Extracorporeal application of high-intensity focused ultrasound for prostatic tissue ablation

OBJECTIVE: To investigate the efficacy and safety of extracorporeal prostatic tissue ablation using high-intensity focused ultrasound (HIFU) in vivo in animals, and in a clinical feasibility study in men, as this is an investigational minimally invasive treatment alternative for locally confined prostatic carcinoma, but may have significant side-effects. PATIENTS, MATERIALS AND METHODS: Ultrasound (1.04 MHz excitation frequency) was generated by an extracorporeal cylindrical piezo-ceramic element and focused by a paraboloidal reflector to a focal size of 32 x 4 mm. The focal distance and aperture diameter were both 100 mm. HIFU was applied extracorporeally at different intensities and pulse duration (up to 6 s) to 11 dog prostates in vivo (median intensity 1192 W/cm2) and eight patients (median intensity 3278 W/cm2, range 2384-3576) under general anaesthesia. The lesions were assessed macroscopically and histologically after HIFU and any side-effects evaluated. RESULTS: Thermoablation was feasible in vivo and in all patients. Macroscopic analysis and histology showed sharply demarcated coagulative necrosis. Side-effects, including skin and rectal burns, occurred only after transvesical application in the in vivo study. There were no side-effects in patients after perineal application. CONCLUSION: Extracorporeal HIFU is technically feasible and induces sharply demarcated tissue damage in the prostate. From the early results of this phase 1 study, the perineal approach seems to be safe.     

Whole-gland Ablation of Localized Prostate Cancer with High-intensity Focused Ultrasound: Oncologic Outcomes and Morbidity in 1002 Patients

Background

High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa).

Objective

The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study.

Design, setting, and participants

Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence.

Intervention

Whole-gland prostate ablation with transrectal HIFU.

Outcome measurements and statistical analysis

Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2–13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression.

Results and limitations

A total of 1002 patients were included. The median nadir prostate-specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA ≤0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients.

Conclusions

HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity.     

Salvage high‐intensity focused ultrasound for biopsy‐confirmed local recurrence of prostate cancer after radical prostatectomy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To present experience in high‐intensity focused ultrasound (HIFU) used as a salvage therapy for biopsy‐confirmed local recurrence at the vesico‐urethral anastomosis after radical prostatectomy (RP).

PATIENTS AND METHODS

From July 2006, four patients diagnosed with prostate cancer recurrence after RP were treated with HIFU, with or without salvage radiotherapy, using the Sonablate® 500 (Focus Surgery, IN, USA). Biochemical failure was defined as in increase in prostate‐specific antigen (PSA) level of >0.2 ng/mL. No patients received any adjuvant therapy after HIFU therapy before reporting failure.

RESULTS

The mean age and initial PSA level before RP was 74 years and 10.0 ng/mL, respectively. After RP, one patient was stage T2aN0M0, two were stage T3N0M0 and the last had an unknown pathological stage. Three patients received external beam radiotherapy as salvage therapy after RP. The mean PSA level before HIFU, tumour volume at the vesico‐urethral lesion and operative duration were 4.3 ng/mL, 4.6 mL and 27 min, respectively. Adenocarcinomas were confirmed by biopsy of the tumour at the vesico‐urethral anastomotic lesion before HIFU. At 24 months of follow‐up, patients 2 and 4 were classified a biochemically disease‐free. Biopsies at the anastomotic site after HIFU in three patients showed no malignancy, with fibrosis. There were no complications.

CONCLUSION

Salvage HIFU for patients with recurrence after RP is feasible, even though they received salvage radiotherapy before HIFU. More patients and a longer follow‐up are needed to evaluate the safety and oncological adequacy of this new approach.     

前列腺癌微创治疗进展

通常来说,诊断为早期局限性前列腺癌且全身情况较好预期寿命大于10年的患者,可选择的治疗途径包括根治性手术、外放疗或积极监测,但是很多患者难以接受长期监测带来的巨大的心理压力以及根治性治疗相关并发症如尿失禁、勃起功能障碍等带来的痛苦和生活质量损害。对局限性前列腺癌采用局部消融治疗是介于二者之间的一种微创治疗方式,包括冷冻消融、高能聚焦超声治疗、射频消融、微波热疗等治疗方法,随着科学技术的发展,这些微创治疗方法在一部分患者中能够有效地控制肿瘤进展且并发症发生率较低,有望给患者带来福音。然而,目前仍缺乏大样本前瞻性的随机对照研究全面评估各种前列腺癌微创治疗方式的优势及其临床局限性。本文通过文献查阅,综述了前列腺癌微创治疗的新技术、临床应用情况及应用前景。     

HIFU消融治疗弥漫型和局限型子宫腺肌病的近远期疗效

目的比较HIFU治疗弥漫型和局限型子宫腺肌病的近远期疗效。方法收集308例接受HIFU治疗的子宫腺肌病患者,依据术前MRI将其分为弥漫组和局限组,计算消融率及消融发生率,并评估2组患者术前、术后痛经及月经量情况。结果共297例患者进行了有效随访,随访时间1~50个月,其中弥漫组177例,局限组120例。297例患者消融发生率为99.33%(295/297),弥漫组及局限组消融率分别为(26.00±13.36)%、(44.32±19.93)%。2组患者术后痛经及月经量评分与术前比较均有明显降低(P均0.05)。痛经症状总缓解率在术后3、6、12、24及36个月分别为92.96%(264/284)、86.18%(237/275)、73.51%(197/268)、60.71%(136/224)及46.83%(59/126);各随访时段局限组痛经缓解率均高于弥漫组,且在术后6、24及36个月差异有统计学意义(P0.05)。月经量过多症状总缓解率在术后3、6、12、24及36个月分别为87.38%(187/214)、83.09%(172/207)、68.63%(140/204)、63.64%(105/165)及45.92%(45/98);各随访时段局限组均高于弥漫组,但差异均无统计学意义(P均0.05)。结论 HIFU治疗子宫腺肌病疗效显著,局限型与弥漫型近期疗效相当,远期疗效局限型优于弥漫型。     

磁共振导航高强度聚焦超声的临床应用及进展

磁共振导航高强度聚焦超声（MRgHIFU）是基于磁共振导航下解剖定位、实时测温和高强度聚焦超声组合的无创治疗方法,相对于外科手术更具优势。该技术已在临床应用于子宫肌瘤、子宫腺肌症、乳腺肿瘤、疼痛性骨转移、前列腺癌、肝肿瘤、脑肿瘤的消融治疗,而在功能性神经外科治疗和急性脑血管意外治疗领域中的临床前研究也在进行之中。本文对MRgHIFU的治疗原理、临床应用现状及进展进行综述。     

弥漫型和局限型子宫腺肌病超声消融安全性对比分析

目的评价超声消融治疗弥漫型子宫腺肌病的安全性。方法对308例子宫腺肌病患者行高强度聚焦超声(HIFU)消融治疗,并于术后1天行MR检查,其中弥漫型子宫腺肌病184例(弥漫组),局限型子宫腺肌病124例(局限组)。评估并比较两组的消融治疗效果、术中及术后不良反应及并发症情况。结果对308例患者均顺利完成治疗,消融发生率为99.35%(306/308),弥漫组消融率[(25.47±13.29)%]低于局限组[(45.00±20.44)%],差异有统计学意义(P0.01)。HIFU术中弥漫组较局限组发生皮肤烫的风险增加1.80倍,局限组较弥漫组发生腹股沟区痛的风险增加2.12倍;术后局限组较弥漫组发生下肢感觉异常的风险增加6.28倍。308例中,65例(65/308,21.10%)因并发症接受简单治疗[国际放射治疗协会(SIR)-B级],其中弥漫组与局限组分别为39例(39/184,21.20%)和26例(26/124,20.97%),差异无统计学意义(P0.05)。两组均未发生SIR-C~SIR-F级并发症。结论在严格控制消融范围的情况下,对弥漫型与局限型子宫腺肌病同样行HIFU治疗是安全、可行的。     

To what extent does the prostate‐specific antigen nadir predict subsequent treatment failure after transrectal high‐intensity focused ultrasound therapy for presumed localized adenocarcinoma of the prostate?

OBJECTIVE: To explore the association between the prostate-specific antigen (PSA) nadir after transrectal high-intensity focused ultrasound (HIFU) therapy for organ-confined prostate cancer and subsequent treatment failure, as defined by the presence of residual disease at biopsy 6 months after treatment. PATIENTS AND METHODS: Between January 1999 and January 2005, 115 patients in a Japanese hospital were treated using a transrectal HIFU system (Sonablate, Focus Surgery, IN, USA) for presumed localized adenocarcinoma of the prostate. All treatments were primary and none of the patients had received hormone therapy. The PSA level was measured at 2-monthly intervals and all patients had a transrectal prostate biopsy taken at 6 months. Multiple logistic regression was used to examine the relationship between PSA nadir and treatment failure, as defined by the presence of disease at biopsy. RESULTS: The PSA nadir was strongly associated with treatment failure (P < 0.001). Patients with a PSA nadir of 0.0-0.2 ng/mL had a treatment failure rate of only 11% (four of 36), compared to 46% (17 of 37) in patients with a PSA nadir of 0.21-1.00 ng/mL and 48% (20 of 42) with a PSA nadir of >1.0 ng/mL. In addition, the PSA nadir was strongly associated with both preoperative PSA level and residual prostate volume. CONCLUSION: There is a clear and intuitive association between the PSA nadir and the risk of treatment failure after HIFU. These data can be used to predict the risk of residual disease in patients with prostate cancer undergoing HIFU therapy. They can also be used to inform where the target PSA nadir should be set for this novel therapy.     

超声联合微泡介导肝癌靶向治疗的研究进展

随着超声影像技术的不断发展和造影剂制备工艺的不断改进,超声造影剂正在从诊断领域向治疗领域拓展。作为一种新的药物和基因载体,造影剂受到广泛关注,同时其在增强超声介导疾病治疗方面也显示出一定优势。本文就造影剂联合超声辐照介导肝癌靶向治疗的研究进展进行综述。     

经直肠高强度聚焦超声系统治疗前列腺癌57例疗效分析

目的:探讨经直肠高强度聚焦超声系统(HIFU)治疗PCa的疗效。方法:使用Sonablate500型经直肠HIFU治疗系统,对57例PCa患者进行HIFU治疗,其中局限性PCa27例,晚期PCa30例。在确定生化复发之前,对局限性PCa仅行经直肠HIFU治疗;对于晚期PCa,在行经直肠HIFU治疗的同时,联合应用内分泌治疗。结果:HIFU治疗平均手术操作时间为111(86～153)min,平均术后住院时间为3.2(2～18)d。平均随访时间18(6～30)个月。局限性PCaHIFU治疗后,生化检查阴性率(PSA(4.0μg/L)在治疗后的1、2、3年分别为86%、81%和79%。30例晚期PCa治疗平均8个月(3～24个月)后,26例血清PSA<4.0μg/L(其中20例血清PSA<0.5μg/L)、21例患者前列腺体积缩小>50%。治疗后6个月时与治疗前相比,前列腺体积缩小、PSA水平降低、Qmax增加及IPSS改善差异均有显著性(P<0.05)。HIFU治疗后无严重尿道直肠瘘、尿失禁等并发症发生。结论:经直肠HIFU治疗PCa,安全、有效,并发症少,近期疗效较好,是一种可选择的PCa微创治疗方法。     

影响高强度聚焦超声消融治疗剖宫产切口部妊娠辐照剂量的因素

目的 采用最优尺度回归分析观察影响高强度聚焦超声(HIFU)消融治疗剖宫产切口部妊娠(CSP)总辐照剂量的因素。方法 纳入131例接受HIFU消融联合超声引导下清宫术的CSP患者,分析总辐照剂量与临床及超声指标的相关性;采用最优尺度分析观察影响总辐照剂量的因素,并建立模型预测总辐照剂量。结果HIFU治疗CSP总成功率为96.95%(127/131)。总辐照剂量与CSP患者体质量指数(BMI,X1)、停经时间(X2)、血β-人绒毛膜促性腺激素(X3)、孕囊与膀胱间子宫肌层厚度(X4)及孕囊最大径线(X5)均显著相关(P均<0.05),预测模型为:总辐照剂量=0.273×X1+0.044×X2+0.113×X3-0.033×X4+0.327×X5。最优尺度回归分析显示,BMI及孕囊最大径线(r=0.295、0.448,P均<0.05)是影响总辐照剂量的重要因素,其重要性分别为0.294和0.535。结论 患者BMI(17.9~29.3 kg/m²)和孕囊最大径线是影响HIFU消融治疗CSP总辐照剂量最为重要的因素。     

相变纳米液滴和微泡增强HIFU在体模中所致凝固性坏死的对比

目的 对比研究相变纳米液滴-包裹相变温度29℃的全氟戊烷的脂质纳米液滴(L-PFP)和微米级微泡(SonoVue)增强HIFU在体模中的消融效果.方法 分别将0.3 ml的生理盐水、L-PFP和SonoVue各自加入到100 ml的蛋清体模中,制成对照组、L-PFP组、SonoVue组.然后在B超引导下进行HIFU定点辐照,声功率100 W、辐照时间10 s、辐照深度14 mm.比较3组辐照前后凝固性坏死的体积和能效因子(EEF).结果 辐照后即刻,B超图像上3组的靶区均出现强回声,L-PFP组强回声范围最大;HIFU在体模中形成的凝固性坏死体积为L-PFP组 >SonoVue组 >对照组(P <0.05);3组的EEF为对照组 >SonoVue组 >L-PFP组(P <0.05).HIFU辐照过程中L-PFP组的开始温升速度和最高温度均大于SonoVue组.结论 与微米级微泡相比,相变脂质纳米液滴的对HIFU辐照的增效效果更加明显.     

高强度聚焦超声消融后大鼠胰腺组织学结构和内分泌功能的恢复

目的观察高强度聚焦超声(HIFU)消融SD大鼠部分胰腺组织后胰岛的病理转归和血清学变化。方法将108只SD大鼠随机分为HIFU 1/4组(n=36)、HIFU 1/2组(n=36)及假辐照组(n=36)。辐照后监测大鼠空腹血糖、血清胰岛素、血清胰高血糖素,同时观察靶区组织的病理学变化。结果辐照后即刻、28天、56天,各辐照组间空腹血糖差异有统计学意义(P均0.05);各辐照组间空腹血清胰岛素差异无统计学意义;辐照后2h及7、14、28、42天,各辐照组间空腹胰高血糖素差异有统计学意义(P均0.05)。辐照后胰腺组织中出现新生胰管结构,但未发现胰岛组织。结论HIFU辐照胰腺部分组织对大鼠胰腺内分泌功能无明显影响;辐照后56天胰岛重建不完善。     

MRI影像组学及临床特征联合模型预测高强度聚焦超声治疗子宫肌瘤效果

目的 观察基于MRI影像组学及临床特征建立的联合模型预测高强度聚焦超声(HIFU)治疗子宫肌瘤效果的效能。方法 回顾性分析257例接受HIFU治疗的单发子宫肌瘤患者,基于治疗前盆腔轴位T2WI、T1WI、T1对比增强(T1C)及表观弥散系数(ADC)图提取病灶影像组学特征。分别以XGBoost特征选择算法及XGBoost分类器建立预测HIFU即刻消融率和随访肌瘤体积缩小率的影像组学联合临床特征模型A和B。按8∶2比例将数据集分为训练集(n=202)和测试集(n=52),采用受试者工作特征(ROC)曲线和混淆矩阵评估模型的预测效能。结果 经XGBoost算法选择后纳入10个影像组学特征,包括4个T1WI、2个T2WI、1个T1C及3个ADC图影像组学特征,结合肌瘤背侧距骶骨距离和T2WI信号强度构建模型A;纳入10个影像组学特征,含4个T1WI、3个TIC及3个ADC图影像组学特征,结合肌瘤T2WI信号强度构建模型B。ROC曲线结果显示,模型A预测训练集和测试集HIFU治疗肌瘤即刻消融率的曲线下面积(AUC)分别为0.94[95%CI(0.90,0.96)]和0.90[95%CI(0.81,0.97)],模型B预测训练集和测试集肌瘤体积缩小率的AUC分别为0.98[95%CI(0.97,0.99)]、0.91[95%CI(0.81,0.98)]。结论 MRI影像组学联合临床特征模型可有效预测HIFU治疗子宫肌瘤近期及远期效果。     

血管位置及血管与声轴角度对HIFU表面消融效果影响的体模实验

目的探讨靶区内血管位置及血管与声轴角度对HIFU表面消融效果的影响。方法将56块含血管的仿组织体模分为A组(血管位置)和B组(血管角度),A组按血管中心与HIFU表面消融最深层面(顶面)距离d分为A_1(d=0)、A_2(d=10mm)、A_3(d=20mm)亚组,B组按血管长轴与声轴之间夹角角度α分为B_1(0~5°)、B_2(60°~65°)、B_3(90°~95°)、B_4(115°~120°)亚组。另设A_4、B_5亚组为空白对照组。测量各组血管内径、管壁厚度,观察辐照后损伤形态,计算能效因子(EEF)。结果 A、B各亚组间血管内径、管壁厚度差异均无统计学意义(P均0.05)。损伤形态:A_1、B_1亚组靶区完全消融,无残留;余各亚组血管深侧靶区有残留。A组中A_4亚组、A_1亚组、A_2亚组(由小到大排列)EEF两两比较差异均有统计学意义(P均0.05),A_1与A_3亚组差异无统计学意义(P0.05);B组中B_5亚组、B_2亚组、B3亚组(由小到大排列)EEF两两比较差异均有统计学意义(P均0.05),B_2亚组与B_4亚组、B_5亚组与B_1亚组的EEF差异无统计学意义(P均0.05)。结论血管中心距HIFU表面消融最深层面10mm、靶区内血管与声轴角度90°~95°对靶区消融影响最大,效率最低,消融时应注意调整以提高消融效率。     

Current salvage methods for recurrent prostate cancer after failure of primary radiotherapy

We reviewed the current salvage methods for patients with local recurrent prostate cancer after primary radiotherapy (RT), using a search of relevant Medline/PubMed articles published from 1982 to 2008, with the following search terms: ‘radiorecurrent prostate cancer, local salvage treatment, salvage radical prostatectomy (RP), salvage cryoablation, salvage brachytherapy, salvage high‐intensity focused ultrasound (HIFU)’, and permutations of the above. Only articles written in English were included. The objectives of this review were to analyse the eligibility criteria for careful selection of appropriate patients and to evaluate the oncological results and complications for each method. There are four whole‐gland re‐treatment options (salvage RP, salvage cryoablation, salvage brachytherapy, salvage HIFU) for RT failure, although others might be in development or investigations. Salvage RP has the longest follow‐up with acceptable oncological results, but it is a challenging technique with a high complication rate. Salvage cryoablation is a feasible option, especially using third‐generation technology, whereby the average biochemical disease‐free survival rate is 50–70% and there are fewer occurrences of severe complications such as recto‐urethral fistula. Salvage brachytherapy, with short‐term cancer control, is comparable to other salvage methods but depends on cumulative dosage limitation to target tissues. HIFU is a relatively recent option in the salvage setting. Both salvage brachytherapy and HIFU require more detailed studies with intermediate and long‐term follow‐up. As these are not prospective, randomized studies and the definitions of biochemical failure varied, there are limited comparisons among these different salvage methods, including efficacy. In the focal therapy salvage setting, the increased use of thermoablative methods for eligible patients might contribute to reducing complications and maintaining quality of life. The problem to effectively salvage patients with locally recurrent disease after RT is the lack of diagnostic examinations with sufficient sensitivity and specificity to detect local recurrence at an early curable stage. Therefore, a more strict definition of biochemical failure, improved imaging techniques, and accurate specimen mapping are needed as diagnostic tools. Furthermore, universal selection criteria and an integrated definition of biochemical failure for all salvage methods are required to determine which provides the best oncological efficacy and least comorbidity.     

Peroperative transrectal ultrasonography-guided bladder neck dissection eases the learning of robot-assisted laparoscopic prostatectomy

OBJECTIVE

To study the role of peroperative transrectal ultrasonography (peTRUS) for the dissection of the bladder neck during robot‐assisted laparoscopic prostatectomy (RALP).

PATIENTS AND METHODS

Integrated peTRUS in the da Vinci S system (Intuitive Surgical, Sunnyvale, CA, USA) was used for bladder neck identification and dissection in the initial 80 patients with clinically localized prostate cancer operated by two urologists. The clinical and pathological results were compared with the initial 80 patients who had RALP with no peTRUS. The location of positive margins was recorded.

RESULTS

The operative duration, blood loss, hospital stay, catheter dependency, clinical and pathological T‐stage and Gleason sum score were no different between the groups. The prostate‐specific antigen level at time of diagnosis was slightly higher for patients in the peTRUS group. Basal surgical margins (bladder neck and basal areas of both prostate lobes) were positive for tumour in 9.1% and 2.3% of patients treated without and with peTRUS, respectively (P = 0.001). Although the use of peTRUS improved the basal margin rate in the initial 30 patients in each group, it did not in the last 30 in each group, when the urologist’s experience apparently improved. In a multivariate analysis the use of peTRUS and pathological T‐stage were the best predictors of basal margin status. Pad use at 6 months after surgery was similar for both groups.

CONCLUSION

peTRUS during RALP decreased the positive surgical margin rate at the base of the prostate during the initial experience of RALP.