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1、纳米刀的治疗进展纳米刀的治疗进展 内容大纲内容大纲一、一、IRE IRE 作用机制及优势作用机制及优势二、国际二、国际临床前研究临床前研究及临床研究进展及临床研究进展三、中国三、中国CFDACFDA准入美国准入美国IREIRE设备设备四、四、IREIRE临床肿瘤消融应用举例临床肿瘤消融应用举例五、五、IREIRE治疗的并发症及不良反应治疗的并发症及不良反应六、经验总结及病例讨论六、经验总结及病例讨论七、在研项目简介七、在研项目简介HOW IS IRE DIFFERENT?v Predominantly “non-thermal”v Spares collagenous skeletonv In
2、tact adventitia & lamina visible at 2 days with no smooth muscle cells presentv Smooth muscle in the media is repopulated at 2 weeksv Endothelium in the intima largely repopulates at 2 days目前使用的IRE 装置是美国AngioDynamics 公司制造的NanoKnife 系统。该系统已接受美国FDA上市前通告，并享受FDA的临床试验器械豁免，用于临床试验。IRE设备及配件设备及配件电流可直接刺激神经肌肉接
3、点，引起强力肌肉抽搐，因此治疗时需全身麻醉，使用肌松剂。电流可刺激心脏，引起心律失常。应用心电同步激发，可避免此种并发症。如果组织内电导率不均匀（如肺），IRE消融可能产生不均质性。Sync device (e.g. AccuSync 72) senses the rising slope of the R-wave, and sends a signal to the NanoKnife. The NanoKnife waits 50 milliseconds (.05 sec) and delivers 1 energy pulse. The energy pulse is deliver
4、ed during (or just before) the ventricular refractory period.IRE术中运用心电同步技术术中运用心电同步技术采用心电同步采用心电同步IRE消融技术，在绝对消融技术，在绝对不应期释放电脉冲不应期释放电脉冲可避免显著的心律可避免显著的心律失常失常Deodhar A, Dickfeld T, Single G W, et al. Irreversible electroporation near the heart: ventricular arrhythmias can be prevented with ECG synchronizat
5、ionJ. AJR Am J Roentgenol, 2011, 196 (3):W330-335.二、二、临床前临床前实验实验研究研究 实验的靶组织有肝、肾、胰腺、前列腺、肺、实验的靶组织有肝、肾、胰腺、前列腺、肺、心脏、骨和头颈部心脏、骨和头颈部等；等； 动物实验研究显示动物实验研究显示IREIRE消融消融具有具有安全性和有效安全性和有效性性肝组织肝组织IRE消融后病理学改变消融后病理学改变ABB细胞发生凋亡细胞发生凋亡1 Lee E. W., Thai S., Kee S. T. Irreversible electroporation: a novel image-guided can
6、cer therapyJ. Gut Liver, 2010, 4 Suppl 1:S99-S104.边界清晰，血管、胆管边界清晰，血管、胆管结构保存完整；结构保存完整；表现为核固缩、核破裂表现为核固缩、核破裂；1 Lee E. W., Thai S., Kee S. T. Irreversible electroporation: a novel image-guided cancer therapyJ. Gut Liver, 2010, 4 Suppl 1:S99-S104.IRE消融区在术中及术后即刻实时可见消融区在术中及术后即刻实时可见ACB超声超声CTMRI（A）超声能实时监测IRE。
7、IRE消融区显示低回声区。（B）肝增强CT显示延迟相消融区低密度，周围呈增强影。（C）使用对比剂脂肪饱和T1加权MR也能显示IRE消融区，表现为消融区轻度增强1 Charpentier K. P., Wolf F., Noble L., et al. Irrevrsible electroporation of the pancreas in swine: a pilot studyJ. HPB (Oxford), 2010, 12 (5):348-351.胰腺消融后出血、胰腺消融后出血、水肿水肿胰腺消融后，胰腺消融后，腺泡组织受破腺泡组织受破坏，保留血管、坏，保留血管、胰管胰管胰腺胰腺IRE
8、消融后病理学改变消融后病理学改变2424小时后腺小时后腺体明显出血体明显出血2424小时后尿道粘膜下出血严重，小时后尿道粘膜下出血严重，结构仍然完整结构仍然完整2 2周后周后，神经血管束神经血管束的的血管和神血管和神经干都未出现坏死经干都未出现坏死前列腺前列腺IRE消融后病理学改变消融后病理学改变二、二、 IRE临床研究进展临床研究进展 胰腺癌的胰腺癌的IREIRE； IREIRE在肝肿瘤治疗中的应用；在肝肿瘤治疗中的应用； 前列腺癌的前列腺癌的IREIRE消融；消融； 肾癌的肾癌的IREIRE消融消融 IRE治疗胰腺癌的局部复发率和无进展生存期ReferenceTumor typenFoll
9、ow-up time（months）Local recurrence rates（%）PFS（months）Narayanan G, et alLAPC/M11/35.5-14Martin R C, et alLAPC541527.8%14Martin R C, et alLAPC2730%-Dunki-Jacobs E M, et alLAPC652326.2%5.5（recurrence）/12.6（no recurrence）note：M means metastatic pancreatic cancer ；LAPC means Locally advanced pancreatic
10、cancer； 胰腺癌的不可逆电穿孔消融胰腺癌的不可逆电穿孔消融a:IRE术前；术前；b：IRE7天后显示病灶水肿；天后显示病灶水肿；c：3月后显示病灶无活性。月后显示病灶无活性。A.IRE消融后腹腔干开放；消融后腹腔干开放；B.肿瘤包绕血管情况改善肿瘤包绕血管情况改善international researchFIG. 1 Overall survival of the 54 patient with LAP treated with IRE and standard chemotherapy and/or radiation therapy versus the 85 patients t
11、reated with just chemotherapy and/or radiation therapy aloneIRE联合放化/疗组较放/化疗组有效延长局部进展性胰腺癌患者生存期 (20.2 vs. 11 months, p = 0.03)1.Martin R C, 2nd, McFarland K, Ellis S, Velanovich V. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survivalJ. Ann Surg Oncol,
12、 2013, 20 Suppl 3:S443-449.IRE联合放化疗治疗胰腺癌联合放化疗治疗胰腺癌不可逆电穿孔在肝肿瘤治疗中的应用不可逆电穿孔在肝肿瘤治疗中的应用作者作者肿瘤平均直肿瘤平均直径（径（cm）病例数病例数（例）（例）消融肿瘤数消融肿瘤数（个）（个）完全消完全消融率融率 （%）术式术式中位随中位随访时间访时间（月）（月）术后残留术后残留率（率（%）局部复发率（局部复发率（%）Kingham TP1.0286592.4手术（79%）/经皮（21%）61.95.7Cannan R2.74448100经皮（76.5）-2.6（3月）、5.4（6月）、40.5（12月）Cheung W2.
13、4111872经皮1827.80Eisele RM1.5131493经皮 (53.8%)/腹腔镜(30.8%)/手术（15.4%）621.421Scheffer HJ2.4101090经皮并切除-Hosein PJ2.7295897经皮225-Eller A2141886经皮12.97.117表1 IRE治疗肝肿瘤临床研究汇总international researchPre treatment 1 month postinternational research(A)CT of liver during arterial phase demonstrates an enhancing HCC
14、 in segment II (arrow). (B) CT liver during portal venous phase immediately after IRE ablation demonstrates the non-enhancing ablation zone (arrow) abutting the inferior aspect of the pericardium (black arrowheads). (C) CT of liver during portal venous phase 9 months after IRE ablation demonstrates
15、a markedly contracted, non-enhancing ablated scar in segment II (arrow). ABCinternational researchTechnol Cancer Res Treat. 2013 Jun;12(3):233-41. doi: 10.7785/tcrt.2012.500317. Epub 2013 Jan 25.1 month 1 year 15 month follow upinternational research Overview table of current data on focal therapy f
16、or prostate cancer with IRE前列腺癌的不可逆电穿孔消融前列腺癌的不可逆电穿孔消融1 Scheltema M J ，et al. Irreversible electroporation, a new modality in Focal Therapy for prostate cancer.J. Archivos espanoles de urologia, 2016, Vol.69 (6), pp.337-44。（n/m; not mentioned） 局限性前列腺癌局限性前列腺癌IRE消融安全有效消融安全有效Figure 2. Images of prostate
17、 treated with IREinternational research1 Murray K S, Ehdaie B, Musser J, et al. Pilot Study to Assess Safety and Clinical Outcomes of Irreversible Electroporation for Partial Gland Ablation in Men with Prostate CancerJ. J Urol., 2016, 196 (3):883-890.Fig. 1 Patient in lithotomy position with three t
18、ransperineally inserted electrodes under ultrasound guidance1 van den Bos W, de Bruin DM, Jurhill RR, Savci-Heijink CD, Muller BG, Varkarakis IM, et al. The correlation between the electrode configuration and histopathology of irreversible electroporation ablations in prostate cancer patients. World
19、 J Urol Internet. 2015; Epubinternational researchFig. 2 a Ultrasound image showing the three inserted electrodes. b The area within the electrode configuration is delineated. c H&E slide with the outlined ablation zone. d The ablation zone is delineated1 van den Bos W, de Bruin DM, Jurhill RR, Savc
20、i-Heijink CD, Muller BG, Varkarakis IM, et al. The correlation between the electrode configuration and histopathology of irreversible electroporation ablations in prostate cancer patients. World J Urol Internet. 2015; Epubinternational researchA). Sharp demarcation between viable and nonviable tissu
21、e. Reduced from 2.5; B).Affected neural tissue in neurovascular bundle.Reduced from 20;C).Prostatic urethra with denudation of urothelium. Reduced from 2.5AB1 van den Bos W ，et al. Histopathological Outcomes after Irreversible Electroporation for Prostate Cancer: Results of an Ablate and Resect Stud
22、y.J. The Journal of urology, 2016, Vol.196 (2), pp.552-9.Cinternational researchCEUS, T2-MRI images corresponding with histopathology section and H&E slide.1 van den Bos W ，et al. Histopathological Outcomes after Irreversible Electroporation for Prostate Cancer: Results of an Ablate and Resect Study
23、.J. The Journal of urology, 2016, Vol.196 (2), pp.552-9.international research The first in-man clinical study with IRE treatment on kidney by Pech In 2010肾癌的不可逆电穿孔消融肾癌的不可逆电穿孔消融Fig1 A view of the IRE procedure being conducted. The needle in the operators hand is a bipolar electrodeFig2 The hockey-st
24、ick curve shows the envelope of the kidney; the dark central mass is the tumour; and the slightly off- horizontal line passing through it is the electrode12Cardiovasc Intervent Radiol. 2011 Feb;34(1):132-8. doi: 10.1007/s00270-010-9964-1. Epub 2010 Aug 15.A-C:Transverse ultrasound images of prostate
25、 (dark region, dashed outline) from human trial (A) prior to electrode insertion, (B) immediately following electrode insertion, showing the four electrodes inserted as two pairs (white and black arrow pairs) with pulses delivered between dashed lines for two ablations, and (C) 35minfollowing IRE el
26、ectricpulses, showing gas formation (arrowheads).Prostate. 2014 May;74(5):458-68. doi: 10.1002/pros.22760. Epub 2014 Jan 17.international research三、中国中国CFDA准入美国准入美国IRE设备设备四、四、 IREIRE临床肿瘤消融应用举例临床肿瘤消融应用举例video2015.7.1 中国首例胰腺癌中国首例胰腺癌IRE消融消融Percutaneous IRE-ablationIRE-ablation for Liver Cancer Guided b
27、y MAXIO Navigation System in Fuda Cancer Hospital 2015-7-17percutaneous IRE-ablation（ Video file ）5066565070162015.10.16A：tumor size 5.8x4.8cm；B. IRE C. 1 week after IRE 4.2x3.4cmABCDIRE-ablation for the head of pancreatic cancer1牛立志，曾健滢，张怡惿等.不可逆性电穿孔消融治疗胰腺癌的安全性及近期疗效观察.介入放射学杂志.2016，25（3）232-235.ABCA.
28、术前术前MR示胰头示胰头下方肿瘤大小下方肿瘤大小2.82.3cm ;B. CT引导下术中引导下术中插针，针间距插针，针间距1.3cm；C. 术后术后CT显示病显示病灶范围较前增大，灶范围较前增大，肿瘤中心大部分肿瘤中心大部分液化坏死；液化坏死；D. 插针方位插针方位2015-08-05 5067821 1IRE-ablation for the head of pancreatic cancerDABA. tumor size 6.8x5.4cm；B. CT IRE 1.5cm；F. After IRE 1 MONTH，tumor size 5.8x4.9cmCDEF2015-09-01506
29、876Male patient, 71 years old, pancreas cancer. Stage B. Tumor size is 2.5x1.8cm 2016.02.16 2016.07.02After 5 monthsBeforeInsert needlesabc 2016.07.18 2016.10.28After 3.5 monthsDuring IREAfter 1 week治疗前肿瘤大小为治疗前肿瘤大小为3.3 cm3.5个月复查肿瘤大小为个月复查肿瘤大小为2.4cm术前（术前（2016.7.4）术后术后4.5个月（个月（2016.11.23）肿瘤标志物肿瘤标志物CA19
30、-9显著下降显著下降胰腺癌患者女73岁术前肿瘤6.8cm,术后3个月肿瘤缩小到3.1cm体重增加6kg 胰腺癌患者女，73岁术前肿瘤6.8cm,术后3个月肿瘤缩小到3.1cm，体重增加6kg Enhancement CT shows a completely necrosis of pancreatic cancer after IRE treatment. patient is from Beijing province 2015.8.252015.9.12015.10.21Before IREDuring IRE1.5 months after IREMale patient, HCC.
31、Stage B. Tumor size is 3.9x3.5cm508201原发性肝癌原发性肝癌 T3bN0M0 b期期508211左眼葡萄膜黑色左眼葡萄膜黑色素瘤术后肝转移素瘤术后肝转移瘤，肝门区肿瘤瘤，肝门区肿瘤约约5.7x 6.1cm术前术前术后术后1周周508227右眼恶性黑色素右眼恶性黑色素瘤术后瘤术后 IV期，肝期，肝S7段肿瘤，范围段肿瘤，范围约约4.4x3.6cm术前术前术后术后1周周Male patient, 47 years old, HCC. pT2N0M0 II. Tumor size is 5.34.4 cm507256术后术后1周周术后术后10个月个月术后术后6个月
32、个月术前术前术后立即术后立即术中挪针术中挪针术中布针术中布针IRE TREATMENT ZONE24 HR POST IRE5 WEEKS POST5 MONTHS POST治疗前肿瘤大小治疗前肿瘤大小为为7.9x5.7x6.1cm4个月复查肿瘤大小为个月复查肿瘤大小为6.0 x4.7x5.1cmIRE治疗治疗 介入栓塞化疗介入栓塞化疗IV期原发性肝癌介入栓塞化疗联合期原发性肝癌介入栓塞化疗联合IRE消融消融术前术前术后术后4个月个月术后肿瘤标志物术后肿瘤标志物AFP显著下降显著下降不可逆性电穿孔消融治疗胰腺癌的安全性不可逆性电穿孔消融治疗胰腺癌的安全性及近期疗效观察及近期疗效观察图2 胰体部
33、肿瘤IRE消融术后影像学改变术前CT增强示肿瘤包绕腹腔干、脾动、静脉、肠系膜动静脉，肿瘤大小为5.6x4.6cm；术中超声示两支电极消融时针道区出现气泡，呈现高回声；术后24h增强CT示肿瘤中心小气泡影，肿瘤边缘强化；术后30dCT增强扫描示肿瘤大小为4.8x4.0cm术后30d内不良反应有穿刺点疼痛（5例，占41.7%）、恶心呕吐（3例，占25%）、咳嗽、术后低血糖、低钾血症、胃壁和十二指肠水肿（各2例，占16.7%）、胃储留、发热及胸闷气促（各1例，8.3%），经对症治疗后好转，未见治疗相关性大出血、胆漏或胰漏等严重并发症。术后24h、7d血液淀粉酶与术前相比，无统计学意义（P0.05）。
34、术后（307）d评价效果：完全缓解（CR）1例，部分缓解（PR）9例，稳定（SD）2例，肿瘤缓解率（CR+PR）为83.3%。1 牛立志, 曾健滢, 张怡湜, et al. 不可逆电穿孔消融治疗胰腺癌的安全性及近期疗效观察J. 介入放射学杂志, 2016, 25 (3):225-230.Fig. 1 The appearance of the breast before, during, and after IRE ablation in case 1. (a) The right breast, harboring the breast tumor, was enlarged, and th
35、e nipple was retracted. (b) The two IRE probes were inserted into the breast tumor. (c) There was no bleeding post-IRE and the skin in the ablated area displayed some reddening. These are representative images.Fig. 2 (a) Preoperative enhanced CT scan indicating a mild-moderate contrast-enhanced brea
36、st tumor. (b) The two IRE electrodes (black arrows) were inserted into the tumor with the assistance of ultrasound. (c) Post-IRE enhanced CT scan showed no obvious contrast enhancement in the tumor region. These are representative images from case 1.Irreversible Electroporation Ablation Therapy for
37、Breast Cancer: A Presentation of Four CasesLizhi Niu1, Jiannan Li2, Jianying Zeng1, Huimin Tao1, Gang Fang2, Liang Zhou2, Kecheng Xu1,*, Kai Zhang2,*1Fuda Cancer Hospital, Jinan University School of Medicine, Guangzhou 510665, ChinaThe First Case of VIPoma IRE-Ablation in Nov. 5, 2015CD56(+)CgA(+)CK
38、19(+)NSE(+)Syn(+) 100 100 100 100 100 100HE stainingFig. 3. Electron microscopy examination of the pancreatic tumour tissues. Fig. 2. Pathological and immunohistochemical examination of the pancreatic tumour tissues (magnification, 100). Fig. 1. CT scans taken before, during and after IRE ablation.
39、(A) A contrast-enhanced CT scan taken before IRE shows a 6.0 5.0 cm contrast-enhanced lesion in the neck and body of the pancreas. (B) Two IRE electrodes were inserted into the tumour. (C) A contrast-enhanced CT scan taken a week after IRE shows a 6.0 4.8 cm lesion with a large area of necrosis in t
40、he neck and body of the pancreas.胃癌术后复发性病变的不可逆电穿孔消融胃癌术后复发性病变的不可逆电穿孔消融1例例1牛立志，曾健滢，罗小美等.胃癌术后复发性病变的不可逆电穿孔消融1例.介入放射学杂志，2016,25（1）50-51.图14 肝细胞肝癌患者，肿瘤邻近胆囊，无法外科手术切除。图1 术前增强CT白箭头示肝S5段肿瘤大小为3.2 cm2.8 cm2.8 cm，黑箭头示肿瘤邻近胆囊()；图2 CT引导下经皮穿刺插入2根IRE探针，针间距2 cm；图3 术后7 d复查CT，白箭头示病灶范围较前略增大，密度较前更加不均，增强未见明显强化，黑箭头示肿瘤邻近胆囊无胆
41、漏等并发症()；图4 术后1个月MR复查示肝S5段肿瘤大小约2.6 cm 2.5 cm 3.0 cm，T1加权序列呈高信号，凝固性坏死表现，增强后病灶未见明显强化 肝恶性肿瘤不可逆电穿孔消融的安全性肝恶性肿瘤不可逆电穿孔消融的安全性和近期疗效和近期疗效术后30 d内不良反应腹痛7例次、腹腔积液5例次、胸腔积液4例次、发热3例次、咳嗽及恶心呕吐各2例次、胆道感染及血小板减少各1例次，均经对症治疗后好转；未发生治疗相关大出血、胆漏等严重并发症。术后24 h 肝功谷氨酸转移酶（ALT）、天冬氨酸转移酶（AST）一过性升高至（637597）U/L、（510396）U/L，予以保肝处理后7 d恢复正常。
42、1 牛立志, 刘桂凤, 曾健滢, et al. 肝恶性肿瘤不可逆电穿孔消融的安全性和近期疗效J. 中华放射学杂志, 2016, 50 (7):56-61.五、五、 IREIRE治疗并发症及不良反应治疗并发症及不良反应Adverse effects of irreversible electroporation of malignant liver tumors1 Dollinger M., Beyer L. P., Haimerl M., et al. Adverse effects of irreversible electroporation of malignant liver tumo
43、rs under CT fluoroscopic guidance: a single-center experienceJ. Diagn Interv Radiol, 2015, 21 (6):471-475. Complications and Adverse Events in Pancreatic Tumors1 Rombouts S. J., Vogel J. A., van Santvoort H. C., et al. Systematic review of innovative ablative therapies for the treatment of locally a
44、dvanced pancreatic cancerJ. Br J Surg, 2015, 102 (3):182-193. DOI: 10.1002/bjs.9716Figure. ad. A 66-year-old male patient with hepatocellular carcinoma. T2-weighted MRI image six days before intervention shows a hyperintense HCC lesion (a, arrow) in segment V of the liver located within a perimeter
45、of 1 cm of a segmental portal vein branch (not shown on the figure). A peri-interventional contrast-enhanced CT scan shows extrahepatic hematoma (b, thick arrow) with active extravasation of contrast medium (b, arrowhead) due to active bleeding. The ablation zone (b, thin arrow) contains intralesion
46、al gas bubbles (b, curved arrow). Immediate digital subtraction angiography with selective angiography of the right internal thoracic artery (c) shows extravasation of contrast medium (arrowhead) from one of its branches (thin arrow). Consecutively, the vessel was successfully embolized with an ethy
47、lene vinyl alcohol copolymer (Onyx, ev3 Inc.) (d). K, kidney.1 Dollinger M., Beyer L. P., Haimerl M., et al. Adverse effects of irreversible electroporation of malignant liver tumors under CT fluoroscopic guidance: a single-center experienceJ. Diagn Interv Radiol, 2015, 21 (6):471-475. International
48、 researchFigure 2 Electrocardiogram during IRE treatment. A: Tracing obtained during IRE treatment of the hepatic mass in segment 4 with the synchronization device. The distance from the electrode to the inferior border of the heart is 1.7 cm based on US measurement. IRE pulses are incorrectly deliv
49、ered on the T wave (arrows), resulting in an episode of ventricular extrasystoles (asterisks). B: The synchronization device failed to operate properly during treatment.1 Sugimoto K., Moriyasu F., Takeuchi H., et al. Case study to assess the safety of irreversible electroporation near the heartJ. Sp
50、ringerplus, 2015, 4:74. International research针尖距离心脏下边界1.7cm，引发室性早搏Target OrganCases (n) Percentage (%) Major complications (%)No. Adverse effects Hepatic malignant tumor2929%0(0.0)89Pancreatic malignant tumor 3737%5(13.5)74Breast cancer88%0(0.0)5Other tumors2626%0(0.0)67100 cases of malignant tumor