Intrarectal Foley catheter-assisted high-intensity focused ultrasound ablation for benign uterine diseases beyond the treatment region

Abstract Objective To evaluate the feasibility of using an intrarectal Foley catheter during ultrasound-guided high-intensity focused ultrasound (US-HIFU) in patients with benign uterine diseases of the posterior wall beyond the HIFU therapeutic range. Methods Patients were treated with US-HIFU and lesion changes were monitored using contrast-enhanced MRI from June 2020 to September 2021. A Foley catheter was inserted into the rectum to facilitate a successful US-HIFU ablation. Complications and lesion responses were recorded during the treatment and follow-up. Results Thirteen patients with 14 lesions beyond the device’s treatable area were enrolled. The average placement time and insertion depth of the intrarectal Foley catheter was 7.6 ± 2.7 min and 23.2 ± 7.6 cm, respectively. A median of 50 mL degassed water was injected into the Foley catheter balloon. All 14 lesions were successfully pushed into a treatable area and subjected to HIFU. The average treatment time, irradiation time, and total therapeutic energy of HIFU were 44.2 ± 17.3 min, 394.4 ± 295.7 s, and 73.3 ± 46.6 kJ, respectively. The mean non-perfusion volume (NPV) in all treated lesions was 23.2 ± 19.2 cm3, and the mean NPV ratio was 57.8 ± 16.9%. Major complications were not observed. Conclusion Intrarectal Foley catheter-assisted US-HIFU is effective and safe. Its clinical application could benefit patients with benign uterine diseases outside the HIFU therapeutic range.


Introduction
Benign uterine diseases are common in patients of reproductive age.Among these, hysteromyoma and adenomyosis are the most common.Although these diseases remain asymptomatic, they can sometimes cause heavy uterine bleeding, abdominal pain, anemia, increased urination frequency, infertility, and miscarriage, which negatively impact the quality of life [1,2].Approximately 50% of patients reportedly wish to preserve the uterus, with most of them preferring noninvasive treatments for hysteromyoma [3].
High-intensity focused ultrasound (HIFU) is a noninvasive method for ablating target regions by coagulation necrosis, owing to the thermal and mechanical effects of the focused ultrasound beam.Moreover, HIFU is a real-time monitoring, precision, and conformal therapy.Hysteromyoma and adenomyosis are suitable indications for HIFU, especially in young women who desire to retain their uterus [4][5][6][7].Anatomically, the intestinal tract blocks the sonication path to the uterus; thus, the therapeutic ultrasound beam cannot safely reach the target region.An extracorporeal balloon filled with degassed water is generally used to push the intestinal tract away to establish an acoustic channel and avoid damage during HIFU.This method is referred to as the auxiliary extracorporeal balloon method.A retropositioned uterus is tilted backward and is thus far away from the anterior abdominal wall.Therefore, lesions in the posterior uterine wall may be completely or partially beyond the HIFU's therapeutic range.Moreover, the rectum, which is located just behind the lesion, has an increased risk of burning during HIFU.Methods to overcome these situations have been tried, such as injecting ultrasound coupling gel [8], a solution of psyllium fibers [9], or a condom filled with 100-150 ml of saline solution [10] into the rectum.
A Foley catheter balloon can be placed in the bladder by a well-trained registered nurse and fixed by inflating it with an injection of normal saline inside.We were inspired by this to construct a safe intrarectal water balloon.The Foley catheter is made of histocompatible material and rarely causes damage.We hypothesized that inserting a Foley catheter into the rectum would move the lesion into the HIFU beam's therapeutic range without causing severe iatrogenic injuries.
In this study, the Foley catheter was placed inside the rectum as important auxiliary equipment in hysteromyoma/adenomyosis management.Herein, we aimed to investigate the feasibility of intrarectal Foley catheter insertion in the ultrasound-guided HIFU (US-HIFU) treatment of out-of-range hysteromyoma/adenomyosis of the posterior uterine wall.

Patients
This study was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China, (No: (2020) 506) and performed in accordance with the Declaration of Helsinki.All patients signed informed consent forms prior to participation in the study.
Patients who met the inclusion criteria between June 2020 and September 2021 were enrolled in the study and underwent a single HIFU treatment session.Data, including personal information, pre-and post-operative imaging, lesion characteristics, test parameters, test results, and follow-up data, were recorded and analyzed.The inclusion criteria were as follows: (1) patients with hysteromyoma/adenomyosis in the posterior uterine wall; (2) lesions outside the HIFU beam's treatment range; (3) patients without pedunculated fibroids, suspected malignancies, extensive pelvic adhesions, or major lower abdominal surgery, and those who have not undergone other treatments; (4) patients not on their menstrual cycle; and (5) patients who fully understood this study and were willing to undergo HIFU treatment.

US-HIFU treatment
A JC Focused Ultrasound Tumor Therapeutic System (Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China) was used by the same surgeon in our hospital.The equipment was guided by a two-dimensional grayscale ultrasound with a lower therapeutic transducer and mediated by degassed water.The diagnostic ultrasound probe operated at frequencies ranging from 3.5 MHz to 5.0 MHz.Therapeutic ultrasound was produced using a 141-mm diameter therapeutic transducer with a focal length of 120 mm, frequency of 1.0 MHz, and focal peak intensities of 1,000 to 20,000 W/cm2 .The focal region was an ellipsoid (transverse diameter: 3 mm; longitudinal diameter: 8 mm).
Before HIFU treatment, the patients were sedated with intravenous midazolam (1-4 mg) and fentanyl (50-400 lg) to minimize discomfort.With the patient lying in a prone position, a urinary Foley catheter (Weili Medical Device Co., LTD, Guangzhou, China) was placed in the bladder.The patient's anterior abdominal wall was placed in contact with a balloon containing degassed cold water when the bowel was visible in the acoustic pathway.The lesions were scanned using the US.The supposed treatment ranges were 10 mm from the bladder, 15 mm from the bowel, and 15 mm from the endometrium.To place the region intended for treatment within the HIFU therapeutic range, the size of the extracorporeal balloon was modified by infusing or removing degassed water.The bladder size is usually modified in a similar way when using a urinary catheter.
If the treatment regions were still outside the therapeutic range, a Foley catheter was placed in the rectum between the uterus and sacrum under US guidance.A nurse checked the integrity of the Foley catheter balloon, tested its elasticity and size, lubricated it with paraffin oil, and placed it in the rectum, under real-time US guidance.The balloon at the end of the Foley catheter, which fixes it in place, was filled with 30-120 ml of degassed water until the region to be treated moved into the HIFU therapeutic range.The length of the Foley catheter within the rectum and the volume of the injected water were recorded.The patients' feelings of discomfort during Foley catheter placement, such as pain and emotional distress, were also recorded.This procedure is shown in Figure 1.
Under real-time US guidance, a treatment plan was developed, and the HIFU was focused from the deep to the superficial regions of the lesion.The lesion was scanned spot-by-spot with a sonication power ranging from 100 to 400 W. The nurse recorded vital signs, any movements of the extracorporeal balloon and intrarectal catheter, sense of defecation, and discomfort in the anorectal region.
The patient's vital signs were kept stable and they were requested to report any discomfort during HIFU ablation.The study flow is shown in Figure 2.

Magnetic resonance imaging and evaluation
All patients underwent pre-and post-treatment contrastenhanced magnetic resonance imaging (MRI) within 2 days.Based on the images, three dimensions of the lesion were measured before (A1, B1, and C1) and after (A2, B2, and C2) the procedure.The non-enhancing area on contrastenhanced T1-weighted images (T1WIs) after treatment reflected the non-perfused volume (NPV).The lesion volume and NPV were calculated using the following formula: ), which was the percentage of hysteromyoma or adenomyotic volume being ablated and a marker of subsequent treatment success, was calculated using the following formula: The number of lesions, lesion location, blood supply, T2-weighted image (T2WI) signal, and distance between the lesion and abdominal skin were recorded on preoperative MRI.The lesion's blood supply was classified as rich, moderate, or poor based on the enhancement on T1WIs [11].Myometrium enhancement was used as a reference standard; values higher than the reference value indicated rich supply, those similar to the reference value indicated moderate supply, and those lower than the reference value indicated poor supply (Figure 3).Signal intensity on T2WI was classified as low (equal to skeletal muscle signal), isointense (signal strength between that of skeletal muscle and myometrium), high (equal to myometrium signal), or mixed (existence of two or three signal types) [5].

Complications
All symptoms were recorded during treatment, and all patients were followed up for 3 months after HIFU.Complications were evaluated according to the Society of Interventional Radiology's Standards of Practice Committee's Classification of Complications by Outcome [12].Major complications were those in Class C or higher.The complications were classified as requiring therapy or minor hospitalization for < 48 h (Class C); requiring major therapy, unplanned increase in the level of care, or prolonged hospitalization for > 48 h (Class D); causing permanent adverse sequelae (Class E); or resulting in death (Class F) [13].Severe complications included serious skin burns, nerve injury, bowel injury and perforation, bladder injury, endometrial impairment, massive hemorrhage, acute pre-renal failure, rectal ischemia, and anal canal tears.

Statistical analysis
Statistical analyses were performed using SPSS (version 22.0; IBM, Armonk, NY, USA).Normal distribution was analyzed using the Kolmogorov-Smirnov test.Normally distributed continuous variables are reported as the mean 6 SD, and data not distributed normality are reported as median (interquartile range [IQR]).A p-value of < 0.05 was considered statistically significant.

Baseline characteristics of patients and lesions
A total of 174 cases were treated between June 2020 and September 2021.We included 14 lesions in 13 participants (aged 40.0 6 7.1 years) outside the full or partial HIFU therapeutic range in this study.Among the 24 lesions, 10 fibroids in 9 patients and 4 were adenomyosis in 4 patients.The baseline characteristics of the patients and tumors are summarized in Table 1.

Treatment results
All 14 lesions were treated with HIFU.The treatment duration was 40.8 6 17.3 min, the HIFU sonication time was 394.4 6 295.7 s, and the median total energy was 51.7 kJ.The postoperative lesion size was measured on the first post-HIFU MRI.The dimensions were 30.368.9 mm in the axial direction and 36.2 6 13.0 mm in the transverse direction, and 33.1 6 11.9 mm in the anteroposterior direction.The NPV and NPVR were 23.1 6 19.2 ml and 58.5 6 18.3%, respectively.During HIFU treatment, a Foley catheter (median volume 50 ml) was inserted (23.6 6 7.4 mm) into the rectum during 7.6 ± 2.7 min (range 5-12min), with a Foley catheter normal saline balloon radius of 2.42 6 0.30 cm (Table 2).

Follow-up and complications
One day after HIFU, the patients were asked to describe the feeling of intrarectal Foley catheter placement.Three patients felt uncomfortable, while the other 10 participants reported no uncomfortable feelings.All 13 patients were followed up for 3 months.No severe complications were observed during treatment or the followup.Only one patient complained of lower abdominal pain on days 3-7.No therapeutic intervention was required, and the pain resolved on its own.

Discussion
Currently, HIFU is used to treat various benign and malignant diseases; tens of thousands of patients with symptomatic hysteromyoma/adenomyosis are treated annually.Uterine artery embolization (UAE), HIFU, and radiofrequency ablation (RFA) are three common interventional therapies for hysteromyoma/adenomyosis [13].Hysterectomy is considered the most effective method for treating adenomyosis.Compared to other methods, HIFU ablation is a noninvasive treatment that causes no radiation injury and retains organ function.US-HIFU does not influence ovarian reserve [14][15][16].Additionally, Qu et al. who conducted a multicenter study on anti-M€ ullerian hormone, determined that US-HIFU did not affect the ovarian reserves [16].Therefore, HIFU is preferred in women of reproductive age.
Some studies have confirmed that a retroverted uterus is a negative factor for HIFU ablation [17,18].Furthermore, some benign uterine lesions cannot be treated because of their posterior position, outside the transducer range [8,[19][20][21].Fibroids > 10 [9], 12 [22], or 13 cm [23] in diameter have been previously excluded, possibly because the HIFU focus did not cover the region to be treated.In the present study, the distance from the skin to the deep margins of the lesions was 123.3 6 13.7 mm.With an extracorporeal water balloon placed between the abdominal wall and the transducer during HIFU, that distance is longer than that of the HIFU therapeutic range (120 mm).With the assistance of an intrarectal Foley catheter, the benign uterine lesions outside the therapeutic range were moved forward into the HIFU therapeutic range.The Foley catheter was inserted 23.66 7.4 cm into the rectum and its balloon was injected with degassed water (median volume, 50 ml) depending on the forward movement of the lesion.All 13 HIFU procedures were performed successfully for lesions that were considered untreatable without an intrarectal Foley catheter.In our study, the NPV was calculated to evaluate the efficacy of HIFU treatment.The final NPVR was 58.5 618.3%, which was acceptable.Benign uterine lesions in the posterior uterine wall reportedly have a smaller NPVR than those in the anterior uterine wall because of the long distance from the skin to the lesions, posterior location, and nerve injury-related energy limitation [5,17,18].Cui et al. [24] calculated the post-HIFU NPVR of uterine adenomyosis; it was significantly different between lesions in the anterior (93.4 6 12.1%) and posterior (69.8 6 17.2%) wall.Zhang et al. [25] also reported a significant difference in fibroid NPVR between anteverted and extroverted uteri (87.7611.8% vs. 85.2618.7%,p < 0.05).Difficulties in HIFU ablation of posterior uterine wall lesions were also observed in a greater number of patients.A study involving 9,988 patients reported a post-HIFU NPVR of 83.1 6 15.6% for uterine fibroids and 73.2 6 23.6% for uterine adenomyosis [26].In another study involving 27,053 patients the post-HIFU NPVR was 85% for uterine fibroids and 72% for uterine adenomyosis [17].The NPVR of uterine adenomyosis varies greatly between studies, ranging from 34% to 73% [6].Patients with uterine adenomyosis have a lower NPVR.Although the comparison of differences in post-HIFU NPVR between benign lesions in the anterior and posterior uterine walls were not accurate, they elucidated that the relatively small NPVR of posterior wall lesions could be because adenomyosis generally grows in the posterior uterine wall.Hence, NPVR of untreatable posterior wall lesions indicates the treatability of the lesions.
Several efforts have been made to shorten the distance from the skin to the deep margins of the lesions.In one study [8], an ultrasound coupling gel was used to fill the rectum, which enabled bowel displacement during MRI-guided HIFU therapy.The volume of gel injected was fixed at 100 ml, and the patients reported a temporary sense of defecation immediately after rectal filling, which was tolerable.Verpalen et al. [9] reported a new method, called the BRB maneuver.The rectum was filled with a 1:1 (v:v) solution of ultrasound gel and saline solution or a modified solution created by adding 1 sachet (3.4 g) of psyllium fibers (MetamucilV R ;) to a 60 ml syringe.The amount of rectal filling ranged from 240 to 480 ml based on patient tolerance.The BRB maneuver was usually maintained for approximately 1 h; it was ineffective for several hours of MRI-HIFU therapy.The modified solution of psyllium fibers displaced the uterine fibroids more anteriorly and was tolerated by the patients without complaints of a sense of defecation or constipation.Wu et al. [10] prepared a bowel manipulation device to increase the distance between the sacrococcygeal area and the treatment window with an intrarectal condom filled with 100-150 ml of saline.The authors concluded that bowel manipulation with anal catheterization for reaching posterior uterine wall masses was safe and effective in reducing potential HIFU-related nerve complications.These studies supported our hypothesis that an intrarectal Foley catheter can move benign uterine lesions from an area outside the therapeutic range to an area within the HIFU therapeutic range.Herein, we concentrated on increasing the distance from the sacrum to the uterus with a filled condom and found that the distended rectum moved the uterus toward the abdominal wall.only 30-70 ml of degassed water was required to fill the water balloon in the present study.The primary difference was that we placed the water balloon in an appropriate position in the rectum instead of filling the entire rectum.In addition, the degassed water could be removed from the water balloon and the Foley catheter from the rectum immediately after the HIFU treatment.These factors made the placement of the Foley catheter water balloon easy and simple, requiring 7.6 6 2.7 min compared with the 20-45 min required for the BRB maneuver.
A retrospective study of 9,988 patients treated with US-HIFU reported that 10.6% of patients developed adverse events, of which only 2.4% had complications equal to or beyond Class C. Vaginal discharge, abdominal pain, and skin burns were the most common adverse events, except for two patients with serious complications of intestinal perforation [26].In the present study, complications of Class C or higher did not occur; abdominal pain occurred in only one patient, which was believed to be an inflammatory reaction.In addition, only three patients felt uncomfortable with the placement of the Foley catheter into the rectum during the HIFU.This may have been a psychological discomfort because there was no record of rectal injury.This satisfactory outcome of HIFU treatment for posterior uterine wall diseases, which has a higher treatment risk than lesions in other uterine regions, strongly validates the intrarectal Foley catheter-assisted method.Foley catheters are harmless medical devices made of biocompatible materials with abundant clinical applications that rarely cause severe damage [27].Furthermore, the rectum has a similar physiological structure to the urethra, which allows for the safe insertion of a Foley catheter.This new method pushes the uterus close to the anterior abdominal wall, bringing it to within the focal length of the HIFU.Energy deposits in the acoustic fields were spread unevenly, and the foci were much more intense compared to those in the near and far fields.Thermal and mechanical effects are primarily achieved at the foci by damaging the target tissue [28,29].Consequently, very few serious complications occur in the near or far fields.
The limitations of this study are its relatively small sample size and single-center design.Therefore, a larger multicenter cohort study should be conducted to follow up on the implementation of regulatory protocols.

Conclusion
In summary, all 13 patients with lesions in the posterior uterine wall were successfully treated with US-HIFU, assisted by an intrarectal Foley catheter.No severe adverse events were observed.Thus, this new method is effective, safe, and feasible for hysteromyoma/adenomyosis management and could be beneficial for women with fibroids in the posterior uterine wall.

Figure 1 .
Figure 1.(A) The intrarectal Foley catheter was in the rectum without degassed water injection.The lesion was off range, which was infeasible for HIFU.(B) The degassed water balloon of the intrarectal Foley catheter moved the uterus forward, and the lesion was in range.(C) The Foley catheter used in the present study (Weili Medical Device Co., LTD, Guangzhou, China).(D) The end balloon was filled with degassed water.This was used to fix the catheter in the bladder.(E) The size of the degassed water balloon was 60 mm Â 45 mm, which could move the uterus 22.5 mm forward to the abdominal wall.Ã The green square in A and B is the range square of the HIFU treatment range.

Figure 3 .
Figure 3. MR images of the lesion on T2WI: (A) and (C) are pretreatment images; (B) and (D) are post-HIFU images.Contrast-enhanced MR images of the lesion on T1WI: (E) pretreatment image in the arterial phase, (G) and (I) pretreatment images in the venous phase; (F) post-HIFU image in the arterial phase, (H) and (J) post-HIFU images in the venous phase.

Table 2 .
Treatment results of patients treated by HIFU.

Table 1 .
Baseline characteristics of patients and lesions.