超声消融子宫肌瘤对机体创伤及肿瘤局部效应安全性研究
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摘要
研究背景
外科手术发展趋势是采用对人体损伤更小的技术治疗疾病，高强度聚焦超声是近年来新兴的一种非侵入性肿瘤治疗方式,提供了一个可精确定位治疗却没有治疗通道切开暴露或穿刺通道的完全非侵入性的治疗方法。子宫肌瘤是女性生殖系统最常见的良性肿瘤，高强度聚焦超声治疗子宫肌瘤通过体外超声能量聚焦体内，使子宫肌瘤出现凝固性坏死，逐渐吸收，达到改善症状，恢复子宫形态的目的。
随着高强度聚焦超声（High Intensity Focused Ultrasound，HIFU）广泛应用于子宫肌瘤的治疗，目前已有各个中心关于治疗安全性的临床观察报道，但尚无基于超声消融“无创性”特点，与传统“有创”治疗的安全性比较评价。超声消融子宫肌瘤的特点是实现了保留子宫、不开刀、不穿刺、不麻醉治疗子宫肌瘤方法的“无创”治疗，以及为避免影响邻近组织而实行瘤内治疗的原则。而关于超声消融技术的安全性研究就是考虑在HIFU“无创”特点的前提下，对比传统手术治疗，评价治疗本身对机体的创伤，来研究新技术的安全性。以及探讨HIFU治疗后残余未治疗肿瘤（非靶区瘤组织）的转归及相关机制，研究残余瘤对机体的影响。
本研究旨在通过前瞻性同期对照临床试验研究HIFU消融子宫肌瘤对机体的创伤，评估技术的“无创性”。同时，通过对HIFU消融后非靶区子宫肌瘤的影像学数据的随访及分析，探讨影响非靶区瘤组织转归的相关影响因素，获得肿瘤局部安全性评价的临床证据并建立预测非靶区肌瘤转归的模型。研究拟基于临床资料，初步研究肿瘤超声消融的局部效应及机制，获得肿瘤局部效应评价的实验室依据。研究拟为系统评价HIFU消融子宫肌瘤安全性奠定了临床及实验室基础，为HIFU消融子宫肌瘤的临床治疗方案的制定及进一步优化提供了科学依据。
目的
1.综合评价HIFU消融子宫肌瘤与经腹子宫肌瘤剔除手术对机体的创伤程度；
2．分析临床资料，研究HIFU消融后残余部分肿瘤（非靶区肌瘤）的转归及影响因素，探讨超声消融子宫肌瘤对非靶区瘤组织的局部效应，评价HIFU消融后的肿瘤安全性；
3．初步探讨超声消融子宫肌瘤对非靶区瘤组织作用机制。
研究内容
1．设计同期随机对照试验（RCT），基于临床观察项目及抽样检测创伤相关血清学指标，研究HIFU消融子宫肌瘤与经腹子宫肌瘤剔除手术比较对机体的创伤程度。
2．分析HIFU消融子宫肌瘤对非靶区瘤组织效应的临床资料，研究HIFU治疗后非靶区肌瘤的转归及相关影响因素，建立预测非靶区肌瘤转归的回归模型。
3．基于回归模型，探讨不同肌瘤体积消融率与非靶区肌瘤转归的相关关系，初步提出可以获得残余部分肿瘤良好转归效应的超声消融方案。
4．模拟临床超声消融方案，建立HIFU消融人离体子宫肌瘤模型，探讨HIFU对非靶区瘤组织生长调控因子表达的影响及机制。
5．培养人原代子宫肌瘤细胞模型，建立HIFU辐照声场内子宫肌瘤细胞模型，探讨HIFU对声场内靶点外子宫肌瘤细胞的效应及相关机制。
资料和方法
第一部分
1．研究对象
2010年9月-2011年12月在重庆医科大学附属第一医院妇科初步诊断为子宫肌瘤并拟行手术治疗患者，共253例。按纳入标准入组共188人。
2．研究设备
JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）核磁共振成像系统Magnetom Symphony1.5T MR Tim（德国西门子公司）
3．研究方法
1）采用前瞻性同期随机对照分组方法（区组随机法），将符合纳入标准的188人作为研究对象随机分配到超声消融组(HIFU组)及经腹子宫肌瘤剔除手术组（肌瘤剔除组），观察临床安全性指标，包括生命体征、术后恢复时间手术不良反应。
2）从188患者中随机抽样每组31例，检测患者手术前后创伤相关血清学指标变化情况，包括：（1）皮质醇、肾上腺素及去甲肾上腺素；（2）IL6、IL2、IL10的水平；（3）外周血白细胞值、中性粒细胞比例及血红蛋白值；（4）外周血中CD4+、CD8+比例及NK细胞的比例。
4.统计方法应用SPSS16.0软件包作统计分析。
第二部分
1．研究对象2007年1月至2010年1月96名行HIFU治疗子宫肌瘤患者的临床资料。
2．研究设备JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）hifu-3DTPS Microsoft基础类应用软件（重庆（HIFU）海扶技术有限公司）
3．研究方法
1）软件自动三维重建并计算非靶区肌瘤体积缩小率，分析影响非靶区肌瘤缩小率的相关因素，建立非靶区肌瘤转归的预测回归模型。
2）将96名行HIFU治疗子宫肌瘤患者按照不同的消融率进行分组，比较不同组的非靶区瘤组织术后3、6、12月的影像学转归，寻找影响非靶区肌瘤的转归趋势的消融率“拐点”。
4．统计方法
应用SPSS16.0软件包作统计分析。
第三部分
1．研究对象
1）人离体子宫肌瘤：2010年4月-2010年11月因子宫肌瘤行子宫次全切除术或子宫全切术患者8例，年龄40.2±3.9（35-47）岁，手术前行核磁共振检查均为T2WI均匀低信号，子宫肌瘤平均体积为48.35±12.02cm3（37.1-65cm3），最大直径为4.38±0.33cm（4.2-5.1cm）术后均经病理证实为子宫肌瘤。
2）人原代子宫肌瘤细胞：取自2010年4月至2011年10月，重庆医科附属第一医院妇科的人子宫肌瘤标本，患者年龄在39-45岁，术前3个月未服用激素治疗。病理学诊断为子宫肌瘤，术中取出新鲜离体子宫肌瘤后立即送实验室培养原代细胞。
2．研究设备
JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）核磁共振成像系统Magnetom Symphony1.5T MR Tim（德国西门子公司）酶联免疫检测仪（宁波自动化仪表研究所）
3．研究方法
1）建立HIFU消融人离体子宫肌瘤模型，研究HIFU消融对非靶区瘤组织雌激素受体、孕激素受体及芳香化酶细胞色素P450表达的影响。
2）培养人原代子宫肌瘤细胞，筛选全部靶区子宫肌瘤细胞致死的最小超声能量参数，建立靶区外声场内子宫肌瘤细胞的HIFU辐照模型，分析聚焦超声对声场内距离焦点不同层面细胞的影响，研究超声对声场内细胞的作用机制。
4．统计方法
应用SPSS16.0软件包作统计分析。
结果
第一部分
1.对比观察HIFU组与肌瘤剔除组临床安全性指标，结果显示：HIFU组与肌瘤剔除组比较，HIFU组对术后的体温、收缩压影响较小，不良反应发生率低，术后恢复时间短，HIFU组术后麻醉类镇痛药使用率明显低于肌瘤剔除组，而两组术后疼痛分值比较差异无统计学意义。
2. HIFU组与肌瘤剔除组对创伤相关的血清学指标的影响：（1）两组术后血清皮质醇、肾上腺素及去甲肾上腺素浓度变化不明显；（2）肌瘤剔除组对机体术后血清IL-6、IL-2、IL-10的浓度影响明显，主要是发生在术后24小时；（3）肌瘤剔除组患者术后外周血WBC计数、中性粒细胞比率高于HIFU组，而术后血红蛋白值明显低于HIFU组；（4）肌瘤剔除组术后外周血CD4+、CD8+及NK细胞受抑制程度比HIFU组明显。
第二部分
1．非靶区肌瘤缩小率的多变量相关关系结果提示：影响非靶区肌瘤转归的因素包括：子宫肌瘤血流分级、T2WI信号强度、超声消融率。建立回归模型为：[=非靶区肌瘤转归趋势（非靶区肌瘤体积缩小率）,χ1=超声消融率（%），χ2=子宫肌瘤血流分级，χ3=子宫肌瘤T2WI信号转化值]
2．通过研究不同体积消融比例后的非靶区瘤组织的影像学转归。结果初步显示超声消融后残留的非靶区瘤组织体积小于子宫肌瘤体积的30%是可以得到满意的影像学转归的。
第三部分
1．靶区周围肌瘤组织温度也有不同程度的温升，并且靶区外组织温度呈逐渐下降。与假照组（对照组）比较，靶区外瘤组织雌、孕激素受体表达无明显差异。免疫组织化学法及免疫印迹发半定量检测P450arom蛋白在靶区外0.5cm及1.0cm处子宫肌瘤组织的表达明显低于对照组，差异有统计学意义。
2．成功培育人原代子宫肌瘤细胞，选择导致靶点人子宫肌瘤细胞死亡的最小超声参数为声功率200W辐照时间为5秒。高强度聚焦超声可以诱导声场内子宫肌瘤细胞发生凋亡，细胞凋亡发生的时间和凋亡率与声场内距离焦点的位置相关，距焦点距离越近凋亡发生越明显。声场内细胞caspase-3也有不同程度的激活，其表达强度及活化情况与声场内距离焦点的位置相关。
结论
1. HIFU组与肌瘤剔除组比较，对机体的创伤更小。
2.非靶区肌瘤的转归与子宫肌瘤的性质及超声消融率相关。超声消融率达到70%以上，可以观察到满意的非靶区子宫肌瘤转归。
3．超声消融部分子宫肌瘤后在一定距离范围内非靶区的子宫肌瘤的生长会被抑制，其机制与温度影响P450酶的蛋白表达有关。
4.高强度聚焦超声可以诱导声场内细胞凋亡，凋亡的发生及凋亡率与距离焦点的声场层面有关，其机制可能与激活Caspase-3有关。
Background
Surgical trend is the development of surgical treatment based on less damage tohuman. High intensity focused ultrasound (HIFU) is a non-invasive therapy of tumouremerged in recent years, it provides non-invasive treatment with precise positioning andno incision. Uterine fibroid is the most common benign tumor of reproductive system.Uterine fibroids are treated with HIFU by focusing ultrasound energy to local fibroidtissue and cause coagulation necrosis and prevent the growth of uterine fibroids.
Along with HIFU therapy is widely applied in the treatment of uterine fibroids,clinical observation reports on safety of HIFU represented by many centers. However,there is no safety evaluation based on the characteristic of HIFU,"no invasive",especially compared with traditional treatment. Ultrasound ablation of uterine fibroids isa noninvasive treatment characterized by retaining uterus, no surgery and no anesthesiamethods, as well as the principle of the treatment is practicing within tumor to avoidaffect neighboring tissue. Considered under the non-invasive characteristic, safetystudies on HIFU ablation is to evaluate the trauma on human compared with traditionalsurgery. The purpose of study was to evaluate the safety of the new technology, and toinvestigate the security of residual untreated tumor (non-target tumor tissue) after HIFUablation and related mechanisms.
This study was designed to study the trauma of HIFU ablation with controlledclinical trials for assessment of noninvasive techniques. Meanwhile, we explored therelated factors affected non-target tumor tissue, evaluated clinical safety evidence of local tumor and built the prediction model of non-target fibroid tissue by follow-up andanalysis of clinical imaging data on HIFU ablation target of uterine fibroids. The studywas to explore the possible mechanisms of local tumor based on clinical data, andconcluded laboratory evidence of local tumor effects. The study provides a clinical andlaboratory basis to evaluate the safety of HIFU ablation for uterine fibroids. It alsoprovides a scientific basis of HIFU therapy for planning and optimizing treatmentprogram.
Objective
1. To evaluate trauma on the body of HIFU ablation for uterine fibroids and abdominalmyomectomy.
2. To study the outcome of residual tumor (non-target fibroid) and influencing factorsby analysis of clinical data, and explore the local effect of non-target fibroid after highintensity focused ultrasound ablation for evaluation the safety of HIFU therapy.
3. To explore the preliminary mechanism of high intensity focused ultrasound ablationon non-target fibroid.Research content
1. Based on clinical observation and trauma-related serum markers, the study wasdesigned to evaluate the trauma of HIFU on patients compare with abdominalmyomectomy through randomized controlled trials (RCT).
2. To explore the related factors affected non-target tumor tissue, evaluated clinicalsafety evidence of local tumor and build the prediction model of non-target fibroidtissue by analysis of clinical imaging data.
3. To explore the relationship of the outcome of non-target fibroids and ablation ratebased on the regression model. It can be initially proposed the treatment program toacquire clinical outcome of non target fibroids.
4. To explore the effect of HIFU on the expression of regulatory factors on growth ofnon-target fibroid tissue and related mechanisms by building HIFU ablation isolated human uterine fibroids model.
5. To explore the he effect and mechanisms of HIFU on human fibroid cells within thesound field of ultrasound with cultured primary human fibroid cell model.Material and MethodsPart one
1. Objective
From September2010to December2011,253patients diagnosed with uterine fibroidand scheduled for surgery were enrolled in the1st Affiliated Hospital of ChongqingMedical University
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)Magnetic resonance imaging system Magnetom Symphony1.5T MR Tim (Siemens,Germany)
3. Methods
1)188patients who meet the inclusion criteria were randomly assigned to high-intensityfocused ultrasound ablation group (HIFU group) and abdominal myomectomy group(myomectomy group) with RCT (block randomized method). The indicators for clinicalsafety were observed, including vital signs, postoperative recovery time, surgicaladverse events and complications.
2)31cases were randomly selected from188patients. All patients was detected withsurgical trauma indicators of peripheral blood before and after therapy, including:(1)cortisol, epinephrine and norepinephrine;(2) IL6, IL2, and IL10;(3) peripheral bloodwhite cell counts, neutrophil percentage and hemoglobin values;(4) CD4+, CD8+andNK ratio of peripheral blood.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Part two
1. Objective Clinical data of96patients treated with HIFU of uterine fibroids from January2007toJanuary2010.
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)hifu-3DTPS Microsoft Foundation Classes application software (Chongqing HIFUTechnology Co., Ltd.)
3. Methods
1) Automatic3D reconstruction and calculation of non-target fibroid volume withsoftware. Analysis of the impact factors on shrink rate of non-target fibroids forestablishing predictive regression model of outcome.
2)96patients with HIFU were assigned to each group according to different ablationratio. We compared the imaging outcome of each group to find out the “inflection point”of ablation ratio affect the trend of non-target fibroid.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Part three
1. Objective
1) Human uterine fibroid: From April2010to November2010,8cases were appliedwith hysterectomy and subtotal hysterectomy due to uterine fibroid. The age was40.2±3.9(35-47) years. The signals of pre-operative T2WI in all patients were uniformly lowsignal. Average volume of uterine fibroids were48.35±12.02cm3(37.1-65cm3), andmaximum diameter was4.38±0.33cm (4.2-5.1cm). The fibroids were confirmed bypathology after surgery, and fresh uterine fibroids were received with ChongqingMedical University Ethics Committee approval and patient consents.
2) Primary uterine fibroid cell: From April2010to October2011, human uterine fibroidspecimens were taken from patients of39-45years in gynecological department of the1st Affiliated Hospital of Chongqing Medical College. All patients were not takinghormone treatment within three months before surgery. The fibroids were confirmed bypathology after surgery, and the fresh fibroids were immediately sent to the laboratory for culturing primary cell.
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)Magnetic resonance imaging system Magnetom Symphony1.5T MR Tim (Siemens,Germany)ELISA analyzer (Ningbo Institute of Automation Instrumentation)
3. Methods
1) To establish the model of isolated human uterine fibroids with HIFU ablation, andstudy the effect of HIFU on expression of estrogen receptor, progesterone receptor andP450in non-target fibroid tissue.
2) To build HIFU sonication model of cultured primary human uterine fibroid cellwithin the sound field by filtering the smallest ultrasound parameters which can causetarget uterine fibroid cell death. To study the mechanism of the effect of ultrasound oncells within the sound field by analysis of different impact of focused ultrasound on thecells represented within different distance to ultrasonic focus.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Results
Part one
1. Clinical safety indicators were observed in HIFU group and myomectomy group. Theresults showed: Compared with myomectomy group, HIFU group had less impact onpostoperative body temperature, systolic blood pressure. Less surgical complicationsand adverse events, shorter recovery time can be found in patients of HIFU group. Nosignificant difference of the postoperative pain score was found in two groups.
2. The effect of HIFU and myomectomy group on the levels of trauma-relatedserological markers:(1) No significant changes of postoperative serum cortisol,epinephrine and norepinephrine concentrations were found in two groups significantly;(2) Patients in myomectomy group affected the levels of serum IL-6, IL-2, IL-10 significantly, especially within24hours after surgery;(3) WBC counts, neutrophil ratioin myomectomy group were higher than HIFU group, postoperative hemoglobin valuewas significantly lower than HIFU group;(4) The ratio of CD4+, CD8+and NK cellswas inhibited in myomectomy group significantly compared with HIFU group.Part two
1. Correlation results of shrink rate of non-target fibroids with multivariate factorssuggest that: The factors which influence the outcome of non-target fibroids includedblood flow grade of uterine fibroid, signal of T2WI, non perfused volume ratio. Theregression model was:[=Non-target fibroid volume reduction ratio，Χ1=ultrasound ablation rate (%), χ2=uterine fibroids flow grade, χ3=uterine fibroids T2WI signal conversion value]
2. The result of observing on the imaging outcomes of groups with different non-perfused volume ratio (NPV) showed satisfied imaging outcome can be get withnon-target volume less than30%of target fibroid.Part three
1. Different degrees of temperature rise in non target fibroid tissue outside target fibroid,and temperature decreased gradually along with the distance outside target area.Compared with the control group, no significant difference was found in the expressionof estrogen receptor and progesterone receptor in non target fibroid.Immunohistochemical staining and Western blot semi-quantitative detection ofP450arom protein represented at0.5cm and1.0cm outside target area showed lowerlevel significantly than the control group, the difference was statistically significant.
2. Primary human uterine fibroid cell was successfully cultivated. Smallest ultrasonicparameters (power200W,5seconds) lead to cell death was screened ultrasoundparameters of cells positioned in focus. High intensity focused ultrasound can induceuterine fibroid cell apoptosis positioned within sound field. The occurrence of apoptosisand apoptosis rate was related with the distance from focus. Different degree of caspase-3activation appeared in cells within sound field, and the expression ofcaspase-3the strength was related with the distance from focus.Conclusions
1. Compared with myomectomy group, the result of HIFU group showed smallertrauma on patients.
2. Outcome of non-target fibroids was related to NPV. NPV of more than70%can beobserved to get satisfactory outcome of non-target uterine fibroids.
3. The growth of non-target fibroid within a certain range will be suppressed after HIFUablation part of uterine fibroid, and the mechanism was related to P450protein affectedby temperature.
4. HIFU can induce uterine fibroid cell apoptosis positioned within the sound field. Andthe occurrence of cell apoptosis was related with the distance from focus, themechanism of apoptosis may be associated with activation of caspase-3.
外科手术发展趋势是采用对人体损伤更小的技术治疗疾病，高强度聚焦超声是近年来新兴的一种非侵入性肿瘤治疗方式,提供了一个可精确定位治疗却没有治疗通道切开暴露或穿刺通道的完全非侵入性的治疗方法。子宫肌瘤是女性生殖系统最常见的良性肿瘤，高强度聚焦超声治疗子宫肌瘤通过体外超声能量聚焦体内，使子宫肌瘤出现凝固性坏死，逐渐吸收，达到改善症状，恢复子宫形态的目的。
随着高强度聚焦超声（High Intensity Focused Ultrasound，HIFU）广泛应用于子宫肌瘤的治疗，目前已有各个中心关于治疗安全性的临床观察报道，但尚无基于超声消融“无创性”特点，与传统“有创”治疗的安全性比较评价。超声消融子宫肌瘤的特点是实现了保留子宫、不开刀、不穿刺、不麻醉治疗子宫肌瘤方法的“无创”治疗，以及为避免影响邻近组织而实行瘤内治疗的原则。而关于超声消融技术的安全性研究就是考虑在HIFU“无创”特点的前提下，对比传统手术治疗，评价治疗本身对机体的创伤，来研究新技术的安全性。以及探讨HIFU治疗后残余未治疗肿瘤（非靶区瘤组织）的转归及相关机制，研究残余瘤对机体的影响。
本研究旨在通过前瞻性同期对照临床试验研究HIFU消融子宫肌瘤对机体的创伤，评估技术的“无创性”。同时，通过对HIFU消融后非靶区子宫肌瘤的影像学数据的随访及分析，探讨影响非靶区瘤组织转归的相关影响因素，获得肿瘤局部安全性评价的临床证据并建立预测非靶区肌瘤转归的模型。研究拟基于临床资料，初步研究肿瘤超声消融的局部效应及机制，获得肿瘤局部效应评价的实验室依据。研究拟为系统评价HIFU消融子宫肌瘤安全性奠定了临床及实验室基础，为HIFU消融子宫肌瘤的临床治疗方案的制定及进一步优化提供了科学依据。
目的
1.综合评价HIFU消融子宫肌瘤与经腹子宫肌瘤剔除手术对机体的创伤程度；
2．分析临床资料，研究HIFU消融后残余部分肿瘤（非靶区肌瘤）的转归及影响因素，探讨超声消融子宫肌瘤对非靶区瘤组织的局部效应，评价HIFU消融后的肿瘤安全性；
3．初步探讨超声消融子宫肌瘤对非靶区瘤组织作用机制。
研究内容
1．设计同期随机对照试验（RCT），基于临床观察项目及抽样检测创伤相关血清学指标，研究HIFU消融子宫肌瘤与经腹子宫肌瘤剔除手术比较对机体的创伤程度。
2．分析HIFU消融子宫肌瘤对非靶区瘤组织效应的临床资料，研究HIFU治疗后非靶区肌瘤的转归及相关影响因素，建立预测非靶区肌瘤转归的回归模型。
3．基于回归模型，探讨不同肌瘤体积消融率与非靶区肌瘤转归的相关关系，初步提出可以获得残余部分肿瘤良好转归效应的超声消融方案。
4．模拟临床超声消融方案，建立HIFU消融人离体子宫肌瘤模型，探讨HIFU对非靶区瘤组织生长调控因子表达的影响及机制。
5．培养人原代子宫肌瘤细胞模型，建立HIFU辐照声场内子宫肌瘤细胞模型，探讨HIFU对声场内靶点外子宫肌瘤细胞的效应及相关机制。
资料和方法
第一部分
1．研究对象
2010年9月-2011年12月在重庆医科大学附属第一医院妇科初步诊断为子宫肌瘤并拟行手术治疗患者，共253例。按纳入标准入组共188人。
2．研究设备
JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）核磁共振成像系统Magnetom Symphony1.5T MR Tim（德国西门子公司）
3．研究方法
1）采用前瞻性同期随机对照分组方法（区组随机法），将符合纳入标准的188人作为研究对象随机分配到超声消融组(HIFU组)及经腹子宫肌瘤剔除手术组（肌瘤剔除组），观察临床安全性指标，包括生命体征、术后恢复时间手术不良反应。
2）从188患者中随机抽样每组31例，检测患者手术前后创伤相关血清学指标变化情况，包括：（1）皮质醇、肾上腺素及去甲肾上腺素；（2）IL6、IL2、IL10的水平；（3）外周血白细胞值、中性粒细胞比例及血红蛋白值；（4）外周血中CD4+、CD8+比例及NK细胞的比例。
4.统计方法应用SPSS16.0软件包作统计分析。
第二部分
1．研究对象2007年1月至2010年1月96名行HIFU治疗子宫肌瘤患者的临床资料。
2．研究设备JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）hifu-3DTPS Microsoft基础类应用软件（重庆（HIFU）海扶技术有限公司）
3．研究方法
1）软件自动三维重建并计算非靶区肌瘤体积缩小率，分析影响非靶区肌瘤缩小率的相关因素，建立非靶区肌瘤转归的预测回归模型。
2）将96名行HIFU治疗子宫肌瘤患者按照不同的消融率进行分组，比较不同组的非靶区瘤组织术后3、6、12月的影像学转归，寻找影响非靶区肌瘤的转归趋势的消融率“拐点”。
4．统计方法
应用SPSS16.0软件包作统计分析。
第三部分
1．研究对象
1）人离体子宫肌瘤：2010年4月-2010年11月因子宫肌瘤行子宫次全切除术或子宫全切术患者8例，年龄40.2±3.9（35-47）岁，手术前行核磁共振检查均为T2WI均匀低信号，子宫肌瘤平均体积为48.35±12.02cm3（37.1-65cm3），最大直径为4.38±0.33cm（4.2-5.1cm）术后均经病理证实为子宫肌瘤。
2）人原代子宫肌瘤细胞：取自2010年4月至2011年10月，重庆医科附属第一医院妇科的人子宫肌瘤标本，患者年龄在39-45岁，术前3个月未服用激素治疗。病理学诊断为子宫肌瘤，术中取出新鲜离体子宫肌瘤后立即送实验室培养原代细胞。
2．研究设备
JC型聚焦超声肿瘤治疗系统（重庆海扶（HIFU）技术有限公司）核磁共振成像系统Magnetom Symphony1.5T MR Tim（德国西门子公司）酶联免疫检测仪（宁波自动化仪表研究所）
3．研究方法
1）建立HIFU消融人离体子宫肌瘤模型，研究HIFU消融对非靶区瘤组织雌激素受体、孕激素受体及芳香化酶细胞色素P450表达的影响。
2）培养人原代子宫肌瘤细胞，筛选全部靶区子宫肌瘤细胞致死的最小超声能量参数，建立靶区外声场内子宫肌瘤细胞的HIFU辐照模型，分析聚焦超声对声场内距离焦点不同层面细胞的影响，研究超声对声场内细胞的作用机制。
4．统计方法
应用SPSS16.0软件包作统计分析。
结果
第一部分
1.对比观察HIFU组与肌瘤剔除组临床安全性指标，结果显示：HIFU组与肌瘤剔除组比较，HIFU组对术后的体温、收缩压影响较小，不良反应发生率低，术后恢复时间短，HIFU组术后麻醉类镇痛药使用率明显低于肌瘤剔除组，而两组术后疼痛分值比较差异无统计学意义。
2. HIFU组与肌瘤剔除组对创伤相关的血清学指标的影响：（1）两组术后血清皮质醇、肾上腺素及去甲肾上腺素浓度变化不明显；（2）肌瘤剔除组对机体术后血清IL-6、IL-2、IL-10的浓度影响明显，主要是发生在术后24小时；（3）肌瘤剔除组患者术后外周血WBC计数、中性粒细胞比率高于HIFU组，而术后血红蛋白值明显低于HIFU组；（4）肌瘤剔除组术后外周血CD4+、CD8+及NK细胞受抑制程度比HIFU组明显。
第二部分
1．非靶区肌瘤缩小率的多变量相关关系结果提示：影响非靶区肌瘤转归的因素包括：子宫肌瘤血流分级、T2WI信号强度、超声消融率。建立回归模型为：[=非靶区肌瘤转归趋势（非靶区肌瘤体积缩小率）,χ1=超声消融率（%），χ2=子宫肌瘤血流分级，χ3=子宫肌瘤T2WI信号转化值]
2．通过研究不同体积消融比例后的非靶区瘤组织的影像学转归。结果初步显示超声消融后残留的非靶区瘤组织体积小于子宫肌瘤体积的30%是可以得到满意的影像学转归的。
第三部分
1．靶区周围肌瘤组织温度也有不同程度的温升，并且靶区外组织温度呈逐渐下降。与假照组（对照组）比较，靶区外瘤组织雌、孕激素受体表达无明显差异。免疫组织化学法及免疫印迹发半定量检测P450arom蛋白在靶区外0.5cm及1.0cm处子宫肌瘤组织的表达明显低于对照组，差异有统计学意义。
2．成功培育人原代子宫肌瘤细胞，选择导致靶点人子宫肌瘤细胞死亡的最小超声参数为声功率200W辐照时间为5秒。高强度聚焦超声可以诱导声场内子宫肌瘤细胞发生凋亡，细胞凋亡发生的时间和凋亡率与声场内距离焦点的位置相关，距焦点距离越近凋亡发生越明显。声场内细胞caspase-3也有不同程度的激活，其表达强度及活化情况与声场内距离焦点的位置相关。
结论
1. HIFU组与肌瘤剔除组比较，对机体的创伤更小。
2.非靶区肌瘤的转归与子宫肌瘤的性质及超声消融率相关。超声消融率达到70%以上，可以观察到满意的非靶区子宫肌瘤转归。
3．超声消融部分子宫肌瘤后在一定距离范围内非靶区的子宫肌瘤的生长会被抑制，其机制与温度影响P450酶的蛋白表达有关。
4.高强度聚焦超声可以诱导声场内细胞凋亡，凋亡的发生及凋亡率与距离焦点的声场层面有关，其机制可能与激活Caspase-3有关。
Background
Surgical trend is the development of surgical treatment based on less damage tohuman. High intensity focused ultrasound (HIFU) is a non-invasive therapy of tumouremerged in recent years, it provides non-invasive treatment with precise positioning andno incision. Uterine fibroid is the most common benign tumor of reproductive system.Uterine fibroids are treated with HIFU by focusing ultrasound energy to local fibroidtissue and cause coagulation necrosis and prevent the growth of uterine fibroids.
Along with HIFU therapy is widely applied in the treatment of uterine fibroids,clinical observation reports on safety of HIFU represented by many centers. However,there is no safety evaluation based on the characteristic of HIFU,"no invasive",especially compared with traditional treatment. Ultrasound ablation of uterine fibroids isa noninvasive treatment characterized by retaining uterus, no surgery and no anesthesiamethods, as well as the principle of the treatment is practicing within tumor to avoidaffect neighboring tissue. Considered under the non-invasive characteristic, safetystudies on HIFU ablation is to evaluate the trauma on human compared with traditionalsurgery. The purpose of study was to evaluate the safety of the new technology, and toinvestigate the security of residual untreated tumor (non-target tumor tissue) after HIFUablation and related mechanisms.
This study was designed to study the trauma of HIFU ablation with controlledclinical trials for assessment of noninvasive techniques. Meanwhile, we explored therelated factors affected non-target tumor tissue, evaluated clinical safety evidence of local tumor and built the prediction model of non-target fibroid tissue by follow-up andanalysis of clinical imaging data on HIFU ablation target of uterine fibroids. The studywas to explore the possible mechanisms of local tumor based on clinical data, andconcluded laboratory evidence of local tumor effects. The study provides a clinical andlaboratory basis to evaluate the safety of HIFU ablation for uterine fibroids. It alsoprovides a scientific basis of HIFU therapy for planning and optimizing treatmentprogram.
Objective
1. To evaluate trauma on the body of HIFU ablation for uterine fibroids and abdominalmyomectomy.
2. To study the outcome of residual tumor (non-target fibroid) and influencing factorsby analysis of clinical data, and explore the local effect of non-target fibroid after highintensity focused ultrasound ablation for evaluation the safety of HIFU therapy.
3. To explore the preliminary mechanism of high intensity focused ultrasound ablationon non-target fibroid.Research content
1. Based on clinical observation and trauma-related serum markers, the study wasdesigned to evaluate the trauma of HIFU on patients compare with abdominalmyomectomy through randomized controlled trials (RCT).
2. To explore the related factors affected non-target tumor tissue, evaluated clinicalsafety evidence of local tumor and build the prediction model of non-target fibroidtissue by analysis of clinical imaging data.
3. To explore the relationship of the outcome of non-target fibroids and ablation ratebased on the regression model. It can be initially proposed the treatment program toacquire clinical outcome of non target fibroids.
4. To explore the effect of HIFU on the expression of regulatory factors on growth ofnon-target fibroid tissue and related mechanisms by building HIFU ablation isolated human uterine fibroids model.
5. To explore the he effect and mechanisms of HIFU on human fibroid cells within thesound field of ultrasound with cultured primary human fibroid cell model.Material and MethodsPart one
1. Objective
From September2010to December2011,253patients diagnosed with uterine fibroidand scheduled for surgery were enrolled in the1st Affiliated Hospital of ChongqingMedical University
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)Magnetic resonance imaging system Magnetom Symphony1.5T MR Tim (Siemens,Germany)
3. Methods
1)188patients who meet the inclusion criteria were randomly assigned to high-intensityfocused ultrasound ablation group (HIFU group) and abdominal myomectomy group(myomectomy group) with RCT (block randomized method). The indicators for clinicalsafety were observed, including vital signs, postoperative recovery time, surgicaladverse events and complications.
2)31cases were randomly selected from188patients. All patients was detected withsurgical trauma indicators of peripheral blood before and after therapy, including:(1)cortisol, epinephrine and norepinephrine;(2) IL6, IL2, and IL10;(3) peripheral bloodwhite cell counts, neutrophil percentage and hemoglobin values;(4) CD4+, CD8+andNK ratio of peripheral blood.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Part two
1. Objective Clinical data of96patients treated with HIFU of uterine fibroids from January2007toJanuary2010.
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)hifu-3DTPS Microsoft Foundation Classes application software (Chongqing HIFUTechnology Co., Ltd.)
3. Methods
1) Automatic3D reconstruction and calculation of non-target fibroid volume withsoftware. Analysis of the impact factors on shrink rate of non-target fibroids forestablishing predictive regression model of outcome.
2)96patients with HIFU were assigned to each group according to different ablationratio. We compared the imaging outcome of each group to find out the “inflection point”of ablation ratio affect the trend of non-target fibroid.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Part three
1. Objective
1) Human uterine fibroid: From April2010to November2010,8cases were appliedwith hysterectomy and subtotal hysterectomy due to uterine fibroid. The age was40.2±3.9(35-47) years. The signals of pre-operative T2WI in all patients were uniformly lowsignal. Average volume of uterine fibroids were48.35±12.02cm3(37.1-65cm3), andmaximum diameter was4.38±0.33cm (4.2-5.1cm). The fibroids were confirmed bypathology after surgery, and fresh uterine fibroids were received with ChongqingMedical University Ethics Committee approval and patient consents.
2) Primary uterine fibroid cell: From April2010to October2011, human uterine fibroidspecimens were taken from patients of39-45years in gynecological department of the1st Affiliated Hospital of Chongqing Medical College. All patients were not takinghormone treatment within three months before surgery. The fibroids were confirmed bypathology after surgery, and the fresh fibroids were immediately sent to the laboratory for culturing primary cell.
2. Equipments
JC focused ultrasound tumor therapy system (Chongqing HIFU Technology Co., Ltd.)Magnetic resonance imaging system Magnetom Symphony1.5T MR Tim (Siemens,Germany)ELISA analyzer (Ningbo Institute of Automation Instrumentation)
3. Methods
1) To establish the model of isolated human uterine fibroids with HIFU ablation, andstudy the effect of HIFU on expression of estrogen receptor, progesterone receptor andP450in non-target fibroid tissue.
2) To build HIFU sonication model of cultured primary human uterine fibroid cellwithin the sound field by filtering the smallest ultrasound parameters which can causetarget uterine fibroid cell death. To study the mechanism of the effect of ultrasound oncells within the sound field by analysis of different impact of focused ultrasound on thecells represented within different distance to ultrasonic focus.
4. Statistical methods
SPSS16.0package was applied for statistical analysis.
Results
Part one
1. Clinical safety indicators were observed in HIFU group and myomectomy group. Theresults showed: Compared with myomectomy group, HIFU group had less impact onpostoperative body temperature, systolic blood pressure. Less surgical complicationsand adverse events, shorter recovery time can be found in patients of HIFU group. Nosignificant difference of the postoperative pain score was found in two groups.
2. The effect of HIFU and myomectomy group on the levels of trauma-relatedserological markers:(1) No significant changes of postoperative serum cortisol,epinephrine and norepinephrine concentrations were found in two groups significantly;(2) Patients in myomectomy group affected the levels of serum IL-6, IL-2, IL-10 significantly, especially within24hours after surgery;(3) WBC counts, neutrophil ratioin myomectomy group were higher than HIFU group, postoperative hemoglobin valuewas significantly lower than HIFU group;(4) The ratio of CD4+, CD8+and NK cellswas inhibited in myomectomy group significantly compared with HIFU group.Part two
1. Correlation results of shrink rate of non-target fibroids with multivariate factorssuggest that: The factors which influence the outcome of non-target fibroids includedblood flow grade of uterine fibroid, signal of T2WI, non perfused volume ratio. Theregression model was:[=Non-target fibroid volume reduction ratio，Χ1=ultrasound ablation rate (%), χ2=uterine fibroids flow grade, χ3=uterine fibroids T2WI signal conversion value]
2. The result of observing on the imaging outcomes of groups with different non-perfused volume ratio (NPV) showed satisfied imaging outcome can be get withnon-target volume less than30%of target fibroid.Part three
1. Different degrees of temperature rise in non target fibroid tissue outside target fibroid,and temperature decreased gradually along with the distance outside target area.Compared with the control group, no significant difference was found in the expressionof estrogen receptor and progesterone receptor in non target fibroid.Immunohistochemical staining and Western blot semi-quantitative detection ofP450arom protein represented at0.5cm and1.0cm outside target area showed lowerlevel significantly than the control group, the difference was statistically significant.
2. Primary human uterine fibroid cell was successfully cultivated. Smallest ultrasonicparameters (power200W,5seconds) lead to cell death was screened ultrasoundparameters of cells positioned in focus. High intensity focused ultrasound can induceuterine fibroid cell apoptosis positioned within sound field. The occurrence of apoptosisand apoptosis rate was related with the distance from focus. Different degree of caspase-3activation appeared in cells within sound field, and the expression ofcaspase-3the strength was related with the distance from focus.Conclusions
1. Compared with myomectomy group, the result of HIFU group showed smallertrauma on patients.
2. Outcome of non-target fibroids was related to NPV. NPV of more than70%can beobserved to get satisfactory outcome of non-target uterine fibroids.
3. The growth of non-target fibroid within a certain range will be suppressed after HIFUablation part of uterine fibroid, and the mechanism was related to P450protein affectedby temperature.
4. HIFU can induce uterine fibroid cell apoptosis positioned within the sound field. Andthe occurrence of cell apoptosis was related with the distance from focus, themechanism of apoptosis may be associated with activation of caspase-3.
引文
[1] Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterineleiomyoma in black and white women: ultrasound evidence. Am J ObstetGynecol.2003;188(1):100-107.
[2]王智彪.治疗超声原理与应用[M]。南京大学出版社，2008，172-173.
[3]高强度聚焦超声肿瘤治疗系统临床应用指南（试行）[J].中华医学杂志,2005,85:796-797.
[4] Morita Y, Ito N, Hikida H, et al. Non-invasive magnetic resonance imaging-guidedfocused ultrasound treatment for uterine fibroids: early experience[J]. Eur J ObstetGynecol Reprod Biol.2008,139(2):199-203.
[5] Taran FA, Tempany CM, Regan L.Magnetic resonance-guided focused ultrasound(MRgFUS) compared with abdominal hysterectomy for treatment of uterineleiomyomas[J].Ultrasound Obstet Gynecol.2009，34(5):572–578.
[6] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyoma symptomsby using focused ultrasound surgery [J]. Obstet Gynecol,2007,110:279-287.
[1] Chen WZ, High intensity focused ultrasound for larger volume ablation of uterinemyomas: a feasibility study.7th International Symposium on TherapeuticUltrasound（ISTU2007）,Seoul, Korea, June12-15,2007,06:53.
[2] Yi HL, Ting KL, Hung JW, et al. Treatment of Uterine Fibroids by Using MagneticResonance-guided Focused Ultrasound Ablation: the initial experience in Taiwan[J].Chin J Radiol.2009,34(4):263-271.
[3] Fennessy FM, Tempany CM, McDannold NJ, et al. Uterine Leiomyomas: MRImaging-guided Focused Ultrasound Surgery--Results of Different TreatmentProtocols [J].Radiology.2007,243（3）：885-893.
[4] So MJ, McDannold N, Fennessy FM, et al. Evaluation of the impact of body massand abdominal fat on MR-guided focused ultrasound surgery for uterine fibroids[J]. Magnet Resonce Med.2005,13:2141-2145.
[5]田国刚,黄运佰,朱才义.全麻复合硬膜外阻滞麻醉对肝癌患者HIFU治疗围术期β-EP的影响[J].海南医学院学报.2009,(9):89-91.
[6] S.J波可克著,郭日典,秦绍明译.临床治疗科研方法学[M].天津,天津科技翻译出版公司.1991:54-58.
[7] Magnetic resonance image-guided transcutaneous focused ultrasound ablation foruterine fibroids，http://www.nice.org.uk/IPG231.
[8]倪宗囊．临床试验设计[M]．北京,人民卫生出版社．1996:11-65.
[9] Stephen J S, Malone D E. Sedation and analgesia in adult patients: evaluation of astaged-dose system based on body weight for use in abdominal interventionalradiology [J]. Radiology.2000,216(4):653–659.
[10]朱丽,陈文直,陈锦云.咪唑安定-芬太尼镇静镇痛在高强度聚焦超声子宫肌瘤中的应用研究[J].重庆医科大学学报.2009,34(11):1556-1558.
[11] Sietses C，Beelen RH，Meijer S，et al. Immunologic consequences of laparoscopicsurgery: speculations on the cause and clinical implications [J]. Langenbecks ArchSurg.1999,384(3):250-258.
[12] Cruickshank AM, Fraser WD, Burns HJ, et al. Response of serum interleukin-6inpatients undergoing elective surgery[J]. Clinical Sciecn.1990,79(1):160.
[13] Grzelak I, Olszewski WL, Zaleska M. Blood cytokine levels rise even after minorsurgical trauma [J]. J Clin Immunol.1996,16(3):159-64.
[14] Clement GT. Perspectives in clinical uses of high-intensity focused ultrasound[J].Ultrasonics.2004,42(10):1087-1093.
[15] Schneemilch CE, Ittenson A, Ansorge S.Effect of2anesthetic techniques on thepostoperative proinflammatory and anti-inflammatory cytokine response andcellular immune function to minor surgery [J]. J Clin Anesth.2005,17(7):517-27.
[16] O’Sullivan ST，Lederer JA，Horgan AF，et al. Major injury leads to Predominanceof The heipr-2-lymPhocyte Phenotype and diminished interleukin-12Productionassociated with decreased resistance to infection [J].Ann Surg.1997,22(2):482-92.
[17] Shah PK, Falk E et al. Human monocyte-driven acrophages induce collagen weakdown in fibrous caps of atherosclerotic plaque: potential role of matrix degradingmetal proteinases and implications for plaque rupture [J].Circulation.1995,92(6):1565-1569.
[18] Vallina VL, Velasco JM. The influence of laparoscopy on lymphocytesubpopulations in the surgical patients [J].Surg Endosc.1996,10(1):481-484.
[19] A. Halevy, G. Lin, R, et al. Comparison of serum C-reactive protein concentrationsfor laparoscopic versus open cholecystectomy [J].Surg Endosc.1995,9(3):280-282.
[20] Yue Q, Ma R.Effects of laparoscopically-assisted vaginal hystererectomy comparedwith abdominal hysterectomy on immune function [J].The Journal of InternationalMedical Research.2009,37(1):855-861.
[21] Evans C, Galustian C, Kumar D, et al. Impact of surgery on immunologic function:comparison between minimally invasive techniques and conventional laparotomyfor surgical resection of colorectal tumors [J].Am J Surg.2009,197(2):238-245.
[22] Hong JY, Lim KT. Effect of preemptive epidural analgesia on cytokine Responseand Postoperative pain in laparoscopic radical hysterectomy for cervical cancer [J].Regional Anesthesia and Pain Medicine.2008,33(1):44-51.
[23] Hansbrough JF，Bender EM，Sirvent RZ. Altered helper and suppresso lymphocytepopulations in surgical patients: A measure of postoperative immuno suppression[J].Am J Surg.1984,148(3):303-307.
[24] Ogawa K, Hirai M, Katsube T, et al. Suppression of cellular immunity by surgicalstress [J].Surgery.2000,127:329-336.
[25] Matthias W, Wichmann, MD, Thomas P, et al. Immunological Effects ofLaparoscopic vs Open Colorectal Surgery [J]. Arch Surg.2005,140(2):692-697.
[26] Salo M. Effects of anaesthesia and surgery on the immune response [J].ActaAnaesthesiol Scand.1992,36(3):201-220.
[27] Matthias W, Wichmann, MD, Thomas P. Immunological Effects of Laparoscopic vsOpen Colorectal Surgery [J]. Arch Surg.2005,140(7):692-697.
[28] Barbieri C, Fujisawa MM, Yasuda CL.Effect of surgical treatment on the cellularimmune response of gastric cancer patients [J]. Braz J BiolRes.2003,36(3):339-345.
[29] Torres A, Torres K, Paszkowski T,et al. Cytokine response in the postoperativeperiod after surgical treatment of benign adnexal masses: comparison betweenlaparoscopy and laparotomy [J].Surg Endosc.2007,21(10):1841-1848.
[30] Tatsumi H, Ura H, Ikeda S. Surgical influence on TH1/TH balance and monocytesurface antigen expression and its relation to infectious complications [J].World JSurg.2003,27(5):522–528.
[31] Hong JY, Lim KT. Effect of preemptive epidural analgesia on cytokine Responseand Postoperative pain in laparoscopic radical hysterectomy for cervical cancer [J].Regional Anesthesia and Pain Medicine.2008,33(1):44-51.
[32] Frick VO, Justinger C, Rubie C. Thoracotomy procedures effect cytokine levelsafter thoraco abdominal esophagectomy [J]. Oncol Rep.2011,10(6):3892.
[33] Kim TK, Yoon JR. Comparison of the neuro-endocrine and inflammatory responsesafter laparoscopic and abdominal hysterectomy [J].Korean J Anesthesiol.2010,59(4):265-269.
[34] Delgado S, Lacy AM, Filella X, Castells A, Garcia-Valdecasas JC, Pique JM,Momblan D, Visa J. Acute phase response in laparoscopic and open colectomy incolon cancer: randomized study [J]. Dis Colon Rectum.2001,44(2):638-646.
[35] Ordemann J, Jacobi CA, Schwenk W. Cellular and homoral inflammatory responseafter laparoscopic and conventional colorectal resections [J].Surg Endosc.2001,15(6):600-608.
[36] Wichmann MW. Immunological Effects of Laparoscopic vs Open ColorectalSurgery [J].Arch Surg.2005,140(1):692-697.
[37] Torres A, Torres K, Paszkowski T, et al. Cytokine response in the postoperativeperiod after surgical treatment of benign adnexal masses: comparison betweenlaparoscopy and laparotomy [J]. Surg Endosc.2007,21(10):1841-8.
[38] Maruszynski M, Pojda Z. Interleukin6(IL-6) levels in the monitoring of surgicaltrauma: a comparison of serum IL-6concentration in patients treated bycholecystectomy via laparotomy or laparoscopy [J]. Surg Endosc.1995,9(4):882-885.
[39]刘春福,曹启迪.白细胞—血红蛋白指数在创伤早期对伤情判断的临床意义[J].中华创伤骨科杂志.2002,4(1):65-66．
[1] Kroencke TJ，Scheurig C, Poellinger A, et al. Uterine artery embolization forleiomyomas: percentage of infarction predicts clinical outcome [J].Radiology.2010,255(3):834-841.
[2] Hanafi M. Predictors of leiomyoma recurrence after myomectomy [J]. ObstetGynecol.2005,105(4):877-881.
[3] Burbank F. Childbirth and fibroid treatment by uterine artery occlusion: Do theyshare a common biology?[J]. J Am Gynecol Laparosc.2004,11(2):138-152.
[4]乐杰.妇产科学.第5版.北京：人民卫生出版社,2008:6.
[5]史常旭，辛晓燕.现代妇产科治疗学.3版.北京：人民军医出版社，2010:160-168.
[6] Stewart EA, Faur AV, Wise LA, Reilly RJ, Harlow BL. Predictors of subsequentsurgery for uterine leiomyomata after abdominal myomectomy [J]. Obstet Gynecol.2002,99(4):426–32.
[7] Elizabeth A, Stewart, Romana A. Nowak. Leiomyoma related bleeding: a classichypothesis updated for the molecular era [J].Human Reproduction Update.1996,2(4):295–306.
[8]徐刚，蔡泳，宋昕等.相关回归与多因素分析.上海口腔医学[J].2004,13(5)：426-429.
[9] Kennedy JE. High-intensity focused ultrasound in the treatment of solid tumours[J].Nat Rev Cancer.2005,5(4):321-327.
[10] Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation:standardization of terminology and reporting criteria [J].Radiology.2005,235(3):728-739.
[11] Walocha JA, Litwin JA, Miodoński AJ.Vascular system of intramural leiomyomatarevealed by corrosion casting and scanning electron microscopy [J]. HumReprod.2003,18(5):1088-1093.
[12] Funaki K, Fukunishi H, Sawada K.Clinical outcomes of magneticresonance-guided focused ultrasound surgery for uterine myomas:24-monthfollow-up [J]. Ultrasound Obstet Gynecol.2009;34(5):584-589.
[13] Funaki K, Fukunishi H, Funaki T, et al. Magnetic resonance-guided focusedultrasound surgery for uterine fibroids: relationship between the therapeutic effectsand signal intensity of preexisting T2-weighted magnetic resonance images [J].AmJ Obstet Gynecol.2007,196(2):184.e1-184.e6.
[14] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyomasymptoms by using focused ultrasound surgery [J].Obstet Gynecol.2007,110(7):279-287.
[15]陈文直,唐良萏,杨武威,等.超声消融治疗子宫肌瘤的安全性及有效性[J].中华妇产科杂志.2010,45(12):909-912.
[16]朱丽,陈文直,陈锦云,等.子宫肌瘤超声消融与MRI信号特征关系的研究[J].第三军医大学学报.2009,31(14):1370-1373.
[17] Fennessy FM, Tempany CM, Mc Dannold NJ, et al. Uterine leiomyomas: MRimaging-guided focused ultrasound surgery results of different treatment protocols[J].Radiology.2007,243(3):885-893.
[18]牛陵川，邹文兵，张炼，等.乳腺癌高强度聚焦超声消融后残留肿瘤增殖能力的变化.上海交通大学学报（医学版）[J].2010,30(2):200-203.
[19]戴良图,张宣东.沿海子宫肌瘤患者射频治疗对免疫淋巴细胞的影响[J].中华航海医学与高气压医学杂志.2005,12(2):104-105.
[1] Sumitani H, Shozu M, Segawa T, et al. In situ estrogen synthesized by aromataseP450in uterine leiomyoma cells promotes cell growth probably via anautocrine/intracrine mechanism [J]. Endocrinology.2000,141(10):3852-61.
[2] Shozu M, Sumitani H, Segawa T, Yang HJ, Murakami K, Inoue M. Inhibition of insitu expression of aromatase P450in leiomyoma of the uterus by leuprorelinacetate.[J].J Clin Endocrinol Metab.2001,86(11):5405-11.
[3] Englund K, Blank A, Gustav,xson I, et a1. Sex Steroid receptors in humanmyometrium and fibroids: changes during the menstrual cycle andgonadotropin-releasing hormone treatment [J].J Clin Endormol Metab，1998，83(11)：4092-4096.
[4]乔清理.组织消融一般模型的建立与其温度分布的分析与解析计算.中国生物医学工程学报.2002,21(l):74-78.
[5] Rudolf S, Peter WA, Dietrich H, et al.Temperature monitoring of interstitial thermaltissue coagulation using MR phase images [J].JMRI.1997,8(2):188-196.
[6]罗新,宋雯霞,吴秀枝,常明伟,邱学华.射频消融技术对子宫肌瘤组织中ER、PR表达影响的临床试验研究[J].2003,12(3):204-206.
[7]熊正爱等.高强度聚焦超声体外照射猴子宫近远期影响研究[J].中国超声医学杂志，2002,18(10):20-22.
[8]贺雪梅，熊欣，陈菲，邹建中.超声消融子宫肌瘤后靶区边缘雌孕激素受体表达研究.[J]重庆医科大学学报.2011,36(1):5-7.
[9]Hilger I, Rapp A, Greulich KO. Assessment of DNA damage in target tumor cellsafter thermoablation in mice [J].Radiology.2005,237(2):500-506.
[10]王智彪,李发琪,冯若.《治疗超声原理与应用》南京大学出版社.2008,6:78-120.
[11] Carreau P, Mercedes B. Aromatase distribution and regulation in fish [J]. FishPhysiol Biochem.2005,31(2):215-226.
[12] Daisuke Uchida, Michiaki Yamashita, Takeshi Kitano, Taisen Iguchi.An aromataseinhibitor or high water temperature induce oocyte apoptosis and depletion of P450aromatase activity in the gonads of genetic female zebrafish during sex-reversal [J].Comparative Biochemistry and Physiology.2004,13(7):11–20.
[13] Duffy TA, Picha ME, Won ET, Borski RJ, McElroy AE, Conover DO. Ontogenesisof gonadal aromatase gene expression in atlantic silverside (Menidia menidia)populations with genetic and temperature-dependent sex determination [J].J ExpZool A Ecol Genet Physiol.2010,313(7):421-31.
[14]熊正爱,杜永洪,邹建中等.高强度聚焦超声照射猴子宫对卵巢功能的影响研究[J].中华超声影像学杂志.2003,12(11):687-689.
[15] Meaney PM, Cahill MD, Ter Haar GR.The intensity dependence of lesion positionshift during focused ultrasound surgery [J].Ultrasound Med Biol.2000,26(3):441-450.
[16] Poff JA, Allen CT, Traughber B, et al. Pulsed high-intensity focused ultrasoundenhances apoptosis and growth inhibition of squamous cell carcinoma xenograftswith proteasome inhibitor bortezomib [J]. Radiology.2008,248(2):485-91.
[17]黎清,徐建平,罗惠娟.凋亡基因Caspase23在子宫肌瘤中的表达及相关性研究[J].2007,28(6):605-606.
[18]徐青,仇黎丽,徐昌芬.子宫平滑肌瘤细胞原代培养及鉴定.南京医科大学学报(自然科学版)[J].2007,27(9):967-969.
[19]王智彪,李发琪,冯若.《治疗超声原理与应用》南京大学出版社.2008,6:105.
[20]刘丽霞,叶欣,王海波.高强度聚焦超声不同辐照时间对CT26肿瘤细胞的急性生物学效应研究[J].中国组织工程研究与临床康复,2007,11(9):1704-1706
[21] Kennedy JE, Ter Haar GR, Cranston D.High intensity focused ultrasound: surgeryof the future?[J].Br J Radiol,2003,76(909):590-599.
[22]郭倩.不同辐照模式聚焦超声诱导人胰腺癌细胞凋亡的量效关系[J].中国医学影像技术,2011,27(3):479-484.
[23]吴飞翔，章卫平.JNK信号转导与细胞凋亡.生命的化学,2002,22(4):346-347.
[1] Pavna K. Brahma, Kristina M. Martel.Future Directions in Myoma Research [J].2006,33(1):199-224.
[2] Butori N, et al. Interest of uterine artery embolization with gelatin sponge particlesprior to myomectomy for large and/or multiple fibroids. Eur J Radiol (2009), doi:10.1016/j.ejrad.2009.09.028.
[3]郎景和，主编．妇科手术笔记[M]第1版．北京：中国科学技术出版社，2001,67.
[4]张庆霞，朱兰，刘珠凤等．开腹与微创子宫肌瘤剔除术的临床结局分析[J]．中国实用妇科与产科杂志,2008,24(4):278-281.
[5] Hanafi Magdi. Predictors of leiomyoma recurrence after myomectomy [J].ObstetGynecol.2005,105(4):877-881.
[6]曹泽毅主编．中华妇产科学[M]．北京：人民卫生出版社，1999,1822.
[7]旷红艺,李慧,熊焰等.经腹子宫肌瘤剔除术缝合方式的改进[J].中国现代临床医学，2008,12(7):13-16.
[8] Benassi L，Rossi T，Kaihura CT，et a1．Abdominal or vaginal hysterectomyfor enlarged uteri：a randomized clinical tria1[J].Am J Obstet Gynecol.2002,187(6):1561-1565．
[9]夏平，林红，艾婷华．经阴道与经腹子宫肌瘤剔除术的比较[J].中国微创外科杂志，2005，5(10)：819-82
[10] Rossetti A, Sizzi O, Chiarotti F, et a1. Developments in techniques forlaparoscopicmyomectomy [J].JSLS.2007,11(1):34-40．
[11] Doridot V, Dubuisson JB, Chapron C,et al.Recurrence of leiomyoma afterlaparoscopic myomectomy [J].Journalof the American Association of GynecologicLaparoscopists.2001,8(4):495-500.
[12] Rossetti A, Sizzi O, Soranna L, et al. Long-term results of laparoscopic recurrencerate in comparison with abdominal myomectomy [J]. Hum Reprod.2001,16(4):770-774.
[13] Malzoni M, Rotond C, et al. Fertility after laparoscopic myomectomy of largeuterine myomas: operative technique and preliminary results [J].Eyr J GynecolOncol.2003,24(1):79-82.
[14] Sesti F, Melgrati L, Damiani A, et a1. Isobaric (gasless)laparoscopic uterinemyomectomy: an overview[J].Eur J Obstet Gynecol Reprod Biol.2006,29(1):9-14．
[15]刘海防，刘彦．无气腹腹腔镜手术的临床应用[J].中国实用妇科与产科杂志.2007,23(8):587-588.
[16] Liang Z，Xu H，Chen Y，et a1．Laparoscopic blockage of uterine artery andmyomectomy：a new method of treating symptomatic uterine leiomyomas[J]．SurgEndosc.2006,20(6):983-986．
[17] Camran Nezhat, Michael Lewis, Sumathi Kotikela. Robotic versus standardlaparoscopy for the treatment of endometriosis [J].Fertility and Sterility.2010,94(7):2758-2760.
[18] Tulandi T. Endoscopic nyomectomy: laparoscopy and hysteroscopy [J]. ObstetGynecol Clin North Am.1999,26(1):l35-l38．
[19] Shokeir TA，Hysteroscopic management in submucous fibroids to improve fertility[J].Arch Gyntcol obstet.2005,273(1):50-54．
[20]宫华芳，王晓雷，夏明静等. B型超声监测在官腔镜电切术治疗子宫粘膜下肌瘤中的应用.[J]中国妇幼保健2008,(23):1442-1443
[21]王丽等.超声监导宫腔镜子宫肌瘤切除术的应用价值[J].实用医学影像杂志.2003,(40):271-272.
[22] Ravina JH, Herbreteau D, Ciraru VN, et a1. Arterial embolization to treat uterinemyomata [J].Lancet.1995,346(3):671-672．
[23] Goodwin SC, Bradley LD, Lipmm JC, et a1. Uterine artery embolization versusmyomectomy: a muhicenter comparative study[J].Fertil Steril.2006,85(1):14-21．
[24] Pinto I, Chimeno P, Romo A, et al.Uterine fibroids: uterine artery embolizationversus abdominal hysterectomy for treatment: a prospective, randomized andcontrolled clinical trial [J]. Radiology.2003,226:425-431.
[25] Hehenkamp WJK, Volkers NA, et al. Uterine artery embolization versushysterectomy in the treatment of symptomatic uterine fibroids (EMMY trial): peri-and postprocedural results from a randomized controlled trial [J]. Am J ObstetGynecol.2005,193:1618-1629.
[26] Edwards RD, Moss JG, Lumsden MA, et al. Uterine artery embolization versussurgery for symptomatic uterine fibroids [J]. N Engl J Med.2007,356(4):360-370.
[27] Goodwin SC, Spies JB, Worthington-Kirsch R, et al. Uterine artery embolizationfor treatment of leiomyomata: long-term outcomes from the fibroidregistry[J].Obstet Gynecol.2008,111(1):22-33
[28] Kitamura Y, Ascher SM, Cooper C, et al. Imaging manifestations of complicationsassociated with uterine artery embolization [J].Radiographics.2005,25(1):119-132.
[29]罗新，宋文霞.射频消融微创技术的进展及其在妇科领域的应用[J]．中国实用妇科与产科杂志.2003,19(4):247-249．
[30]戴良图，曾敏华，许恒.子宫肌瘤射频治疗对卵巢功能的影响．海军医学杂志，2003,24(4):309-311．
[31] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyomasymptoms by using focused ultrasound surgery [J]. Obstet Gynecol.2007,110(2):279-287.
[32] Morita Y, Ito N, Hikida H, et al. Non-invasive magnetic resonance imaging-guidedfocused ultrasound treatment for uterine fibroids-early experience [J].Eur J ObstetGynecol Reprod Biol.2008,139(2):199-203.
[33] Stewart EA, Rabinovici J, Tempany CM, et al. Clinical outcomes of focusedultrasound surgery for the treatment of uterine fibroids [J]. Fertil Steril.2006,85(1):22-29.
[34] Leon-Villapalos J, Kaniorou-Larai M, Dziewulski P. Full thickness abdominal burnfollowing magnetic resonance guided focused ultrasound therapy [J].Burns.2005,(31):1054-1055.
[35] Tempany Cm，Stewart EA，Mcdannold N，et a1．MR imaging—guidea focusedultrasound surgery of uterine leiomyomas：a‘feasibility study[J]．Radiology2003，226：897-905．
[36]Miriam M. F. Hanstede, M.D., Clare M. C. et al. Focused ultrasound surgery ofintramural leiomyomas may facilitate fertility: A case report [J]. Fertility andSterility.2007,88(2):497.e5-e7.
[37] Jaron Rabinovici, Matthias David, et al.Pregnancy outcome after magneticresonance–guided focused ultrasound surgery (MRgFUS) for conservativetreatment of uterine fibroids [J].Fertility and Sterility.2010,93:199-209.
[1] Arya J诱导凋亡—一种抗肿瘤的策略[J].Surgery.2000,127(4):366-369.
[2] Ferreira CG, Epping M, Kruyt F, et al. Apoptosis: Target of Cancer Therapy [J].Clin Cancer Res.2002,8:2024–2034.
[3]徐静,许川山,夏新蜀.低强度超声对小鼠肝癌H22细胞抑制效应的初步研究[J].激光杂志.2009,30(6):69-71.
[4]杨志宏,王智彪,胡凯.聚焦超声对卵巢癌细胞株COC1细胞凋亡和Bcl-2/bax基因表达的影响[J].中国医学物理学杂志.2004,21(4):207-210.
[5] Wu F, Wang ZB, Zhu H, et al. Feasibility of US-guided high-intensity focusedultrasound treatment in patients with advanced pancreatic cancer: initial experience[J]. Radiology.2005,236(3):1034-1040.
[6] Poff JA, Allen CT, Traughber B, et al. Pulsed high-intensity focused ultrasoundenhances apoptosis and growth inhibition of squamous cell carcinoma xenograftswith proteasome inhibitor bortezomib[J]. Radiology.2008,248(2):485-91.
[7]王萍,夏新蜀,王志刚.低强度超声壤联合光敏剂对癌细胞的杀伤作用[J].激光杂志.2009,30(4):75-76.
[8] Yu T, Ba i J, H u K, et al. The effect o f free rad ica l scavenger and antiox idant onthe increase in intracellular adriamyc in accumulation induced by ultrasound [J].Ultrasond Sonochem.2003,10(1):33-35.
[9]叶欣,徐兴鲁,沈绍华等.非致死剂量高强度聚焦超声逆转K562/AO2细胞多药耐药的实验研究[J].中华医学超声杂志(电子版),2008,5(4):571-582.
[10] Tachibana K，Uehida T，Tamura K，et a1．Enhanced eytotoxie effect of Ara-C bylow intensity ultrasound to HL-60cells[J]. Cancer Letters.2000,149(1-2):189-194．
[11]王修杰,袁淑兰,张洁等.高强度聚焦超声对人乳腺癌细胞的生长抑制作用及机理研究[J].四川大学学报(医学版),2004,35(1):60-63.
[12]叶欣,邹玉红,刘丽霞等.高强度聚焦超声制备肿瘤抗原致敏DC及其体外诱导T细胞产生IFN-r的研究[J].中华医学超声杂志(电子版),2006,3(3):5-10.
[13]邹玉红,叶欣,刘丽霞等.高强度聚焦超声破坏结肠癌细胞株的实验观察[J].中国临床康复,2006,10(29):129-131.
[14]刘丽霞,叶欣,王海波等.高强度聚焦超声不同辐照时间对CT-26细胞的急性生物学效应[J].中国组织工程研究与临床康复,2007,11(9):1704-1706.
[15] Aaush H,Rozenszajn LA,Blass M, et al.Apoptosis induction of human myeloidleukemic cells by ultrasond exposure [J].Cancer Res.2000,60(4):1014-1020.
[16] Honda H,Kondo T,Zhao QL,et al.Role of intracellular calcium ions and reactiveqxygen species in apoptosis induced by ultrasound [J].Ultrasound Med Biol.2004,30(5):283-692.
[17] Lagneaux L, de Meulenaer EC, Delforge A, et al. Ultrasonic low-energy treatment:a novel approach to induce apoptosis in human leukemic cel［lJ.Exp Hematol.2002,30(11):1293-1301.
[18]郭倩,姜立新,胡兵等．不同辐照模式聚焦超声诱导人胰腺癌细胞凋亡的量效关系[J].中国医学影像技术.2011,27(3)
[19]许川山,余茜,吴士明等．高温治疗与细胞凋亡[J].中华理疗杂志，2001，24(3)：185-187.
[20] Vykhodtseva N, Mcdannold N, Martin H, et al. Apoptosis in ultrasoundddproduced threshold lesions in the rabbit brain[J].Ultrasound Med Biol,2001,27(1)111-117.
[21] Madiol DP，van Gelderen P，Despres D, et al. On the feasibility of MRI-guidedfocused ultrasound for local induction of gene expression [J].J Magn Reson Imaging，1998,8(l):101-104
[22]张俊霞,黄晶,王新等.超声辐照对血管平滑肌细胞增殖和凋亡的影响[J].重庆医科大学学报,2005,30(5):636-639.
[23] Wu G, Yang GY, Qiao TV, et al. Inhibition effects of high intensity focusedultrasound in combination with cisplatin on human bladder cancer cell in vitro[J].Chinese J Ultrasound Med.2000,16(5):321-324.
[24] Watkin NA，Morris SB，Rivens IH，Woodhouse CR，ter Haar GR．A feasibilitystudy for the non-·invasive treatment of superficial bladder tumors with focusedultrasound [J].British Journal of Urology.1996,78(5):7l5-721.
[25] Nelson J L，Roeder B L，Carmer J C，et a1．Ultrasonically activated chemotherapydrug delivery in a rat model [J].Cancer Res.2002,62:7280-7283.
[26]王昕娜,许川山,夏新蜀.低强度超声对鼻咽癌细胞生物学效应的研究[J].激光杂志.2009,30(6):70-71.
[27] Nie Jing, Liu Lin, Zheng, Wei, et al. microRNA-365, down-regulated in coloncancer, inhibits cell cycle progression and promotes apoptosis of colon cancer cellsby probably targeting Cyclin D1and Bcl-2[J].Carcinogenesis.2012,33(1):220-225.
[28] Itoi T, Takei K, Sofuni A, et al. Immunohistochemical analysis of p53and MIB-1in tissue specimens obtained from endoscopic ultrasonography-guided fine needleaspiration biopsy for the diagnosis of solid pancreatic masses[J]. Oncol Rep.2005,13(2):229-34.
[29] Doan N,Reher P，Meghji S,et al. In vitro effects therapeutic ultrasound on cellproliferation, protein synthesis，and cytokine production by human fibroblasts，osteoblasts，and monocytes [J].J Oral Maxillofac Surg.1999,57(4):409-420.
[30] Manabu Kinoshita, Yutaka Eguchi, Kullervo Hynynen. Activation of Bak inultrasound-induced, JNK and p38independent apoptosis and its inhibition by Bcl-2[J].Biochem Biophys Res Commun.2007,353(2):515–521.
[31]王修杰,袁淑兰,张洁等.高强度聚焦超声对人乳腺癌细胞的生长抑制作用及机理研究[J].四川大学学报(医学版),2004,35(1):60-63.
[32] Hrazdira I，Skorpikove J，Dolnikova M，et a1．Ultrasonicaiiy induced alterationsof cultured tumour cells [J].Eur J Ultrasound.1998,8(1):43-49.
[33] Abdollahi A, Domhan S, Jenne JW, et al. Apoptosis signals in lymphoblastsinduced by focused ultrasound [J]. FASEB J.2004,18(12):1413-1414.
[34] Firestein F;Rozemzain LA;Shemesh-Darvish L et a1．Induction of apoptosis byultrasound application in human malignant lymphoid cells：role of mitochondriacaspase pathway activation [J].Ann N Y Acad Sci.2003,1010:163-166．
[35] Hutcheson JD, Schlicher RK, Hicks HK, et al. Saving cells fromultrasound-induced apoptosis: quantification of cell death and uptake followingsonication and effects of targeted calcium chelation [J].Ultrasound Med Biol.2010,36(6):1008-1021.
[36] Feng Y, Tian Z, Wang M. Bioeffects of low-intensity ultrasound in vitro: apoptosis,protein profile alteration, and potential molecular mechanism [J].J Ultrasound Med.2010,29(6):963-74.
[37]马燕，陈宝安，吴巍等．低频低强度超声波诱导白血病细胞株k562凋亡的研究[J].东南大学学报(医学版),2006,25(3):154-159.
[2]王智彪.治疗超声原理与应用[M]。南京大学出版社，2008，172-173.
[3]高强度聚焦超声肿瘤治疗系统临床应用指南（试行）[J].中华医学杂志,2005,85:796-797.
[4] Morita Y, Ito N, Hikida H, et al. Non-invasive magnetic resonance imaging-guidedfocused ultrasound treatment for uterine fibroids: early experience[J]. Eur J ObstetGynecol Reprod Biol.2008,139(2):199-203.
[5] Taran FA, Tempany CM, Regan L.Magnetic resonance-guided focused ultrasound(MRgFUS) compared with abdominal hysterectomy for treatment of uterineleiomyomas[J].Ultrasound Obstet Gynecol.2009，34(5):572–578.
[6] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyoma symptomsby using focused ultrasound surgery [J]. Obstet Gynecol,2007,110:279-287.
[1] Chen WZ, High intensity focused ultrasound for larger volume ablation of uterinemyomas: a feasibility study.7th International Symposium on TherapeuticUltrasound（ISTU2007）,Seoul, Korea, June12-15,2007,06:53.
[2] Yi HL, Ting KL, Hung JW, et al. Treatment of Uterine Fibroids by Using MagneticResonance-guided Focused Ultrasound Ablation: the initial experience in Taiwan[J].Chin J Radiol.2009,34(4):263-271.
[3] Fennessy FM, Tempany CM, McDannold NJ, et al. Uterine Leiomyomas: MRImaging-guided Focused Ultrasound Surgery--Results of Different TreatmentProtocols [J].Radiology.2007,243（3）：885-893.
[4] So MJ, McDannold N, Fennessy FM, et al. Evaluation of the impact of body massand abdominal fat on MR-guided focused ultrasound surgery for uterine fibroids[J]. Magnet Resonce Med.2005,13:2141-2145.
[5]田国刚,黄运佰,朱才义.全麻复合硬膜外阻滞麻醉对肝癌患者HIFU治疗围术期β-EP的影响[J].海南医学院学报.2009,(9):89-91.
[6] S.J波可克著,郭日典,秦绍明译.临床治疗科研方法学[M].天津,天津科技翻译出版公司.1991:54-58.
[7] Magnetic resonance image-guided transcutaneous focused ultrasound ablation foruterine fibroids，http://www.nice.org.uk/IPG231.
[8]倪宗囊．临床试验设计[M]．北京,人民卫生出版社．1996:11-65.
[9] Stephen J S, Malone D E. Sedation and analgesia in adult patients: evaluation of astaged-dose system based on body weight for use in abdominal interventionalradiology [J]. Radiology.2000,216(4):653–659.
[10]朱丽,陈文直,陈锦云.咪唑安定-芬太尼镇静镇痛在高强度聚焦超声子宫肌瘤中的应用研究[J].重庆医科大学学报.2009,34(11):1556-1558.
[11] Sietses C，Beelen RH，Meijer S，et al. Immunologic consequences of laparoscopicsurgery: speculations on the cause and clinical implications [J]. Langenbecks ArchSurg.1999,384(3):250-258.
[12] Cruickshank AM, Fraser WD, Burns HJ, et al. Response of serum interleukin-6inpatients undergoing elective surgery[J]. Clinical Sciecn.1990,79(1):160.
[13] Grzelak I, Olszewski WL, Zaleska M. Blood cytokine levels rise even after minorsurgical trauma [J]. J Clin Immunol.1996,16(3):159-64.
[14] Clement GT. Perspectives in clinical uses of high-intensity focused ultrasound[J].Ultrasonics.2004,42(10):1087-1093.
[15] Schneemilch CE, Ittenson A, Ansorge S.Effect of2anesthetic techniques on thepostoperative proinflammatory and anti-inflammatory cytokine response andcellular immune function to minor surgery [J]. J Clin Anesth.2005,17(7):517-27.
[16] O’Sullivan ST，Lederer JA，Horgan AF，et al. Major injury leads to Predominanceof The heipr-2-lymPhocyte Phenotype and diminished interleukin-12Productionassociated with decreased resistance to infection [J].Ann Surg.1997,22(2):482-92.
[17] Shah PK, Falk E et al. Human monocyte-driven acrophages induce collagen weakdown in fibrous caps of atherosclerotic plaque: potential role of matrix degradingmetal proteinases and implications for plaque rupture [J].Circulation.1995,92(6):1565-1569.
[18] Vallina VL, Velasco JM. The influence of laparoscopy on lymphocytesubpopulations in the surgical patients [J].Surg Endosc.1996,10(1):481-484.
[19] A. Halevy, G. Lin, R, et al. Comparison of serum C-reactive protein concentrationsfor laparoscopic versus open cholecystectomy [J].Surg Endosc.1995,9(3):280-282.
[20] Yue Q, Ma R.Effects of laparoscopically-assisted vaginal hystererectomy comparedwith abdominal hysterectomy on immune function [J].The Journal of InternationalMedical Research.2009,37(1):855-861.
[21] Evans C, Galustian C, Kumar D, et al. Impact of surgery on immunologic function:comparison between minimally invasive techniques and conventional laparotomyfor surgical resection of colorectal tumors [J].Am J Surg.2009,197(2):238-245.
[22] Hong JY, Lim KT. Effect of preemptive epidural analgesia on cytokine Responseand Postoperative pain in laparoscopic radical hysterectomy for cervical cancer [J].Regional Anesthesia and Pain Medicine.2008,33(1):44-51.
[23] Hansbrough JF，Bender EM，Sirvent RZ. Altered helper and suppresso lymphocytepopulations in surgical patients: A measure of postoperative immuno suppression[J].Am J Surg.1984,148(3):303-307.
[24] Ogawa K, Hirai M, Katsube T, et al. Suppression of cellular immunity by surgicalstress [J].Surgery.2000,127:329-336.
[25] Matthias W, Wichmann, MD, Thomas P, et al. Immunological Effects ofLaparoscopic vs Open Colorectal Surgery [J]. Arch Surg.2005,140(2):692-697.
[26] Salo M. Effects of anaesthesia and surgery on the immune response [J].ActaAnaesthesiol Scand.1992,36(3):201-220.
[27] Matthias W, Wichmann, MD, Thomas P. Immunological Effects of Laparoscopic vsOpen Colorectal Surgery [J]. Arch Surg.2005,140(7):692-697.
[28] Barbieri C, Fujisawa MM, Yasuda CL.Effect of surgical treatment on the cellularimmune response of gastric cancer patients [J]. Braz J BiolRes.2003,36(3):339-345.
[29] Torres A, Torres K, Paszkowski T,et al. Cytokine response in the postoperativeperiod after surgical treatment of benign adnexal masses: comparison betweenlaparoscopy and laparotomy [J].Surg Endosc.2007,21(10):1841-1848.
[30] Tatsumi H, Ura H, Ikeda S. Surgical influence on TH1/TH balance and monocytesurface antigen expression and its relation to infectious complications [J].World JSurg.2003,27(5):522–528.
[31] Hong JY, Lim KT. Effect of preemptive epidural analgesia on cytokine Responseand Postoperative pain in laparoscopic radical hysterectomy for cervical cancer [J].Regional Anesthesia and Pain Medicine.2008,33(1):44-51.
[32] Frick VO, Justinger C, Rubie C. Thoracotomy procedures effect cytokine levelsafter thoraco abdominal esophagectomy [J]. Oncol Rep.2011,10(6):3892.
[33] Kim TK, Yoon JR. Comparison of the neuro-endocrine and inflammatory responsesafter laparoscopic and abdominal hysterectomy [J].Korean J Anesthesiol.2010,59(4):265-269.
[34] Delgado S, Lacy AM, Filella X, Castells A, Garcia-Valdecasas JC, Pique JM,Momblan D, Visa J. Acute phase response in laparoscopic and open colectomy incolon cancer: randomized study [J]. Dis Colon Rectum.2001,44(2):638-646.
[35] Ordemann J, Jacobi CA, Schwenk W. Cellular and homoral inflammatory responseafter laparoscopic and conventional colorectal resections [J].Surg Endosc.2001,15(6):600-608.
[36] Wichmann MW. Immunological Effects of Laparoscopic vs Open ColorectalSurgery [J].Arch Surg.2005,140(1):692-697.
[37] Torres A, Torres K, Paszkowski T, et al. Cytokine response in the postoperativeperiod after surgical treatment of benign adnexal masses: comparison betweenlaparoscopy and laparotomy [J]. Surg Endosc.2007,21(10):1841-8.
[38] Maruszynski M, Pojda Z. Interleukin6(IL-6) levels in the monitoring of surgicaltrauma: a comparison of serum IL-6concentration in patients treated bycholecystectomy via laparotomy or laparoscopy [J]. Surg Endosc.1995,9(4):882-885.
[39]刘春福,曹启迪.白细胞—血红蛋白指数在创伤早期对伤情判断的临床意义[J].中华创伤骨科杂志.2002,4(1):65-66．
[1] Kroencke TJ，Scheurig C, Poellinger A, et al. Uterine artery embolization forleiomyomas: percentage of infarction predicts clinical outcome [J].Radiology.2010,255(3):834-841.
[2] Hanafi M. Predictors of leiomyoma recurrence after myomectomy [J]. ObstetGynecol.2005,105(4):877-881.
[3] Burbank F. Childbirth and fibroid treatment by uterine artery occlusion: Do theyshare a common biology?[J]. J Am Gynecol Laparosc.2004,11(2):138-152.
[4]乐杰.妇产科学.第5版.北京：人民卫生出版社,2008:6.
[5]史常旭，辛晓燕.现代妇产科治疗学.3版.北京：人民军医出版社，2010:160-168.
[6] Stewart EA, Faur AV, Wise LA, Reilly RJ, Harlow BL. Predictors of subsequentsurgery for uterine leiomyomata after abdominal myomectomy [J]. Obstet Gynecol.2002,99(4):426–32.
[7] Elizabeth A, Stewart, Romana A. Nowak. Leiomyoma related bleeding: a classichypothesis updated for the molecular era [J].Human Reproduction Update.1996,2(4):295–306.
[8]徐刚，蔡泳，宋昕等.相关回归与多因素分析.上海口腔医学[J].2004,13(5)：426-429.
[9] Kennedy JE. High-intensity focused ultrasound in the treatment of solid tumours[J].Nat Rev Cancer.2005,5(4):321-327.
[10] Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation:standardization of terminology and reporting criteria [J].Radiology.2005,235(3):728-739.
[11] Walocha JA, Litwin JA, Miodoński AJ.Vascular system of intramural leiomyomatarevealed by corrosion casting and scanning electron microscopy [J]. HumReprod.2003,18(5):1088-1093.
[12] Funaki K, Fukunishi H, Sawada K.Clinical outcomes of magneticresonance-guided focused ultrasound surgery for uterine myomas:24-monthfollow-up [J]. Ultrasound Obstet Gynecol.2009;34(5):584-589.
[13] Funaki K, Fukunishi H, Funaki T, et al. Magnetic resonance-guided focusedultrasound surgery for uterine fibroids: relationship between the therapeutic effectsand signal intensity of preexisting T2-weighted magnetic resonance images [J].AmJ Obstet Gynecol.2007,196(2):184.e1-184.e6.
[14] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyomasymptoms by using focused ultrasound surgery [J].Obstet Gynecol.2007,110(7):279-287.
[15]陈文直,唐良萏,杨武威,等.超声消融治疗子宫肌瘤的安全性及有效性[J].中华妇产科杂志.2010,45(12):909-912.
[16]朱丽,陈文直,陈锦云,等.子宫肌瘤超声消融与MRI信号特征关系的研究[J].第三军医大学学报.2009,31(14):1370-1373.
[17] Fennessy FM, Tempany CM, Mc Dannold NJ, et al. Uterine leiomyomas: MRimaging-guided focused ultrasound surgery results of different treatment protocols[J].Radiology.2007,243(3):885-893.
[18]牛陵川，邹文兵，张炼，等.乳腺癌高强度聚焦超声消融后残留肿瘤增殖能力的变化.上海交通大学学报（医学版）[J].2010,30(2):200-203.
[19]戴良图,张宣东.沿海子宫肌瘤患者射频治疗对免疫淋巴细胞的影响[J].中华航海医学与高气压医学杂志.2005,12(2):104-105.
[1] Sumitani H, Shozu M, Segawa T, et al. In situ estrogen synthesized by aromataseP450in uterine leiomyoma cells promotes cell growth probably via anautocrine/intracrine mechanism [J]. Endocrinology.2000,141(10):3852-61.
[2] Shozu M, Sumitani H, Segawa T, Yang HJ, Murakami K, Inoue M. Inhibition of insitu expression of aromatase P450in leiomyoma of the uterus by leuprorelinacetate.[J].J Clin Endocrinol Metab.2001,86(11):5405-11.
[3] Englund K, Blank A, Gustav,xson I, et a1. Sex Steroid receptors in humanmyometrium and fibroids: changes during the menstrual cycle andgonadotropin-releasing hormone treatment [J].J Clin Endormol Metab，1998，83(11)：4092-4096.
[4]乔清理.组织消融一般模型的建立与其温度分布的分析与解析计算.中国生物医学工程学报.2002,21(l):74-78.
[5] Rudolf S, Peter WA, Dietrich H, et al.Temperature monitoring of interstitial thermaltissue coagulation using MR phase images [J].JMRI.1997,8(2):188-196.
[6]罗新,宋雯霞,吴秀枝,常明伟,邱学华.射频消融技术对子宫肌瘤组织中ER、PR表达影响的临床试验研究[J].2003,12(3):204-206.
[7]熊正爱等.高强度聚焦超声体外照射猴子宫近远期影响研究[J].中国超声医学杂志，2002,18(10):20-22.
[8]贺雪梅，熊欣，陈菲，邹建中.超声消融子宫肌瘤后靶区边缘雌孕激素受体表达研究.[J]重庆医科大学学报.2011,36(1):5-7.
[9]Hilger I, Rapp A, Greulich KO. Assessment of DNA damage in target tumor cellsafter thermoablation in mice [J].Radiology.2005,237(2):500-506.
[10]王智彪,李发琪,冯若.《治疗超声原理与应用》南京大学出版社.2008,6:78-120.
[11] Carreau P, Mercedes B. Aromatase distribution and regulation in fish [J]. FishPhysiol Biochem.2005,31(2):215-226.
[12] Daisuke Uchida, Michiaki Yamashita, Takeshi Kitano, Taisen Iguchi.An aromataseinhibitor or high water temperature induce oocyte apoptosis and depletion of P450aromatase activity in the gonads of genetic female zebrafish during sex-reversal [J].Comparative Biochemistry and Physiology.2004,13(7):11–20.
[13] Duffy TA, Picha ME, Won ET, Borski RJ, McElroy AE, Conover DO. Ontogenesisof gonadal aromatase gene expression in atlantic silverside (Menidia menidia)populations with genetic and temperature-dependent sex determination [J].J ExpZool A Ecol Genet Physiol.2010,313(7):421-31.
[14]熊正爱,杜永洪,邹建中等.高强度聚焦超声照射猴子宫对卵巢功能的影响研究[J].中华超声影像学杂志.2003,12(11):687-689.
[15] Meaney PM, Cahill MD, Ter Haar GR.The intensity dependence of lesion positionshift during focused ultrasound surgery [J].Ultrasound Med Biol.2000,26(3):441-450.
[16] Poff JA, Allen CT, Traughber B, et al. Pulsed high-intensity focused ultrasoundenhances apoptosis and growth inhibition of squamous cell carcinoma xenograftswith proteasome inhibitor bortezomib [J]. Radiology.2008,248(2):485-91.
[17]黎清,徐建平,罗惠娟.凋亡基因Caspase23在子宫肌瘤中的表达及相关性研究[J].2007,28(6):605-606.
[18]徐青,仇黎丽,徐昌芬.子宫平滑肌瘤细胞原代培养及鉴定.南京医科大学学报(自然科学版)[J].2007,27(9):967-969.
[19]王智彪,李发琪,冯若.《治疗超声原理与应用》南京大学出版社.2008,6:105.
[20]刘丽霞,叶欣,王海波.高强度聚焦超声不同辐照时间对CT26肿瘤细胞的急性生物学效应研究[J].中国组织工程研究与临床康复,2007,11(9):1704-1706
[21] Kennedy JE, Ter Haar GR, Cranston D.High intensity focused ultrasound: surgeryof the future?[J].Br J Radiol,2003,76(909):590-599.
[22]郭倩.不同辐照模式聚焦超声诱导人胰腺癌细胞凋亡的量效关系[J].中国医学影像技术,2011,27(3):479-484.
[23]吴飞翔，章卫平.JNK信号转导与细胞凋亡.生命的化学,2002,22(4):346-347.
[1] Pavna K. Brahma, Kristina M. Martel.Future Directions in Myoma Research [J].2006,33(1):199-224.
[2] Butori N, et al. Interest of uterine artery embolization with gelatin sponge particlesprior to myomectomy for large and/or multiple fibroids. Eur J Radiol (2009), doi:10.1016/j.ejrad.2009.09.028.
[3]郎景和，主编．妇科手术笔记[M]第1版．北京：中国科学技术出版社，2001,67.
[4]张庆霞，朱兰，刘珠凤等．开腹与微创子宫肌瘤剔除术的临床结局分析[J]．中国实用妇科与产科杂志,2008,24(4):278-281.
[5] Hanafi Magdi. Predictors of leiomyoma recurrence after myomectomy [J].ObstetGynecol.2005,105(4):877-881.
[6]曹泽毅主编．中华妇产科学[M]．北京：人民卫生出版社，1999,1822.
[7]旷红艺,李慧,熊焰等.经腹子宫肌瘤剔除术缝合方式的改进[J].中国现代临床医学，2008,12(7):13-16.
[8] Benassi L，Rossi T，Kaihura CT，et a1．Abdominal or vaginal hysterectomyfor enlarged uteri：a randomized clinical tria1[J].Am J Obstet Gynecol.2002,187(6):1561-1565．
[9]夏平，林红，艾婷华．经阴道与经腹子宫肌瘤剔除术的比较[J].中国微创外科杂志，2005，5(10)：819-82
[10] Rossetti A, Sizzi O, Chiarotti F, et a1. Developments in techniques forlaparoscopicmyomectomy [J].JSLS.2007,11(1):34-40．
[11] Doridot V, Dubuisson JB, Chapron C,et al.Recurrence of leiomyoma afterlaparoscopic myomectomy [J].Journalof the American Association of GynecologicLaparoscopists.2001,8(4):495-500.
[12] Rossetti A, Sizzi O, Soranna L, et al. Long-term results of laparoscopic recurrencerate in comparison with abdominal myomectomy [J]. Hum Reprod.2001,16(4):770-774.
[13] Malzoni M, Rotond C, et al. Fertility after laparoscopic myomectomy of largeuterine myomas: operative technique and preliminary results [J].Eyr J GynecolOncol.2003,24(1):79-82.
[14] Sesti F, Melgrati L, Damiani A, et a1. Isobaric (gasless)laparoscopic uterinemyomectomy: an overview[J].Eur J Obstet Gynecol Reprod Biol.2006,29(1):9-14．
[15]刘海防，刘彦．无气腹腹腔镜手术的临床应用[J].中国实用妇科与产科杂志.2007,23(8):587-588.
[16] Liang Z，Xu H，Chen Y，et a1．Laparoscopic blockage of uterine artery andmyomectomy：a new method of treating symptomatic uterine leiomyomas[J]．SurgEndosc.2006,20(6):983-986．
[17] Camran Nezhat, Michael Lewis, Sumathi Kotikela. Robotic versus standardlaparoscopy for the treatment of endometriosis [J].Fertility and Sterility.2010,94(7):2758-2760.
[18] Tulandi T. Endoscopic nyomectomy: laparoscopy and hysteroscopy [J]. ObstetGynecol Clin North Am.1999,26(1):l35-l38．
[19] Shokeir TA，Hysteroscopic management in submucous fibroids to improve fertility[J].Arch Gyntcol obstet.2005,273(1):50-54．
[20]宫华芳，王晓雷，夏明静等. B型超声监测在官腔镜电切术治疗子宫粘膜下肌瘤中的应用.[J]中国妇幼保健2008,(23):1442-1443
[21]王丽等.超声监导宫腔镜子宫肌瘤切除术的应用价值[J].实用医学影像杂志.2003,(40):271-272.
[22] Ravina JH, Herbreteau D, Ciraru VN, et a1. Arterial embolization to treat uterinemyomata [J].Lancet.1995,346(3):671-672．
[23] Goodwin SC, Bradley LD, Lipmm JC, et a1. Uterine artery embolization versusmyomectomy: a muhicenter comparative study[J].Fertil Steril.2006,85(1):14-21．
[24] Pinto I, Chimeno P, Romo A, et al.Uterine fibroids: uterine artery embolizationversus abdominal hysterectomy for treatment: a prospective, randomized andcontrolled clinical trial [J]. Radiology.2003,226:425-431.
[25] Hehenkamp WJK, Volkers NA, et al. Uterine artery embolization versushysterectomy in the treatment of symptomatic uterine fibroids (EMMY trial): peri-and postprocedural results from a randomized controlled trial [J]. Am J ObstetGynecol.2005,193:1618-1629.
[26] Edwards RD, Moss JG, Lumsden MA, et al. Uterine artery embolization versussurgery for symptomatic uterine fibroids [J]. N Engl J Med.2007,356(4):360-370.
[27] Goodwin SC, Spies JB, Worthington-Kirsch R, et al. Uterine artery embolizationfor treatment of leiomyomata: long-term outcomes from the fibroidregistry[J].Obstet Gynecol.2008,111(1):22-33
[28] Kitamura Y, Ascher SM, Cooper C, et al. Imaging manifestations of complicationsassociated with uterine artery embolization [J].Radiographics.2005,25(1):119-132.
[29]罗新，宋文霞.射频消融微创技术的进展及其在妇科领域的应用[J]．中国实用妇科与产科杂志.2003,19(4):247-249．
[30]戴良图，曾敏华，许恒.子宫肌瘤射频治疗对卵巢功能的影响．海军医学杂志，2003,24(4):309-311．
[31] Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyomasymptoms by using focused ultrasound surgery [J]. Obstet Gynecol.2007,110(2):279-287.
[32] Morita Y, Ito N, Hikida H, et al. Non-invasive magnetic resonance imaging-guidedfocused ultrasound treatment for uterine fibroids-early experience [J].Eur J ObstetGynecol Reprod Biol.2008,139(2):199-203.
[33] Stewart EA, Rabinovici J, Tempany CM, et al. Clinical outcomes of focusedultrasound surgery for the treatment of uterine fibroids [J]. Fertil Steril.2006,85(1):22-29.
[34] Leon-Villapalos J, Kaniorou-Larai M, Dziewulski P. Full thickness abdominal burnfollowing magnetic resonance guided focused ultrasound therapy [J].Burns.2005,(31):1054-1055.
[35] Tempany Cm，Stewart EA，Mcdannold N，et a1．MR imaging—guidea focusedultrasound surgery of uterine leiomyomas：a‘feasibility study[J]．Radiology2003，226：897-905．
[36]Miriam M. F. Hanstede, M.D., Clare M. C. et al. Focused ultrasound surgery ofintramural leiomyomas may facilitate fertility: A case report [J]. Fertility andSterility.2007,88(2):497.e5-e7.
[37] Jaron Rabinovici, Matthias David, et al.Pregnancy outcome after magneticresonance–guided focused ultrasound surgery (MRgFUS) for conservativetreatment of uterine fibroids [J].Fertility and Sterility.2010,93:199-209.
[1] Arya J诱导凋亡—一种抗肿瘤的策略[J].Surgery.2000,127(4):366-369.
[2] Ferreira CG, Epping M, Kruyt F, et al. Apoptosis: Target of Cancer Therapy [J].Clin Cancer Res.2002,8:2024–2034.
[3]徐静,许川山,夏新蜀.低强度超声对小鼠肝癌H22细胞抑制效应的初步研究[J].激光杂志.2009,30(6):69-71.
[4]杨志宏,王智彪,胡凯.聚焦超声对卵巢癌细胞株COC1细胞凋亡和Bcl-2/bax基因表达的影响[J].中国医学物理学杂志.2004,21(4):207-210.
[5] Wu F, Wang ZB, Zhu H, et al. Feasibility of US-guided high-intensity focusedultrasound treatment in patients with advanced pancreatic cancer: initial experience[J]. Radiology.2005,236(3):1034-1040.
[6] Poff JA, Allen CT, Traughber B, et al. Pulsed high-intensity focused ultrasoundenhances apoptosis and growth inhibition of squamous cell carcinoma xenograftswith proteasome inhibitor bortezomib[J]. Radiology.2008,248(2):485-91.
[7]王萍,夏新蜀,王志刚.低强度超声壤联合光敏剂对癌细胞的杀伤作用[J].激光杂志.2009,30(4):75-76.
[8] Yu T, Ba i J, H u K, et al. The effect o f free rad ica l scavenger and antiox idant onthe increase in intracellular adriamyc in accumulation induced by ultrasound [J].Ultrasond Sonochem.2003,10(1):33-35.
[9]叶欣,徐兴鲁,沈绍华等.非致死剂量高强度聚焦超声逆转K562/AO2细胞多药耐药的实验研究[J].中华医学超声杂志(电子版),2008,5(4):571-582.
[10] Tachibana K，Uehida T，Tamura K，et a1．Enhanced eytotoxie effect of Ara-C bylow intensity ultrasound to HL-60cells[J]. Cancer Letters.2000,149(1-2):189-194．
[11]王修杰,袁淑兰,张洁等.高强度聚焦超声对人乳腺癌细胞的生长抑制作用及机理研究[J].四川大学学报(医学版),2004,35(1):60-63.
[12]叶欣,邹玉红,刘丽霞等.高强度聚焦超声制备肿瘤抗原致敏DC及其体外诱导T细胞产生IFN-r的研究[J].中华医学超声杂志(电子版),2006,3(3):5-10.
[13]邹玉红,叶欣,刘丽霞等.高强度聚焦超声破坏结肠癌细胞株的实验观察[J].中国临床康复,2006,10(29):129-131.
[14]刘丽霞,叶欣,王海波等.高强度聚焦超声不同辐照时间对CT-26细胞的急性生物学效应[J].中国组织工程研究与临床康复,2007,11(9):1704-1706.
[15] Aaush H,Rozenszajn LA,Blass M, et al.Apoptosis induction of human myeloidleukemic cells by ultrasond exposure [J].Cancer Res.2000,60(4):1014-1020.
[16] Honda H,Kondo T,Zhao QL,et al.Role of intracellular calcium ions and reactiveqxygen species in apoptosis induced by ultrasound [J].Ultrasound Med Biol.2004,30(5):283-692.
[17] Lagneaux L, de Meulenaer EC, Delforge A, et al. Ultrasonic low-energy treatment:a novel approach to induce apoptosis in human leukemic cel［lJ.Exp Hematol.2002,30(11):1293-1301.
[18]郭倩,姜立新,胡兵等．不同辐照模式聚焦超声诱导人胰腺癌细胞凋亡的量效关系[J].中国医学影像技术.2011,27(3)
[19]许川山,余茜,吴士明等．高温治疗与细胞凋亡[J].中华理疗杂志，2001，24(3)：185-187.
[20] Vykhodtseva N, Mcdannold N, Martin H, et al. Apoptosis in ultrasoundddproduced threshold lesions in the rabbit brain[J].Ultrasound Med Biol,2001,27(1)111-117.
[21] Madiol DP，van Gelderen P，Despres D, et al. On the feasibility of MRI-guidedfocused ultrasound for local induction of gene expression [J].J Magn Reson Imaging，1998,8(l):101-104
[22]张俊霞,黄晶,王新等.超声辐照对血管平滑肌细胞增殖和凋亡的影响[J].重庆医科大学学报,2005,30(5):636-639.
[23] Wu G, Yang GY, Qiao TV, et al. Inhibition effects of high intensity focusedultrasound in combination with cisplatin on human bladder cancer cell in vitro[J].Chinese J Ultrasound Med.2000,16(5):321-324.
[24] Watkin NA，Morris SB，Rivens IH，Woodhouse CR，ter Haar GR．A feasibilitystudy for the non-·invasive treatment of superficial bladder tumors with focusedultrasound [J].British Journal of Urology.1996,78(5):7l5-721.
[25] Nelson J L，Roeder B L，Carmer J C，et a1．Ultrasonically activated chemotherapydrug delivery in a rat model [J].Cancer Res.2002,62:7280-7283.
[26]王昕娜,许川山,夏新蜀.低强度超声对鼻咽癌细胞生物学效应的研究[J].激光杂志.2009,30(6):70-71.
[27] Nie Jing, Liu Lin, Zheng, Wei, et al. microRNA-365, down-regulated in coloncancer, inhibits cell cycle progression and promotes apoptosis of colon cancer cellsby probably targeting Cyclin D1and Bcl-2[J].Carcinogenesis.2012,33(1):220-225.
[28] Itoi T, Takei K, Sofuni A, et al. Immunohistochemical analysis of p53and MIB-1in tissue specimens obtained from endoscopic ultrasonography-guided fine needleaspiration biopsy for the diagnosis of solid pancreatic masses[J]. Oncol Rep.2005,13(2):229-34.
[29] Doan N,Reher P，Meghji S,et al. In vitro effects therapeutic ultrasound on cellproliferation, protein synthesis，and cytokine production by human fibroblasts，osteoblasts，and monocytes [J].J Oral Maxillofac Surg.1999,57(4):409-420.
[30] Manabu Kinoshita, Yutaka Eguchi, Kullervo Hynynen. Activation of Bak inultrasound-induced, JNK and p38independent apoptosis and its inhibition by Bcl-2[J].Biochem Biophys Res Commun.2007,353(2):515–521.
[31]王修杰,袁淑兰,张洁等.高强度聚焦超声对人乳腺癌细胞的生长抑制作用及机理研究[J].四川大学学报(医学版),2004,35(1):60-63.
[32] Hrazdira I，Skorpikove J，Dolnikova M，et a1．Ultrasonicaiiy induced alterationsof cultured tumour cells [J].Eur J Ultrasound.1998,8(1):43-49.
[33] Abdollahi A, Domhan S, Jenne JW, et al. Apoptosis signals in lymphoblastsinduced by focused ultrasound [J]. FASEB J.2004,18(12):1413-1414.
[34] Firestein F;Rozemzain LA;Shemesh-Darvish L et a1．Induction of apoptosis byultrasound application in human malignant lymphoid cells：role of mitochondriacaspase pathway activation [J].Ann N Y Acad Sci.2003,1010:163-166．
[35] Hutcheson JD, Schlicher RK, Hicks HK, et al. Saving cells fromultrasound-induced apoptosis: quantification of cell death and uptake followingsonication and effects of targeted calcium chelation [J].Ultrasound Med Biol.2010,36(6):1008-1021.
[36] Feng Y, Tian Z, Wang M. Bioeffects of low-intensity ultrasound in vitro: apoptosis,protein profile alteration, and potential molecular mechanism [J].J Ultrasound Med.2010,29(6):963-74.
[37]马燕，陈宝安，吴巍等．低频低强度超声波诱导白血病细胞株k562凋亡的研究[J].东南大学学报(医学版),2006,25(3):154-159.
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