HepaSphere栓塞微球临床应用及病例分享

HepaSphere栓塞微球临床应用及病例分享,1990 : 由日本教授Hori发明，名称：SAP*1992 : 首次应用于临床 2000 : 应用于HCC的初步研究2004 : 获得欧盟认证，名称：HepaSphere2006 : 获得美国认证，名称：QuadraSphere,历史,*SAP：Superabsorbent Polymer Microsphere,HepaSphere的材质,乙酸乙烯和丙烯酸甲酯经聚合皂化反应生成的共聚物聚丙烯酸钠乙烯醇(poly vinylalcohol-co-acrylic acid),HepaSphere栓塞微球干态包装，每瓶25mg500-100um粒径，139,000微粒/瓶30-60um粒径，815,000微粒/瓶,HepaSphere的粒径,小粒径微球才更有可能实现末梢栓塞，效果才会更好,可压缩直径的80%,良好的弹性，撤掉外力即可恢复原来的形状可变形，能复原像棉花糖一样,HepaSphere的物理性能,TACE精准的靶向性（Targeted）良好的吸收性（Absorbing）高度的随形性（Conforming）真正的载药性（Eluting）,HepaSphere的特性,HepaSphere微球粒径分布均一50-100um粒径HepaSphere微球，95%在40-110um区间内粒径均匀，更易完成指定层面栓塞,Guido Poggi et al. Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors, Anticancer Res. 2008 Nov-Dec;28(6B):3835-42,精准的靶向性（Targeted）,HepaSphere不会在血管近端或者远端发生聚集在体内栓塞的血管直径与其粒径大小一致,Khankan AA, Osuga K, Hori S et al.Embolic effects of superabsorbent polymer microspheres in rabbit renal model: comparison with tris-acryl gelatin microspheres and polyvinyl alcohol. Radiat Med 22:384390 Bilbao Jl, De Luis E, Garcia De Jalon JA et al. Comparative study of four different spherical embolic particles in an animal model: a morphologic and histologic evaluation. J Vasc Interv Radiol. 2008 Nov;19(11):1625-38,精准的靶向性（Targeted）,注射前需要水合 水合时产品能较好吸收水基溶液，吸收部分药液吸收后以球形方式膨胀，直径为原来的2-4倍,良好的吸收性（Absorbing）,良好的吸收性（Absorbing）,Hepa膨胀的大小受控于水基溶液的离子浓度,HepaSphere可以像血管腔的模子一样堵在血管腔内，形成完全的栓塞 HepaSphere与血管腔高度随形，在血管内不断裂，也不移位，平均每个血管腔内一个颗粒HepaSphere很软，容易压缩，所以能够适合管腔的形状并实现完全堵塞,Khankan AA, Osuga K, Hori S et al.Embolic effects of superabsorbent polymer microspheres in rabbit renal model: comparison with tris-acryl gelatin microspheres and polyvinyl alcohol. Radiat Med 22:384390 Bilbao Jl, De Luis E, Garcia De Jalon JA et al. Comparative study of four different spherical embolic particles in an animal model: a morphologic and histologic evaluation. J Vasc Interv Radiol. 2008 Nov;19(11):1625-38,高度的随形性（Conforming）,在人体组织上得到的证实：与血管内皮紧密接触并随形，从而达到完全性栓塞的效果,Klass et al 2014. ANTICANCER RESEARCH 34: 3597-3606 (2014),高度的随形性（Conforming）,Bilbao et al. “Comparative Study of Four Different Spherical Embolic Particles in an Animal Model: A Morphologic and Histologic Evaluation.” J Vasc Interv Radiol 2008; 19(11): 1625-38.,载药微球与肿瘤血管内皮接触越紧密，抗癌药物缓释到肿瘤内部的效果越好,Photos courtesy of Keigo Osuga,高度的随形性（Conforming）,机械吸收HepaSphere由干燥的颗粒变成水合微球约在10分钟内完成正负电荷结合HepaSphere微球带负电荷的丙烯酸酯与带正电荷的盐酸多柔比星之间形成离子键1,Kos S et al., Elution characteristics of doxorubicin-loaded microspheres differ by drug-loading method and microsphere size, J Vasc Interv Radiol. 2011 Mar;22(3):361-8,真正的载药性（Eluting）,HepaSphere为整体载药1，2,Sebastian Kos et al. Elution Characteristics of Doxorubicin-loaded Microspheres Differ by Drug-loading Method and Microsphere Size, J vasc Interv radiol 2011; 22: 361-368David M. Liu et al. Optimization of Doxorubicin Loading for Superabsorbent Polymer Microspheres: in vitro Analysis, Cardiovasc Intervent Radiol (2012) 35: 391-398,真正的载药性（Eluting）,HepaSphere可加载多种药物：多柔比星1顺铂2,3,4伊立替康5奥沙利铂6,Kos S et al. Elution characteristics of doxorubicin-loaded microspheres differ by drug-loading method and microsphere size, J Vasc Interv Radiol. 2011 Mar;22(3):361-8Maeda N et al., In vivo evaluation of cisplatin-loaded superabsorbent polymer microspheres for use in chemoembolization of VX2 liver tumors, J Vasc Interv Radiol. 2012 Mar;23:397-404Maeda N et al., In vitro characterization of cisplatin-loaded superabsorbent polymer microspheres designed for chemoembolization, J Vasc Interv Radiol. 2010;21(6):87781Huppert P, Transcatheter Arterial Chemoembolization (TACE) of Colorectal Cancer Liver Metastases by Irinotecan-Eluting Microspheres in a Salvage Patient Population, Cardiovasc Intervent Radiol. 2013 May; 37(1): 154-164Poggi G, Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors, Anticancer Res. 2008 Nov-Dec;28(6B):3835-42Poggi G, Oxaliplatin-eluting microspheres for the treatment of intrahepatic cholangiocarcinoma: a case report, Anticancer Res . 2008 Sep-Oct;28(5B):2987-90,真正的载药性（Eluting）,HepaSphere的载药时间,Merit brochure,50-100m HepaSphere: 15 分钟加载95%以上的多柔比星按照麦瑞通推荐的载药方法可以达到这种载药效果,Kos S et al. Elution characteristics of doxorubicin-loaded microspheres differ by drug-loading method and microsphere size, J Vasc Interv Radiol. 2011 Mar;22(3):361-8,HepaSphere的载药时间,3组VX2兔模型，分别为HepaSphere加载阿霉素，碘油+阿霉素+Embo栓塞的 cTACE，以及经肝动脉灌注阿霉素（HAI）Hepa组14天后局部药物浓度仍可以达到治疗效果,Gupta et al. “Hepatic Arterial Embolization with Doxorubicin-Loaded Superabsorbent Polymer Microspheres in a Rabbit Liver Tumor Model.” Cardiovasc Intervent Radiol 2011; 34(5):1021-30,Hepa组：14天肿瘤内部药物浓度大于50ng/mgcTACE组：第3天已经接近为0,HepaSphere的药代动力学特性,HepaSphere的药代动力学特性,HepaSphere能够有效加载多柔比星HepaSphere做到了持续释放，在各时间点均可提高肿瘤内多柔比星的浓度,Lee et al. “Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer.” Cardiovasc Intervent Radiol 2010; 33(3): 57682.,HepaSphere的药代动力学特性,Hepa提高了肿瘤局部的药物浓度,术后第7天HepaSphere载药组肿瘤坏死率为90% ，而空白栓塞组为60% HepaSphere载药组的肿瘤坏死率明显高于空白栓塞组,Lee et al. “Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer.” Cardiovasc Intervent Radiol 2010; 33(3): 57682.,HepaSphere的肿瘤反应率,HepaSphere载药组肿瘤坏死率明显高于空白栓塞组,Grosso et al. “Transarterial Chemoembolization for Hepatocellular Carcinoma with Drug-Eluting Microspheres: Preliminary Results from an Italian Multicentre Study.” Cardiovasc Intervent Radiol 2008; 31:1141-49.,OR在1个月和6个月时分别为84%和77.4%9个月的生存率为92%,HepaSphere的肿瘤反应率,Seki et al 2011. Cardiovasc Intervent Radiol (2011) 34:557565,病灶平均直径为6.4cm（4-12cm），证实针对大肝癌，HepaSphere也是有效的,HepaSphere的肿瘤反应率,25,OR为68.9%，DCR为 88.9%，1年生存率为100%,Malagari et al 2014. Cardiovasc Intervent Radiol (2014) 37:165175,HepaSphere的肿瘤反应率,p 0.0001,P = 0.007,Malagari et al 2014. Cardiovasc Intervent Radiol (2014) 37:165175,HepaSphere显著降低AFP水平,Italy,Greece,Malagari et al 2014. Cardiovasc Intervent Radiol (2014) 37:165175Dekervel et al 2014. J Vasc Interv Radiol 2014 Feb;25(2):248-55Seki et al 2011. Cardiovasc Intervent Radiol (2011) 34:557565,77%,73.7%,100%,HepaSphere能延长生存期,HepaSphere的肿瘤反应率及生存期,Malagari K. et al. Chemoembolization of hepatocellular carcinoma with HepaSphere. Hepatic Oncology, Vol. 2, No. 2, Pages 147-157(2015).,CR：22.2-48%，PR：43.7%-51%1年生存率：73.7-100%,van Malenstein H et al. “A Randomized Phase II Study of Drug-Eluting Beads versus Transarterial Chemoembolization for Unresectable Hapetocellular Carcinoma.” Onkologie 2011;34:368-76.,Hepa组的血液阿霉素峰值药物浓度和药物曲线下面积均较对照组明显降低：降低全身性的药物毒副作用多柔比星相关的全身不良反应发生率显著降低不良反应更少，未发现3级及4级骨髓抑制,HepaSphere的安全性,van Malenstein H et al. “A Randomized Phase II Study of Drug-Eluting Beads versus Transarterial Chemoembolization for Unresectable Hapetocellular Carcinoma.” Onkologie 2011;34:368-76.,肝功能保护好，安全可靠Hepa组的肝功能变化平稳，基本与术前无变化cTACE组肝功能变化很大，术后一个月才降低到术前水平,HepaSphere的安全性,Malagari et al 2014. Cardiovasc Intervent Radiol (2014) 37:165175,HepaSphere的安全性,Van Malenstein et al. ILCA 2009,HepaSphere的安全性,多项研究显示Hepa的PES发生率小于20%,Malagari et al 2014. Cardiovasc Intervent Radiol (2014) 37:165175Grosso et al 2008. Cardiovasc Intervent Radiol. 2008 Nov-Dec;31(6):1141-9Seki et al 2011. Cardiovasc Intervent Radiol (2011) 34:557565,HepaSphere的安全性,HepaSphere临床应用病例,黄xx主诉：上腹部闷胀1月当地全腹部CT：1.考虑胰腺炎，考虑少量积液；2.左肾上极占位，考虑肾癌与错构瘤鉴别。2015-09-24我院行PETCT提示：1.左肾上极占位性病变，病灶局部糖代谢未见异常（等代谢病变），结合CT动态增强密度改变，考虑左肾透明细胞癌（低级别）。2.左肺上叶磨玻璃阴影，病灶糖代谢稍增高，考虑早期肺浸润性腺癌与炎性病变鉴别，前者可能性较大。,2015-09-24我院PETCT：,左肾上极见一类圆形肿块影，大小约为2.82.6cm，边界清楚。三期增强扫描示病变皮质期明显强化，强化程度接近皮质强化程度，实质期及延迟期病变强化程度减低，局部FDG药物摄取未见明显增高。延迟2小时扫描可见FDG药物摄取未见增高，病灶FDG摄取分布与肾组织影分界不清。,2015-9-30 行经皮肾动脉栓塞术，DSA示：左肾上级病灶，实质期可见肿瘤染色。使用微导管进入肿瘤动脉，配置THP载药微球，经微导管注入载药微球共 5ml，后造影示肿瘤供血动脉血流较前明显减慢，再经微导管注入300-500um栓塞微球。术后1月返院复查2015/11/06腹部CT：双肾及双肾上腺:形态、大小未见明显异常；左肾上极见类圆形低密度灶，边界清晰，增强扫描呈明显不均匀性强化；病灶向肾轮廓外突起；大小约21mm18mm；双侧肾盂、肾盏未见明显扩张积水。,术后1月返院复查 2015/11/06腹部CT：,双肾及双肾上腺:形态、大小未见明显异常；左肾上极见类圆形低密度灶，边界清晰，增强扫描呈明显不均匀性强化；病灶向肾轮廓外突起；大小约21mm18mm；双侧肾盂、肾盏未见明显扩张积水。,彭xx主诉：体检发现肝内占位1月当地全腹部CT：马来西亚当地医院行上腹增强MRI提示肝恶性肿瘤（具体报告未见）,查AFP：904ug/L。2015-08-06于我院行全身PET/CT检查示：肝S8、4可见一巨大软组织肿块影，大小为9.9*9.5cm，边界尚清，肝S8、4肿块及肝多发结节代谢不同程度增高，考虑肝癌并肝内多发子灶形成。,2015-08-06于我院行全身PET/CT检查示：,肝S8、4可见一巨大软组织肿块影，大小为9.99.5 cm，边界尚清，平扫为低密度，密度不均匀，内见多发斑片状低密度区，增强扫描动脉期呈全瘤范围不均匀强化，高于正常肝实质密度，但低于同层主动脉密度。门脉期及静脉期肿块强化迅速降低，明显低于正常肝实质。三期增强扫描符合“快进快出”强化模式。肿块FDG摄取浓聚增高。肝S4及S6可见数个类似强化结节影，较大约2.72.4cm，局部FDG摄取增高。,2015-08-06于我院行全身PET/CT检查示：,肝S8、4可见一巨大软组织肿块影，大小为9.99.5 cm，边界尚清，平扫为低