Development of High-Intensity Focused Ultrasound Therapy for Inferior Turbinate Hypertrophy

Objective To explore the effects of high intensity focused ultrasound (HIFU) ablation on skeletal growth in infant rats bearing human neuroblastoma.Methods A total of 135 healthy 4-week-old male Sprague-Dawley (SD) rats were divided randomly into normal control group (A),HIFU group (B) and surgery group (C) (n =45 each).Human neuroblastoma SK-N-SH cells were inoculated into renal fascia of left adrenal gland for constructing a tumor-bearing rat model in HIFU and surgery groups.The rats of HIFU group received HIFU with a power of 70-90 W at Days 7-9 post-inoculation (tumor diameter 1.0-1.5 cm).While those of normal control and surgery groups were untreated.The data of length,skeletal malformations under macroscopic observation and radiography were recorded at study entry and after 3 days,2 weeks and 4 weeks in all groups.The serum level of bone alkaline phosphatase (BALP) was measured by enzyme-linked immunosorbent assay (ELISA)and histopathological examinations of spine and ribs around HIFU radiation zone were made with hematoxylin & eosin stain.Results No obvious macroscopic and radiographic malformations were found at study entry and different stages after HIFU.The height growth at day 3 in HIFU group [(0.900 ± 0.338) cm] was significantly lower than that in control group [(1.497 ± 0.362) cm] and surgery group [(1.243 ± 0.378) cm](P＜0.05).At week 2,it was also lower in HIFU group (2.500 ± 0.445) cm than control group (3.633 ± 0.434) cm and surgery group [(3.333 ± 0.372) cm] (P＜ 0.05).However,no difference existed among HIFU group [(2.533 ± 0.543)cm],control group [(2.900 ± 0.541) cm] and surgery group [(2.633 ± 0.696) cm] at Week 4 (P＞ 0.05).The serum concentration of BALP decreased after HIFU treatment 3 days in HIFU group [(951.697 ± 251.618)pg/ml] than that in control group [(1 168.847 ± 121.638) pg/ml] and surgery group [(1 088.359 ± 176.919) pg/ml](P＜0.05).Significant statistical differences existed when HIFU group [(1 037.507 ± 297.013) pg/ml] compared with control group [(1 675.691 ± 309.506) pg/ml] and surgery group [(1 915.433 ± 212.364) pg/ml] at 2 weeks later(P＜0.05).However,no statistical difference existed in the serum concentration of BALP among HIFU group [(1 106.551 ± 235.832) pg/ml],control group [(1 219.494 ± 77.615) pg/ml] and surgery group [(1 092.835 ± 164.593) pg/ml] at Week 4(P ＞0.05).Histopathological examination showed that bone trabeculae narrowed,primary marrow cavity significantly expanded at day 3 and week 2 post-HIFU in HIUF group.At week 4,bone trabecular density was similar in three groups.Conclusions HIFU may transiently inhibit skeletal growth in infant rats bearing human neuroblastoma.Such an effect shall disappear with a peak of adolescent bone growth and development. Key words: Neuroblastoma; High intensity focused ultrasound ablation; Skeleton

Increased infiltration of activated tumor-infiltrating lymphocytes after high intensity focused ultrasound ablation of human breast cancer

To decrease side effects observed after high-intensity focused ultrasound (HIFU) treatment for localized prostate cancer and to re-establish normal micturition in a patient population that often presents with concomitant prostate enlargement, the impact of a combined transurethral resection of the prostate (TURP) and HIFU has been evaluated. TURP and HIFU treatments were performed under the same spinal anesthesia. For the HIFU treatments, the Ablatherm device (EDAP SA, Lyon, France) was used. Selection criteria for HIFU treatment were localized prostate cancer, no previous treatment for prostate cancer, and prostate-specific antigen (PSA) pound 15 ng/mL at diagnosis. All patients meeting these criteria were considered for treatment and analysis. PSA nadir and stability, histology, International Prostate Specific Score (IPSS) and IPSS-quality of life, and morbidity were assessed during follow-up; 271 patients were selected: 96 in the HIFU group and 175 in the TURP plus HIFU group. A statistically significant impact was observed on catheter time (40.0 days versus 7.0 in median), incontinence (15.4% versus 6.9%), urinary infection (47.9% versus 11.4%), and the evolution of the post-treatment IPSS (8.91 versus 3.37 in average) in favor of the TURP plus HIFU group. No significant changes were observed regarding efficacy during short-term follow-up when considering a 25% retreatment rate in the HIFU group versus a 4% retreatment rate in the TURP plus HIFU group. The combination of a TURP and HIFU treatment reduces the treatment-related morbidity significantly. The patient management after a combined TURP and HIFU treatment is comparable with the management after a single TURP.

Objective: To compare the treatment efficacy and safety of high intensity focused ultrasound (HIFU) on its own, HIFU combined with levonorgestrel-releasing intrauterine system (LNG-IUS) and HIFU combined with gonadotropin-releasing hormone agonist (GnRHa).Method: Seventy-eight patients with adenomyosis who underwent HIFU treatment were retrospectively analyzed. Among them, 45 patients were treated only with HIFU, 15 patients were treated with HIFU combined with LNG-IUS and 18 patients were treated with HIFU combined with GnRHa. Dysmenorrhea scores, menstrual blood volumes, uterine volumes and adenomyotic lesion volumes were evaluated 1, 6 and 12 months after HIFU.Result: After treatment, dysmenorrhea score, menstrual blood volume, uterine volume and adenomyotic lesion volume significantly decreased in all three groups (p < 0.05). No significant difference was observed among the HIFU group, HIFU with LNG-IUS group and HIFU with GnRHa group 1 month after HIFU. However, 6 and 12 months after HIFU, dysmenorrhea score, menstrual blood volume, uterine volume and adenomyotic lesion volume decreased significantly more in the HIFU with LNG-IUS group and HIFU with GnRH-a group than in the group treated with HIFU on its own (p < 0.05).Conclusion: HIFU can be effectively used in the management of adenomyosis. Based on the results of this study with a limited number of patients, our study suggested that combining HIFU with LNG-IUS or GnRHa may provide a superior clinical effect compared to HIFU treatment on its own.

BackgroundThe purpose of this study was to explore the efficacy and safety of high intensity focused ultrasound (HIFU) in gastric cancer with liver metastasis (GCLM) patients who were contraindicated for either hepatectomy or radiofrequency ablation (RFA).MethodsThis is a prospective, observational study on GCLM patients with 1–3 liver metastases. The primary gastric lesions were thoroughly resected and any case that exhibited extra-hepatic metastasis was excluded. A 1:2:2 propensity score-matching analysis was performed using a logistic regression model on the HIFU group, best supportive care (BSC) group, and palliative chemotherapy (PC) group. The primary endpoints include progression-free survival (PFS) and overall survival (OS).ResultsForty patients were finally included, there were 8 cases in HIFU group, 16 cases in BSC group, and 16 cases in PC group. The median follow-up time for the entire cohort was 10 months. The median PFS was 16.5 months in HIFU group, 2 months in BSC group, and 5 months in PC group. The median OS was 27.5 months in the HIFU group, 7 months in the BSC group, and 11.5 months in the PC group. Additionally, no grade 3 or higher adverse events occurred in the HIFU group.ConclusionThe results of this study showed that HIFU treatment could improve the long-term prognosis of GCLM patients without a significant increase in the occurrence of adverse events. Compared with PC and BSC, HIFU is the preferred treatment option when GCLM patients without extra-hepatic metastasis are unable to undergo either surgery or RFA.

Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty‐one Dunning AT2 tumour‐bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU‐chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control group volumes were significantly greater than those of the chemotherapy‐only (p = 0.006) or HIFU‐only group (p = 0.006). The greatest difference was observed between the chemotherapy plus HIFU combined group and the control group. Additionally, tumour‐doubling times were 7.7 days for the control group, 13.2 days for the HIFU‐only group, and 31.2 days for the chemotherapy plus HIFU group. The differences in tumour growth rates between the chemotherapy plus HIFU combined group and a chemotherapy‐only + HIFU‐only grouping was 3.8% (p = 0.0020). Thus, the combined chemotherapy plus HIFU treatment was clearly more effective in reducing the tumour size than HIFU only or chemotherapy only, which indicates a synergy between the two types of treatment. Our results suggest that this combined therapy could be useful for the treatment of high‐risk prostate cancer.

Objective To investigate the prevalence of pelvic adhesions in patients with uterine fibroids after high-intensity focused ultrasound (HIFU) treatment, then analyze the influencing factors of pelvic adhesions. Materials and methods From October 2010 to March 2020, a total of 2619 patients with uterine fibroids underwent either hysterectomy, myomectomy, or cesarean section in Suining Central Hospital of Sichuan province. Of the 2619 patients, 810 were excluded because of a documented history of either pelvic infections, endometriosis, prior abdominopelvic surgery, or gynecological malignancies; 1809 patients were enrolled and the data were retrospectively assessed for the prevalence and patterns of pelvic adhesions. Among them, 96 patients with uterine fibroids had had prior HIFU treatment (HIFU group), 1713 patients had not had HIFU or surgical treatments (control group). Results Among the 96 patients in the HIFU group, adhesions were detected in 42 patients, the incidence of pelvic adhesion being 43.75%; the 1713 patients in the control group, adhesions were detected in 619 patients, the prevalence of pelvic adhesion being 36.14%. No statistically significant difference in the incidence of adhesion between the two groups was observed (p = .132), no significant difference in location of pelvic adhesions between the two groups and no significant difference in the severity of adhesions between the two groups was observed (p > .05). Conclusions Based on our results with limited numbers, we concluded that HIFU treatment did not significantly increase the risk of pelvic adhesions.

Objective The aim of this study was to compare the treatment effects of high-intensity focused ultrasound (HIFU) and laparoscopic excision (LE) in patients with adenomyosis and infertility. Materials and methods A total of 93 patients with adenomyosis and infertility who were treated with HIFU (50 patients) or LE (43 patients) from January 2012 to January 2017 at the Third Xiangya Hospital of Central South University were retrospectively analyzed. Clinical characteristics including dysmenorrhea severity pain score, menorrhagia severity scores, reproductive outcomes, complications during pregnancy and delivery, adverse effects, surgical complications, and other clinical variables were compared between the HIFU and LE groups. Results Of the total 93 patients with adenomyosis and infertility, 50 were treated with HIFU and 43 underwent LE. Both HIFU and LE treatments achieved significant relief of dysmenorrhea and menorrhagia. The total hospital stay was shorter in patients treated with HIFU than in those who underwent LE surgery. Neither HIFU nor LE treatment led to severe complications after treatment. Most importantly, patients treated with HIFU showed significantly higher pregnancy rates and natural conception rates than those who underwent LE surgery. Notably, in the HIFU treatment group, those with diffuse adenomyotic lesions had significantly lower postoperative pregnancy rates than those with focal adenomyosis. Conclusion HIFU showed a safe and effective profile as a therapeutic management option for patients with adenomyosis. In comparison with LE, HIFU treatment achieved better postoperative reproductive outcomes. HIFU treatment should be encouraged and implemented in clinical practice.

To compare the survival benefit and safety of the low power cumulative and traditional high intensity focused ultrasound (HIFU) for locally advanced pancreatic cancer. We retrospectively analyzed 38 patients with locally advanced, inoperable, stage III pancreatic patients received HIFU treatment between January 2008 and April 2014 in the Department of Surgery, the Second Affiliated Hospital, Zhejiang University, School of Medicine. 11 of them received the low power cumulative HIFU treatment, while other 27 received the traditional HIFU treatment. The HIFU device used was the FEP-BY02 (Yuande Biomedical Engineering Co. Ltd, Beijing, China). Serum biochemistry and adverse events were assessed before and after treatment. All the patients were followed up until death. The survival rate and adverse events of two groups were compared. In 38 patients, the baseline characteristics including gender, age, Karnofsky performance status (KPS) score, tumor location of two groups were generally well balanced (P>0.05). The median overall survival (OS) for low power cumulative HIFU group was 10.3months (95%CI, 6.3-14.3months), which is significantly longer than traditional HIFU group with 6.0months (95%CI, 5.2-6.8months) (P=0.018). In low power cumulative HIFU group, the 6-month and 12-month survival rates were higher than traditional group, 100% v.s 44.4%, 11.1% v.s 36.4%, respectively. The adverse events in both groups include abdominal pain, fever, C-reactive protein (CRP) elevated. The incidence was lower in low power cumulative HIFU group, however, without statistical significance. The low power cumulative HIFU treatment showed a statistical significance in survival benefit with better safety profile compared to the traditional HIFU treatment in patients with locally advanced pancreatic cancer.

Objective: To identify the expression of apoptosis-associated genes of high- intensity focused ultrasound(HIFU) in xenograft with human pancreatic cancer. Methods: Mice implated with human pancreatic cancer cells (YY-1) were divided into HIFU group or control group. Tumor cell apoptosis was verified by TUNEL. The expression of the apoptosis-associated genes was analyzed by Agilent Human Gene Expression. Selected genes was validated by quantitative real-time PCR(RT-PCR)and Western blot. Results: The rate of tumor cell apoptosis in HIFU group was higher than that of control group at 7, 14 days after HIFU treatment ((63.6%±15.2%)vs (19.0%±2.4%), P<0.01)and ((41.4%±7.3%)vs(18.0%±2.4%), P<0.01). Gene expression profiling revealed a total of 69 differentially expressed genes in related to apoptosis pathway, among which 44 genes were up-regulated, and 25 genes down-regulated. The RT-PCR results of selected 4 genes were consistent with those of gene expression profiling. The results of Western blot analysis at 7, 14 days after HIFU treatment showed that the expressions level of Bax protein in HIFU group was greater that of in control group ((0.39±0.11)vs (0.20±0.09), P<0.05)and ((0.46±0.12)vs(0.24±0.10), P<0.05), while the expressions level of Bcl-2 protein in HIFU group was lower than that of in control group ((0.68±0.14)vs(1.56±0.21), P<0.05)and((0.51±0.16)vs(1.57±0.22), P<0.05). Conclusions: HIFU could induce apoptosis and results in dramatic changes in gene expression, indicating that multiple pathways are involved. Although intrinsic pathway might be predominantly involved in HIFU-elicited apoptosis, further research is needed to clarify the detailed mechanisms.

Purpose: The aim of this study was to investigate the effect of high-intensity focused ultrasound (HIFU) on immune function in patients with uterine fibroids, in a randomised comparison to conventional myomectomy.Methods: The patients were assigned (1:1) to the HIFU group or the myomectomy (MY) group. Venous blood samples were collected 24 h before and 24 h and 72 h after operation. The percentages of CD4+ and CD8+ T cells and natural killer (NK) cells were quantified by flow cytometry (FCM). Serum levels of interleukin-2 (IL-2), IL-6 and IL-10 were determined using enzyme-linked immunosorbent assay.Results: HIFU was associated with early ambulation, fewer post-operative complications, and shorter hospital stay (p < 0.001). The percentages of CD4+ and CD8+ T cells and NK cells in the HIFU group were not significantly altered after treatment compared with before treatment. In contrast, the numbers of these cells in the MY group decreased significantly 24 h after conventional myomectomy (p < 0.001). The CD4+/CD8+ T cell ratios were also decreased significantly 24 h and 72 h after conventional myomectomy (p < 0.001). Serum levels of IL-6 and IL-10 increased after treatment in both groups. Peak IL-6 and IL-10 levels were significantly lower in the HIFU group than in the MY group (p < 0.001). In contrast, IL-2 level decreased significantly in the MY group compared to the HIFU group at 24 h post-operation (p < 0.001).Conclusions: Short-term post-operative immune function is better preserved after HIFU treatment. Better preserved immune function may reflect a reduction in tissue trauma after HIFU treatment and contribute to reduced post-operative complications.

：Objective To study theeffect of high intensity focused ultrasound(HIFU)ablation on microvessel density(MVD)andvascular endothelial growth factor(VEGF)in rabbit hepatcocellular carcinoma(HCC)models.Methods The VX2 t umor cells were planted in the hepatic left-central lobe on30 rabbits.All animals were divided into two groups randomly:HIFU group(n=25)and controlgroup(n=5).The MVD and the expression of VEGF in the HCC was detected byimmunohistochemical SABC methods in control group and 0,1,3.7,16 d after the operation inHIFU group.Results The MVD and the expression of VEGF in the HCC tissue after HIFUtreatment in the HIFU group were decreased significantly as compared with those in thecontrol group (P＜0.01).However,there was no significant difference inMVD and the expression of VEGF in the HCC tissue after HIFU treatment in the HIFU groupamong the different time points(P＞0.05).Conclusions HIFU treatment can effectively destroythe micovessel,repress the neovascularization and reduce the blood supply of the HCC. Key words: Ultrasonography; Ultrasound,high-intensity focused; Liverneoplasms; Endothelial growth factors

Unresectable colorectal cancer liver metastasis (CRLM) remains a challenging obstacle that often prevents curative treatment. In this study, we retrospectively analyzed the efficacy and safety of high-intensity focused ultrasound (HIFU) as a local adjuvant therapy for systemic chemotherapy for patients with unresectable CRLM. HIFU is a noninvasive method previously demonstrated as efficacious for various solid malignancies. Propensity score matching was used for the combination therapy group (HIFU group, n = 59) and the observation group receiving systemic therapy only (No-HIFU group, n = 59). In addition, the survival benefit, adverse effects, and factors affecting prognosis following HIFU were evaluated. The disease control rate was 77.9% and 62.7%, and the objective remission rate was 18.9% and 6.8% in the HIFU and non-HIFU groups, respectively. The survival analysis showed that median progression-free survival (mPFS) was 12.0 months and 11.0 months for the HIFU and non-HIFU groups, respectively (p = 0.002). The univariate and multivariate analysis showed that pre-treatment colorectal cancer liver metastasis lesion size was significantly associated with mPFS. In addition, patients that received a combination treatment for CRLM lesions <5.0 cm had a longer mPFS when compared to those receiving systemic therapy alone (13.0 months vs. 11.0 months, p = 0.001). In the HIFU group, patients with lesions <5.0 cm had a longer mPFS than patients with lesions ≥5.0 cm (13.0 months vs. 10.0 months, p = 0.04) (Figure3B,C). Most treatment-related adverse events observed in both groups were grade 1-2. Only four cases (6.8%) of grade 1-2 skin burns were observed in patients in the HIFU group; no other statistically significant adverse events were observed. Our study showed that HIFU ablation targeting unresectable CRLM alongside systemic therapy safely and significantly improved local control rates and prolonged mPFS, especially for lesions smaller than 5.0 cm.

To explore the anti-tumor effect of high-intensity focused ultrasound (HIFU) combined with herpes simplex virus thymidine kinase (HSV-TK) gene-loaded ultrasound-targeted microbubbles on VX2 rabbit liver tumors. Seventy-five New Zealand white rabbits were randomly divided into five groups after the models of VX2 rabbit liver tumors were established: (a) HIFU group; (b) HIFU and HSV-TK group (HIFU + HSV-TK); (c) HIFU, HSV-TK and ultrasound group (HIFU + HSV-TK + US); (d) HIFU, HSV-TK gene-loaded microbubbles and ultrasound group (HIFU + HSV-TK-MBs + US); and (e) HSV-TK gene-loaded microbubbles and ultrasound group (HSV-TK-MBs + US). After 2 weeks of VX2 liver tumor implantation, rabbits in groups (a), (b), (c) and (d) received HIFU to establish rabbit models of residual tumor by ablating 80% of the tumor volume. After HIFU ablation, rabbits in different groups received MBs wrapped around HSV-TK or HSV-TK solution via marginal ear veins and/or local ultrasonic irradiation to the tumor. Six rabbits in each group were sacrificed 48 h after the corresponding treatment, and tumors were extracted for in vitro experiments. Thymidine kinase mRNA was detected by the real-time polymerase chain reaction. The green fluorescent protein expression in liver tumor was detected by western blotting and immunohistochemistry. Tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. The growth curves of VX2 liver tumors and survival curves of rabbits were compared. Forty-eight hours after treatment, TK mRNA and protein were the highest in the HIFU + HSV-TK + US + MBs group and the HSV-TK + US + MBs group (p < 0.05). At 48 h after treatment, the apoptotic index of tumor cells in HIFU + HSV-TK-MBs + US group was the highest (p < 0.05). Compared to other groups, HIFU combined with MBs wrapped HSV-TK suicide gene significantly inhibited tumor growth in vivo (p < 0.05) and prolonged the survival time of animals (p < 0.05). HIFU combined with HSV-TK gene-loaded ultrasound-targeted MBs significantly inhibited the growth of VX2 rabbit liver tumors in vivo and prolonged the survival time of the animals, providing a novel gene delivery method and a novel strategy for liver tumor treatment.

1356 BIOCHEMICAL VERSUS IMAGING PARAMETERS FOR ASSESSING ONCOLOGICAL OUTCOMES FOLLOWING FOCAL THERAPY FOR LOCALISED PROSTATE CANCER