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二维超声监控HIFU治疗子宫肌瘤及疗效评价
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摘要
研究背景
     子宫肌瘤是育龄妇女生殖系统常见的良性肿瘤,尽管其恶变率很低,但是对患者生活质量有较大影响。对有症状的子宫肌瘤传统治疗方法以手术为主。由于子宫动脉供给卵巢的血液约占卵巢总供血量的50%~60% ,据报道绝经前切除子宫者,即使保留卵巢,也常致更年期综合症、冠心病及骨质疏松提早发生。因而,保留子宫的治疗对减轻或消除临床症状,提高患者生活质量有重要意义。所以近年来微创或无创治疗子宫肌瘤备受注目。
     高强度聚焦超声(high intensity focused ultrasound,HIFU )治疗子宫肌瘤,是利用超声波良好的组织穿透性和可聚焦性将体外的超声能量聚积到肿瘤组织中,使靶区肿瘤组织瞬间升到60~100℃的高温,从而达到原位“切除”或热消融肿瘤的目的。国内外有学者对磁共振(Magnetic resonance imaging,MRI)引导HIFU治疗子宫肌瘤进行研究,验证了MRI引导HIFU治疗子宫肌瘤的可行性和安全性。但是MRI对硬件要求高、价格昂贵,不利于这项技术的普及。超声引导HIFU治疗子宫肌瘤虽有报道,目前仍未形成系统而规范的术中监控、实时疗效评价和治疗后疗效评价标准。该课题由超声医疗国家工程研究中心资助
     目的
     利用二维超声图像对HIFU治疗子宫肌瘤进行监控和疗效评价,并把超声二维图像和MRI图像对比分析,旨在提高二维超声监控的准确性。进一步对超声图像进行量化分析,探索建立二维超声半定量疗效评价标准,有利于指导临床治疗。
     材料及方法
     1实验设备及临床资料
     1.1实验设备:
     采用JC型聚焦超声肿瘤治疗系统(重庆海扶(HIFU)技术有限公司),治疗头频率0.8MHz,焦距142mm,声功率100~400W;
     PHILIPS HD3型彩色超声诊断仪(探头频率3.5MHz)。二维超声设定条件:G50/P90/93dB/余辉6,D15.00cm,MI1.1,TIS0.4;
     灰度处理软件由重庆海扶(HIFU)技术有限公司提供;
     MAGNETOM Symphony Timαsystem(SIEMENS 1.5T)。设备条件:线圈:Body Matrx/Large Loop coil;采用快速自旋回波序列(TSE);T1WI:TR502ms,TE12ms;T2WI:TR:4000ms,TE98ms;视野(FOV)230mmx230mm~260mmx320mm
     对比造影剂:对比造影剂为钆双胺注射液(0.5mmol/ml),剂量为15~20ml
     1.2临床资料:
     入选标准:临床、超声及MRI诊断为子宫肌瘤的患者;绝经前妇女,有保留子宫的要求;机载超声可显示的肌瘤;肌瘤最大径不超过10cm;肌壁间肌瘤;非带蒂的浆膜下和粘膜下肌瘤;愿意接受镇静镇痛方法及HIFU治疗的子宫肌瘤患者。
     排除标准:宫颈肌瘤;血管型平滑肌瘤;宫颈细胞学检查提示异常细胞;合并妇科其他疾病者(如阴道炎、盆腔炎、肿瘤等);妇科检查及影像学检查怀疑有盆腔内组织、器官粘连;子宫后倾固定,俯卧位时,子宫肌瘤或子宫仍压迫直肠者;两次剖宫产史或子宫体部剖宫产史者;月经期妇女、孕妇(妊娠试验阳性)及哺乳期妇女;结缔组织病或接受过腹部大剂量放疗者;放置心脏起搏器的患者;心脏病患者(不稳定性心绞痛、半年内心机梗塞、心律失常需用药物控制者、严重的高血压及心力衰竭者);其他有核磁共振及麻醉禁忌的患者;听力、智力障碍,精神障碍,沟通困难,不能准确表达意愿,不合作或不愿意接受镇静镇痛及HIFU治疗的患者。
     入选病例95例(共108个肌瘤),年龄27~51岁,平均年龄37.65岁。肌瘤平均体积50.81cm3(1.09~566.41cm3)。95例患者有86例有不同程度的月经异常和/或贫血。
     2实验方法
     2.1术前准备
     ①术前常规检查;
     ②肠道准备:治疗前3天清淡少渣饮食,治疗前1天肠道准备,治疗当天清洁灌肠;
     ③皮肤准备:术前治疗区皮肤备皮、脱脂、脱气;
     ④膀胱准备:术前导尿,并向膀胱注射300~400ml生理盐水;
     ⑤体位:充分暴露治疗区,患者俯卧于治疗台上;
     ⑥建立静脉通道。术前30分给予5%GS500ml+格拉司琼3mg静脉滴注,并且根据患者的心率加入适当的阿托品。
     2.2术中监控
     ①定位:使用机载超声作为术中监控设备。纵向扫描患者盆腔,找准肌瘤位置。通过导尿管调整膀胱充盈程度,在不改变体位的情况下,使子宫及肌瘤能够清晰显示并且保证焦点能到达肌瘤的各个部位。仔细观察肌瘤的大小、数量、部位,同时观察声通道上有无肠道,必要时在患者腹部与治疗头之间放置水囊以推开肠道。最后确定治疗的起止点;
     ②预扫描:确定治疗的起止点后,纵向从左向右以5mm一层的间距对治疗区进行预扫描;
     ③镇静镇痛:用芬太尼1 ug/Kg、咪唑安定0.03mg/Kg,间隔时间为40分、60分。术中密切观察患者生命体征并且随时了解患者有无疼痛及疼痛的部位、性质;
     ④治疗:术中在机载超声的监控下对肌瘤区域进行治疗。采用定点点打的方式,声功率100~400W。首先采用较小功率进行辐照,根据患者的反应及肌瘤的灰度变化情况提高声功率,在患者能够耐受的范围类治疗。由点到线、由线到面,逐层治疗直至覆盖整个肌瘤。术中以肌瘤的灰度发生明显变化作为治疗有效的主要标志。治疗过程中实时监控声通道上及病变周围器官、组织结构有无异常改变,一旦发生立即终止治疗;
     ⑤治疗结束前再次用机载超声图像评价治疗效果,如灰度增加不明显,可对该区再次补充能量。最后存图进行测量和分析。
     2.3术后处理
     术后患者常规抗感染,注意观察皮肤、下腹部、阴道流液及小便情况。
     2.4影像学检查
     患者术前,术后即刻,术后1、3、6月分别行超声及MRI检查。保证前后检查时MRI序列及扫描参数设定一致,超声的总增益、分段增益、频率等参数一致。
     2.4.1二维超声图像与MRI图像比较
     根据术后1月MRI增强图像的结果,按照肌瘤坏死程度把肌瘤分为:完全坏死、部分坏死和未坏死三类。
     ①超声与MRI测量肌瘤体积的比较;②术中超声回声变化与坏死程度比较;③术中超声灰度值变化与坏死程度比较;④术中能量给予方式与坏死程度比较;⑤术中辐照方式与坏死程度比较治疗;⑥治疗后1、3、6月超声灰度值变化与坏死程度比较。
     2.4.2术后超声随访
     分析不同的超声图像特征和表现,寻找可用于疗效评价的指标。
     ①子宫体积变化:②肌瘤体积变化;③肌瘤灰度变化;④肌瘤均匀度变化;⑤子宫和肌瘤的缩小率。
     2.5影响疗效因素探讨
     对术前不同体积(分为<4cm3、4~65 cm3、>65 cm3三类)、不同类型(分为肌壁间、浆膜下、粘膜下三类)、不同灰度(分为高回声型、等回声型、低回声型三类)、不同均匀度(分为回声均匀、回声欠均匀、回声不均匀三类)的肌瘤分类进行疗效比较,分析影响因素。
     2.6制定HIFU治疗子宫肌瘤术后疗效超声评价评分表
     综合术前子宫及肌瘤的位置、肌瘤的不同声像图表现、术中回声变化情况、术中灰度值变化情况、术后肌瘤缩小程度及术后肌瘤灰度值变化情况,初步拟定HIFU治疗子宫肌瘤术后二维超声疗效评价评分表,并对治疗后肌瘤进行评分,总结出超声评价有效的分值。
     3统计学分析
     结果应用SPSS11.5统计软件包和Microsoft Excel软件进行分析。
     结果
     1.坏死明显的肌瘤和坏死不明显的肌瘤在术中的超声表现各异。坏死明显的肌瘤在术中表现为超声灰度值增加明显(>25)、内部出现团块状回声增高区或整体灰度增加。坏死不明显的肌瘤在术中表现为灰度值增加不明显、肌瘤内部也未见明显回声增高区。故而术中肌瘤灰度值变化及回声变化情况可作为术中监控判断疗效的指标。
     2.治疗时以功率≥250W为主(≥250W辐照时间占总辐照时间的50%以上)的肌瘤共37个,未坏死者2个;治疗时以功率<250W为主(<250W辐照时间占总辐照时间的50%以上)的肌瘤共12个,未坏死者5个。可见治疗时采用大功率治疗坏死范围较大。
     3.术后6月子宫平均缩小率为24.20%,肌瘤平均缩小率为56.31%。肌瘤内部灰度值在治疗后增加到术后1月到达最高,随后逐渐降低。子宫及肌瘤的体积变化、肌瘤灰度值变化术前与术后比较有差异,可作为HIFU治疗子宫肌瘤后二维超声疗效评价的指标。肌瘤内部均匀度的变化术前与术后比较无差异,不能作为疗效评价指标:
     4.不同声像图特征的肌瘤疗效各异:体积在4~65cm3、肌壁间、高回声型及回声不均匀的肌瘤疗效较好。
     5.根据术前子宫及肌瘤的位置、肌瘤的各种声像图表现、术中肌瘤灰度变化情况、术后肌瘤缩小及灰度值变化情况等因素综合,初步拟定的二维超声疗效评分表,分值≥22可以视为治疗有效。
     结论
     1.超声可以实现实时监控HIFU辐照过程,术中的超声回声变化及灰度值变化可以作为疗效判断的标准。
     2.术后超声图像反应的子宫及肌瘤的体积变化、肌瘤内部灰度值变化能够准确地反映治疗效果,可以作为疗效评价的指标。
     3.通过对肌瘤治疗前超声图像的分析,有助于预测疗效。
     4.初步拟定的二维超声疗效评分表能够较直观地反映治疗效果,分值≥22可以视为治疗有效。
Background
     Uterine fibroids are common benign tumors of the reproductive system of women of childbearing, despite its low rate of malignant transformation, but the quality of life have been effected . The symptomatic uterine fibroids are treated by traditional surgery. However, due to uterine artery supply ovarian blood about 50% to 60% , it was reported that premenopausal women without uterine, even if ovarian are reservated often have menopause syndrome, coronary heart disease and osteoporosis. As a result, it is significant that a method is used to treat Uterine fibroids with uterine reserved to reduce or eliminate symptoms and improve the quality of life. So in recent years, it is well known that uterine fibroids were treated by minimally invasive or non-invasive methods .
     Treating uterine fibroids by HIFU (High Intensity Focused Ultrasound,HIFU) makes the use of ultrasonic sound which penetrats organizations and accumulates vitro ultrasonic energy in tumor tissue, makes tumor tissue momently risen to 60 ~100℃temperature, so as to achieve in-situ "removal" or thermal ablation of the tumor. Some scholars conducted the treatment of uterine fibroids by MRI (Magnetic resonance imaging, MRI) guiding HIFU . Researchs have shown it’s feasibility and safety. Because it is very expensive, it has not conducted to the popularity of this technology, nor the formation of a standardized treatment plan and effective evaluation criteria. Although ultrasound-guided HIFU in the treatment of uterine fibroids has been reported, the system has not yet the criteria which it is about systematic monitoring and immediate efficacy and post-op efficacy.
     Objective
     Monitoring HIFU treatment of uterine fibroids with Two-dimensional ultrasound images and comparing two-dimensional ultrasound images and MRI image aim at improving the accuracy of two-dimensional ultrasound monitoring. Through analyzing Ultrasound images on digital image, two-dimensional ultrasound half of the number of evaluation criteria is explored and created to guide clinical treatment.
     Materials and Methods
     1 Experimental equipment and clinical data
     1.1 experiment equipment:
     JC-focused ultrasound tumor therapeutic system, the treatment of frequency 0.8 MHz, 142 mm focal length, Sound Power 100 ~ 400 W(Chongqing Haifu (HIFU) Technology Co., Ltd.);
     PHILIPS HD3-color ultrasonic machine (transducer frequency 3.5 MHz);
     Magnetom Symphony Tim 1.5T (SIEMENS) equipment;
     Gray processing software Provided by Chongqing Haifu (HIFU) Technology Co., Ltd.
     1.2 clinical data:
     Selected criteria: patients with uterine fibroids diagnosed clinically and with ultrasound and MRI; pre-menopausal women, the uterus is asked to be retained; myoma can be shown with Airborne ultrasound; fibroids maximal diameter are not more than 10 cm; muscle intramural fibroids; non-pedunculated subserosal and the submucosal fibroids; women willing to accept such sedation analgesia methods and the treatment
     Exclusion criteria: Cervical fibroids; vascular smooth muscle tumor; abnormal cervical cytology tips cells; combined with gynecologic other diseases (such as vaginitis, pelvic inflammatory disease, tumors, etc.); pelvic tissues and organs adhesion suspected by gynaecological examinations and imaging examination; uterus after dumping fixed, prone position, uterine fibroids or uterine still oppression rectum; history of cesarean section two of the uterus or the history of cesarean section; menstrual period, pregnant women (pregnancy test was positive) and breast-feeding women; connective tissue disease or have undergone major abdominal dose radiotherapy; placed pacemaker patients with heart disease (unstable angina, heart-year infarction, arrhythmias require drug control, hypertension and serious effort Failure); NMR and other taboos anesthesia patients.
     Selected cases of 95 cases (a total of 108 fibroids), aged 27 to 51 years old, the average age of 37.65 years old. Leiomyoma volume averages 50.81 cm3 (1.09 ~ 566.41cm3). 86 out of 95 cases with varying degrees of menstrual abnormalities and / or anemia.
     2 Experimental methods
     2.1 Preoperative preparation
     ①Preoperative routine examination;
     ②Bowel preparation: three days before light therapy less residue diet, one day before treatment bowel preparation, clean enema at treatment the same day;
     ③Skin preparations: treatment areas skin preparating, degreasing, degassing;
     ④Bladder prepared: preoperative catheterization and bladder injection of 300 ~ 400 ml saline;
     ⑤Position: exposure therapy areas, pronation;
     ⑥Establish intravenous access. Preoperative 30 points, Infusion 5% GS500ml + granisetron 3mg and appropriate atropine based on patients’heart rate .
     2.2 Intraoperative monitoring
     ①Positioning: Using ultrasound as an airborne operation and monitoring equipment. vertical scan pelvic to pinpoint the location of fibroids. The position unchanged, adjust bladder through the catheter, to make sure uterus and myoma can be clearly shown and ensure that the focus can reach all parts of the leiomyoma. Carefully observe the fibroids the size, number, location, at the same time observe whether intestinal in the sound channel . If necessary, place a cystic between patients’abdominal and probe to open them. Final determine the beginning and ending points;
     ②Pre-scan: After determining the beginning and ending points, vertical scan from left to right to a 5 mm distance between the treatment of pre-scanning area;
     ③Sedation analgesia: fentanyl 1 ug / Kg, midazolam 0.03 mg / Kg, the time interval of 40 minutes, 60 minutes. Closely observe vital signs and pain with their location and nature;
     ④Treatment: treat fibroids region by intraoperative ultrasound. Sentinel point play, sound power 100 ~ 400 W. First used for smaller power irradiation, then in accordance with the response of patients with fibroids and changes in the gray increase sound power, in the scope of patients are able to tolerate such treatment. From points to lines from the line to face, layer by layer until the entire treatment of fibroids. Fibroids gray change significantly as the main indicator of effective treatment. Real-time monitoring in the course of treatment access and voice around the organ lesions, abnormal changes in the organizational structure, in that case the treatment must be terminated immediately;
     ⑤Evaluate again therapeutic effect before the end of treatment using ultrasound image, if the gray increases not obvious, added energy once again in the area .Finally , map for measurement and analyzing.
     2.3 After treatment
     Patients conventional anti-infection, take note of the skin, lower abdominal, vaginal fluid and urine situation.
     2.4 Imaging examination
     Patients are examed by ultrasound and MRI before, immediately after, after 1, 3, 6, respectively. Ensure that the conditions of the same before and after the inspection.
     2.4.1 Ultrasound image compared with MRI image
     According to MRI images after HIFU 1 month, in accordance with the degree of fibroid necrosis fibroids are: complete necrosis, partial necrosis and un-necrosis.
     ①comparing leiomyoma volumes measured by ultrasound and MRI respectively ;②compare gray-scale intraoperative ultrasound with the extent of necrosis;③compare intraoperative ultrasound image changes with the extent of necrosis;④Analyse intraoperative dose and the extent of necrosis;⑤Analyse treatment options and the extent of necrosis;⑥compare gray-scale ultrasound after HIFU1,3,6months with MRI enhanced images after HIFU 1month .
     2.4.2 Postoperative follow-up ultrasound
     15 Analyzing different features and performance of ultrasound image, finding the target Evaluation
     ①uterine volume changes:②leiomyoma volume changes;③fibroids gray change;④fibroids uniformity of change;⑤uterine fibroids and reduce rates.
     2.5 Clinical factors affecting
     Comparing the effect of different size (divided into <4 cm3, 4 to 65 cm3,> 65 cm3), different types (intramural into muscle, serosa, submucosal), different gray (divided into high Echo type, echo type, echo-low type), different uniformity (evenly divided into echo, echo less homogeneous, heterogeneous echo) of the leiomyoma and analyzing the influence factors.
     2.6 Develop ultrasonic score Evaluation Table after uterine fibroids are treated by HIFU
     According to implications of different location, type, volume, echo Etc, and ultrasound changes during and after the treatment, ultrasonic score Evaluation Table is developed preliminary after HIFU . Score and assess the leiomyoma after the HIFU and sum up surplus Sound effective evaluation scores.
     3 statistical analysis
     Results are analysed by SPSS11.5 statistical software package, and Microsoft Excel.
     Results
     1. Fibroids with Necrosis obvious and without visible necrosis are different ultrasound image. Fibroids with Necrosis obvious were gray value increased significantly (> 25), Mission massive internal echo or higher increased overall gray. Leiomyomas without visible necrosis were not obvious gray value increase, fibroids no obvious echo within the district increased. Therefore, leiomyoma gray’s change and change in the echo can be used in the monitoring of the indicators of judgement. 2. Treatment to the main power≥250 W (≥250 W irradiation time is about more than 50 per cent of the total irradiation time) of a total of 37 fibroids, two are not necrosis; treatment to power <250 W mainly (<250 W irradiation time is about more than 50 per cent of the total irradiation time), a total of 12 myoma, five are not necrosis,. This shows that treatment using high-power range of necrosis.
     3. After 6months an average rate of uterine narrow 24.20 percent, narrowing the leiomyoma was 56.31 percent. The gray increased to reach the highest after 1 mouth, then gradually decreased. The volume changes of Uterine and fibroid and changes of fibroids’can be used as HIFU treatment of uterine fibroids after the two-dimensional ultrasound evaluation of the effect of indicators. Changes of fibroids internal evenness is no difference between before and after. So it can not be used as indicators of Evaluation
     4. Different leiomyomas with different ultrasonographic characteristics have the different effecacy: Volume 4 ~ 65 cm3, muscle intramural and high-echo echo uneven fibroids are better efficacy than others.
     5. According to preoperative uterine fibroids and the location of the fibroids performance of audio, visual map, with changes in leiomyoma gray, gray and narrow after fibroid changes in the value of such factors, developed a standard efficacy score, score≥22 can be considered an effective treatment.
     Conclusion
     1. Ultrasound can monitor real-timely HIFU irradiation process change in the ultrasonic echo and Gray’s changes can be used as standard.
     2. Ultrasound images Reaction of the volume of changes and within the gray values after treatment can accurately reflect the treatment as indicators Evaluation.
     3. Analysis of ultrasound before treatment can predict efficacy
     4. Preliminary designed score table can be more directly reflect the therapeutic effect. It can be regarded as an effective treatment if the score≥22
引文
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