successfully pregnant during the follow-up period. The authors concluded that the findings of this preliminary study suggested that ultrasound-guided HIFU is a non-invasive, safe and effective method to treat selected placenta accreta patients after vaginal delivery who have stable vital signs and desire fertility preservation. These preliminary findings need to be validated by well-designed studies.

Renal Sympathetic Denervation in the Treatment of Resistant Hypertension

Wang et al (2013) examined the feasibility of non-invasive renal sympathetic denervation (RSD) by using the novel approach of extracorporeal HIFU. Under the guidance of Doppler flow imaging, therapeutic ablations (250 W × 2 s) were performed by using extracorporeal HIFU on the bilateral renal nerves (36.3 ± 2.8 HIFU emissions in each animal) in a mean 27.4-min procedure in 18 healthy canines of the ablation group. Similar procedures without acoustic energy treatment were conducted in 5 canines of the sham group. The animals were killed on day 6 or 28. Blood pressure (BP), plasma noradrenaline (NA) level, and renal function were determined on days 0, 6, and 28. Pathological examinations were performed on all retrieved samples. All of the animals survived the treatment. After ablation, BP and NA significantly decreased compared with the baseline values (BP changed -15.9/-13.6 mmHg, NA changed -55.4 % [p < 0.001] 28 days after ablation]) and compared with the sham group on days 6 and 28. Ablation lesions around the renal artery adventitia were observed on day 6. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation on day 28. No procedure-related complications were observed. The authors concluded that effective RSD was successfully achieved by using the extracorporeal HIFU method in canines. Thus, non-invasive HIFU may be further explored as an important and novel strategy for RSD.

Cao et al (2014) noted that renal denervation is a new, catheter-based procedure to reduce renal and systemic sympathetic over-activity by disruption of renal sympathetic efferent and afferent nerves through RF or US energy delivered to the endoluminal surface of both renal arteries. These investigators reviewed the advances in studies on renal denervation. References concerning renal denervation and resistant hypertension cited in this review were collected from PubMed published in English and those of renal denervation devices from official websites of device manufacturers up to January 2014. Articles with keywords "renal denervation" and "resistant hypertension" were selected. Although several studies have shown the safety and effectiveness of renal denervation in the treatment of resistant hypertension and the potential benefit of the procedure in other diseases, Symplicity HTN-3 study, the most rigorous clinical trial of renal denervation to-date, failed to meet its primary end-point. Furthermore, the procedure has other limitations (e.g., the lack of long-term, safety and effectiveness data and the lack of the predictors for the BP-lowering response and non-response to the procedure).  The authors concluded that renal denervation is a promising therapeutic approach in the management of resistant hypertension and other diseases characterized by sympathetic over-activity. In its early stage of clinical application, the effectiveness of the procedure is still controversial. They stated that large-scale blinded RCTs are needed to address the limitations of the procedure.

Miscellaneous Indications

Kovatcheva et al (2014) investigated the long-term safety and effectiveness of US-guided HIFU treatment in patients with primary hyperparathyroidism (PHPT).  In this prospective study, 13 of 72 screened patients with PHPT were eligible for HIFU treatment, which was performed in 1 or 2 sessions.  Parathyroid adenoma size and function were evaluated at baseline, 1, 3, 6, 9, and 12 months after the final HIFU session.  In 11 females and 2 males, mean age of 55.2 ± 12.41 years, the mean applied energy was 15.2 ± 7.7 kJ.  Parathyroid size and parathyroid hormone decreased significantly 1 month after HIFU therapy (p < 0.002 and p < 0.02, respectively).  Calcium concentration decreased slowly to reach significant reduction 9 months later (p < 0.05).  Complete remission was noted in 3 patients (23 %) after 1 year, good disease control was achieved in 9 (69 %), and procedure was unsuccessful in 1 patient (8 %).  Number of sessions was significantly related to treatment success (p < 0.05).  Transitory side effects were impaired vocal cord mobility in 3 patients (23.1 %), subcutaneous edema in 3 patients (23.1 %), and a combination of both in 2 patients (15.4 %).  The authors concluded that HIFU is a promising non-invasive technique for PHPT treatment, which could serve as therapeutic alternative for selected patients.

In a preliminary study, Xiao and colleagues (2014) examined if ultrasound-guided (HIFU can play a role in treating cesarean scar pregnancy (CSP).  Between November 2011 and December 2012, a total of 16 patients with CSP were treated with ultrasound-guided HIFU ablation.  Successful treatment was defined as disappearance of CSP mass, undetectable serum beta human chorionic gonadotropin (HCG), and no serious complications such as severe bleeding, uterine rupture, or hysterectomy.  All patients were successfully treated in the out-patient department and none required re-admission.  After 2 to 5 treatment sessions, the mean time for achieving undetectable serum beta HCG was 4.94 ± 2.32 weeks, and the mean time for CSP mass disappearance was 6.69 ± 3.36 weeks.  Three patients experienced moderate abdominal pain that subsided in 1 to 2 days, and 9 patients experienced mild vaginal bleeding (less than 30 ml) that resolved within 2 to 3 days.  All 16 patients had recovered their normal menstruation function at follow-up.  The authors concluded that these preliminary findings suggested that ultrasound-guided HIFU ablation is a non-invasive, feasible, and effective method for the treatment of CSP.  These preliminary findings need to be validated by well-designed studies.

In a recent review, Duc and Keserci (2019) listed the following as emerging clinical applications of HIFU -- Alzheimer’s disease, benign prostatic hyperplasia, bone metastasis, breast cancer, breast fibroadenoma, epilepsy, essential tremor, extra-abdominal desmoid tumors, liver tumors, low-flow vascular malformations, neuropathic pain, obsessive compulsive disorder, osteoarthritis, osteoid osteoma, pancreatic cancer, Parkinson’s disease, prostate cancer, renal tumors, thyroid nodules, and uterine leiomyomas and adenomyosis.  The authors concluded that HIFU is an emerging alternative therapeutic option for various benign and malignant diseases.  It is a novel, minimally invasive and innovative therapeutic method for patients who are ineligible for surgery or have contraindications to surgery.  These researchers stated that further randomized clinical trial studies should be launched to validate and compare the safety and effectiveness of HIFU with other current available treatments in various diseases.

Movement Disorders

Ghanouni et al (2015) noted that MRgFUS is a new minimally invasive method of targeted tissue thermal ablation that may be of use to treat central neuropathic pain, essential tremor (ET), Parkinson tremor, and brain tumors.  The system has also been used to temporarily disrupt the blood-brain barrier to allow targeted drug delivery to brain tumors.

Chang et al (2015) noted that several options exist for surgical management of ET, including radiofrequency lesioning, deep brain stimulation and gamma-knife radiosurgery of the ventralis intermedius nucleus of the thalamus.  Recently, MRgFUS has been developed as a less-invasive surgical tool aimed to precisely generate focal thermal lesions in the brain.  Patients underwent tremor evaluation and neuroimaging study at baseline and up to 6 months after MRgFUS.  Tremor severity and functional impairment were assessed at baseline and then at 1 week, 1 month, 3 months and 6 months after treatment.  Adverse effects were also sought and ascertained by directed questions, neuroimaging results and neurological examination.  The current feasibility study attempted MRgFUS thalamotomy in 11 patients with medication-resistant ET.  Among them, 8 patients completed treatment with MRgFUS, whereas 3 patients could not complete the treatment because of insufficient temperature.  All patients who completed treatment with MRgFUS showed immediate and sustained improvements in tremors lasting for the 6-month follow-up period.  Skull volume and maximum temperature rise were linearly correlated (linear regression, p = 0.003).  Other than 1 patient who had mild and delayed post-operative balance, no patient developed significant post-surgical complications; about 50 % of the patients had bouts of dizziness during the MRgFUS.  The authors concluded that these findings demonstrated that MRgFUS thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory ET.  However, they stated that several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment.

An UpToDate review on “Functional movement disorders” (Miyasaki, 2015) does not mention high intensity focused ultrasound as a therapeutic option.

Picillo and Fasano (2016) stated that while no real breakthrough in the medical treatment of ET has recently emerged, surgical field is expanding exponentially.  These investigators reviewed the recent and future developments of the surgical treatments for ET.  Technological advances are shaping the present and the future application of deep brain stimulation (DBS) in ET.  New electrode configurations as well as new implantable pulse generators are now available.  Application of closed-loop or adaptive stimulation in clinical practice will allow DBS to deliver stimulation in a truly physiological way to restore aberrant neurological circuits on demand, thus avoiding side effects, tolerance and also saving the battery life.  Besides DBS and standard thalamotomy, novel surgical approaches for ET are on the horizon.  The development of MRgFUS technique has been the new frontier of deep brain lesional therapies.  While the benefit of motor cortex stimulation is yet to be defined, this minimally invasive approach remains intriguing.  The authors concluded that although the advances of surgical treatments along the clinical and technological directions will certainly contribute to a successful management of ET patients, future studies need to consider critical issues such as the heterogeneity of ET and the development of tolerance.

Moosa and colleagues (2019) MR-guided focused US is a novel, minimally invasive surgical procedure for symptomatic treatment of Parkinson’ disease (PD).  With this technology, the ventral intermediate nucleus (VIN), sub-thalamic nucleus (STN), and internal globus pallidus (IGP) have been targeted for therapeutic cerebral ablation, while also minimizing the risk of hemorrhage and infection from more invasive neurosurgical procedures.  In a double-blinded, prospective, sham-controlled RCT of MR-guided focused US thalamotomy for treatment of tremor-dominant PD, 62 % of treated patients demonstrated improvement in tremor scores from baseline to 3 months post-operatively, as compared to 22 % in the sham group.  There has been only 1 open-label trial of MR-guided focused US sub-thalamotomy for patients with PD, demonstrating improvements of 71 % for rigidity, 36 % for akinesia, and 77 % for tremor 6 months after treatment.  Among the 2 open-label trials of MR-guided focused US pallidotomy for patients with PD, dyskinesia and overall motor scores improved up to 52 % and 45 % at 6 months post-operatively.  Although MR-guided focused US thalamotomy is now approved by the U.S. Food and Drug Administration for treatment of parkinsonian tremor, additional high-quality RCTs are needed and are underway to determine the safety and efficacy of MR-guided focused US sub-thalamotomy and pallidotomy for treatment of the cardinal features of PD.  The authors stated that these findings will be paramount to aid clinicians in determining the ideal ablative target for individual patients.  These researchers stated that additional work will be needed to examine the durability of MR-guided focused US lesions, ideal timing of MR-guided focused US ablation in the course of PD, and the safety of performing bilateral lesions.

Obsessive-Compulsive Disorder

Jung and colleagues (2015) stated that despite optimal pharmacotherapy and cognitive-behavioral treatments, a proportion of patients with obsessive-compulsive disorder (OCD) remain refractory to treatment.  Neurosurgical ablative or non-destructive stimulation procedures to treat these refractory patients have been investigated.  However, despite the potential benefits of these surgical procedures, patients show significant surgery-related complications.  This preliminary study investigated the use of bilateral thermal capsulotomy for patients with treatment-refractory OCD using MRgFUS as a novel, minimally invasive, non-cranium-opening surgical technique.  Between February and May 2013, 4 patients with medically refractory OCD were treated with MRgFUS to ablate the anterior limb of the internal capsule.  Patients underwent comprehensive neuropsychological evaluations and imaging at baseline, 1 week, 1 month and 6 months following treatment.  Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), and treatment-related adverse events were evaluated.  The results showed gradual improvements in Y-BOCS scores (a mean improvement of 33 %) over the 6-month follow-up period, and all patients showed almost immediate and sustained improvements in depression (a mean reduction of 61.1 %) and anxiety (a mean reduction of 69.4 %).  No patients demonstrated any side effects (physical or neuropsychological) in relation to the procedure.  In addition, there were no significant differences found in the comprehensive neuropsychological test scores between the baseline and 6-month time points.  The authors concluded that the findings of this study demonstrated that bilateral thermal capsulotomy with MRgFUS can be used without inducing side effects to treat patients with medically refractory OCD.  They stated that if larger trials validate the safety, effectiveness and long-term durability of this new approach, this procedure could considerably change the clinical management of treatment-refractory OCD.

Furthermore, an UpToDate review on “Treatment of obsessive-compulsive disorder in children and adolescents” (Rosenberg, 2015) does not mention high intensity focused ultrasound as a therapeutic option.

Jung and colleagues (2018) stated that obsessive compulsive disorder (OCD) is a debilitating condition characterized by recurrent obsessive thoughts and compulsive reactions.  A great portion of the OCD patients are managed successfully with psychiatric treatment such as selective serotonin-reuptake inhibitor (SSRI) and cognitive behavioral psychotherapy, but more than 10 % of patients are remained as non-responder who needs neurosurgical treatments.  These patients are potential candidates for the neurosurgical management.  There had been various kind of operation, lesioning such as leucotomy or cingulotomy or capsulotomy or limbic leucotomy, and with advent of stereotaxic approach and technical advances, DBS was more chosen by neurosurgeon due to its characteristic of reversibility and adjustability.  Gamma knife radiosurgery are also applied to make lesion targeting based on MRI, but the complication of adverse radiation effect is not predictable.  In the neurosurgical field, MR-guided focused US has advantage of being a less invasiveness, real-time monitored procedure that is now growing to attempt to apply for various brain disorder.  The authors concluded that although various neurosurgical procedures using RFA or gamma knife radiosurgery or DBS showed some benefit to treatment refractory OCD patients, they are still experimental therapies with low level of evidence.  These researchers stated that much more prospective studies are needed, and from these results, the consensus regarding the target or choosing procedures should be made by multi-disciplinary teams. With the advent of technological developments, MRgFUS could be one of the procedures for the psychiatric disorder in the near future.


Yuan et al (2015) stated that HIFU has been demonstrated to enhance anti-tumor immunity, however, the mechanism of which has not been well elucidated.  Emerging evidence indicates that miRNAs play important roles in immune response.  In this study, these investigators used the B16F10 melanoma allograft mouse model to investigate the role of miRNAs in HIFU-enhanced anti-tumor immunity.  They found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues.  Further, these researchers determined that miR-134 directly binds to the 3'UTR of CD86 mRNA to suppress its expression in B16F10 cells.  When B16F10 cells transfected with miR-134 were co-cultured with normal splenic lymphocytes, the secretion of IFN-γ and TNF-α from lymphocytes was reduced and B16F10 cell survival was increased.  The authors concluded that HIFU exposure efficiently decreased miR-134 while increased CD86 expression in B16F10 cells in-vitro; CD86 knockdown with siRNA markedly rescued the viability of HIFU-treated B16F10 cells that co-cultured with lymphocytes.  They stated that these findings suggested that HIFU down-regulated miR-134 to release the inhibition of miR-134 on CD86 in melanoma cells, thereby enhancing anti-tumor immune response.


Walling and co-workers (2016) noted that chronic migraines (CM) afflict approximately 16.6 % of adults and negatively impact quality of life.  Furthermore, although some CM can be treated with steroids, occipital nerve block, radiofrequency therapy, or medical therapy, approximately 15 % of patients remain refractory to treatment.  These researchers explored HIFU as a therapy allowing for ablation or pulse modulation of the occipital nerve in a validated rodent model of CM.  Male Sprague-Dawley rats received inflammatory media via an epidural cannula over 3 weeks to induce a CM state; HIFU was applied over the occiput to
  1. ablate (n = 10) or
  2. pulse modulate (n = 3) the occipital nerve.
Mechanical thresholds assessed during peak headache, immediately after HIFU, 24 hours post-HIFU, and 48 hours post-HIFU using vonFrey filaments in the forepaw, hind paw, and periorbital regions.  Mechanical thresholds obtained also compared to CM rats receiving electrical occipital nerve stimulation (ONS) (n = 9) in a prior study.  Ablation of the occipital nerve using HIFU at 10 W for 3 minutes increased forepaw (p = 0.09) and periorbital region (p < 0.05, n = 10) mechanical thresholds.  Pulse modulation of the occipital nerve using HIFU also increased mechanical thresholds in the forepaw of CM rodents the day of and 24 hours following HIFU application (p < 0.05, n = 2 to 3 rats [only 2 rats were tested on 2-day time-point]).  Pulse modulation of the occipital nerve can also produce similar improvements in mechanical thresholds to ablative focused HIFU or ONS.  The authors concluded that these findings suggested that HIFU may be an effective non-invasive treatment for refractory CM.  Furthermore, by using pulse modulation instead of ablative settings, mechanical thresholds can be improved without causing damage to the occipital nerves, avoiding the aversive side effects of ablation.  They stated that future studies should address whether this non-invasive treatment is ideal and reliably effective for medically refractory CM patients.

Neuropathy / Neuropathic Pain

Youn and associates (2016) noted that vincristine is a commonly used chemotherapeutic agent but is associated with debilitating peripheral neuropathy that is often refractory to traditional medication.  These researchers examined the effects of HIFU in the treatment of vincristine-induced neuropathy (VIN) in the animal model.  VIN rodents were created using a previously used animal model, and neuropathy was confirmed by mechanical and thermal testing using Von Frey Filaments (VFF), Randal-Selitto (RS), hot plate (HP), and tail-flick tests (TF).  The VFF and RS tests were measures of innocuous and noxious mechanical thresholds, respectively, and the HP and TF were measures of paw and tail withdrawal times to thermal stimuli.  These tests were performed before neuropathy induction, after a 2-week induction period, at 24 hours after HIFU and at 48 hours after HIFU.  HIFU was applied to the L5 dorsal root ganglion of the left hind paw at 3 W for 2 minutes.  Although these researchers only have 1 animal in their HIFU group thus far, their preliminary data suggested that HIFU increases mechanical and thermal thresholds compared with HIFU sham animals (n = 5).  Specifically, innocuous and noxious mechanical thresholds were increased as measured with the VFF and RS tests, and thermal thresholds were also increased as measured by the HP test at 48 hours after HIFU application.  Their HIFU animal did not exhibit increased TF thresholds.  The authors concluded that these preliminary data suggested that HIFU may be an effective way to increase mechanical and thermal thresholds in VIN.

Twin-Twin Transfusion Syndrome / Twin Reversed Arterial Perfusion (TRAP) Sequence

Shaw and colleagues (2016) examined the effectiveness, materno-fetal responses, and safety of using HIFU for non-invasive occlusion of placental vasculature compared to sham treatment in anesthetized pregnant sheep.  This technique for non-invasive occlusion of placental vasculature may be translatable to the treatment of conditions arising from abnormal placental vasculature, such as twin-twin transfusion syndrome (TTTS).  A total of 11 pregnant sheep were instrumented with maternal and fetal arterial catheters and time-transit flow probes to monitor cardiovascular, acid-base, and metabolic status, and then exposed to HIFU (n = 5) or sham (n = 6) ablation of placental vasculature through the exposed uterine surface.  Placental vascular flow was occluded in 28 of 30 targets, and histological examination confirmed occlusion in 24 of 30 targets.  In both HIFU and sham exposures, uterine contact reduced maternal uterine artery flow, but delivery of oxygen and glucose to the fetal brain remained normal.  The authors concluded that HIFU can consistently occlude in-vivo placental vessels and ablate blood flow in a pregnant sheep model.  Cardiovascular and metabolic fetal responses suggested that the technique is safe in the short-term and potentially translatable to human pregnancy.

Ichizuka et al (2016) developed a HIFU transducer more suitable for clinical use in fetal therapy for twin reversed arterial perfusion (TRAP) sequence.  These researchers created a cooling and degassed water-circulating-type HIFU treatment device.  HIFU was applied to renal branch vessels in 3 rabbits.  Sequential HIFU irradiation contains a trigger wave, heating wave, and rest time.  The duration of HIFU application was 10 s/course.  Targeting could be achieved by setting the imaging probe in the center and placing the HIFU beam and imaging ultrasonic wave on the same axis.  These investigators confirmed under sequential HIFU irradiation with a total intensity of 1.94 kW/cm2 (spatial average temporal average intensity) that the vein and artery were occluded in all 3 rabbits.  The authors concluded that simultaneous occluding of the veins and arteries was confirmed with trigger waves and a resting phase using the HIFU transducer treatment device created for this study.  They stated that clinical application appeared possible and may represent a promising option for fetal therapy involving TRAP sequence.


Alkins and Mainprize (2018) noted that ultrasound (US) in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of biological effects, including thermal ablation of brain tumors.  Therapeutic US has been studied for many years, but only within the past 10 years has the technology reached a point where it is safe and practical for clinical adoption.  Using large, multi-element arrays, US can be focused through the skull, and combined with MRI for image guidance and real-time thermometry, to create lesions in the brain with millimeter accuracy.  Using this technology, true non-invasive surgery can be accomplished with immediate tumor killing.  Combining the ablative capabilities of focused US with its other unique effects, such as blood-brain barrier (BBB) disruption and radio-sensitization, may eventually result in change of the current glioma treatment paradigm.

Furthermore, UpToDate reviews on “Clinical presentation, initial surgical approach, and prognosis of high-grade gliomas” (Dietrich, 2018) and “Management of low-grade gliomas in adults” (Recht et al, 2018) do not mention high intensity focused ultrasound as a therapeutic option.

Graves’ Disease

Lang and colleagues (2017) evaluated the safety and efficacy of US-guided HIFU ablation as a treatment for medically refractory Graves’ disease (GD).  After ethics approval, a prospective trial was performed from November 2015 to February 2016.  A total of 30 patients underwent ablation of the entire right and left thyroid lobes, with areas near the tracheal-esophageal groove and common carotid artery left un-ablated.  Serum thyroid-stimulating hormone (TSH), free T4 (FT4), anti-thyroid autoantibodies, and TSH receptor (TSHR) antibody levels were evaluated afterward, and US color Doppler, US volumetry, and eye assessment were performed.  The primary outcome was the 12-month relapse rate.  Relapse referred to hyperthyroidism (FT4 greater than 23 pmol/L) afterward.  Variables associated with relapse were analyzed by using binary logistic regression.  The technical success rate was 96.7 %.  The cohort comprised entirely women, with a median age of 38.2 years (IQR, 29.5 to 49.0 years).  After 12 months, 8 patients (26.7 %; 95 % CI: 14.19 %, 44.95 %) experienced relapse; 1 patient (3.3 %; 95 % CI: 0.59 % to 16.67 %) experienced vocal cord palsy, while 2 patients (6.7 %; 95 % CI: 1.85 % to 21.33 %) experienced Horner syndrome, but none of these conditions was permanent.  No changes in gland volume, anti-thyroid autoantibody levels, and ophthalmic parameters were found at 12-month follow-up.  Baseline TSHR was found to have decreased significantly at 6- and 12-month follow-up (p < 0.001 for both); TSHR antibody (odds ratio [OR] = 1.414; 95 % CI: 1.018 to 1.965; p = 0.039) and gland volume (OR = 0.557; 95 % CI: 0.353 to 0.880; p = 0.012) were associated with 12-month relapse, with higher antibody levels conferring a higher likelihood and smaller gland volumes conferring a lower likelihood.  The authors concluded that US-guided HIFU of the thyroid may be a safe and effective treatment in patients with persistent or relapsed GD; however, further study is needed before it could become mainstream for this indication.


In a prospective interventional study, Deb-Joardar and Reddy (2018) examined the efficacy of HIFU in Indian patients with open-angle glaucoma (OAG).  This trial was designed to treat 73 eyes of 73 patients with OAG with the EyeOP1 device equipped with 6 miniaturized cylindrical piezoelectric transducers.  Two treatment protocols of US delivery depending on exposure time (8 s and 10 s of shot per transducer) were used.  Complete ophthalmic examination, ocular biometry and anterior segment optical coherence tomography (AS-OCT) were performed pre-operatively and patients were followed-up at day 1, day 7 and months 1, 2, 3, 6, and 12.  The primary outcome measure was "successful" intra-ocular pressure (IOP) control defined as IOP reduction greater than or equal to 20 % from baseline and IOP value of greater than 5 mm Hg at the last follow-up visit.  Secondary outcomes were the occurrence of complications and mean IOP during the follow-up period.  In all patients, the mean IOP decreased from 23.5 ± 3.0 mmHg before treatment to 15.7 ± 5.4 mmHg at 12 months (p < 0.05).  Successful IOP control after a single procedure was 78.3 % (79 % and 78 % in the 8 s and 10 s groups, respectively) at 12 months.  Overall, the mean IOP reduction achieved in responding patients was 41 % (SD = 12 %).  Notwithstanding minor side effects such as transient pain, anterior chamber reaction, and refractive error changes, no major intra-operative or post-operative complications (severe hypotony or phthisis) were observed during the follow-up.  The authors concluded that these short-term results showed that US cycloplasty is a simple, safe, and non-invasive procedure that significantly reduced the IOP in patients with OAG.  Moreover, they stated that further research is ongoing to study the IOP control at longer follow-up period as well as to extend its indication to angle-closure and secondary glaucoma.

The authors noted that the drawbacks of this study included its relatively small sample size (n = 73), uneven distribution of patients in groups as well as a limited follow-up period (up to 12 months).  Moreover, they stated that further prospective randomized clinical trials are needed to compare the safety and efficacy and safety of US cycloplasty vis-à-vis diode trans-scleral cyclophotocoagulation (CPC) and filtration surgery.

In a retrospective, single-center study, Graber and associates (2018) compared the efficacy of 2 cyclo-destructive treatments for refractory glaucoma: HIFU cyclo-coagulation and trans-scleral diode laser cyclophotocoagulation (cyclodiode).  This trial included all patients who underwent cyclo-destruction for refractory glaucoma by either HIFU cyclo-coagulation or cyclodiode.  "Refractory glaucoma" was defined as an uncontrolled high intra-ocular pressure (IOP) despite medical treatment and at least 1 filtering surgery.  Uncontrolled high IOP was defined as an IOP greater than or equal to 16 mm Hg.  The diagnosis of glaucoma was confirmed by automated visual field (VF) testing and peripapillary retinal nerve fiber layer (RNFL) scans using a time-domain ocular coherence tomography (OCT) device.  Treatment success was defined as: post-operative IOP between 5 mm Hg and 21 mm Hg and IOP reduction greater than or equal to 20 % as compared to pre-operative values.  Among the 99 eyes of 86 patients included in this study, 29 eyes were treated by cyclodiode and 70 eyes by HIFU.  Median follow-up was 3 months (IQR 3 to 6) for the cyclodiode group and 6 months (IQR 3 to 8) for the HIFU group.  Average pre-operative IOP was 34.3 ± 11.1 mm Hg (cyclodiode group) and 23 ± 6.8 mm Hg (HIFU group).  The treatment success rate at last follow-up was 52 % (34 to 70) for the cyclodiode group and 25 % (15 to 35) for the HIFU group (p = 0.01).  Kaplan-Meier survival analysis showed that the mean estimated time to failure was 5.9 months (4.4 to 7.5) for the cyclodiode group and 3.7 months (2.8 to 4.7) for the HIFU group (log-Rank test, p = 0.02).  A 2-line visual acuity (VA) loss was observed for 31 % of the patients treated by cyclodiode and 17 % for those treated by HIFU.  In the cyclodiode group 4 cases of hypotony were reported versus none in the HIFU group.  The authors concluded that the success rate was significantly higher for cyclodiode treatment as compared to HIFU cyclo-destruction when treating refractory glaucoma.  However, significantly fewer complications were observed with HIFU cyclo-coagulation as compared to cyclodiode.

Posarelli and colleagues (2019) stated that glaucoma is usually first managed medically, with incisional surgery as a 2nd step.  Non-invasive glaucoma procedures attempt to fill the gap between medical and surgical treatments and may work synergistically with them; HIFU induces a selective and controlled thermal ablation of the distal part of the ciliary body, and this effect is independent from the degree of tissue pigmentation with limited damage to adjacent structures.  This selective and innovative treatment decreases IOP by reducing aqueous humor production and by increasing uveo-scleral outflow.  However, the effectiveness of this approach has not been established.

UpToDate reviews on “Open-angle glaucoma: Treatment” (Jacobs, 2019), “Angle-closure glaucoma” (Weizer, 2019) and “Primary infantile glaucoma” (Olitsky and Reynolds, 2019) do not mention HIFU as a therapeutic option.

Osteoid Osteoma

In a pilot study, Ji and colleagues (2017) evaluated clinical feasibility and safety of MR-HIFU treatment of symptomatic osteoid osteoma and compared clinical response with standard of care treatment.  A total of 9 subjects with radiologically confirmed, symptomatic osteoid osteoma were treated with MR-HIFU in an institutional review board (IRB)-approved clinical trial.  Treatment feasibility and safety were assessed.  Clinical response was evaluated in terms of analgesic requirement, visual analog scale (VAS) pain score, and sleep quality.  Anesthesia, procedure, and recovery times were recorded.  This MR-HIFU group was compared with a historical control group of 9 consecutive patients treated with radiofrequency ablation (RFA).  A total of 9 subjects (7 male, 2 female; 16 ± 6 years) were treated with MR-HIFU without technical difficulties or any serious AEs.  There was significant decrease in their median pain scores 4 weeks within treatment (6 versus 0, p < 0.01).  Total pain resolution and cessation of analgesics were achieved in 8 of 9 patients after 4 weeks.  In the RFA group, 9 patients (8 male, 1 female; 10 ± 6 years) were treated in routine clinical practice.  All 9 demonstrated complete pain resolution and cessation of medications by 4 weeks with a significant decrease in median pain scores (9 versus 0, p < 0.001); 1 subject developed a 2nd-degree skin burn, but there were no other AEs.  Procedure times and treatment charges were comparable between the 2 groups.  The authors concluded that the findings of this pilot study showed that MR-HIFU treatment of osteoid osteoma refractory to medical therapy was feasible and could be performed safely in pediatric patients.  Clinical response was comparable with standard of care treatment but without any incisions or exposure to ionizing radiation.  These preliminary findings need to be validated by well-designed studies.

The authors stated that this pilot study was limited by a small sample size in both treatment groups (n = 9 in each group).  Some of the patients in both groups had previous treatments that might affect sensitivity to MR-HIFU or RFA.  In addition, the use of a retrospective historical RFA control group precluded comparison to all of the data collected prospectively for the MR-HIFU group.  Furthermore, both the small sample size and the retrospective comparison group made matching based on patient or lesion characteristics challenging.  These investigators stated that a larger, prospective randomized clinical trial directly comparing MR-HIFU with RFA would address these drawbacks.

Uterine Arterio-Venous Malformation

In a case report, Yan and colleagues (2017) examined the effects of HIFU for the treatment of uterine arterio-venous malformation (AVM).  The diagnosis of uterine AVM was made through MRI; US-guided HIFU (USgHIFU) ablation was performed.  The patient had reduction of the lesion volume and obvious symptom relief, without significant adverse effects.  The authors concluded that HIFU could be used as a new therapeutic option for uterine AVM.  These preliminary findings need to be validated by well-designed studies.

Abdominal Wall Endometriosis

In a retrospective study, Shi and colleagues (2020) examined the effectiveness of HIFU ablation for the treatment of abdominal wall endometriosis.  A total of 30 patients with abdominal wall endometriosis were treated from May 2013 to December 2015; 13 patients were treated with HIFU ablation, and 17 patients were treated with surgical resection.  Color Doppler US and MRI were used to observe the lesions before and after treatment.  In addition, recovery time, complications, and adverse reactions of the 2 groups were compared.  Menstrual pain was relieved after treatment in all 30 patients.  After treatment, the lesions in patients who underwent HIFU ablation decreased gradually, and there was no recurrence.  Symptoms recurred in 1 patient in the surgery group 12 months after surgery.  The post-treatment hospital length of stay (LOS) of the HIFU ablation group (1.00 ± 0 days) was significantly shorter than that of the surgical group (5.23 ± 1.24 days; p < 0.001).  The incidence of fever (0 % versus 11.8 %; p = 0.049) and complications of the urinary system (7.7 % versus 17.6 %; p = 0.43) in the HIFU ablation group was significantly lower than that of the surgical group.  The authors concluded that HIFU ablation therapy is a promising treatment for abdominal wall endometriosis, and further study is needed.

Breast Fibromatosis

Zhao and colleagues (2019) noted that aggressive breast fibromatosis (referred to as a desmoid tumor) is a rare, locally invasive, non-metastasizing tumor with high recurrence rate.  The therapeutic modalities range from surgery and radiotherapy to medical treatments.  However, the optimal treatment is controversial, especially in a situation of repeated recurrence.  These investigators presented a case of a patient with aggressive breast fibromatosis with multiple recurrence after surgeries, who underwent HIFU treatment effectively without side effects.  The authors stated that to their knowledge, this was the 1st reported case of HIFU treatment in aggressive breast fibromatosis, which indicated that HIFU might be a novel, promising modality for this rare disease.  These researchers stated that further studies are expected.

Gynecological Tumors Within the Pelvis

In a pilot study, Giles and colleagues (2019) examined the feasibility of targeting recurrent gynecological tumors with MR-guided HIFU (MRgHIFU).  A total of 20 patients with recurrent gynecological tumors were prospectively scanned on a Philips/Profound 3 T Achieva MR/ Sonalleve HIFU system.  Gross tumor volume (GTV) and planning target volume (PTV) were delineated on T 2W and diffusion-weighted imaging (DWI).  Achievable treatment volumes that assumed bowel and/or uro-genital tract preparation could be used to reduce risk of damage to organs-at-risk (TVoptimal), or assumed no preparations were possible (TVno-prep) were compared with PTV on virtual treatment plans.  Patients were considered treatable if TVoptimal was greater than or equal to 50 % PTV; 11/20 patients (55 %) were treatable if preparation strategies were used: 9 had central pelvic recurrences, 2 had tumors in metastatic locations.  Treatable volume ranged from 3.4 to 90.3 ml, representing 70 ± 17 % of PTVs.  Without preparation, 6/20 (30 %) patients were treatable (4 central recurrences, 2 metastatic lesions).  Limiting factors were disease beyond reach of the HIFU transducer, and bone obstructing tumor access; DWI assisted tumor outlining, but differences from T 2W imaging in GTV size (16.9 ± 23.0 %) and PTV location (3.8 ± 2.8 mm in phase-encode direction) limited its use for treatment planning.  The authors concluded that these findings showed the potential accessibility of different sites of recurrent gynecological disease to MRgHIFU, finding that greater than or equal to 50 % of tumors could be targeted in more than 50 % of the patients if clinically acceptable strategies for bowel and uro-genital tract emptying and filling were considered.  These researchers stated that disease beyond the reach of the transducer, and bone preventing an adequate acoustic window were limitations.  The real-time adjustments based on heating patterns observed on intra-procedural thermometry, however, will fundamentally determine safety and efficacy of MRgHIFU in this setting, and remain to be established in a treatment study.


In a randomized, single-blinded, split-face, pilot study, Vachiramon and colleagues (2020) examined the safety and efficacy of HIFU for the treatment of melasma in Asians.  Each side of the face of 25 melasma patients was randomized to receive 3-monthly sessions of HIFU treatment or serve as control.  Lightness index, Melasma Area and Severity Index of malar area (MASIm ) by blinded dermatologists, self-evaluated improvement and satisfaction scales by patients, and side effects were assessed every 4 weeks for 20 weeks.  A total of 21 patients with Fitzpatrick skin type III and IV completed the study.  There was a greater reduction of relative lightness index and MASIm after treatment in HIFU-treated side.  However, there were no statistically significant differences between both sides.  More than 50 % improvement on treatment side was rated in 11 patients (52.4 %); side effects were minimal; no subject had worsening of melasma.  The authors concluded that HIFU may be an adjuvant for treatment of melasma.  These researchers stated that further studies with larger sample size and proper parameter settings are needed to determine its efficacy.

Adenomyosis-Related Symptoms

In a systematic review and meta-analysis, Santos Marques and colleagues (2020) examined the efficacy of HIFU in reducing adenomyotic lesions, patients' pain and bleeding symptoms, and the impact on patients' QOL.  They carried out a search via PubMed/Medline and Cochrane databases.  All available studies published in the English language in the last 10 years that evaluated the effects of HIFU for adenomyosis were selected for analysis.  These investigators carried out a systematic review following PRISMA guidelines.  A meta-analysis was conducted on data from homogeneous studies.  Pooled results from the meta-analysis showed that after HIFU treatment for adenomyosis, a large effect was observed in reducing the uterine volume at 12 months (standard mean difference [SMD] = 0.85), a significant reduction in dysmenorrhea at 3 months (SMD = 1.83) and 12 months (SMD = 2.37), and a significant improvement in QOL at 6 months (SMD = 3.0) and 12 months (SMD = 2.75).  Adverse reactions after HIFU were reported in 55.9 % of patients.  The authors concluded that the findings of this review suggested a potential benefit for HIFU in the treatment of adenomyosis-related symptoms; however, findings of the meta-analysis were based on fewer, non-uniform studies, which did not equally account for each specific symptom/parameter across the board.  Results showed that there appeared to be a potential of HIFU in the treatment of adenomyosis-related symptoms.  To-date, there are no comparative and randomized clinical trials comparing the HIFU technique with other conservative treatment options.  As yet, there are insufficient data regarding fertility and pregnancy outcomes.

Hepatocellular Carcinoma

Sehmbi and colleagues (2021) noted that HIFU is an emerging non-invasive, targeted treatment of malignancy.  In a systematic review, these investigators examined the safety, efficacy, and optimal technical parameters of HIFU in the treatment of malignant lesions of the hepatobiliary system.  They carried out a systematic search of the English literature until March 2020, examining PubMed, Embase and Cochrane Library databases.  The following keywords were input in various combinations: 'HIFU', 'High intensity focused ultrasound', 'Hepatobiliary', 'Liver', 'Cancer' and 'Carcinoma'.  Extracted content included: Application type, exposure parameters, patient demographics, as well as treatment outcomes.  A total of 24 articles reported on the clinical use of HIFU in 940 individuals to treat malignant liver lesions; 21 studies detailed the use of HIFU to treat HCC only.  Mean tumor size was 5.1 cm.  Across all studies, HIFU resulted in complete tumor ablation in 55 % of patients.  Data on technical parameters and the procedural structure were very heterogeneous; 10 studies (n = 537 (57 %) patients) described the use of HIFU alongside other modalities including TACE, RFA and PEI; 66 % of which resulted in complete tumor ablation.  Most common complications were skin burns (15 %), local pain (5 %) and fever (2 %).  The authors concluded that HIFU has shown benefit as a treatment modality for malignant lesions of the hepatobiliary system.  Combining HIFU with other ablative therapies, especially TACE, increased the efficacy without increasing complications.  These researchers stated that future human clinical studies are needed to determine the optimal treatment parameters, better define outcomes and examine the risks and benefits of combination therapies.

Uterine Myomas

Wang and associates (2021) noted that uterine fibroids are common benign tumors among pre-menopausal women; HIFU is an emerging non-invasive intervention that employs the high-intensity US waves from probes to focus on the targeted fibroids.  However, the effectiveness of HIFU in comparison with that of other common therapeutic approaches in clinical procedure remains unclear.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of HIFU with other techniques that are commonly used in clinical settings.  They searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Cumulative Index to Nursing & Allied Health Literature, Web of Science, ProQuest Nursing & Allied Health Database, and 3 Chinese academic databases, including RCTs, non-RCTs, and cohort studies.  The primary outcome was the rate of re-intervention, and the GRADE approach was used to interpret the findings.  About 18 studies met the inclusion criteria.  HIFU was associated with an increased risk of re-intervention rate in comparison with myomectomy (MYO) [pooled OR: 4.05, 95 % CI: 1.82 to 8.9].  The results favored HIFU in comparison with hysterectomy (HYS) on the change of follicle-stimulating hormone [pooled MD: -7.95, 95 % CI: -8.92 to 6.98), luteinizing hormone (MD: -4.38, 95 % CI: -5.17 to 3.59), and estradiol (pooled MD: 43.82, 95 % CI: 36.92 to 50.72)].  HIFU had a shorter duration hospital LOS in comparison with MYO (pooled MD: -4.70, 95 % CI: -7.46 to 1.94, p < 0.01).  It had a lower incidence of fever (pooled OR: 0.15, 95 % CI: 0.06 to 0.39, p < 0.01) and a lower incidence of major AEs (pooled OR: 0.04, 95 % CI: 0.00 to 0.30, p < 0.01) in comparison with HYS.  The authors concluded that HIFU may help maintain femininity and shorten the hospital LOS.  Moreover, these researchers stated that evidence on the use of HIFU in this systematic review was mainly available online at non-randomized studies, and robust evidence of evaluating comparative safety and efficacy of HIFU for the treatment of uterine fibroids in these studies remains lacking.  They stated that high-quality clinical studies with a large sample size, a long-term follow-up, and the newest HIFU treatment protocol are needed to further examine the re-intervention rate of HIFU.  

Tsai and colleagues (2021) stated that uterine myomas are one of the most common gynecologic tumors in pre-menopausal women.  The conventional surgical treatments are myomectomy and hysterectomy, but HIFU is a new non-invasive treatment creating no surgical wound.  In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of HIFU compared with conventional surgery for patients with uterine myomas.  PubMed, Embase, and the Cochrane Library were searched for studies published before January 2021.  Studies comparing the outcome of HIFU and conventional surgery -- myomectomy and hysterectomy -- for patients with uterine myomas were included.  These researchers carried out meta-analyses by using a random effects model.  Uterine myoma symptom score and QOL score were analyzed using the mean difference (MD).  The recovery time and frequency of major AEs were also evaluated.  A total of 10 studies were included; HIFU relieved uterine myoma symptoms significantly when compared with conventional surgery at 6 (MD -1.61; 95 % CI: -2.88 to -0.33) and 12 (MD -2.44; 95 % CI: -3.68 to -1.20) months after treatment.  Similarly, HIFU improved the QOL score significantly at 6 (MD 2.14; 95 % CI: 0.86 to 3.42) and 12 (MD 2.34; 95 % CI: 0.82 to 3.86) months after treatment when compared with the surgery group.  The authors concluded that HIFU could be a safe and effective therapeutic option for patients with uterine myomas; however, one of its side effects, skin burns, requires further research and discussion.  These researchers also stated that the data they collected were based on only 1 RCT and several moderate retrospective studies; thus, more precise RCTs with longer follow-up periods are needed to examine the effect of HIFU on uterine myomas.

The authors stated that this study had several drawbacks.  First, this meta-analysis included studies with various designs, and the quality of some of the designs was not sufficiently high.  Second, several outcomes were reported without standard deviations or using different measuring methods and thus could not be pooled.  Furthermore, the included studies relied on patient-reported outcomes and lacked substantial evidence for the primary endpoint.  Moreover, patients with more than 3 uterine myomas or larger myomas were not included in any of the studies, and 4 studies recruited patients with only certain types of uterine myoma; therefore, the effectiveness of HIFU for various uterine myoma types remains unclear.

Malignant Biliary Obstruction

Yang and associates (2020) examined the effectiveness and long-term outcomes in patients with distal biliary obstruction (DBO) secondary to pancreatic carcinoma (PC) who were treated by self-expanded metallic stent (SEMS) insertion with or without HIFU ablation.  The long-term outcomes were compared between the 2 groups.  During the included period, 75 patients underwent SEMS insertion with (n = 34) or without (n = 41) HIFU ablation in the authors’ center.  SEMS insertion was successfully performed in all patients.  Liver function was significantly improved following SEMS insertion in both groups.  An average of 2.9 HIFU treatment sessions per patient were carried out; 20 patients (stent + HIFU group: 7; stent-only group: 13) experienced stent dysfunctions (p = 0.278).  The clinical response rate to HIFU ablation was 79.4 %.  The median stent patency was significantly longer in the stent with HIFU group than in the stent-only group (175 versus 118 days, p = 0.005).  The median survival was significantly longer in the stent with HIFU group compared with the stent-only group (211 versus 136 days, p = 0.004).  An Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 (HR: 0.300; p = 0.002) and subsequent HIFU ablation (HR: 0.508; p = 0.005) were associated with prolonged survival.  The authors concluded that HIFU ablation following stent insertion could prolong the stent patency and survival for patients with DBO secondary to PC.  Moreover ,these researchers stated that the findings of this study need to be confirmed in a larger, multi-center study.

The authors stated that this study had several drawbacks.  First, it was a retrospective study and a selective bias existed.  Second, a subset of patients also received chemotherapy or radiotherapy during the follow-up, and this may also cause a selective bias.  Obviously, these researchers could not deny patients’ appropriate alternative anti-cancer treatments; thus, they also compared the survival between the 2 groups after removing the patients who underwent chemotherapy or radiotherapy from both groups and found that this made the survival difference between the 2 groups even greater.  Third, this was a single-center study and the sample size was not large.  Furthermore, the sample size has not been calculated and this added another bias to this study.  

In a systematic review and meta-analysis, Cai and colleagues (2021) examined the efficacy of stent insertion with HIFU ablation for the treatment of malignant biliary obstruction (MBO).  PubMed, Embase, and Cochrane Library databases were searched for all relevant studies published through July 2020.  The meta-analysis was carried out using RevMan v5.3, with analyzed study endpoints including the rate of stent dysfunction, time to stent dysfunction, stent patency, complication rate, and overall survival (OS).  A total of 35 potentially relevant studies were initially identified, of which 6 were ultimately included in this meta-analysis.  These 6 studies included 429 MBO patients who were treated either only via stenting (n = 221) or via stenting in combination with HIFU ablation (n = 208).  Pooled stent dysfunction rates in the stent and stent with HIFU groups were 25.9 % and 18.0 %, respectively (OR: 1.59; 95 % CI: 0.88 to 2.84, p = 0.12).  The average time to stent dysfunction was significantly longer in the stent with HIFU group relative to the stent group (MD: -3.15; 95 % CI: -3.53 to -2.77, p < 0.0001).  Pooled complication rates in the stent and stent with HIFU groups were 17.1 % and 19.6 %, respectively (OR: 0.88; 95 % CI: 0.49 to 1.58, p = 0.67).  Stent patency and OS were both significantly longer in the stent with HIFU group relative to the stent group (p < 0.0001 and 0.0001, respectively).  Funnel plot analyses did not reveal any significant evidence of publication bias linked to the selected study endpoints.  The authors concluded that this meta-analysis found that a combined stenting and HIFU ablation approach could achieve better stent patency and OS in MBO patients relative to stent insertion alone.  These researchers stated that future RCTs are needed to validate these findings.

The authors stated that this review/meta-analysis had several drawbacks.  First, all studies included were retrospective, and as such, they were susceptible to selection bias.  Second, the included studies enrolled MBO patients with a range of different cancer types, potentially biasing the overall results.  Third, data pertaining to specific endpoints were absent in some of the included studies, potentially limiting the widespread applicability of these findings.


The above policy is based on the following references:

  1. Abreu AL, Peretsman S, Iwata A, et al. High intensity focused ultrasound hemigland ablation for prostate cancer: Initial outcomes of a United States series. J Urol. 2020;204(4):741-747.
  2. Alkins RD, Mainprize TG. High-intensity focused ultrasound ablation therapy of gliomas. Prog Neurol Surg. 2018;32:39-47.
  3. Asimakopoulos AD, Miano R, Virgili G, et al. HIFU as salvage first-line treatment for palpable, TRUS-evidenced, biopsy-proven locally recurrent prostate cancer after radical prostatectomy: A pilot study. Urol Oncol. 2012;30(5):577-583.
  4. Avedian RS, Bitton R, Gold G, et al. Is MR-guided high-intensity focused ultrasound a feasible treatment modality for desmoid tumors? Clin Orthop Relat Res. 2016;474(3):697-704.
  5. Bai Y, Luo X, Li Q, et al. High-intensity focused ultrasound treatment of placenta accreta after vaginal delivery: A preliminary study. Ultrasound Obstet Gynecol. 2016;47(4):492-498.
  6. Barqawi AB, Crawford ED. Emerging role of HIFU as a noninvasive ablative method to treat localized prostate cancer. Oncology (Williston Park). 2008;22(2):123-129; discussion 129, 133, 137 passim
  7. Baumunk D, Schostak M. Treatment of localized prostate cancer with high-intensity focused ultrasound. Urologe A. 2015;54(2):183-190.
  8. Blana A, Murat FJ, Walter B, et al. First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol. 2008;53(6):1194-1201.
  9. Caballero JM, Borrat P, Paraira M, et al. Extracorporeal high-intensity focused ultrasound: Therapeutic alternative for renal tumors. Actas Urol Esp. 2010;34(5):403-411.
  10. Cai P-F, Gu H, Zhu L-J, et al. Stent insertion with high-intensity focused ultrasound ablation for malignant biliary obstruction: A protocol of systematic review and meta-analysis. Medicine (Baltimore). 2021;100(3):e23922.
  11. Canadian Agency for Drugs and Technologies in Health (CADTH). High-intensity focused ultrasound for prostate cancer. Health Technology Update. Ottawa, ON: CADTH; September 2006.
  12. Cao L, Fu Q, Wang B, Li Z. Renal denervation: A new therapeutic approach for resistant hypertension. Chin Med J (Engl). 2014;127(18):3302-3308.
  13. Castellani D, Branchi A, Claudini R, et al. A structured framework for optimizing high-intensity focused ultrasound ablative treatment in localized prostate cancer. Investig Clin Urol. 2019;60(4):312-318.
  14. 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(4):686-692.
  15. Chang JW, Park CK, Lipsman N, et al. A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up. Ann Neurol. 2018;83(1):107-114.
  16. Chang WS, Jung HH, Kweon EJ, et al. Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: Practices and clinicoradiological outcomes. J Neurol Neurosurg Psychiatry. 2015;86(3):257-264.
  17. Chen W, Zhu H, Zhang L, et al. Primary bone malignancy: Effective treatment with high-intensity focused ultrasound ablation. Radiology. 2010;255(3):967-978.
  18. Cheong CWS, Au JXY, Lim MY, et al. The efficacy and safety of high-intensity focused ultrasound in the treatment of benign thyroid nodules: A systematic review and meta-analysis from 1990 to 2021. Ann Acad Med Singap. 2022;51(2):101-108.
  19. Choi SY, Yoo KH, Oh CT, et al. High intensity focused ultrasound as a potential new modality for the treatment of pigmentary skin disorder. Skin Res Technol. 2016;22(2):131-136.
  20. Cordeiro ER, Cathelineau X, Thüroff S, et al. High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer. BJU Int. 2012;110(9):1228-1242.
  21. Dababou S, Marrocchio C, Rosenberg J, et al. A meta-analysis of palliative treatment of pancreatic cancer with high intensity focused ultrasound. J Ther Ultrasound. 2017;5:9.
  22. Dahm P, Yeung LL, Chang SS, Cookson MS. A critical review of clinical practice guidelines for the management of clinically localized prostate cancer. J Urol. 2008;180(2):451-459; discussion 460.
  23. Deb-Joardar N, Reddy KP. Application of high intensity focused ultrasound for treatment of open-angle glaucoma in Indian patients. Indian J Ophthalmol. 2018;66(4):517-523.
  24. Dickinson L, Ahmed HU, Kirkham AP, et al. A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study. Contemp Clin Trials. 2013;36(1):68-80.
  25. Dietrich J. Clinical presentation, initial surgical approach, and prognosis of high-grade gliomas. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2018.
  26. Dosanjh A, Harvey P, Baldwin S, et al. High-intensity focused ultrasound for the treatment of prostate cancer: A national cohort study focusing on the development of stricture and fistulae. Eur Urol Focus. 2021;7(2):340-346.
  27. Dubinsky TJ,  Cuevas C, Dighe MK, et al. High-intensity focused ultrasound: Current potential and oncologic applications. AJR Am J Roentgenol. 2008;190(1):191-199.
  28. Duc NM, Keserci B. Emerging clinical applications of high-intensity focused ultrasound. Diagn Interv Radiol. 2019;25(5):398-409.
  29. Dussault FP. Le traitement du cancer de la prostate par ultrasons focalises de haute intensite [High-intensity focused ultrasound for prostate cancer]. Note Informative. NI-2008-01. Montreal, QC: Agence d'Evaluation des Technologies et des Modes d'Intervention en Sante (AETMIS); June 18, 2008.
  30. Eggener SE, Scardino PT, Carroll PR; International Task Force on Prostate Cancer and the Focal Lesion Paradigm. Focal therapy for localized prostate cancer: A critical appraisal of rationale and modalities. J Urol. 2007;178(6):2260-2267.
  31. Elias WJ, Huss D, Voss T, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013;369(7):640-648.
  32. Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2016;375(8):730-739.
  33. Esnault O, Franc B, Ménégaux F, et al. High-intensity focused ultrasound ablation of thyroid nodules: First human feasibility study. Thyroid. 2011;21(9):965-973.
  34. Fishman PS, Elias WJ, Ghanouni P, et al. Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor. Mov Disord. 2018 33(5):843-847.
  35. Gallay MN, Moser D, Jeanmonod D. Safety and accuracy of incisionless transcranial MR-guided focused ultrasound functional neurosurgery: Single-center experience with 253 targets in 180 treatments. J Neurosurg. 2019;130:1234-1243.
  36. Gardner TA, Koch MO. Prostate cancer therapy with high-intensity focused ultrasound. Clin Genitourin Cancer. 2005;4(3):187-192.
  37. Ghanouni P, Pauly KB, Elias WJ, et al. Transcranial MRI-guided focused ultrasound: A review of the technologic and neurologic applications. AJR Am J Roentgenol. 2015;205(1):150-159.
  38. Giles SL, Imseeh G, Rivens I, et al. MR guided high intensity focused ultrasound (MRgHIFU) for treating recurrent gynaecological tumours: A pilot feasibility study. Br J Radiol. 2019;92(1098):20181037.
  39. Golan R, Bernstein AN, McClure TD, et al. Partial gland treatment of prostate cancer using high-intensity focused ultrasound in the primary and salvage settings: A systematic review. J Urol. 2017;198(5):1000-1009.
  40. Graber M, Rothschild PR, Khoueir Z, et al. High intensity focused ultrasound cyclodestruction versus cyclodiode treatment of refractory glaucoma: A retrospective comparative study. J Fr Ophtalmol. 2018;41(7):611-618.
  41. Griffin XL, Parsons N, Costa ML, Metcalfe D. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2014;6:CD008579.
  42. Griffin XL, Smith N, Parsons N, Costa ML. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2012;2:CD008579.
  43. Guillez K, Callec R, Morel O, et al. Treatment of fibroadenomas by high-intensity focused ultrasound: What results? Review. Gynecol Obstet Fertil Senol. 2018;46(6):524-529.
  44. Hernandez Fernández C, Lledó García E, Subirá Ríos D, Bueno Chomón G. Conservative treatment of renal cancer using HIFU. Procedure, indications, and results. Actas Urol Esp. 2009;33(5):522-525.
  45. Hu J, Mao H, He Y, et al. Systematic review and meta-analysis of the efficacy and safety of high-intensity focused ultrasound combined with transarterial chemoembolization and transarterial chemoembolization alone in the treatment of liver cancer. Transl Cancer Res. 2022;11(6):1678-1688.
  46. Huang WC, Lee CL, Eastham JA. Locally ablative therapies for primary radiation failures: A review and critical assessment of the efficacy. Curr Urol Rep. 2007;8(3):217-223.
  47. Huisman M, Lam MK, Bartels LW, et al. Feasibility of volumetric MRI-guided high intensity focused ultrasound (MR-HIFU) for painful bone metastases. J Ther Ultrasound. 2014;2:16.
  48. Hummel S, Paisley S, Morgan A, et al. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: A systematic review. Health Technol Assess. 2003;7(33):1-170.
  49. 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(5).
  50. Ichizuka K, Matsuoka R, Aoki H, et al. Basic study of less invasive high-intensity focused ultrasound (HIFU) in fetal therapy for twin reversed arterial perfusion (TRAP) sequence. J Med Ultrason (2001). 2016 2016;43(4):487-492.
  51. Illing R, Chapman A. The clinical applications of high intensity focused ultrasound in the prostate. Int J Hyperthermia. 2007;23(2):183-191.
  52. Ingrosso G, Becherini C, Lancia A, et al. Nonsurgical salvage local therapies for radiorecurrent prostate cancer: A systematic review and meta-analysis. Eur Urol Oncol. 2020;3(2):183-197.
  53. Jacobs DS. Open-angle glaucoma: Treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2019.
  54. Jagannathan J, Sanghvi NT, Crum LA, et al. High-intensity focused ultrasound surgery of the brain: Part 1--A historical perspective with modern applications. Neurosurgery. 2009;64(2):201-210; discussion 210-211.
  55. Ji Y, Hu K, Zhang Y, et al. High-intensity focused ultrasound (HIFU) treatment for uterine fibroids: A meta-analysis. Arch Gynecol Obstet. 2017;296(6):1181-1188.
  56. Jung HH, Chang WS, Kim SJ, et al. The potential usefulness of magnetic resonance guided focused ultrasound for obsessive compulsive disorders. J Korean Neurosurg Soc. 2018;61(4):427-433.
  57. Jung HH, Kim SJ, Roh D, et al. Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: A proof-of-concept study. Mol Psychiatry. 2015;20(10):1205-1211.
  58. Kim M, Jung NY, Park CK, et al. Comparative evaluation of magnetic resonance-guided focused ultrasound surgery for essential tremor. Stereotact Funct Neurosurg. 2017;95(4):279-286.
  59. Klatte T, Marberger M. High-intensity focused ultrasound for the treatment of renal masses: current status and future potential. Curr Opin Urol. 2009;19(2):188-191.
  60. Klein EA. Initial approach to low-risk clinically localized prostate cancer. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2013.
  61. Klingler HC, Susani M, Seip R, et al. A novel approach to energy ablative therapy of small renal tumours: Laparoscopic high-intensity focused ultrasound. Eur Urol. 2008;53(4):810-816; discussion 817-818.
  62. Koch MO, Gardner T, Cheng L, et al. Phase I/II trial of high intensity focused ultrasound for the treatment of previously untreated localized prostate cancer. J Urol. 2007;178(6):2366-2370; discussion 2370-2371.
  63. Komura K, Inamoto T, Masuda H, et al. Experience with high-intensity focused ultrasound therapy for management of organ-confined prostate cancer: Critical evaluation of oncologic outcomes. Acta Biomed. 2012;83(3):189-196.
  64. Konski A. High-intensity focused ultrasound in the treatment of bone tumors: Another treatment option for palliation and primary treatment? Cancer. 2010;116(16):3754-3755.
  65. Konstantinos H. Prostate cancer in the elderly. Int Urol Nephrol. 2005;37(4):797-806.
  66. Kovatcheva R, Guglielmina JN, Abehsera M, et al. Ultrasound-guided high-intensity focused ultrasound treatment of breast fibroadenoma -- a multicenter experience. J Ther Ultrasound. 2015;3(1):1.
  67. Kovatcheva R, Vlahov J, Stoinov J, et al. US-guided high-intensity focused ultrasound as a promising non-invasive method for treatment of primary hyperparathyroidism. Eur Radiol. 2014;24(9):2052-2058.
  68. Lang BH, Woo YC, Wong IY, Chiu KW. Single-session high-intensity focused ultrasound Treatment for persistent or relapsed Graves disease: Preliminary experience in a prospective study. Radiology. 2017;285(3):1011-1022.
  69. Lee I. Sonablate® 500 System for prostate cancer. Horizon Scanning Prioritising Summary. Canberra, ACT: Australian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S); March 2006.
  70. Lee WR, Papagikoa MA, Roach M III, et al, Expert Panel on Radiation Oncology-Prostate Work Group. Locally advanced (high-risk) prostate cancer. Reston, VA: American College of Radiology (ACR); 2006.
  71. Li C, Wu P, Zhang L, et al. Osteosarcoma: Limb salvaging treatment by ultrasonographically guided high-intensity focused ultrasound. Cancer Biol Ther. 2009;8(12):1102-1108.
  72. Li C, Zhang W, Fan W, et al. Noninvasive treatment of malignant bone tumors using high-intensity focused ultrasound. Cancer. 2010;116(16):3934-3942.
  73. Li CC, Wang YQ, Li YP, Li XL. High-intensity focused ultrasound for treatment of pancreatic cancer: A systematic review. J Evid Based Med. 2014;7(4):270-281.
  74. 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(5):462-468.
  75. Ljungberg B, Bensalah K, Bex A, et al. Guidelines on renal cell carcinoma. Arnhem, The Netherlands: European Association of Urology (EAU); March 2013.
  76. Lledo García E, Jara Rascón J, Herranz Amo F, Hernández Fernández C. Current state of high intensity focused ultrasound (HIFU) as treatment of prostatic carcinoma. Actas Urol Esp. 2007;31(6):642-650.
  77. Lovegrove CE, Peters M, Guillaumier S, et al. Evaluation of functional outcomes following a second focal-HIFU in men with primary localised, non-metastatic prostate cancer; results from the High Intensity Focused Ultrasound Evaluation and Assessment of Treatment (HEAT) Registry. BJU Int. 2020;125(6):853-860.
  78. Louis ED. Treatment of medically refractory essential tremor. N Engl J Med. 2016;375(8):792-793.
  79. Lynch JH, Loeb S. The role of high-intensity focused ultrasound in prostate cancer. Curr Oncol Rep. 2007;9(3):222-225.
  80. Marberger M. Energy-based ablative therapy of prostate cancer: High-intensity focused ultrasound and cryoablation. Curr Opin Urol. 2007;17(3):194-199.
  81. McIntosh H, Herbert P, Logan M, et al. Is magnetic resonance guided focused ultrasound surgery (MRgFUS) clinically effective, safe and cost effective compared with radiotherapy or other palliative treatment alternatives for painful bone metastases? Health Improvement Scotland Evidence Note No. 56. Edinburgh, Scotland: Health Improvement Scotland; November 2015.
  82. Misraï V, Rouprêt M, Chartier-Kastler E, et al. Oncologic control provided by HIFU therapy as single treatment in men with clinically localized prostate cancer. World J Urol. 2008;26(5):481-485.
  83. Miyasaki JM. Functional movement disorders. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2015.
  84. Moosa S, Martínez-Fernandez R, Elias WJ, et al. The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson's disease. Mov Disord. 2019;34(9):1243-1251.
  85. Muto S, Yoshii T, Saito K, et al. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Jpn J Clin Oncol. 2008;38(3):192-199.
  86. National Collaborating Centre for Cancer. Prostate cancer: Diagnosis and treatment. London, UK: National Institute for Health and Care Excellence (NICE); January 2014.
  87. National Comprehensive Cancer Network (NCCN). Hepatobiliary cancer. NCCN Clinical Practice Guidelines in Oncology, Version.2.2013. Fort Washington, PA: NCCN; 2013.
  88. National Comprehensive Cancer Network (NCCN). Soft tissue sarcoma. NCCN Clinical practice Guideline in Oncology. Version 1.2015. Fort Washington, PA: NCCN; 2015.
  89. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version.4.2013. Fort Washington, PA: NCCN; 2013.
  90. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 4.2019. Fort Washington, PA. NCCN. 2019.
  91. National Horizon Scanning Centre (NHSC). High intensity focused ultrasound for prostate cancer - horizon scanning review. Birmingham, UK: NHSC; 2002
  92. National Institute for Health and Care Excellence (NICE). Unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson’s disease. Interventional Procedures Guidance [IPG] 606. London, UK: NICE; February 2018.
  93. National Institute for Health and Care Excvellence (NICE). Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor. Interventional Procedures Guidance [IPG] 617. London, UK: NICE; June 2018.
  94. National Institute for Health and Clinical Excellence (NICE). Prostate cancer. Diagnosis and treatment. NICE Clinical Guideline 58. London, UK: NICE; February 2008.
  95. National Institute for Health and Clinical Excellence (NICE). Prostate cancer: Diagnosis and treatment. London, UK: NICE: January 2014.
  96. Navarro L. High intensity focused ultrasound (HIFU) in the treatment of liver cancer [summary]. Technical Consultation. CT02/2008. Barcelona, Spain: Catalan Agency for Health Technology Assessment and Research (CAHTA); July 2008.
  97. Ng KK, Poon RT, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma: A single-center experience. Ann Surg. 2011;253(5):981-987.
  98. Olitsky SE, Reynolds JD. Primary infantile glaucoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2019.
  99. Olweny EO, Cadeddu JA. Novel methods for renal tissue ablation. Curr Opin Urol. 2012;22(5):379-384.
  100. Park MY, Jung SE, Cho SH, et al. Preliminary experience using high intensity focused ultrasound for treating liver metastasis from colon and stomach cancer. Int J Hyperthermia. 2009;25(3):180-188.
  101. Park YS, Jung NY, Na YC, Chang JW. Four-year follow-up results of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor. Mov Disord. 2019;34(5):727-734.
  102. Peek MC, Ahmed M, Douek M. High-intensity focused ultrasound for the treatment of fibroadenomata (HIFU-F) study. J Ther Ultrasound. 2015b;3:6.
  103. Peek MC, Ahmed M, Napoli A, et al. Systematic review of high-intensity focused ultrasound ablation in the treatment of breast cancer. Br J Surg. 2015a;102(8):873-882.
  104. Pfeiffer D, Berger J, Gross AJ. Single application of high-intensity focused ultrasound as a first-line therapy for clinically localized prostate cancer: 5-year outcomes. BJU Int. 2012;110(11):1702-1707.
  105. Pichon-Riviere A, Augustovski F, Garcia Marti S, et al. Usefulness of high-intensity focused ultrasound in prostate cancer [summary]. IRR No. 134. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2008.
  106. Picillo M, Fasano A. Recent advances in essential tremor: Surgical treatment. Parkinsonism Relat Disord. 2016;22 Suppl 1:S171-S175.
  107. Pickles T, Goldenberg L, Steinhoff G. Technology review: high-intensity focused ultrasound for prostate cancer. Can J Urol. 2005;12(2):2593-2597.
  108. Poissonnier L, Murat FJ, Belot A, et al. Locally recurrent prostatic adenocarcinoma after exclusive radiotherapy: Results of high intensity focused ultrasound. Prog Urol. 2008;18(4):223-229.
  109. Posarelli C, Covello G, Bendinelli A, et al. High-intensity focused ultrasound procedure: The rise of a new noninvasive glaucoma procedure and its possible future applications. Surv Ophthalmol. 2019;64(6):826-834.
  110. Ramsay CR, Adewuyi TE, Gray J, et al. Ablative therapy for people with localised prostate cancer: A systematic review and economic evaluation. Health Technol Assess. 2015;19(49):1-490.
  111. Ravi V, Patel SR, Rault CP, DeLaney TF. Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed July 2015.
  112. Rebillard X, Soulié M, Chartier-Kastler E; Association Francaise d'Urologie. High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology. BJU Int. 2008;101(10):1205-1213.
  113. Recht LD, van den Bent M, , Shih HA. Management of low-grade gliomas in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2018.
  114. Rosenberg D. Treatment of obsessive-compulsive disorder in children and adolescents. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2015.
  115. Ruan L, Xie Z, Wang H, et al. High-intensity focused ultrasound treatment for non-neoplastic epithelial disorders of the vulva. Int J Gynaecol Obstet. 2010;109(2):167-170.
  116. Santos Marques AL, Andres MP , Kho RM, Abrao MS. Is high-intensity focused ultrasound effective for the treatment of adenomyosis? A systematic review and meta-analysis. J Minim Invasive Gynecol. 2020;27(2):332-343.
  117. Schmid FA, Schindele D, Mortezavi A, et al. Prospective multicentre study using high intensity focused ultrasound (HIFU) for the focal treatment of prostate cancer: Safety outcomes and complications. Urol Oncol. 2020;38(4):225-230.
  118. Scottish Health Technologies Group. Is magnetic resonance guided focused ultrasound surgery (MRgFUS) clinically effective, safe and cost effective compared with radiotherapy or other palliative treatment alternatives for painful bone metastases? Advice Statement 002/15. Edinburgh, Scotland: Health Improvement Scotland; December 2015.
  119. Sehmbi AS, Froghi S, de Andrade MO, et al. Systematic review of the role of high intensity focused ultrasound (HIFU) in treating malignant lesions of the hepatobiliary system. HPB (Oxford). 2021;23(2):187-196.
  120. Shaw CJ, Civale J, Botting KJ, et al. Noninvasive high-intensity focused ultrasound treatment of twin-twin transfusion syndrome: A preliminary in vivo study. Sci Transl Med. 2016;8(347):347ra95.
  121. Shi S, Ni G, Ling L, et al. High-intensity focused ultrasound in the treatment of abdominal wall endometriosis. J Minim Invasive Gynecol. 2020;27(3):704-711.
  122. Stanislavova N, Karamanliev M, Ivanov T, et al. Is high-intensity focused ultrasound (HIFU) an option for neoadjuvant therapy for borderline resectable pancreatic cancer patients? -- A systematic review. Int J Hyperthermia. 2021;38(2):75-80.
  123. Sumitomo M, Hayashi M, Watanabe T, et al. Efficacy of short-term androgen deprivation with high-intensity focused ultrasound in the treatment of prostate cancer in Japan. Urology. 2008;72(6):1335-1340.
  124. Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177(6):2106-2131.
  125. Thuroff S, Chaussy C. HIFU in urological oncology. Urologe A. 2008;47(4):431-432, 434-438, 440.
  126. Tsai M-C, Chang L-T, Tam K-W, et al. Comparison of high-intensity focused ultrasound and conventional surgery for patients with uterine myomas: A systematic review and meta-analysis. J Minim Invasive Gynecol. 2021;28(10):1712-1724.
  127. Uchida T, Ohkusa H, Yamashita H, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. Int J Urol. 2006;13(3):228-233.
  128. Uddin Ahmed H, Cathcart P, Chalasani V, et al. Whole-gland salvage high-intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy. Cancer. 2012;118(12):3071-3078.
  129. Vachiramon V, Iamsumang W, Chanasumon N, et al. A study of efficacy and safety of high-intensity focused ultrasound for the treatment of melasma in Asians: A single-blinded, randomized, split-face, pilot study. J Cosmet Dermatol. 2020;19(2):375-381.
  130. Veereman G, Jonckheer P, Desomer A, et al. Systematic review of the efficacy and safety of high-intensity focussed ultrasound for localised prostate cancer. Eur Urol Focus. 2015;1(2):158-170. 
  131. Walling IT, Gee L, Neubauer P, et al. Pulse modulation of the occipital nerve using focused high-intensity ultrasound improves mechanical thresholds in a chronic migraine rat model. Neurosurgery. 2016;63 Suppl 1:150-151.
  132. Wang Q, Guo R, Rong S, et al. Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a pre-clinical canine model. J Am Coll Cardiol. 2013;61(21):2185-2192.
  133. Wang Y, Geng J, Bao H, et al. Comparative effectiveness and safety of high-intensity focused ultrasound for uterine fibroids: A systematic review and meta-analysis. Front Oncol. 2021;11:600800.
  134. Weizer JS. Angle-closure glaucoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2019.
  135. Wilt TJ, Shamliyan T, Taylor B, et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Comparative Effectiveness Review No. 13. Prepared by Minnesota Evidence-based Practice Center under Contract No. 290-02-00009. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); February 2008.
  136. Working Group of the Clinical Practice Guideline on Prostate Cancer Treatment. Clinical practice guidelines on prostate cancer treatment. Clinical Practice Guidelines in the NHS I+CS No.. 2006/02. Madrid, Spain: National Plan for the NHS of the MSC, Aragon Institute of Health Sciences (I+CS); 2008. 
  137. Xiao J, Zhang S, Wang F, et al.  Cesarean scar pregnancy: Noninvasive and effective treatment with high-intensity focused ultrasound. Am J Obstet Gynecol. 2014;211(4);356:e1-e7.
  138. Yan X, Zhao C, Tian C, et al. Ultrasound-guided high-intensity focused ultrasound ablation for treating uterine arteriovenous malformation. BJOG. 2017;124 Suppl 3:93-96.
  139. Yang S-Y, Liu F, Liu Y, et al. Stent insertion with high-intensity focused ultrasound ablation for distal biliary obstruction secondary to pancreatic carcinoma. Medicine (Baltimore). 2020;99(6):e19099.
  140. Yonetsuji T, Ando T, Wang J, et al. A novel high intensity focused ultrasound robotic system for breast cancer treatment. Med Image Comput Comput Assist Interv. 2013;16(Pt 3):388-395.
  141. Youn Y, Walling IT, Gee L, et al. High-intensity ultrasound for the treatment of vincristine-induced neuropathic pain. Neurosurgery. 2016;63 Suppl 1:204.
  142. Yuan SM, Li H, Yang M, et al. High intensity focused ultrasound enhances anti-tumor immunity by inhibiting the negative regulatory effect of miR-134 on CD86 in a murine melanoma model. Oncotarget.;6(35):37626-37637.
  143. Zacharakis E, Uddin Ahmed H, Ishaq A, et al. The feasibility and safety of high-intensity focused ultrasound as salvage therapy for recurrent prostate cancer following external beam radiotherapy. BJU Int. 2008;102(7):786-792.
  144. Zafar A, Quadri SA, Farooqui M, et al. MRI-guided high-intensity focused ultrasound as an emerging therapy for stroke: A review. J Neuroimaging. 2019;29(1):5-13.
  145. 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(4):447-452.
  146. Zhao J, Wang Q, Li X, et al. Effective high intensity focused ultrasound treatment in recurrent aggressive breast fibromatosis: A case report. Onco Targets Ther. 2019;12:5251-5256.