High intensity focused ultrasound ablation (HIFU ablation) is a new technology to ablate and kill the tumors in the body without cutting open or puncturing, so HIFU ablation is also called focused ultrasound ablative technology.

Its working principle is similar to using a convex lens to concentrate the sunlight which produces high temperature at the focal point that can lit the paper on fire. Ultrasound can also be focused and travels through the body safely. As a noninvasive therapy, HIFUfocuses the ultrasound energy outside the human body on the target lesion inside the body, producing high temperature (60 ℃ or higher) at the focal point instantly and causing irreversible coagulative necrosis of the target lesion, without damaging the tissues in the acoustic pathway and those surrounding the target lesion. The necrotic tissues will be gradually absorbed or become scars (fibrosis).

Haifu System refers to the Focused Ultrasound Tumor Therapeutic System Developed and manufactured by Chongqing Haifu Medical Technology Co., Ltd with independent intellectual property rights. There are several models of the Haifu System with differences in appearance and clinical indications.

JC

Model JC Focused Ultrasound Tumor Therapeutic System (for benign and malignant tumors)

JC200

Model JC200 Focused Ultrasound Tumor Therapeutic System (for benign and malignant tumors)

JC200D Model JC200D Focused Ultrasound Tumor Therapeutic System (for Gynaecology).

Haifu System is used to treat solid tumors (both malignant and benign), such as uterine fibroids, adenomyosis, liver tumors, pancreatic cancer, kidney tumors, bone tumors, and breast tumors.

Haifu system has been used in 27 countries and regions, including the UK, Germany, Spain, Egypt, Argentina, Singapore, Korea and Japan. Its safety and effectiveness in the treatment of benign and malignant tumors have been internationally recognized.

The John Radcliffe Hospital, one of Oxford University Hospitals, UK, introduced the Haifu System in 2002, becoming the first overseas user of the Haifu System outside China. The Minister of Health of Spain once appealed to list the Haifu System as the preferred option for the treatment of uterine fibroids and adenomyosis. And the University Hospital Mutua de Terrassa and the University Hospital Bonn use Haifu System as a major option for the treatment of such malignant tumors as pancreatic cancer. To date, there have been 21 HIFU centers in Korea using the Haifu System in the treatment of benign and malignant tumors; uterine fibroids, adenomyosis, liver cancer and pancreatic cancer have received Korean FDA approval.

As of December 2019, 151,975 patients have been treated with HIFU ablation performed using Haifu System, confirming the safety and effectiveness of HIFU ablation and HaifuSystem.

Haifu System has been used in clinical practice for over two decades with the number of patients treated reaching 151,975 as of December, 2019. Hundreds of academic papers have been published and have shown that the safety and effectiveness of HIFUtreatment (performed using Haifu System) for both benign and malignant tumors have been shown in hundreds of academic papers. For example, a large 20-center prospective cohort study ledbyProf. LANG Jinghe, Academician of Chinese Academy of Engineering and President of Chinese Obstetricians and Gynecologists Association (COGA), enrolling 2,411 patients with symptomatic fibroids across 20 Chinese hospitals, showed that HIFU ablation (n=1,353) hada similar effect to myomectomy (n=586) and hysterectomy (n=472), but a better safety profile with minimal injury, remarkable symptom relief, improvement of quality of life of patients, considerable shorter hospital stay and lower medical costs. A retrospective case series of

9,988 patients with uterine fibroids (7,438 patients) or adenomyosis (2,549 patients) showed that HIFU ablation for uterine fibroids and adenomyosis is highly effective and safe with light and temporary adverse reactions under conscious sedation, hence an alternative treatment for women with uterine fibroids and adenomyosis. A retrospective case series of 27,053 patients with uterine fibroids (n=17,402), adenomyosis (n=8434), caesarean scar pregnancy (n=876), or placenta accreta (n=341) showed that HIFU is safe in treating patients with benign uterine diseases with low rate of major adverse effects. In addition, HIFUablation for uterine fibroids has been included into the Guidance of National Institute for Health and Care Excellence (NICE Guidance), UK and other international clinical guidelines respectively by the American College of Obstetricians and Gynecologists (ACOG), theSociety of Obstetricians and Gynaecologists of Canada (SOGC), the Korean Society Of Obstetrics and Gynecology (KSOG), and the Chinese Obstetricians and Gynecologists Association (COGA).

The HIFU treatment performed using Haifu System is under the real-time guidance of ultrasound, which means the treatment effect can be seen in a real-time manner and thus the treatment scope and intensity can be adjusted according to the patient’s reaction to the treatment. In addition, as there is no need of general anesthesia or spinal anesthesia duringHIFU treatment of uterine fibroids and adenomyosis and a small amount of sedatives and analgesics will suffice, the patient can communicate with the medical professionals all along the treatment if any discomfort. And medical professionals are also by the side of the patient all the time observing vital signs and hence coping with any situations that may occur in a timely manner. And therefore, the HIFU treatment process is safe and reliable.

The advantages of the Haifu System: 1. no cutting open, no puncturing, no bleeding, less pain, quick recovery and the patient can get out of bed 2 hours after HIFU treatment; 2. no need of general anesthesia or spinal anesthesia in the treatment of benign tumors; 3. the treatment is not subject to the size and shape of tumors; 4. organ-preserving without damaging other normal tissues; 5. usually one single session of ablation treatment will suffice; 6. short treatment time and quick recovery; 7. no radiation; 8. repetitive interventions are plausible.

Theoretically speaking, 80% of the patients with fibroids and/or adenomyosis are suitable for HIFU ablation. But first of all, to confirm whether the patient is suitable or not, she needs to conduct positioning under the guidance of ultrasound imaging to figure out the location, size and blood supply of the lesion and to see if a safe acoustic pathway can be established. Furthermore, the patient can also undergo MRI scanning to check the sensitivity of the lesion to HIFU ablation and the ablation difficulty. Among the patients that are advised by their doctors to undergo hysterectomy, some are suitable for HIFU ablation and hence preserve their uterus.

If the doctor cannot rule out the malignancy of the uterine lesions, surgical treatment is advised as a preferred option and should be performed as soon as possible to determine the pathology. For the patients that are advised hysterectomy only because the fibroids are multiple ones or doctors advise so, they can visit the HIFU center to further assess their conditions to see if the patient is suitable for HIFU ablation; if yes, then the patient can receive HIFU treatment and avoid surgical removal of her uterus.

The Hifu System can achieve HIFU ablation. The temperature at the focal point varies in the

ablative equipment of different manufacturers. It is known that the energy at the focal point of the Haifu System manufactured by Chongqing Haifu Medical is the highest and that HaifuSystem can ablate the lesions in one single session. The Haifu System can achieve complete ablation of the lesions in one single session with a high ablation rate, satisfactory thermal ablative effect and low recurrence rate. As the energy at each treatment cannot meet the requirement for ablation, the ablative equipment of other manufacturers can only achieve hyperthermia, hence requiring multiple sessions, high recurrence rate and low ablation rate.

As a large Chinese medical equipment with complete interdependent intellectual property rights, Haifu System has been approved by the National Medical Products Administration of China (CFDA), CE marked and exported to many other countries and regions. It has been used for treating benign and malignant tumors in nearly 30 countries and regions, such as the UK, Germany, Spain, Argentina, South Africa, Korea, Singapore and Japan.

It is difficult to ablate all the fibroids in one single session. Even the conventional surgeries cannot remove all the fibroids in one session. But the Haifu System can ablate most fibroids and control well the growth rate and clinical symptoms of the fibroids. The patient can receive a second session of HIFU ablation if recurrence occurs. The biggest advantage of Haifu Systemis that it is noninvasive, no need of general anesthesia or spinal anesthesia and repetitive inventions are plausible.

Uterine fibroids are mostly benign lesions. The performance of HIFU ablation is subject to the blood supply and location of the fibroids. Its overall effective rate is over 95 %and it is possible that some cases may encounter unsatisfactory treatment results. The criteria for assessing the effectiveness of HIFU ablation differ from those of conventional surgeries and they include the symptom relief, the shrinkage of the lesion and the improvement of the success rate of pregnancy. However, HIFU ablation has its limitations. If the treatment result is not satisfactory, there are three options: 1. keep on observing if there is partial necrosis of fibroids and no obvious symptoms; 2. a second HIFU ablation can be performed or can follow medication (like GnRH-a) if the patient is considered as suitable for a second HIFUablation; 3. the patient can choose surgical treatment if the effect of a second HIFUablationis

considered as unsatisfactory.

Gynecological preparation: no sexual intercourse within seven days before HIFUablation; make sure IUD is taken out; no acute gynecological inflammation.

Dietary preparation: blank semi-fluid diet two days before treatment, such as porridge (withmince, Chinese yam, etc), steamed egg, egg soup and various fresh fruit juice (fruit flesh filtered), soft noodles, and glucose water. Don’t have milk products (like milk, yogurt), soy products (like soybean milk, tofu), white sugar products (like various drinks, desserts) or fiber-rich vegetables, fruits (especially multi-seed fruit), which may produce plenty of gas and food residue in the intestines and cannot be cleaned by preoperative intestinal preparation and may increase the risk of bowel injury during treatment.

Bladder training: to establish a safe and effective acoustic pathway, the patient should train the elasticity of her bladder three to four times a day by practicing drinking more water, holding back her urine and postponing urination .

It depends on the size of the lesion and the patient’s condition. It only takes around 30minutes for some fibroid and adenomyosis cases. For multiple fibroids and those fibroids and adenomyosis with a rich blood supply, it usually takes one to two hours to ablate them.

For the patient that receives HIFU ablation for the treatment of such benign uterine diseases as uterine fibroids and adenomyosis, she can have sexual intercourse with certain contraceptive measures after one menstrual period. But if the first menstrual period after HIFU ablation comes not long after the treatment, the patient should not have sexual intercourse until one month after HIFU treatment. The patient can get out of bed two hours after HIFU ablation and can go back to work or do travelling one day after HIFUablation. Please do remember that consult your doctor if there are any questions and cooperate with your doctor in follow-up.

As the cause of uterine fibroids and adenomyosis is related to the amount of estrogen in the body, don’t eat or eat less estrogen-rich food or supplements of which you don’t know the ingredients.

Dietary requirements after HIFU ablation:

1) two hours after HIFU treatment: blank liquid diet, such as egg soup, honey and various fruits.

2) 24 hours after HIFUtreatment: semi-liquid diet, such as porridge, green vegetables and various fruits that are easy to digest.

3) 48 hours after HIFU treatment: back to normal diet if there’s no discomfort (such as abdominal pain, abdominal distension, fever, nausea, vomiting).

4) Have plenty of water, vegetables and food that help soften stools, such as sweet potatoes, mulberries, bananas, fragrant-flowered garlic, turnips, spinach, taros; fruits are recommended as well, but not too much.

5) Don’t eat hard food or food that is difficult to digest, such as rice, noodles and fried food, for they may cause abdominal distention, abdominal pain or other intestinal discomfort when the intestinal function is not fully recovered yet due to the strict intestinal preparation before HIFU ablation.

Do moderate exercise every day, for instance, rubbing the stomach, to prevent constipation. Have regular meals with balanced nutrition, plenty of water and careful use of the supplements; no special requirement for daily diet.

Generally speaking, the fibroid or adenomyosis lesions will not shrink or disappear immediately after HIFU ablation. As the lesion tissues have undergone coagulative necrosis, the fibroids are no longer viable although the fibroid outline remains there. The necrotic fibroids will be metabolized and absorbed by the body gradually after a period of time; most fibroids will be absorbed partially, and some completely and disappear at last.

Generally speaking, the absorption of the fibroids is fast in the first three months after HIFU ablation, with most fibroids absorbed at a rate of around 40 % at 3 months, 60%at 6 months and 70% at 12 months. The specific absorption rate and degree are related to the location and type of the fibroids as well as individual differences in patients.

Before HIFU ablation 1 day after HIFU ablation 8 months after HIFUablation

The recurrence of the disease is related to its characteristics, the patient’s condition, treatment

modality and the age, fertility status and lifestyle of the patient. For uterine fibroids, especially multiple fibroids, recurrence may happen even though they are removed with surgical treatment. The purpose of fibroid and adenomyosis management is to make the lesions shrink or stop growing and control the clinical symptoms. The outcomes after HIFUablation for different types of lesions are different. A large number of clinical data have shown that when the ablation rate of HIFU ablation reaches over 70%, its clinical efficacy is comparable to that of laparoscopic myomectomy while its recurrence rate at 2 years is lower than that of myomectomy. As HIFU ablation is noninvasive and repetitive interventions are plausible, young patients or patients with recurrent fibroids due to the strong viability of residual lesion can receive HIFU ablation again as long as the recurrent fibroids are not contraindications for HIFU ablation after evaluation. In addition, studies have shown that satisfactory results can also be achieved after a second HIFU ablation.

Generally speaking, oral drugs are not required. If there is severe pain, the patient can take non-steroidal anti-inflammatory drugs (NSAID), such as ibuprofen and Celebrex, for 1-2 days after HIFU ablation. If vaginal discharge increases after HIFU ablation for submucosal fibroids, the doctor may suggest the patient take oral antibiotics as a prophylactic for 3-5days.

The cost of HIFU ablation is slightly higher than that of conventional surgeries, but the overall cost of HIFU ablation is lower than that of laparoscopic and intervention therapies, for compared to surgical treatment, HIFU ablation boasts shorter treatment time and hospital stay(or even no need of hospital stay), no need of special care after treatment and quick recovery(i.e. the patient can go back to work asap), reducing the patient’s expenditure in terms of manpower and material resources.

Due to the differences in pricing, charging standards and treatment protocol (like medications and hospital stay), the cost of HIFU ablation is between 2,000 and 6,000 US dollars for the treatment of benign tumors and between 5,000 and 12,000 US dollars for the treatment of malignant tumors.

The principle of HIFU ablation is to cause cell disruption and irreversible coagulative necrosis with the instant temperature rise at the focal point. Uterine fibroids become inactivated and necrotic after HIFU ablation; in this case, the fibroid cells are not viable and thus cannot become cancerous. The probability of canceration of uterine fibroids is very low. Close follow-up is required after treatment, be it conventional surgeries or HIFUablation. For fast-growing fibroids along with abnormal uterine bleeding, further examinations are required, and surgical resection should be performed to determine the pathology if necessary.

Yes, you can receive HIFU ablation. As it is noninvasive and will not damage the surrounding normal tissues and organs, HIFU ablation can be performed two weeks after surgical treatment. As long as the incision heals and there are no underlying diseases (such as connective tissue diseases), there will not be additional risks. For the patient that had laparoscopic surgeries before, the doctor should check if there is ultrasound attenuation at the scar under the guidance of the ultrasound imaging and check if a safe acoustic pathway can be established before HIFU ablation so as to evaluate whether the patient is suitable for HIFUablation. A scar will increase the risk of skin burn, but with adequate preoperative evaluation, good intra-operative communication and cooperation, the risk of skin burn is very low.

There is a possibility of complications for any therapies.

Risks of open surgery and laparoscopic surgery include: 1) anesthesia accidents, hemorrhage and uterine perforation but with a low incidence rate; 2) scars on the abdomen after open and laparoscopic surgery; 3) and disseminated implantation of fibroids in the process of morcellation and removing or digging out the fibroids.

Risks of HIFU ablation include: 1) distending pain in the treatment region (usually alleviates two hours after HIFU treatment); 2) and skin burn (with an incidence rate of 0.2%). However, the incidence of complications in HIFU ablation is far less than other therapies. As HIFUablation is noninvasive and repeatable without cutting-open or bleeding, the treatment is easy and the patient can stay awake all along the treatment, hence a quick recovery and short hospital stay.

Intestinal adhesion will increase the risk of intestinal injury during HIFU ablation. Positioning Is required before treatment to confirm whether the adhesive intestines can be pushed away from the acoustic pathway under the guidance of ultrasound imaging. HIFU ablation can be performed as long as a safe acoustic pathway can be established. And strict preoperative dietary preparation is also required for the intestinal safety during treatment.

Over 80% of patients with uterine fibroids are clinically suitable for HIFUablation. Regarding the size, as long as the fibroids can be displayed under the guidance of ultrasound imaging (＞1 cm and ＜ 20 cm) and a safe acoustic pathway can be established, the fibroids are suitable for HIFU ablation. Studies have shown that HIFU treatment has the same effect as surgical resection when the ablation rate reaches 70%; sometimes, HIFUablation can achieve even more thorough satisfactory results than open surgery. For multiple fibroids, recurrence may happen after any treatment. In this case, the advantages of HIFUablation are particularly prominent: it is noninvasive and repetitive interventions are plausible.

In terms of age, young and premenopausal patients are most suitable for HIFUablation. Young patients are more likely to suffer recurrent fibroids, which can fully manifest the advantages of HIFU ablation, that is, it is noninvasive and thus repetitive interventions are plausible. Patients can plan a pregnancy three months after HIFU ablation, which is significantly shorter than the one to two years, the pregnancy preparation time after laparoscopic myomectomy for uterine fibroids.

Premenopausal patients are about to stop menstruating and their fibroids can heal by themselves after menopause without treatment. For those premenopausal patients with symptomatic fibroids, they can choose HIFU ablation for symptom alleviation so as to avoid surgical treatment and surgery-induced injury to their body.

There are two reasons for preoperative MRI or CT scanning: On the one hand, HIFU ablation a noninvasive therapy and there is no way to obtain pathological diagnosis of the lesion tissues, but MRI or CT scanning serves as an important auxiliary tool to check the signs of malignancy of the uterine tumor lesions and helps doctors to tell the nature of lesions at the beginning. On the other hand, MRI or CT scans can manifest the number, size, location, blood supply of the tumors as well as the relationship between the lesions and the surrounding tissues; moreover, doctors can tell the sensitivity of the tumors to HIFU ablation and predict the treatment difficulty and effect according to the manifestations of the tumors on preoperative T2WI.

Obesity is not an absolute contraindication for HIFU ablation, nor a major factor in affecting treatment effect. For obese patients, we need to conduct MRI-based assessment and lesionpositioning under the guidance of ultrasound imaging before treatment to see if the patients are suitable for HIFU ablation.

HIFU ablation is a noninvasive therapy and it does not cause damage to the other tissues or organs but only to the lesions, so the patient will not get severe pain during the treatment. Nevertheless, as ultrasound can penetrate through human tissues and some tissues and organs may be particularly sensitive to it, some patients may have the following reactions: sacrococcygeal pain, lower abdomen pain, pubic symphysis pain and skin burn, and a very small number of patients may feel radiating pain, that is, pain outside the treatment region, such as lower limb pain, a strain feeling in the anus, and a prick in the perineal region, which is tolerable. In addition, the sedatives and analgesics used during HIFU ablation can also help the patient to tolerate the pain and make the treatment more comfortable.

As a non-invasive therapy, HIFU ablation requires no anesthesia but a small amount of sedatives and analgesics, which allows the patient to stay awake during treatment and report her discomfort (if any) to the doctor in time. And the sedatives and analgesics used will be metabolized quickly in the body with almost no side effects.

The gold standard for signs of malignancy is pathological examinations with a 99%accuracy rating. But due to the remarkable development of imaging technologies, the accuracy of the diagnosis of malignancy can reach more than 95% through color Doppler ultrasound, enhanced MRI, and tumor markers. As long as there is a possibility of malignancy, the doctor will advise the patient to receive surgical treatment instead of HIFU, firmly putting the safety of the patient first.

HIFU ablation is a green therapy. It uses green pollution-free ultrasound to treat tumors. Weall know that ultrasound is used for prenatal care, including examinations throughout the pregnancy, so ultrasound therapy is safe. And HIFU ablation is also a precise therapy, that is, it only ablates the target lesions without any injury to the surrounding tissues. As for the preparation for pregnancy after HIFU, it depends on the location and size of the fibroids to be treated. It is suggested to consult your doctor about how long you should wait before planning pregnancy.

We have many patients that got pregnant two to three months after HIFU ablation, carried the baby to term and gave birth. We haven’t found any impact of HIFU on the safety of the mothers or the babies. Currently, there are over 1,500 “Haifu Babies” around the world, but there are no reports of malformations of the babies.

HIFU ablation is a noninvasive therapy without cutting-open or bleeding, and thus a very low incidence rate of complications. However, any therapies may have their related complications. For example, the patient may develop hemorrhage, secondary infection (inflammation), poor wound healing, pelvic adhesions, ureteral injury and leakage of urine after open surgery and laparoscopic surgery. As for HIFU ablation for benign uterine diseases, related injuries may be caused to the skin, bowels, bladder, nerves and sacrococcygeal region, for the ultrasound energy travels through the skin and the above-mentioned tissues and organs are close to the uterus. But bowel perforation and nerve damage are rare complications that occurred in the early stage of clinical practice of HIFU ablation with an incidence rate of one to two cases per year across the globe, far lower than that of aviation accidents; the incidence rate of skin burnis around 0.2% to 0.5% while that of nerve damage is even lower. As the further development of HIFU technology and the improvement of clinical protocols, the incidence of various complications decreases sharply with an overall incidence rate of around 0.2%to 0.4%, of which 99% does not require special treatment and can recover soon.

We have a large multi-center study in which patients with symptomatic fibroids were treated across 20 Chinese hospitals. Of the 2411 women recruited, 1353 underwent HIFU, 472 had hysterectomy and 586 had myomectomy. Statistical analysis showed that major adverse events were significantly lower in HIFU relative to surgery (0.2% vs. 12.6%).