【作者】 李成利；

【导师】 武乐斌；

【作者基本信息】 山东大学 ， 影像医学与核医学， 2007， 博士

【摘要】 目的改进兔VX₂脑瘤模型的制作方法，探讨磁共振导引与监控下氩氦刀冷冻消融治疗兔脑瘤的可行性，评价影像与病理学联系及治疗效果。方法全麻下通过颅骨钻孔种植瘤块的方法建立VX₂移植性脑瘤模型22只（两只颅内感染）。6只兔随机分为A、B两组，脑瘤直径0.8cm时在磁共振实时导引和监控下对肿瘤进行消融治疗，消融时间分别为5分钟、10分钟两个循环，随后分别在术后当时、术后7天、术后14天行MR扫描后两组分别处死一只，进行病理学检查。剩余14只兔随机分为C、D两组，C组在脑瘤直径0.8cm时进行冷冻消融治疗，消融时间为10分钟，两个循环，D组瘤兔不进行治疗，术后MR定期扫描，观察肿瘤大小变化，记录C、D两组兔的死亡时间，自种植脑瘤术后两个月仍不死亡者取截尾值。结果22只新西兰兔除2只感染外，其余全部有脑瘤生长，同时期种植的肿瘤大小较一致，形态规则，肿瘤的MRI表现和病理学改变相一致，能够满足介入治疗的需要。所有冷冻消融手术均成功进行，脑瘤的坏死程度和冷冻时间有明显相关性，5分钟两个循环组（A组）肿瘤细胞部分死亡；10分钟两个循环组（B组）肿瘤细胞死亡彻底，且坏死范围与冰球大小一致。治疗组（C组）瘤兔生存时间明显延长。结论：改良瘤块植入法制作的兔VX₂脑瘤模型成瘤稳定，适合MRI观察和介入治疗研究；脑瘤氩氦刀消融治疗安全可行，10分钟两个循环的消融时间可以使肿瘤细胞彻底坏死，能显著提高兔脑瘤的生存时间。目的：研究MR导引与实时监控经皮氩氦刀冷冻消融治疗全身各系统肿瘤的安全性及可行性，并探讨该技术联合局部¹²⁵I粒子、缓释5—FU植入的临床应用价值。对象及方法：2004年10月～2007年1月应用0.23T开放式MR结合Ipath200光学导引系统对全身各个系统40例肿瘤患者的51个病灶行氩氦刀冷冻消融治疗。其中肝脏恶性肿瘤17例（原发性肝细胞癌9例，胆管细胞癌5例，胃癌肝脏转移2例及肺癌肝脏转移1例）；颅内肿瘤5例（脑内转移瘤2例；脑胶质瘤2例；脑膜瘤1例）；肺肿瘤13例（原发性肺癌12例：Ⅲa期9例；Ⅲb期1例；Ⅳ期2例；肺转移瘤1例）；骨肿瘤4例（骨样骨瘤1例；肺癌骨转移瘤2例；多发骨血管外皮细胞瘤1例）；颌面部造釉细胞瘤1例。肿瘤病灶最大径线1.5cm～12.0cm不等。冷冻消融术采用Cryo-Hit低温冷冻系统（氩氦刀），每个靶部位均经两个冷冻／解冻循环。根据肿瘤的大小和位置选择直径2mm或3mm的冷冻探针。对于较大的病灶，可以在MR实时导引监测下，采用多方向、多点穿刺冷冻消融。40例患者共行106次冷冻消融治疗。冷冻消融术后一周内内行1.5T常规MR扫描结合增强扫描，确定消融毁损区范围，对残余肿瘤，择日可再次对病灶残存区行冷冻消融术。大部分患者冷冻消融术后行局部（125）I放疗粒子及缓释5-氟尿嘧啶化疗粒子植入术。脑肿瘤、肺肿瘤及骨骼肌肉系统的肿瘤冷冻治疗术开始前同时先行MR导引下穿刺活检术，明确病理组织学诊断。所有患者均于术前行血常规及凝血四项检查。脑肿瘤患者术前行fMRI检查。疗效评价标准：按照中国氩氦刀治疗协作组根据WHO标准设定近期疗效评价标准：①临床缓解（CR）：根治性冷冻的患者（即手术中冷冻冰球范围大于肿瘤边缘1-1.5cm以上），手术后CT或MRI检查提示肿瘤病变冷冻后消失，或肿瘤病变冷冻后明显缩小，影像学证实病变无增殖特性，为冷冻后灭活组织，肿瘤血供消失；或CT密度值显著降低、MRI各序列呈低信号的凝固坏死灶，无新病灶出现，临床肿瘤症状、体征消失至少4周，体重增加生活质量明显提高或恢复正常。②部分缓解（PR）：减瘤负荷冷冻治疗或姑息性冷冻治疗者，冷冻范围占肿瘤体积50％以上，手术后CT或MRI检查提示冷冻病变部分完全消失或明显缩小；CT密度值显著下降或MRI各序列呈低信号的凝固坏死灶，残存肿瘤病变无增殖活性，无新病灶出现至少达4周以上，临床症状改善，生活质量明显提高。③临床无变化（SD）：姑息性冷冻治疗的患者，冷冻范围占肿瘤体积50％以下，手术后CT或MRI检查提示冷冻的肿瘤病变消失或明显缩小，CT密度值显著降低或MRI各序列呈低信号的凝固坏死灶。残存肿瘤病变增大25％以下，无新病灶出现，临床症状和生活质量无明显改善。④临床进展（PD）：部分姑息性冷冻治疗的病人，手术后CT或MRI检查提示冷冻的肿瘤病变无明显缩小，并显示新的增殖特性，CT密度无明显降低或MRI各序列信号无改变。残存的肿瘤病变增大25％以上并出现新的病灶，临床症状进一步加重，生活质量下降。结果所有患者在开放式MR导引下均成功准确地穿刺至病变靶点；术中MR能清楚的实时显示冷冻探针及冰球呈逐渐增大的带状和梨形信号缺失。冰球边界清晰，尽可能完全覆盖病灶或超出病灶边缘5～10mm，肺肿瘤治疗时为预防气胸，冰球仅覆盖病灶但不超过病灶范围。在MR实时导引下，根据TPS计划将放射性¹²⁵I粒子及相应剂量5-FU化疗粒子行肿瘤区分层种植，重点分布肿瘤周边区。40例患者的51个病灶共行106次冷冻消融治疗。治疗有效率（CR+PR）／（CR+PR+SD+PD）为82.5％（33／40）。1、17例肝肿瘤患者进行27次冷冻消融术，共39次冷冻消融治疗。4例患者术中同时使用2个冷冻探针。患者手术次数为1-4次不等。患者均同时行局部挖¹²⁵I放疗粒子、缓释5-FU化疗药物植入术。术后无严重并发症。仅1例患者胸片示右侧胸腔少量积液；少数患者可出现体温轻度升高，均未经处理自行好转。术后随访3个月，治疗有效率（CR+PR）为82.35％（14／17）。2、5例脑肿瘤患者进行9次手术，共15次冷冻消融。3例原发肿瘤同时行穿刺活检术。无脑损伤（出血与梗塞）及神经损伤等并发症发生。随访6个月，无肿瘤复发及转移。3、13例肺肿瘤患者共进行26次冷冻消融术。2例患者术中同时使用2个冷冻探针。患者手术次数为1-4次不等。患者均同时行局部¹²⁵I放疗粒子、缓释5-FU化疗药物植入术。1例有慢性支气管炎病史30多年的患者，术后当天出现气胸，行闭式引流术后第三天好转，去除闭式引流；1例中央型肺癌患者术后仍痰中带血，但较术前明显好转。其余患者未出现严重并发症。总有效率（CR+PR）为69.2％。4、1例颌面部巨大造釉细胞瘤，8次肿瘤切除手术后复发，分4次MR介入导引氩氦刀冷冻消融术，行15次冷冻消融治疗。术后患者症状明显好转，面部肿块及疼痛消失，无严重并发症发生。术后7个月复查，肿瘤无复发。5、4例骨肿瘤患者，共进行11次冷冻消融治疗。1例为股骨头骨样骨瘤行MR介入导引穿刺活检及氩氦刀冷冻消融治疗；2例为肺癌腰椎及髂骨转移氩氦刀冷冻消融治疗；1例多发血管外皮细胞瘤行髂骨及腰椎氩氦刀冷冻消融治疗，结合骨水泥灌注成型术辅助治疗，术后肿瘤消融完全，患者术后疼痛症状消失。结论开放性MR导引下经皮介入治疗具有微创伤，可重复性、并发症少等特点，是安全、可行的。联合局部其它辅助治疗(如植入¹²⁵I放射粒子和5-FU缓释粒子)，MR导引与监控下氩氦刀冷冻消融肿瘤使得大多数失去了常规手术根治切除机会的肿瘤患者重新获得微创外科治疗的机会。具有广阔的临床应用前景。更多还原

【Abstract】 PART ONEEXPERIMENTAL STUDY OF CRYOABLATION ON RABBIT’S VX2 BRAIN TUMOR UNDER MRI GUIDANCE AND REAL-TIME MONITORINGObjective: To improve rabbit’s VX₂ model of brain tumor for MRI study, evaluate the feasibility of cryoablation on rabbit brain tumor under interventional MRI guidance, analysis correlation among MRI、pathology, and therapeutic effect.Methods: The procedures were performed under a general anaesthetic. Twenty-two New Zealand white rabbit’s brains were inoculated with VX₂ tumor tissue through cranioaural hole （two rabbits were infected）. Six rabbits were divided into A, B group and cryoablated when diameter of brain tumor grew up to 8mm in size.Cryoablation lasted two cycles in 5 minuts, 10 minuts respectively. In each group one rabbit was exacuted after procedure and MR scanning immediately, 7 days, 14 days. Specimens of rabbit’s brain were examined pathologically, and then compared with its MR appearance. The other 14 rabbits were divided into C, D group. Rabbits of C group were cryoablated with 2 cycles of lasting 10 mimutes while tumors grew up to 8mm in diametet, and rabbits of group D were not treated. Under MRI scanning in Rabbits of C, D group, the ablative area and the residue was observed. The survival time were recorded, while survival time of rabbits not died 2 months later after VX₂ tumor tissue inoculation was censored value.Results: Brain tumor could be found in all New Zealand white rabbits after inoculation except two suffered from inflammation, the size and form of brain tumor uniformity. The correlation between MRI and pathologic appearance of tumors are corresponding. All procedures were performed successfully.Tumor tissue died partly in Group A and died completely in Group B. The survival time of C group was longer than that of D group.Conclusion: The animal models of brain tumor with VX₂ tumor tissue inoculation are stable. It is an ideal model fitting MRI study and interventional therapy. Cryoablation for brain tumor is a safe and feasible therapy. Two cycles cryoablation in 10 minutes can induce complete necrosis of brain tumor cells and ice ball matches the shape and size of necrotic area. Cryoablative therapy can improve survival time of rabbit with brain tumor. PART TWOTHE CLINICAL APPLICATION RESEARCH OF OPEN MRI GUIDANDANCE AND MONITORING CRYOABLATION OF TUMOURSObjective: To assess the feasibility and safety of the percutaneous cryoablations for tumors under the intraprocedural open-configuration magnetic resonance imaging guidance and real-time monitoring, mounted with optical tracking system, then to explore the clinical curative effect with local ¹²⁵I particles insertion, 5-FU insertion.Methods: Total 51 tumors in 40 patients, confirmed histologically or clinically, were treated with percutaneous cryoablation, including liver malignant tumors: 17 cases （9 cases with primary hepatic tumors; 5 cases with cholangiocellular carcinoma; 1 cases with metastasis of lung cancers; 2 cases with metastasis of gastric cancer）; intracranial tumors: 5 cases（1 cases with metastasis of breast cancer, 1 cases with metastasis of lung cancer, 2 cases with glioma, 1 cases with meningioma）; lung tumors: 13 cases（12 cases with primary lung cancer: IIIa 9 cases、IIIb 1case、IV 2cases, and 1 cases with metastasis）; skeletal musculature tumors: 4 cases（1 case with osteoid osteoma, 2 cases with metastasis of lung cancer, 1 case with hemangiopericytoma）; maxillofacial neoplasm: 1 cases（ameloblastoma）. The largest diameter of tumors ranged from 1.5cm to 12.0cm. Cryoablation was performed using a high-pressure argon system（Cryo-Hit system）with a double freeze/thaw cycle. A 2mm or 3mm MR-compatible cryoprobe was advanced into the target according to the size of tumors. Changed cryoprobe angle or multiple sites probing were performed if necessary.Totally 106 cryoablation were performed in 40 cases. For depicting cryonecrosis areas, Gd-DTPA enhance MRI were acquired on 1.5T MR scanner within 1 week after cryoablation. ¹²⁵I particles and 5-FU particles insertion were performed in partial patients. MR-guided biopsy was performed before treatment for intracranial tumors, lung tumors and skeletal musculature tumors. For intracranial tumors, fMRI was necessary before cryoablation. The evaluation of clinical curative effect of the procedures was done according to the standard of short term curative effect for argon-helium system.Results: All procedures were carried out safely and accurately. Intraprocedural MRI enabled clear visualization of the cryoprobe and iceballs as band-like and ellipsoid-like regions of signal losses, respectively. Intraprocedural MR imaging demonstrated sharply marginated iceballs engulfed and expanded out of 0.5～1.0cm tumors. ¹²⁵I particles and 5-FU particles were peripherally inserted masses under MRI guidance. One hundred and six cryoablations were performed for 51 tumors in 40 patients. The curative effect rate was 82.5%.1. Thirty-nine cryoablations were performed for 27 hepatic tumors in 17 patients. One or two cryoprobes were used during the procedures. Meanwhile ¹²⁵I particles and 5-FU particles were inserted. The procedure was performed without serious complication. 1 patient suffered from mild hydrothorax without treatment. During 3 months follow-up, the curative effect rate was 82.35% （14/17）.2. Fifteen cryoablations were performed during 9 procedures in 5 brain tumor’s cases. After 6 month follow-up, there were no recurrent tumors.3. Twenty-six cryoablations were performed for 13 lung tumors in 13 cases. Two cryoprobes were used during the procedure in 2 cases. At the same time ¹²⁵I particles and 5-FU particles were inserted peripherally. 1 patient had pneumothorax recovering after closed drainage. The curative effect rate was 69.2%.4. Fifteen cryoablations were performed during 4 treatments procedures for 1 large tumor in 1 patient with ameloblastoma. After 7 months follow-up, there was no recurrent.5. Eleven cryoablations were performed for 4 patients with bone tumors. The pain was significantly relief after the therapy.Conclusions: On the basis of the present study MRI-guided percutaneous targeting intervention is an accurate procedure. We conclude that MRI-guidance and monitoring cryoablation is safe, feasible, and easy to perform. Combined with insertion of ¹²⁵I and 5-FU particles, MRI-guided cryoablation can be used to substitute more invasive procedures in selected patient groups.更多还原