Accepted Manuscript Safety of Ultrasound-guided Ultrasound Ablation for Uterine Fibroids and Adenomyosis: A Review of 9988 Cases Jinyun Chen, Wenzhi Chen, Lian Zhang, Kequan Li, Song Peng, Min He, Liang Hu PII: DOI: Reference:

S1350-4177(15)00160-1 http://dx.doi.org/10.1016/j.ultsonch.2015.05.031 ULTSON 2890

To appear in:

Ultrasonics Sonochemistry

Received Date: Accepted Date:

30 April 2015 12 May 2015

Please cite this article as: J. Chen, W. Chen, L. Zhang, K. Li, S. Peng, M. He, L. Hu, Safety of Ultrasound-guided Ultrasound Ablation for Uterine Fibroids and Adenomyosis: A Review of 9988 Cases, Ultrasonics Sonochemistry (2015), doi: http://dx.doi.org/10.1016/j.ultsonch.2015.05.031

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Safety of Ultrasound-guided Ultrasound Ablation for Uterine Fibroids and Adenomyosis: A Review of 9988 Cases

Jinyun Chen a，Wenzhi Chen * 1,2，Lian Zhang 2，Kequan Li 3，Song Peng 1 Min， He 3，Liang Hu 1

1 The Institute of Ultrasound Engineering in Medicine, Chongqing Medical University, 1 Yixueyuan Road., Box 153, Chongqing 400016, China. 2 Clinical Center for Tumor Therapy, the 2nd Hospital, Chongqing Medical University, 76 Linjiang Road, Chongqing 400010, China 3 Department of Obstetrics of Chongqing Haifu Hospital, Chongqing 401122, Qingsong Road, Renhe, Yubei District, Chongqing 401121, China

* Corresponding author: Wenzhi Chen Address: Clinical Center for Tumor Therapy, the 2nd Affiliated Hospital of Chongqing Medical University Tel. & fax: +86-23-89012966; E-mail address: [email protected]

Running title: HIFU, uterine fibroid, adenomyosis

ABSTRACT Objective: To evaluate the incidence and severity of adverse reactions to ultrasound-guided ultrasound ablation of uterine fibroids through a multicenter, large-scale retrospective study. Methods: Between July 2006 and June 2007, 9988 patients with uterine fibroids or adenomyosis were enrolled and received ultrasound ablation treatment under conscious sedation. Forty-two doctors administrated the treatment following a standardized clinical protocol. In-treatment and post-treatment side effects and complications were monitored and each patient was followed up for at least 6 months after the treatment. Complications were classified and graded according to the SIR classification system. The technical success and safety of the treatment were evaluated. Results: The mean age of the 9988 patients was 40.4 ± 5.8 years (range, 20–56 years). Among them, 7438 had uterine fibroids and 2549 had adenomyosis. Specifically, 6545 patients had solitary uterine fibroid, 818 had multiple uterine fibroids, and 76 had fibroids complicated with adenomyosis. There were mainly three types of fibroids:

submucous myoma in 89 patients (12.0%),

intramural myoma in 5059 patients (68.0%) and subserosal myoma in 1478 patients (20.0%). In terms of fibroid location, 3496 fibroids were found in the anterior wall (47.0%), 2306 in the posterior wall (31.0%), 447 in the lateral wall (6.0%), and 1190 in fundus (16.0%). The length of treatment for uterine fibroids and adenomyosis averaged 84.2 ± 38.8 min (range, 30.0 - 240.0 min) and 93.3 ± 55.4 min (range, 15.0 240.0 min), respectively; and the lengths of sonication were 1243.8 ± 725.2 sec (range, 506.0 - 2658.0 sec) and 1169.7 ± 707.7 sec (range, 185.0 - 3600.0 sec), respectively. Of the uterine fibroids patients, 98.38% (7319/7439) underwent successful ablation with a mean volume ablation rate of 83.1% ± 15.6% (range, 25%-100%). Of the adenomyosis patients, 94.59 % (2411/2549) underwent successful ablation with a mean volume ablation rate of 73.2% ± 23.6 % (range, 21% - 100%). A total of 1062 patients (10.6%) presented with 1305 events of adverse reactions. According to the SIR classification system, 1228 (94.1%) of these reactions fell under Class A; 45 (3.4%) fell under Class B; 24 (1.8%) fell under Class C; and the rest 8（0.6%) fell

under Class D. Adverse reactions included 874 cases (8.67%) of vaginal secretion, 225 cases (2.23%) of lower abdominal pain 24 hours after the treatment but requiring no painkillers, 76 cases (0.76%) of melosalgia or buttock pain, 52 cases (0.52%) of odynuria, 20 cases (0.20%) of menstruation-like vaginal bleeding, 2 cases (0.2%) of temporary blurred vision, 26 cases (0.26%) of blisters or tangerine pericarp-like burns in the abdominal skin, 16 cases (0.16%) of urinary retention, 4 cases (0.4%) of fever of 38.5˚C, 3 cases (0.3%) of acute renal insufficiency, 2 cases (0.2%) of intestinal perforation, and 1 case（0.01%）of long-term lateral ventral syndrome. No permanent injury or fatal complication occurred. Conclusions: Based on our observations from 9988 cases, ultrasound ablation treatment for uterine fibroid and adenomyosis is highly effective and safe. Adverse reactions to ultrasound ablation under conscious sedation are slight and temporary for both conditions. Hence, this clinically effective and safe treatment is an alternative treatment for women with uterine fibroids and adenomyosis.

Key words: Uterine fibroids; adenomyosis; ultrasound ablation; adverse reaction; complication

INTRODUCTION Ultrasound ablation or focused ultrasound surgery (FUS) is a noninvasive ablative therapy that causes instant coagulation necrosis of tissue lesion （1-3 sec）by focusing high intensity ultrasound onto the target tissue. In 1999, ultrasound-guided ultrasound ablation was applied to clinical treatment of malignant bone tumor for the first time and proved successful [1]. In 2002, Wang et al.[2] reported that ultrasound-guided ultrasound ablation was safe and effective in treating uterine fibroids. With the advancement of imaging monitoring technology and key ultrasound ablation techniques, a viable treatment protocol and doctor training scheme have gradually taken shape after years of clinical research and testing [3-7]. Since July 2006, ultrasound ablation for uterine fibroids and adenomyosis under conscious sedation has been applied in many clinical centers in China, and has even become the first-line therapy for patients in some hospitals [8,9]. Uterine fibroids and adenomyosis are benign lesions of the myometrium. Common clinical symptoms of uterine fibroids include menorrhagia, bradymenorrhea, lower abdominal mass, oppression, etc. Approximately 30% of uterine fibroids cases require treatment due to severe symptoms. Adenomyosis manifests in the presence of functional endometria in the myometrium, accompanied by hypertrophy and proliferation of neighboring myometrium cells causing diffusive or local thickening of the uterine wall. The typical clinical symptom of adenomyosis is progressive dysmenorrhea that seriously affects women of the reproductive age. The symptoms of the above two conditions can be effectively improved by uterine arterial embolization (UAE) or ultrasound ablation other than invasive surgeries. Reports on ultrasound ablation for uterine fibroids and adenomyosis have demonstrated safety for the two indications, and the documented adverse reactions include: thermal injury in the abdominal skin, lower abdominal pain, and melosalgia; rare complications of lower limb DVT, and neurotoxicity of sacral plexus. To date, there have been no reports of death or complications that were fatal or causing permanent damages [4-14]. With the increasingly widespread clinical implementation of ultrasound ablation treatment, it is necessary to evaluate the adverse reactions based on large-scale samples so as to consolidate the foundation for its clinical application in both theory and clinical practice. Employing a unified doctor training scheme and a standardized treatment

protocol, this study analyzed the category, incidence, and severity of adverse reactions to ultrasound ablation for uterine fibroids by reviewing the consecutive data of 9988 patients treated by 42 doctors in 16 clinical centers. The focus of this study is to derive the safety profile of ultrasound ablation for uterine fibroids and adenomyosis. The goal of this retrospective evaluation is to sound a cautionary note to ensure safer and more effective use of ultrasound ablation.

MATERIALS AND METHODS Patients 9988 uterine fibroids and/or adenomyosis patients, who underwent ultrasound ablation therapy under conscious sedation, were enrolled in this study between July 2006 and June 2007. These patients were from 16 clinical centers including the First Affiliated Hospital of Chongqing Medical University and Chongqing Haifu Hospital. Therapies were performed by 42 doctors following a standardized protocol. Patients’ inclusion criteria were: (1) age>18, no pregnancy desire in the near future; (2) clinically diagnosed with uterine fibroids and/or adenomyosis with symptoms like dysmenorrhea and menorrhagia; (3) uterine fibroids and/or adenomyosis confirmed by enhanced MRI examinations; (4) clear imaging of the lesion by ultrasound monitor built in the HIFU treatment system, and ultrasound focal point able to be located inside the lesions with its focal region covering most of the lesion. Ablation of one or multiple dominant tumors was used as the benchmark for the positioning of multiple fibroids; (5) no bone or can't move gas-containing organ found in the ultrasonic path; (6) no allergy to contrast agent or contraindication for MRI examination; (7) free from cognitive impairment, and able to communicate therapeutic experience with the medical staff; (8) consent to ultrasound ablation therapy and having signed the informed consent form; (9) consent to the use of their clinical data and imaging date for medical study and publication. Patients with the following conditions were excluded from the study: (1) with scars in their lower abdomen that could cause obvious sound attenuation or having a history of radiation therapy; (2) suspected of or confirmed as uterine malignancy; (3) with acute infectious pelvic disorders. For nulliparous patients and the uterine fibroids patients whose MRI imaging showed T2WI high signal, an exploratory therapy was adopted, and thus a special informed consent form is required. Patients with both uterine fibroids and adenomyosis were grouped depending on the predominance of clinical symptoms.

HIFU Therapeutic System The ultrasound ablation procedure was performed with a US-guided HIFU (USgHIFU) tumor therapeutic system [JC or JC200, Chongqing Haifu (HIFU) Tech Co., Ltd., Chongqing, China]. The device featuring the built-in B-mode ultrasound (Esaote MyLab70, Italy) that provides real-time visualization during the treatment. Transducer

of 20 cm in diameter worked at a frequency of 0.8 - 1.2 MHz and produced energy of 400W. The focal length was 150 mm, and the dimensions of focal region were 1.5 mm×1.5mm×10 mm. During the procedure, a degassed water balloon was used to push out the bowel in the acoustic pathway.

USgHIFU Ablation Protocol All patients received careful bowel and skin preparations before the procedure. Bowel preparations included having liquid food for 3 days, 12-h fasting and a cleansing enema 2 h prior to procedure. Skin preparation included shaving the hair of the anterior abdomen from the umbilicus to the superior border of the symphysis pubis, degreasing and degassing the skin of the anterior abdominal wall. During the procedure, a urinary catheter was inserted into the bladder, and degassed normal saline was filled in to regulate the bladder volume. HIFU ablation procedure was performed under intravenous conscious sedation (fentanyl, 0.8–1µg/kg, midazolam hydrochloride, 0.02–0.03 mg/kg, administration of both agents was repeated administration of both agents at 30–40min intervals). The purpose of conscious sedation was to relieve discomfort, and to prevent voluntary or involuntary movement. All patients remained conscious, and the vital signs such as respiration, oxygen saturation, heart rate, and blood pressure were monitored during the procedure. Patients were placed in prone position on the HIFU therapeutic system table with anterior abdominal wall in contact with degassed water. Dynamic real-time ultrasonographic imaging was used to observe the target area and the adjacent tissue. Sonication began from the deep to the shallow and the focus was at least 1 cm away from the boundary of the junctional zone and 1.5 cm from the endometrium to prevent normal myometrium injury. The thickness of one section was 5 mm. During the procedure, the therapeutic energy was adjusted based on the feedback from patient's complains and changes in gray scale on ultrasonographic imaging. This process was repeated on a section-by-section basis to achieve complete ablation of the planned ablation area. Once the gray scale covered the planned ablation area, the procedure was terminated. After the procedure, each patient lay in prone position for 2 hours in observation room. While most of patients were discharged from the hospital, some required overnight hospitalization for further observation and were discharged the next morning. Prophylactic antibiotics were prescribed orally for 3 days. Each complication was recorded as it occurred during and after the treatment until

4 weeks after HIFU therapy. Each patient was provided with both written and oral instructions to call the HIFU center service directly should any problems arise. All complications were classified retrospectively according to the SIR classification system [15].

Statistical Analysis Normally distributed data are reported as the mean±SD while non-normally distributed data are reported as median and interquartile range. Data were calculated for each of the complication classes in each of the classification systems using SPSS 19.0.

RESULTS Baseline Characteristics of Patients and Uterine Fibroids As is shown in Table 1, a total of 9988 patients were treated in a single HIFU session, among which 7439 were with uterine fibroids and 2549 were with adenomyosis. The mean age of patients was 40.4±5.8 years (range, 20–56 years). The median uterine volume was 223.0 cm3 (interquartile range, 159.2–328.1 cm3). The number of patients with a solitary fibroid tumor was 6545 (88.0%), and that with multiple fibroids tumor was 818 (11.0%); 76 (1.0%) among the 7439 cases of uterine fibroids were complicated with adenomyosis. The median volume of the dominant fibroid tumor was 67.5 cm3 (interquartile range, 38.1–134.5 cm3). The incidence of the types of dominant fibroid tumor was classified as follows: 12% of submucosal type (I and II, 893 cases); 68.0% of intramural (5059 cases); and 20% of subserosal (1478 cases). The location distribution of the dominant fibroid tumor was as follows: 47.0% of cases were located in the anterior wall (3496 cases); 31.0% of cases were in the posterior wall (2306 cases); 6.0% of cases were in the lateral wall (447 cases); and 16.0% of cases were in the fundus (1190 cases).

Evaluation of Technical Success and Therapeutic Response As is summarized in Table 2, Non-perfused volume (NPV) ratio over 25% of the tumor volume was considered as successful ablation for uterine fibroids. According to this criteria, 98.38% cases (7319/7439) of uterine fibroids obtained successful ablation with 83.1%±15.6% (range, 25%-100%) of non-perfused volume rate. Technical success for adenomyosis was defined as occurrence of non-perfused volume of no less than 1 cm3 (NPV) in the planned ablation area. In this study, 94.59 % (2411/2549) of the patients underwent a successful ablation, with 73.2% ±23.6% (range, 21% -100%) of non-perfused volume rate. The treatment duration was defined as the time from the first sonication to the last sonication. The mean treatment duration was 84.2±38.8 min (range, 30.0-240.0 min) for uterine fibroids, and 93.3±55.4 min (range, 15.0-240.0 min) for adenomyosis, respectively. The sonication duration was 1243.8±725.2 sec (range, 506.0-2658.0 sec) for uterine fibroids, and 1169.7±707.7 sec (range, 185.0-3600.0 sec) for adenomyosis.

Adverse Reactions A total of 1062 (10.6%) patients presented with 1305 adverse reactions. According to the SIR classification system, 1228 (94.1%) of these reactions were graded as Class A; 45 (3.4%) as Class B ; 24 as (1.8%) Class C and 8 (0.6%) as Class D. The most frequent adverse reaction was small volume of vaginal secretion (874 cases), rufous or brown in color that generally lasted between 3 and 14 days. After the ablation therapy, most patients experienced lower abdominal pain and among whom 225 (2.23%) complained of pain 24 hours after rest or pain management, but didn’t need to take painkillers. 76 (0.76%) patients experienced melosalgia or buttock pain. While 19 patients had to take non-steroid anti-inflammatory drug, 2 had prolonged recovery which might have been caused by thermal injury in the nerve adjacent to myomas and so they received physiotherapy (Fig. 1). Fifty-two（0.52%）patients had odynuria but recovered within 3 days without intervention. 20 (0.2%) patients had menstruation-like vaginal bleeding, among which four required hemostatic, and all recovered within 10 days. 2 (0.02%) patients, who had temporary blurred vision possibly caused by sedative and analgesic drugs, recovered without any intervention within one week. 26 (0.26%) patients had blisters or tangerine pericarp-like burns in their abdominal skin, 2 required surgical removal of the necrotic tissue, and all recovered within 2 weeks (Fig 2). 16 (0.16%) patients had urinary retention and recovered within 3 days after catheterization. 4 (0.04%) patients had a fever of 38.5ºC and were given antibiotic therapy. 3 (0.03%) patients were re-hospitalized because of acute renal failure and recovered within 2 to 4 weeks after treatment. 2 (0.02%) patients suffered intestinal perforation 10 days and 20 days respectively after HIFU treatment, which were confirmed and repaired by surgery. One (0.01%) patient who felt hypogastralgia when coughing at one and a half years after HIFU treatment was found to have lateral ventral syndrome. In the plasty, the middle section of musculus rectus abdominis on left side was found to have atrophied or disappeared partially, with hernial sac at its rear; no necrotic tissue or accretion was found (Table 3， ，Table 4， ，Table 5)

DISCUSSION Ultrasound-guided HIFU ablation is a technique that focuses extracorporal low intensity ultrasound onto the targeted zone within the body to form a focal point of high intensity ultrasound that causes instant coagulative necrosis of the tissue in the focal region without noticeable damage to adjacent tissues. Thus, conformal ablation therapy for the whole targeted tissue can be performed by controlling the three-dimensional aggregate motion of the focal point. Good tissue penetration, energy deposition, and energy focusing of ultrasonic wave lay the physical basis for its medical application as therapeutic energy source. Given the physical properties of ultrasound and complexities of the human body and diseases, complications are likely to occur. The incidence and severity of such complications, however, can be reduced through the improvement of the techniques and the clinical protocols. The most common complication of ultrasound ablation therapy is dermal toxicity along the acoustic path, which is manifested by blister or induration. The next is neurotoxicity. Nerve stimulation or aseptic inflammation can recover within a couple of days or longer. The most severe type of neurotoxicity is nerve injury manifested as sensory dysfunction and dyskinesia, with a recovery period of up to 1 year or longer. Intestinal injury is another potential complication that requires active prevention. Complications like urinary retention or urinary tract infection caused by intraoperative indwelling catheter, and water electrolyte imbalance caused by diet preparation or enema also require special observation and prevention. In this retrospective study and analysis, the incidence of dermal toxicity was 0.26%; 0.02% of the patients needed necrectomy due to the tangerine pericarp-like indurations in the old surgical scar. The possible causes for such injuries were: (1) increase of ultrasonic energy deposition in the scar tissue was likely to cause injury; (2) local paresthesia or hypaesthesia of the scar resulted in the untimely judgment of the doctors and patients, which, in turn, led to local injuries. Such injuries can be avoided as experience accumulates. Meanwhile, this group of cases reminded us to be aware of different surgical paths and to protect and observe the old surgical incisions. According to our study, 0.76% of the patients experienced leg numbness and pain. The pain was accurately located, which was in nerve conduction zone of intra-operative radiating pain. These patients recovered at 1 to 3 months after ablation

through active anti-inflammatory, symptomatic and neurotrophic management. One patient had leg pain for three months possibly because of aseptic inflammatory reaction. Therefore, a timely analysis and intervention could speed up recovery and prevent secondary lesions. Deep sedation should be avoided in this treatment, so that patients could respond to negative stimulation and communicate with doctors. During procedure, the focal point should be timely relocated and adjusted, and even withdrawn from the irritated zone on an as-needed basis to prevent or reduce the incidence of neurotoxicity. For ultrasound ablation, bowel preparations must be in place, including catharsis and cleansing enema. Even so, in this large-scaled study, 2 patients (0.2%) had intestinal perforation at 10 days and 12 days respectively after operation, of whom one developed intestinal injury possibly because of the energy reflex caused by the calcification in uterine fibroids. The other patient developed intestinal injury possibly because local tissue ablation reached the outer wall of the uterus, which reminds us that contact with intestines should be strictly avoided during treatment. However, the risk and incidence of intestinal injury can be effectively reduced only through strict preoperative bowel preparations, careful intra-operative intestinal protection, and well-controlled ablation range. Three cases of acute renal insufficiency were found in our analysis but the causes remained unknown. Although the incidence rate for renal insufficiency is extremely low, special attention should nevertheless be paid to the underlying diseases that could cause renal insufficiency. Additionally, renal functions should be assessed after HIFU treatment.

CONCLUSION In conclusion, with a unified and standardized therapeutic protocol for clinical deployment, HIFU ablation of uterine fibroids and adenomyosis under conscious sedation and analgesia causes mostly light side effects and very few severe complications. Retrospective multi-center, large-scale data analyses as we conducted here can enhance our understanding of the safety of HIFU and its complication profile. These observation derived from large clinical cohorts will provide solid scientific evidence that will guide the further improvement of the safety and the efficacy of HIFU, as well as the optimization of the clinical protocols and doctor training scheme.

DISCLOSURE Wen-Zhi Chen is a shareholder and a consultant for Chongqing Haifu Medical Technologies Inc, Chongqing, China. Lian Zhang and Ke-Quan Li are consultants to Chongqing Haifu Medical Technologies Inc, Chongqing, China. However, other authors have no conflicts of interest.

ACKNOWLEDGMENTS This study was supported by National Key Technology Research and Development Program (No. 2011BAI14B01).

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255(3):967-978. [2] W Wang, WY Liu, J Zhou, et al. Treatment of symptomatic uterine leiomyoma with high intensity focused ultrasound: a preliminary clinical study, Chin J Ultrasonography. (2002) (11):161-163. [3] F Wu, ZB Wang, WZ Chen, et al. Extracorporeal high-intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview, Ultrason Sonochem. (2004) (11): 149-154. [4] M Zhou, JY Chen, LD Tang, et al. Ultrasound-guided high-intensity focused ultrasound ablation for adenomyosis: the clinical experience of a single center [J], Fertility and Sterility. (2011) 95(3):900 - 905. [5] J Qin, JY Chen, WP Zhao, et al. Outcome of unintended pregnancy after ultrasound-guided high-intensity focused ultrasound ablation of uterine fibroids, Int J Gynaecol Obstet. (2012) 117(3):273-277. [6] S Peng, Y Xiong, KQ Li, et al. Clinical utility of a microbubble-enhancing contrast ("SonoVue") in treatment of uterine fibroids with high intensity focused ultrasound: A retrospective study, Eur J Radiol. (2012) 81(12):3832-3838. [7] WP Zhao, JY Chen, L Zhang, et al. Feasibility of ultrasound-guided high intensity focused ultrasound ablating uterine fibroids with hyperintense on T2-weighted MR imaging, Eur J Radiol. (2013) 82(1):e43- e49. [8] W Wang , Y Wang , T Wang , et al. Safety and efficacy of US-guided high-intensity focused ultrasound for treatment of submucosal fibroids, Eur Radiol. (2012) 22(11):2553-2558. [9]

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Uterine leiomyomas: MR imaging–guided focused ultrasound surgery—results of different treatment protocols, Radiology. (2007) 243:885–93. [12] FA Taran, CM Tempany, L Regan, et al. Magnetic resonance-guided focused ultrasound (MRgFUS) compared with abdominal hysterectomy for treatment of uterine leiomyomas, Ultrasound Obstet Gynecol. (2009) 34(5):572-578. [13] L Zhang, WZ Chen, YJ Liu, et al. Feasibility of magnetic resonance imaging guided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus, Eur J Radiol. (2010) 73(2):396-403. [14] KR Gorny, DA Woodrum, DL Brown, et al. Magnetic resonance-guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients, J Vasc Interv Radiol. (2011) 22(6):857-864. [15] D Sacks , TE McClenny , JF Cardella , et al. Society of Interventional Radiology clinical practice guidelines, J Vasc Interv Radiol. (2003) 14：S199-202.

FIGURE CAPTIONS Fig 1. A uterine fibroid adjacent to nerve. Uterine fibroids in the left subserosa (A), adjacent to the nerve were completely ablated (B).

Fig 2. Thermal injury occurred at cesarean scar . After HIFU treatment, thermal injury was found in the previous cesarean scar (A); plastic suture was performed after local resection of the necrotic tissue (B).

TABLES Table 1.

Baseline Characteristics of Patients and Uterine fibroids (N= 9988)

Characteristic

Value

Mean Age ± SD (y)

40.4± 5.8 （20-56）

Number

of

patients

with uterine

fibroids

7439 (75.5%)

Uterine volume（cm3）

223.0 ± 156.9（42.1-868.7）*

Dominant fibroid tumor volume（cm3） Uterine Fibroids Solitary fibroid

6545 (88.0%)

Multiple fibroid

818 (11.0%)

Complicated with adenomyosis

76 (1.0%)

Dominant fibroid tumor types Submucosal

893 (12.0%)

Intramura

5059 (68.0%)

Subserosal

1478 (20.0%)

Dominant fibroid tumor location Anterior wall

3496 (47.0%)

Posterior wall

2306 (31.0%)

Lateral wall

447 (6.0%)

Fundus

1190 (16.0%)

Number of patients with adenomyosis

2549 (25.5%)

Note: * mean ± med; those in parenthesis: interquartile range

Table 2. Evaluation on Technical Parameters

Technical Parameters

Uterine Fibroids

Technical Success Rate 98.38 (7319/7439)

Adenomyosis 94.59 (2411/2549)

(%) Treatment duration (min)

84.2 ±38.8

Sonication duration (sec)

1243.8±725.2

1169.7±707.7

(506.0-2658.0)

(185.0-3600.0)

3

Volume of Ablation (cm ) 78.5

(30.0-240.0)

(53.1, 129.4)

93.3±55.4

(15.0-240.0)

48. 7 (5.54，117.4)

* Non-Perfused

Volume 83.1±15.6 (25.0-100.0)

73.2±23.6

(21.0-100.0)

Rate (%) Notes: * Data is indicated by medians (1/4, 3/4); § Data is calculated by using a planned ablation volume as the baseline.

Table 3. Definitions of SIR Class and Percentage Incidence (N =9988)

SIR

Number of

Percentage

patients

patients

of

Description with

Class complications A

No therapy, no consequences

B

Nominal

therapy,

observation,

1228 no

12.29% 0.45%

45 consequences C

Required therapy, minor hospitalization(＜ 26

0.26%

48h) D

Major

therapy, unplanned increase in

6

0.06%

level of care，prolonged hospitalization (＞ 48h) E

Permanent adverse sequelae

0

0

F

Death

0

0

SIR= Society of Interventional Radiology.

Table 4. Description of Adverse Reactions and Classification by SIR system

Number (% of patients

Description

experiencing adverse effects)

SIR

SIR

SIR

SIR

SIR

SIR

class

class

class

class

class

class

A

B

C

D

E

F

None

8926 (89.3)

Vaginal

874(8.75)

874

0

0

0

0

0

225 (2.25)

225

0

0

0

0

0

55

19

2

0

0

0

or 52 (0.52)

52

0

0

0

0

0

24(0.24)

20

4

0

0

0

0

Blurred vision

2 (0.02)

2

0

0

0

0

0

Skin burns

26 (0.26)

0

22

2

2

0

0

Urinary

16(0.16)

0

0

16

0

0

0

Fever

4(0.04)

0

0

4

0

0

0

Acute

renal 3 (0.03)

0

0

0

3

0

0

2 (0.02)

0

0

0

2

0

0

in 1 (0.01)

0

0

0

1

0

0

1228

45

24

8 0

0

(94.1)

(3.4)

(1.8)

(0.6)

secretion Lower abdominal pain Leg or buttock 76 (0.76) pain Odynuria hematuria Uterus bleeding

retention

failure Intestinal perforation hernia

abdominal wall Total

1305*

* A total of 1062 (10.6%) patients experienced 1305 adverse effects.

Table 5. Times of Adverse Reactions after HIFU Procedure

Description

Number (% of

patients

experiencin g

1–7d

8-14d

15-30d

31–90 d

＞90d

adverse

effects)* None

8926 (89.3)

Vaginal secretion

874(8.75)

768

106

0

0

0

abdominal 225 (2.25)

225

0

0

0

0

76 (0.76)

55

12

7

2

0

or 52 (0.52)

52

0

0

0

0

Uterus bleeding

24(0.24)

20

4

0

0

0

Blurred vision

2 (0.02)

2

0

0

0

0

Skin burns

26 (0.26)

22

4

0

0

0

Urinary retention

16(0.16)

16

0

0

0

0

Fever

4(0.04)

4

0

0

0

0

Intestinal

3 (0.03)

0

2

1

0

0

Intestinal

2 (0.02)

0

0

2

0

0

Hernia in abdominal 1 (0.01)

0

0

0

0

1

1164

128

10

2

1

(89.2)

(9.8)

(0.8)

(0.2)

(0.1)

Lower pain

Leg or buttock pain Odynuria hematuria

perforation wall Total

1305

Highlights: ·A multicenter, large-scale retrospective study on high-intensity focused ultrasound (HIFU) ablation

·The size of cohort contains 9988 cases: 7438 cases of uterine fibroids and 2549 cases of adenomyosis.

·Evaluation of the incidence and adverse reactions of HIFU. ·HIFU is a highly effective and safe treatment for uterine fibroids and adenomyosis.