【作者】 李雷；

【导师】 李成利；

【作者基本信息】 山东大学 ， 影像医学与核医学（专业学位）， 2016， 博士

【摘要】 第一部分1.0 T开放式磁共振引导125I放射粒子植入术在脑恶性肿瘤中的应用研究脑恶性肿瘤分为原发性与继发性两种。对于大部分脑原发恶性肿瘤,手术是其主要的治疗方法,术后常辅以放化疗。然而,脑原发恶性肿瘤常呈浸润性生长,侵及脑干、血管等重要器官,致使手术难以完全切除,术后极易复发。转移瘤是脑恶性肿瘤中较常见的一种,单发性转移瘤的首选治疗方法是手术或放疗(立体定向放射外科SRS或立体定向放射治疗SRT),且建议术后或精确放疗后应常规给予WBRT以降低复发率。但手术创伤大,往往影响患者的生存质量,甚至延误治疗。WBRT可以引起脑及神经的放射性损伤,且不能重复应用,研究认为至少有部分患者并没有从WBRT中获益。因此,手术和WBRT在脑转移瘤中的地位受到了质疑。精确放疗,目前主要是指精确外放疗技术,如IMRT, IGRT,VMAT、X刀(SRT)、γ刀(SRS)等,和近距离放疗如125[粒子组织间插植治疗,为脑转移瘤的治疗提供了多种有利选择。1251粒子植入术是一种精确近距离放射治疗技术,其在恶性肿瘤的综合治疗中发挥着重要作用。目前,1251粒子植入术的植入方式分两种,一是在影像引导下进行,二是术中直视下植入。目前MRI引导1251粒子植入治疗恶性肿瘤中的报道越来越多见,但MRI引导1251粒子植入治疗脑恶性肿瘤的报道比较少见,仅国内见少量报道,MRI引导125I粒子植入治疗脑转移瘤目前尚未见报道。研究目的本研究旨在研究1.0 T开放式磁共振导引下125I粒子植入治疗原发脑恶性肿瘤和脑转移瘤患者的可行性和安全性,并对其疗效进行评价。研究方法病历资料：本研究所用病例均来自山东省医学影像学研究所。收集2014年10月至2016年5月就诊于山东省医学影像学研究所的脑恶性肿瘤患者。其中原发性脑恶性肿瘤患者11例,(男5例,女6例,中位年龄47岁),脑单发转移瘤患者18例(男10例,女8例,中位年龄52岁)。本研究经本单位机构的伦理审查委员会批准,所有患者均签署知情同意书。原发脑恶性肿瘤患者入组标准为：①病理检查确诊为脑恶性肿瘤(WHOⅢ-Ⅳ级)；②肿瘤在强化MRI图像上边界清晰；③预计生存期>3个月；④术前检查血常规、血生化、肝功、肾功、心功能以及凝血功能提示患者能够耐受粒子植入术；⑤KPS评分≥50分。脑转移瘤患者入组标准：①肿瘤为单发；②预计生存期>3个月③KPS评分≥30分。手术过程：将患者术前的CT或MR图像导入粒子植入治疗计划系统(Treatment Plan System, TPS)进行三维重建,勾划靶区,设计进针路径,确定125I粒子籽源的活度、数目,模拟布源。未行脑部放疗者MPD设定110Gy,曾行脑部放疗者MPD设定90Gy。设定D90>90%MPD,V200<50%。根据病变位置取合适体位,如仰卧位、侧卧位、俯卧位等,尽量使病人保持舒适姿势。术区放置鱼肝油酸钠定位球,常规行MR平扫及增强扫描(序列)以最佳显示脑内病变位置、形态及大小。根据术前TPS计划确定穿刺路径及皮肤进针点。钻孔成功后再将扫描床移至磁共振扫描仪内,术中在磁共振3D透视下,应用实时引导技术,在两个交互垂直的平面上实时地显示穿刺针的方向及位置,扫描时间间隔1.5s,扫描中实时引导逐步进针,直至穿刺到位。手术完成后,对患者进行CT扫描并将图像传输至TPS系统中进行剂量验证。术后绝对卧床24小时,记录生命体征,对症处理。术后TPS验证。若有不足,可进行二次1251粒子补入手术。观察指标：观察1.0 T开放式磁共振对脑肿瘤、穿刺定位针的显示情况,分析1.0 T开放式磁共振引导125I粒子植入治疗的安全性、粒子植入后剂量的可靠性。125I粒子植入后术后第1、3个月及以后每3个月复查脑MR或CT强化扫描,观察肿瘤体积大小变化情况,随访观察临床症状及认知功能变化情况,并评估其KPS评分的变化情况。肿瘤反应率(response rate, RR)由CR和PR的和表示。计算局部控制率及生存率。统计方法：采用SPSS18.0统计软件进行分析。所有数据均以均数土标准差(a士S)表示,用t检验分析相应实验结果的差异显著性,,应用Kaplan-Meier法计算局部控制率及肿瘤特异性生存率。P值<0.05被认为有统计学意义。研究结果1.1.0 T开放式磁共振多参数多平面成像能够清晰显示脑部病变。清晰准确勾勒完整靶区。2.1.0 T开放式磁共振T1WI-TSE快速序列能够准确显示穿刺定位针的位置,表现为低信号伪影,能够清晰显示穿刺针与病变的位置关系。3.整个手术过程及随后的随访提示,125I粒子植入以1.0 T磁共振为引导是安全的,所得剂量可靠。4.1.0 T开放式磁共振引导125I粒子植入术可以提高脑恶性肿瘤的局控率。我们用CR与PR的和表示肿瘤反应率RR的大小。术后1月RR 21例,占72.41%;术后3月RR 22例,占75.86%；术后6月, RR 22例,占75.86%。51.0 T开放式磁共振引导下125I粒子植入术可以改善患者生存质量。所有患者均在粒子植入术后1月、3月、6月、12月评估其症状缓解情况。所有患者术前均呈不同程度头痛、恶心、呕吐等症状,MR引导下125I粒子植入术后所有患者症状均不同程度缓解。KPS评分得到明显改善。6.1.0 T开放式磁共振引导下125I粒子植入术可以延长病人的生存时间。所有患者随访时间3-19个月,原发脑恶性肿瘤及术后肿瘤复发患者11例,术后6月生存率为100%,术后1年生存率为81.82%。脑转移瘤患者18例,术后6月生存率为94.44%,术后1年生存率为66.67%。第二部分1.0 T开放式磁共振引导125I放射粒子植入术在脊柱转移瘤中的应用研究转移瘤是脊柱最常见的恶性肿瘤,约占其97%。脊柱肿瘤最长见的症状是疼痛,严重影响患者的而生活质量,若肿瘤侵及神经或破坏椎体引塌陷则会出现神经功能障碍和脊柱不稳,危及患者生命。因此,对于脊柱转移瘤应该采取积极的治疗措施。目前,脊柱转移瘤的治疗方案主要是以手术和/或放疗为主的综合治疗方案,治疗目的是改善患者生存质量,尽量延长生存期。手术创伤大,且部分因肿瘤侵犯范围较大而使其应用受限,外放疗则可因脊髓等正常组织的剂量限制而影响其应用。因此,近年来越来越多的目光转向微创治疗。125I粒子的主要应用途径之一是在影像设备引导下的组织间粒子植入治疗。目前125I粒子植入治疗主要是等在超声、CT、MRI等影像设备的引导下进行的。MRI以其无电离辐射、组织分辨率高、多平面成像的优势,不仅用于诊断,而且应用于穿刺活检。近年来,MRI引导也逐渐应用于125I粒子植入治疗中,且显示出一定的优势。但关于MRI引导125I粒子植入治疗脊柱转移瘤一直未见报道。研究目的本研究旨在探讨1.0 T开放式磁共振引导下125I粒子植入治疗脊柱转移瘤的可行性,并进一步探讨其疗效及应用价值。研究方法病例资料：本研究回顾性分析了2014年10月至2016年5月就诊于山东省医学影像学研究所的脊柱转移瘤患者16例。患者的一般情况见表2-1。其中男性10例(62.5%),女性6例(37.5%),年龄范围35-75岁,中位年龄63岁。其中8例转移瘤来源于肺癌,3例来源于肝癌,1例来源于乳腺癌,1例来源于前列腺癌,1例来源于肾癌,1例来源于子宫平滑肌肉瘤,1例来源不详。所有患者均行MR引导下脊柱转移瘤的125I粒子植入术,共18个部位,所有部位均未经过外照射治疗。本研究经本单位审查委员会批准,所有患者均签署影像引导下125I粒子植入治疗恶性肿瘤知情同意书。病例入组标准：病理证实脊柱病变为转移瘤；脊柱转移瘤数目≤3个；不能耐受手术或术后复发；手术切除后有局部残留；不能耐受外放疗或外放疗后复发;外放疗后有局部残留；病灶在MRI上能够清晰显示；KPS评分>40；预计生存期>6个月设备、药物及手术：设备、药物及MRI引导125I粒子植入治疗计划的制定、磁共振扫描序列、1251粒子植入术均基本同第一部分。脊柱转移瘤MPD均为120Gy, D90>90%MPD, V200<50%观察指标：观察1.0 T开放型磁共振对椎体肿瘤、穿刺定位针的显示情况,分析1.0 T开放型磁共振引导125I粒子植入治疗的安全性、粒子植入后剂量的可靠性。术后副反应程度的评估采用肿瘤放射治疗协作组/欧洲癌症治疗研究组织(RTOG/EORTC)的放射治疗毒性标准。125I粒子植入后术后第1、3个月及以后每3个月行MR或CT扫描,评估肿瘤大小的改变；同时随访患者的症状体征改变。具体为：采用数字评分法(NRS)评估疼痛程度,采用美国脊髓损伤协会标准(ASIA)评估脊髓损伤程度,功能改善或恶化定义为A-E级分级改变≥1级。对术后行走功能进行评估；根据WHO实体肿瘤疗效评价标准进行评价,肿瘤无进展即认为治疗有效,即治疗有效率=CR+PR+SD;分析局部控制率及生存率。统计分析：采用SPSS18.0统计软件进行分析,采用t检验对粒子植入术前后的疼痛评分进行分析,应用Kaplan-Meier法计算局部控制率及肿瘤特异性生存率,P<0.05被认为差异有统计学意义。研究结果：1.1.0T开放式磁共振能够清晰显示病变全貌及相应水平脊髓受侵情况。2.1.0T开放式磁共振能够准确显示穿刺定位针的位置,清晰显示穿刺针与病变的位置关系。3.125I粒子植入以1.0T开放式磁共振为引导是安全的,所得剂量可靠。4.术前所有患者的平均NRS评分为6.5土2.18,术后所有患者的平均NRS评分为2.5±2.34,两者相比P<0.01。16例患者中,5例(31.25%)疼痛完全缓解,11例(68.75%)疼痛有所改善,总体有效率100%。5.神经功能改善情况神经功能改变采用ASIA分级标准进行评估。行1.0 T开放式磁共振引导下的125I粒子植入术后,9例(56.25%)患者的神经功能改善明显,其中1例A级转为B级,1例B级转为D级,1例C级转为D级,8例D级中6例转为E级。5例E级患者术后神经功能保持良好。2例D级神经功能与术前相比无明显改善,随访期间内未出现术后神经功能恶化情况。6.患者运动功能改善情况。12例患者(75%)运动功能得到改善,其中4例患者由术前Ⅱ级术后转为Ⅰ级,7例Ⅲ级患者中,术后1例转Ⅰ级,6例术后转Ⅱ级,2例Ⅳ级患者中1例术后转为Ⅱ级。4例患者(25%)术前、术后运动功能无明显改变,其中3例Ⅰ级患者术后运动功能保持良好,1例Ⅳ级患者术后功能未发生明显改变。7.KPS评分改善情况在术前、术后1月、3月对所有的KPS评分进行评估,结果提示MR引导125I粒子植入术可以显著提高脊柱转移瘤患者的KPS评分,改善患者生存质量。8.局部控制率和生存期。所有患者随访3-19个月,中位随访时间12个月,无失访病例。16例患者共18处病变,1年局部控制率为77.8%,1年的生存率为56.3%。结论1.0T开放型MR引导的125I粒子植入治疗脑恶性肿瘤及脊柱转移瘤是安全、可行的,所得放疗剂量是可靠的。1.0T开放型MR引导的125I粒子植入术能有效缓解脑恶性肿瘤及脊柱转移瘤的神经功能损伤症状,提高肿瘤局部控制率,改善患者生存质量,延长生存期。1.0T开放型MR引导的125I粒子植入术是脑恶性肿瘤及脊柱转移瘤治疗的有效选择之一。意义1.为术后复发胶质瘤以及体积较大的脑胶质瘤的治疗提供了一种有效选择。2.为脑转移瘤的治疗提供了一种精准的、微创的、有效的、可重复操作的治疗选择。3.为脊柱转移瘤的治疗提供了一种精准的、微创的、有效的、可重复操作的治疗选择。更多还原

【Abstract】 PartⅠPractical study of 1.0 T open MR guided 125I seed implantation in brain malignanciesBrainl malignancies include primary and secondary tumors. Surgery is the main treatment for most of the primary malignancies, which is often followed by radiotherapy and chemotherapy. However, the invasive growth of primary brain malignancies to brain stem, blood vessels and other important functional region makes it difficult for the complete removal and causes relapse.Metastasis is a common type of brain malignancies. For single metastasis, surgery and radiotherapy such as statistic radiosurgery(SRS) or statistic radiotherapy(SRT), in combination of whole brain radiotherapy, are recommended. However, life quality is often affected by surgery trauma and WBRT injury. Besides, WBRT cannot be used repeatedly.Therefore, benefits of surgery and WBRT are questioned in brain metastasis treatment. Precise radiotherapy, mainly including the precise external radiotherapp technology, such as IMRT, IGRT, VMAT, X knife, etc., and brachytherapy such as 1251 interstitial implantation, provides a variety of good choice.125I particles implantation is a precise radiotherapy technology, which plays important roles in comprehensive treatment of malignancies. At present, the implantation is implemented either under guidance of imaging equipment or directly in operation. The MRI guided 125I particles implantation to treat malignancies is reported more and more often nowadays, but rare studies were found for its application in brain malignancies.ObjectiveThis study was to evaluate the feasibility, safety and the efficiency of the MRI guided 125I particles implantation in brain malignancies.MethodsSamples. Patients with brain malignancies treated in Shandong Medical Imaging Research Institute were included from October 2014 to May 2016.11 patients with primary malignancies(5 males and 6 females, median age 47) and 18 patients with single brain metastases (10 males and 8 females, median age 52) were involved in this study. The study was reviewed and approved by ethical committee of the institute, and all the patients signed the informed consent.Surgery Procedures. CT or MR images were import to the Treatment Plan System(TPS) and 3D reconstruction was performed. After then, target volume, needle path, number and activity of 125I seeds and the whole therapy plan was made. 110Gy was set as the MPD for patients who never received radiotherapy of brain and 90Gy was set for ones who had already received brain radiotherapy. D90>90% MPD, V200 <50% was accepted. Appropriate position was selected according to the site of the tumor and the comfort level of patients. Ball containing sodium morrhuate was used as marker for positioning. Postoperative dose verification was carried out within 24 hours after the seed implantation, and additional seed was implanted if the dose could not reached the setting levels.Observation parameters. Display condition of the tumor and the needle was observed, and the safety and the dose reliability was evaluated. After a follow-up in the first month, the third month and every 3 months after seed implantation, the tumor volume, clinical manifestation and the KPS change was observed. Response rate was calculate as the sum of CR and PR. Local control rate and survival was analysed.Statistical method. SPSS 18.0 statistical software was used for analysis. Data was expressed as mean ±standard deviation (S). t-test was used to analyze the significance and Kaplan-Meier method was used to calculate the local control rate and survival of the patients. P values< 0.05 is considered to have statistical significance.Results1.1.0 T magnetic resonance imaging could clearly display the brain lesions due to the multiple parameters multiplanar imaging.2. puncture needle which was displayed as artifact of low signal, and the relationship between the needle and the lesion was showed clearly with the 1.0T open magnetic resonance.3.125I seed implantation was safe and the dose was reliable.4. MR guided 125I particles implantation can improve the local control rate of malignant brain tumor. We use the CR and PR to depict the change of RR. Of the 29 patients,21 cases reached RR accounting for 72.41% 1 month after seed implantation; 22 cases reached RR accounting for 75.86% 2 months after seed implantation; and the cases of RR remains the same 3 months after seed implantation.5. Life quality was improved after MR guided 125I particles implantation. Symptomatic relief was evaluated in 1,2 and 3 months after seed implantation. Symptoms such as headache, nausea, vomiting was relived in different level. KPS was significantly improved, either.6. Survival was prolonged after MR guided 125I seed implantation A follow-up of 3 to 19 months was performed to all the patients. All the 11 cases with the primary brain malignancies survived 6 months, and 81.82% survived 1 year. Of the 18 cases with brain metastases,94.44% survived 6 months, and 66.67% survived 1 year.Part ⅡPractical study of 1.0 T open MR guided 125I seed implantation in spinal metastasisSpinal metastasis accounts for about 97% of the spine tumors, which caused pain, and seriously influence the living quality of patients. When invasion of spinal cord, nerve or the vertebrae happened, dysneuria or spinal instability came up, which make a risk for life. So an active management would be needed to relieve malignant pain and to improve quality of life.Right now, surgery and radiotherapy are the main measures in the traditional comprehensive treatment of spinal metastasis. But large injury or wide tumor invasion may limit the application of surgery, while dose-related toxicity may be an obstacle of external radiotherapy. Recently, minimal invasive therapy has gained more and more focus. Imaging guided 125I seed implantation is a kind of precise radiotherapy. Its guidance equipment mainly includes ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). MRI is expensive, but the excellent image resolution, the multi-dimensional imaging and none radiation characteristics indicate a good prospect as a guiding method.MRI displays superiority both in clinical diagnosis and as guidance method in aspiration biopsy. But no studies was found about the treatment of spinal metastasis using MRI guided 125I seed implantation.ObjectiveIn this study, we will evaluate the feasibility and effectiveness of MRI-guided interstitial iodine-125 seed implantation in treating spinal metastasis.MethodsPatients. This study involved 16 patients who were diagnosed as spinal metastasis from October 2014 to May 2016 in Shandong Medical Imaging Research Institute. Details of the patients’information were listed in table 1. All the patients were treated with iodine-125 seed implantation under MRI guidance for the spinal metastasis with 18 sites totally. The study was approved by ethical committee of Shandong University and an informed consent was signed by each patient involved in this study.Equipment, drugs and seed implantation. Equipment, drugs, the treatment planning, scanning sequence and the implantation procedure was almost the same as in part I. MPD was 120Gy, and D90>90%MPD, V200<50% was set.Observation parameters. Display condition of the tumor and the needle was observed, and the safety and the dose reliability was evaluated. Complicaitons was evaluated using RTOG/EORTC standard. After a follow-up in the first month, the third month and every 3 months after seed implantation, the tumor volume, clinical manifestation and the KPS change was observed. Specific as follows:adopting NRS to assess pain degree, using standard American spinal injury association (ASIA) to assess the degree of spinal cord injury, functional improvement or deterioration is defined as 1 or more level change in A-E class. Walking function was evaluated, the. The therapeutic effect was evaluated according to the WHO standard of solid tumors and treatment effectiveness=CR+PR+SD; Local control rate and survival was analysed.Statistical method. SPSS 18.0 statistical software was used for analysis. Data was expressed as mean ±standard deviation (S). t-test was used to analyze the significance and Kaplan-Meier method was used to calculate the local control rate and survival of the patients. P values< 0.05 is considered to have statistical significance.Results1. LOT open MRI can clearly show the vertebrae lesions and conditions of the spinal cord.2.1.0 T open MRI can show the specific condition of the puncture needle.3. LOT open MRI guided 125I seed implantation was safe, and the achieved dose was reliable.4. LOT open MRI guided 125I seed implantation could relieve pain of spinal metastasis.NRS of all the 16 patients before seed implantation was 6.5±2.18, while the score was 2.5±2.34 after seed implantation, with P value<0.1. Among the 16 patients,5 cases acquires complete pain relief, while 11 cases acquires partially pain relief, with a total response rate of 100%.5. LOT open MRI guided 125I seed implantation could improve neurological function of spinal metastasis.ASIA standard was used. Of the 16 patients,9 cases (56.25%) acquires obvious improvement in neurological function, with 1 case from A level to B level, 1case from B level to D level, lease from C level to D level,6 cases from D level to E level.5 cases of E level and 2 cases of D level remained the same after seed implantation. No deterioration of neurological function was found in this study.6. LOT open MRI guided 125I seed implantation could improve motor function of patients with spinal metastasis.Of all the 16 cases of spinal metastasis,12 cases (75%) acquires improvement of motor function, with 4 cases from level II to level I,7 cases from level III to level I (1 case), level II (6 cases) separately, leases from level IV to level II.4 cases (25%) remained the same motor function after seed implantation.7. LOT.open MRI guided 125I seed implantation could improve the life quality of patients with spinal metastasis by comparison of KPS changesn before and after the surgery.8. LOT open MRI guided 125I seed implantation could improve local control rate and prolong the survival.The median follow-up was 12 months (range from 3-19 months). The local control rate at 1 st year was 77.8% and survival at the 1 st year was 56.3%.Conclusions1.0 T Open MR guided 125I seed implantation is safe and feasible in treating brain malignancies and spinal metastasis. Dosimetry verification manifested that PTV dose after seed implantation is reliable. Symptoms of brain malignancies and spinal metastasis was relieved after implantation. All that suggested that 1.0 T Open MR guided 1251 seed implantation is an effective choice of brain malignancies and spinal metastasis.Significance1. This study provided an effective treatment choice for recurrent glioblastoma and big glioblastoma.2. This study provided a precise, minimal invasive, effective treatment choice for brain metastasis, and this method can be applied repeatedly.3.This study provided a precise, minimal invasive, effective treatment choice for spinal metastasis, and this method can be applied repeatedly.更多还原