The authors have no acknowledgements. 
The phase II study is financially supported by Delcath Systems.

注意:在病人符合所有纳入标准，由肿瘤内科，外科医生和麻醉师进行仔细评估，病人被列入研究。所有患者签署知情同意书。这两个临床研​​究是由荷兰莱顿大学医学中心的地方医学伦理委员会批准，并按照赫尔辛基宣言的道德标准执行。 1.预程序通过介入放射造影<ol><li>在对PHP程序编写，执行前的程序性血管造影到PHP动脉解剖映射20数天前。在此过程中执行的肠系膜动脉（SMA），腹腔干和肝动脉血管造影术。21 <ol><li>在血管造影术，用泵喷射到使用2.4F或2.7F微导管的肝动脉和肺叶动脉使用造影剂。 （ 材料列表中，7项）。 </li><li>注入在5毫升/秒的从肝总动脉的速率为血管造影的15ml未稀释的对比度（碘普罗胺300）（ 物料清单 ，第14项）和12ml在为大叶性肺炎注射3毫升/秒。21 </li><li>划定肝血管解剖和血管瘤供给通过如步骤1.1.2中描述注入对比度。21 </li><li>确定化疗剂的回流的风险hepatico肠吻合（如胃或胃右动脉）。21确定血管的变体，例如异常右侧或左侧肝动脉。21 </li><li>在回流的可能的风险的情况下，如果有合适的肝动脉远端胃十二指肠动脉（GDA）小于约1厘米，栓塞此动脉可拆卸微线圈或血管塞（ 物料清单 ，项目15和16）。还栓塞其它胃 - 和/或肠溶吻合，以防止chemothe的流raputic药物的其他结构。21 </li><li>栓塞动脉分支远端的血管供应，胃，胰腺和膈肌的肠道输注部位。21 </li></ol></li></ol> 2. PHP程序一:准备和创建灌注环路<ol><li>通过额外的肉体灌注师准备（ECP） <ol><li>收集chemosaturation tubingpack，chemofilters和离心泵。 （ 物料清单 ，物品1b和12），这些项目被包装在由制造商提供的框。 </li><li>冲洗用CO 2气体完全体外循环回路。 </li><li>素与包括过滤器的NaCl 0.9％和肝素（2000 IU / L）的电路。 <ol><li>冲洗体外循环系统用6L肝素的0.9％NaCl的，​​最初由重力作用的手段作为超准已经存在于系统中。碳过滤器完全水化后，用离心pUMP施加更大的压力上的过滤器，以除去剩余的气泡。 注:有点锤可用于通过振动和共振以除去气泡。 <ol><li>总理双球囊导管线和旁通管线。 </li><li>素左chemofilter（1升）和去泡，然后素权利chemofilter（1升）和去泡。 </li><li>系统初始启动后慢慢水合物chemofilters（每盒3升）。这可能需要每chemofilter 10-20分钟。 </li><li>贷泡沫陷阱（动脉过滤器）。 </li></ol></li></ol></li><li>检查和校准流量传感器和压力监视器，如在离心泵软件菜单编程，根据制造商的说明。 </li></ol></li><li>血管造影室由麻醉师病人准备<ol><li>成立了麻醉管理所需的监控: <ol><li>放置一个血压频带用于非侵入性的血压测量心电图对病人的心电监护胸部以及血氧饱和监护电极。 </li></ol></li><li>放置在患者的前额一个双频指数量表（BIS）的传感器来测量麻醉的病人的深度，在这种情况下，麻醉师被用来与此工作。 </li><li>根据制造商的说明，包括通过通气机和气管内导管的ET-CO 2设置通风设备。放置在其中的IR站立的患者的相反侧的通气机的指示，由制造商。 </li><li>放置在血管造影室的桌子病人，直接盖上温暖的空气毯子十个分量常温病人。 </li><li>发生在右臂静脉第四麻醉药和静脉输液给药外周静脉通路。 </li><li>诱导麻醉（与麻醉师的偏好麻醉剂），进行气管插管，并开始INTermittent正压通气（IPPV）。 </li><li>维持麻醉到BIS = 50，MAP = 65毫米汞柱，0.5毫升/ kg / hr的normuria。 </li><li>将鼻咽体温温度计。 </li><li>地方对神经肌肉阻滞监测四（TOF）电极列车在制造商的说明（在麻醉师的偏好）。 </li><li>设置并准备作为制造商的说明快速的流体管理系统/或液体加热器（ 物料清单 ，第2项）。 </li><li>打开先进的显示器屏幕（ 物料清单 ，项目4）上，并连接所有电缆。 </li><li>插入一个22克动脉线成平均动脉压（MAP）监测左桡动脉。 （ 材料清单 ，第3项）。 </li><li>放置在左内颈静脉中心静脉压测量中心静脉线。 </li><li>插入膀胱导管。 </li><li>保持常温bŸ暖空气的毯子和温暖的静脉输液。 </li><li>使用整个程序的高级监视器（ 物料清单 ，项目4）显示器CVP和动脉血压。 </li><li>通过绘制一个血液样品和将其放置在对ACT计确定基线活化凝血时间（ACT）。 </li><li>此外，在感应静脉给予头孢唑啉1克，泮托拉唑40毫克的氢化可的松300毫克。 </li></ol></li><li>药剂师准备<ol><li>重组美法仑（3.0毫克/千克体重（最大剂量220毫克）（ 物料清单 ，第9项））通过使用无菌针10毫升供给稀释剂的迅速直接注入冻干粉末的小瓶（20克或更大的针直径）和注射器。 </li><li>直到得到明确的解决方案，立即摇瓶剧烈。这提供了美法仑的5毫克/毫升的溶液。 </li><li>立即稀释剂量以在NaCl 0.9％注射，USP，在浓度不大于0.45毫克/毫升更高。 </li><li>重建的60分钟内完成管理工作。 </li></ol></li><li>准备在血管造影室由介入放射（IR） <ol><li>在一张桌子布置了必要的工具和用品（无菌）。 （ 材料清单 ，物品1A，3,5,6,7,8,11）。 </li><li>盖上无菌床单病人。 </li></ol></li><li>通过IR护套的位置<ol><li>使用超声引导为笔杆的内部颈静脉（IJV）左，右的位置。 </li><li>放置一个7.5F三腔静脉留置针，在左侧颈内静脉20厘米（ 物料清单 ，项目5）。此鞘是由麻醉师为CVP测量和拟交感神经药输注使用。 </li><li>放置在右颈内静脉一10F静脉回流导管（ 物料清单 ，项目1A）。此护套被用于过滤的血液的体外chemofiltratio后静脉回流ñ。 </li><li>放置5F鞘进入左股总动脉（CFA）（ 物料清单 ，项目6）。 注意:此鞘用于同轴放置微导管注入化疗剂。 </li><li>放置一个18F护套与8-10F和12-14F扩张器串行散瞳后右股总静脉（CFV）（ 物料清单 ，项目8）。使用扩张器来调整插入口大小合适，最终正确放置18F护套。注:此套用于引入双球囊导管（隔离抽吸导管）。 </li></ol></li><li>肝静脉的分离和主体外创建电路<ol><li>辖肝素鞘全部已放置后;在300 IU /公斤（ 物料清单 ，项目11）的初始剂量。 </li><li>保持高于50秒的活化凝血时间（ACT）用另外的肝素推注剂量在整个过程中根据需要。 </li><li>站RT去甲肾上腺素（50毫升为0.2mg / ml）的0.1-2微克/公斤/分钟和去氧肾上腺素（50毫升0.1毫克/毫升）0.1-2微克/千克/分钟，输液（500毫升晶体液），以保持密切的血流动力学参数至65毫米汞柱的平均动脉压（MAP），和0.5毫升/公斤/小时尿量。 </li><li>通过在左股总动脉的5F鞘，引入2.7F微导管（ 物料清单 ，项目7）同轴并放置在用血管造影术监测适当的肝动脉或肺叶动脉。 </li><li>通过在右股总静脉18F护套，引入16F双气囊导管（隔离抽吸导管）中，用在使用血管造影术监测右心房的尖端放置。 </li><li>导管的放置后直接，这些附加使用特殊的连接点体外循环系统;静脉回流线在IJV外皮和流出线路的隔离导管。 </li><li>开始的C如制造商所描述entrifugal泵: 注:所有线路现在是开放的，流动是运行在旁路管线。 </li><li>的0.5升的胶体溶液（ 物料清单 ，项目13）静脉输注后，膨胀用50％盐水 ​​和50％的造影剂混合物颅气球。 </li><li>与尾气球仍然瘪，慢慢缩回双气囊导管，直到颅气球是在右心房和下腔静脉（IVC）的连接点，就在肝右静脉上述（气球现在是楔形，如在图2中示出）。 </li><li>膨胀尾球囊用90％盐水和10％造影剂的混合物中，直到膨胀的气球的横向边缘开始成为由下腔静脉抹去。 注意:气球充气造影介质的不同混合物。尾气囊膨胀以阻塞肾静脉上方的下腔静脉，使肝静脉流出分离˚F<html> ROM全身静脉循环。最大的38毫升卷可能被注入到每一个气球。 </li><li>检查气球的定位和静脉造影排除泄漏<ol><li>通过注入加入20ml对比度进行静脉造影（ 即，碘普胺300）通过使用手注射双气囊静脉双气囊导管的开窗口。 </li></ol></li><li>如果对比度泄漏所看到的，重新定位气球或进一步膨胀气球和如在步骤2.6.11.1（ 见图2）中所述重复静脉造影。 </li></ol></li></ol><img alt="图2" src="/files/ftp_upload/53795/53795fig2.jpg" /> 图2.每程序血管造影。静脉双气囊导管在适当的肝动脉的下腔静脉和动脉灌注导管。逆行对比度经由静脉导管注入。从预程序血管造影和栓塞线圈到位。ww.jove.com/files/ftp_upload/53795/53795fig2large.jpg"目标="_空白"&gt;点击此处查看该图的放大版本。 <ol start="7"><li>闭合电路<ol><li>注入另一0.5L的胶体溶液中。确保这两个chemofilters是在这个时刻关闭，而旁通是开放的。 </li><li>尝试完成足够流量（Q = 400-500毫升/分钟）与安全压力近端（通常&lt;-70毫米汞柱）和远端离心泵（ 物料清单 ，项目12）（&lt;100毫米汞柱）。 </li><li>滴定去甲肾上腺素0.1-2微克/千克/分钟和苯福林0.1-2微克/千克/分钟和流体施用到保持为160毫米汞柱的收缩压和0.5毫升/公斤/小时的尿量。 </li><li>当足够的流量和压力被达到，打开一个过滤器之一。 注意:血液通道虽然过滤器将hemofiltrate血液和去除大部分的化学治疗剂。血液滤过发生在整个procedu重以及在"洗脱"期间直接以下化疗输注期间。在此洗脱期，即从肝组织返回化疗剂，从循环"洗出"。 </li><li>在140-160毫米汞柱之间的收缩压已经达到，关闭旁通管线。 注意:麻醉师应该准备遇到血压下降从预压的降低导致由于腔静脉闭塞，从血液穿过由chemofilters和chemofilters去除血管活性剂（ 例如，去甲肾上腺素和肾上腺素）的周围血管扩张可能内源NO产生的血管舒张作用。调整去甲肾上腺素和肾上腺素的输注速率相应保持65毫米汞柱的地图。 </li><li>通过执行造影（如在步骤2.6.11.1描述）检查双气囊导管的定位。 </li><li>通过注射进行反政府的血管造影T（碘普罗胺300）通过肝动脉微导管排除动脉痉挛。如果痉挛看出，辖硝化甘油100-200微克到肝动脉（如在步骤1.1和子步骤也描述）。 </li></ol> </li></ol> 3. PHP程序II:化疗间歇期的输液<ol><li>美法仑的输液 注意:输送系统电路的放置，美法仑的输注到肝动脉是通过微导管启动之后。 <ol><li>当建立一个稳定的流率，无泄漏存在，并且患者的血压是稳定的，剂量为3毫克/公斤到适当的肝动脉或依次到两个肺叶动脉注入美法仑。 <ol><li>不要开始化疗输液，直到MAP高于65毫米汞柱。 </li></ol></li><li>注入剂量的使用自动注射器将100ml药物在0.4毫升/秒的速率，约30分钟，unti微升完整剂量注射。 </li><li>输液过程中，每隔一段时间，执行动脉造影监测血管痉挛的发生和位置，并检查双气囊导管的通货膨胀对比度潮红。 （请参阅有关的造影剂信息的步骤2.6.11.1（静脉造影）和1.1和2.7.9（血管造影））。 </li><li>在血管痉挛的情况下，管理硝化甘油（100-200微克）。 </li><li>化疗药物输液30分钟后，继续血液滤过额外30分钟的清除期（见注步骤2.7.5）。 </li><li>辖术后疼痛控制10毫克静脉吗啡。 </li><li>在洗脱期后慢慢放气在腔静脉的两个气球。 </li></ol> </li><li>在输液的端部和导管的去除<ol><li>在清除期的结束时，清空体外循环回路尽可能然后停止体外灌注。 </li><li>停止centrifu加仑泵并断开管。 </li><li>取出双气囊导管和输液微，但保留访问鞘到位，直至凝固的标准化。血管闭合装置可被放置在共同的股动脉来实现止血。 </li><li>保持正确的颈内静脉回导管到位，直至凝血功能进行了标准化。 </li><li>保持7.5F在左侧颈内静脉三腔静脉留置针的地方本可以在麻醉后监护室（PACU）一起使用。 </li></ol> </li><li>麻醉和肝素化的结束 注意:在该过程的结束执行下列步骤，当自动输血结束。 <ol><li>关闭并删除旁路电路。 </li><li>停止去甲肾上腺素和肾上腺素的输液双气囊放气后立即生效。这是可能的，因为足够预紧返回到右侧心脏和chemofiltration的终止。 </l我&gt; <li>正常化与鱼精蛋白（1:1）凝固，新鲜冰冻血浆和/或冷沉淀物有或无血小板输血。检查之后ACT。 </li><li>血流动力学稳定和去甲肾上腺素和肾上腺素输注结束后，终止麻醉剂维持用药。 </li><li>病人已​​返回到自主呼吸和意识后，拔管患者的气管。 </li><li>病人转移到恢复室进行的重要功能（血压和凝血参数）监测的24小时。 </li><li>取出血管鞘，一旦血小板计数&gt; 50×10 9 / L，APTT &lt;1.5×正常，INR &lt;1.5。应用手工压迫达到止血和超过两个腹股沟施加压力绷带。 </li></ol> </li><li>术后护理<ol><li>监测患者在麻醉恢复室进行手术后的第一个24小时。 </li><li>检查导管inserti止血网站上与显示器脉搏，血压，温度，通风，体液平衡和疼痛分数以及凝结。 </li><li>病人转移到病房，术后1-2天。 </li><li>术后第2天的3放电病人，最后血液学和血液化学试验后。检查肝，创造毒性后续的基准-正常范围内的正常上限2秒内凝血酶原时间（PT），活化部分凝血活酶时间（APTT），血小板&gt; 75000 / 立方毫米无血小板输注或&gt; 100,000 /毫米3与输血，血红蛋白&gt; 10克/分升（&gt; 6.2毫摩尔/ L）和天冬氨酸转氨酶和丙氨酸氨基转移酶（AST / ALT）基准水平的10％以内返回。 </li><li>辖细胞集落刺激生长因子的支持（pegfilgastrim，0.6毫升一次性注射器），出院后或PHP处理后48小时之内。 </li></ol> </li></ol>

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L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increased+local+cytostatic+drug+exposure+by+isolated+hepatic+perfusion:+a+phase+I+clinical+and+pharmacologic+evaluation+of+treatment+with+high+dose+melphalan+in+patients+with+colorectal+cancer+confined+to+the+liver.">Increased local cytostatic drug exposure by isolated hepatic perfusion: a phase I clinical and pharmacologic evaluation of treatment with high dose melphalan in patients with colorectal cancer confined to the liver.</a> Br J Cancer. 82 (9), 1539-1546 (2000).</li><li>Rothbarth, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+high-dose+melphalan+for+the+treatment+of+colorectal+metastasis+confined+to+the+liver.">Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver.</a> Br J Surg. 90 (11), 1391-1397 (2003).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+200+mg+melphalan+for+advanced+noncolorectal+liver+metastases.">Isolated hepatic perfusion with 200 mg melphalan for advanced noncolorectal liver metastases.</a> Ann Surg Oncol. 15 (7), 1891-1898 (2008).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+melphalan+perfusion+of+colorectal+liver+metastases:+outcome+and+prognostic+factors+in+154+patients.">Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients.</a> Ann Oncol. 19 (6), 1127-1134 (2008).</li><li>Alexander, H. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+I-II+study+of+isolated+hepatic+perfusion+using+melphalan+with+or+without+tumor+necrosis+factor+for+patients+with+ocular+melanoma+metastatic+to+liver.">A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver.</a> Clin Cancer Res. 6 (8), 3062-3070 (2000).</li><li>Olofsson, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+for+ocular+melanoma+metastasis:+registry+data+suggests+a+survival+benefit.">Isolated hepatic perfusion for ocular melanoma metastasis: registry data suggests a survival benefit.</a> Ann Surg Oncol. 21 (2), 466-472 (2014).</li><li>Curley, S. 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R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusion+for+unresectable+metastatic+melanoma+or+sarcoma+to+the+liver:+a+single+institution+experience.">Chemosaturation with percutaneous hepatic perfusion for unresectable metastatic melanoma or sarcoma to the liver: a single institution experience.</a> J Surg Oncol. 109 (5), 434-439 (2014).</li><li>Deneve, J. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusion+for+unresectable+isolated+hepatic+metastases+from+sarcoma.">Chemosaturation with percutaneous hepatic perfusion for unresectable isolated hepatic metastases from sarcoma.</a> Cardiovasc Intervent Radiol. 35 (6), 1480-1487 (2012).</li><li>Kandarpa, K., Machan, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Handbook of Interventional Radiologic Procedures. , 269-270 (2011).</li><li>Hofmann, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Unresectable+isolated+hepatic+metastases+from+solid+pseudopapillary+neoplasm+of+the+pancreas:+a+case+report+of+chemosaturation+with+high-dose+melphalan.">Unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas: a case report of chemosaturation with high-dose melphalan.</a> Pancreatology. 14 (6), 546-549 (2014).</li><li>Miao, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+hepatic+perfusion+in+patients+with+metastatic+liver+cancer:+anesthetic,+hemodynamic,+and+metabolic+considerations.">Percutaneous hepatic perfusion in patients with metastatic liver cancer: anesthetic, hemodynamic, and metabolic considerations.</a> Ann Surg Oncol. 15 (3), 815-823 (2008).</li><li>Vogl, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusions+of+melphalan+for+hepatic+metastases:+experience+from+two+European+centers.">Chemosaturation with percutaneous hepatic perfusions of melphalan for hepatic metastases: experience from two European centers.</a> Rofo. 186 (10), 937-944 (2014).</li><li>Pingpank, J. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+III+random+assignment+trial+comparing+percutaneous+hepatic+perfusion+with+melphalan+(PHP-mel)+to+standard+of+care+for+patients+with+hepatic+metastases+from+metastatic+ocular+or+cutaneous+melanoma.">A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma.</a> J Clin Oncol. 28, 18s (2010).</li><li>Rothbarth, J., Vahrmeijer, A. L., Mulder, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modulation+of+cytostatic+efficacy+of+melphalan+by+glutathione:+mechanisms+and+efficacy.">Modulation of cytostatic efficacy of melphalan by glutathione: mechanisms and efficacy.</a> Chem Biol Interact. 140 (2), 93-107 (2002).</li><li>Bartlett, D. L., Libutti, S. K., Figg, W. D., Fraker, D. L., Alexander, H. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+for+unresectable+hepatic+metastases+from+colorectal+cancer.">Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer.</a> Surgery. 129 (2), 176-187 (2001).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+oxaliplatin+combined+with+100+mg+melphalan+in+patients+with+metastases+confined+to+the+liver:+A+phase+I+study.">Isolated hepatic perfusion with oxaliplatin combined with 100 mg melphalan in patients with metastases confined to the liver: A phase I study.</a> Eur J Surg Oncol. , (2014).</li><li>Rothbarth, J., Tollenaar, R. A., van de Velde, C. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+trends+and+future+perspectives+in+isolated+hepatic+perfusion+in+the+treatment+of+liver+tumors.">Recent trends and future perspectives in isolated hepatic perfusion in the treatment of liver tumors.</a> Expert Rev Anticancer Ther. 6 (4), 553-565 (2006).</li><li>van Etten, B., de Wilt, J. H., Brunstein, F., Eggermont, A. M., Verhoef, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hypoxic+hepatic+perfusion+with+melphalan+in+patients+with+irresectable+ocular+melanoma+metastases.">Isolated hypoxic hepatic perfusion with melphalan in patients with irresectable ocular melanoma metastases.</a> Eur J Surg Oncol. 35 (5), 539-545 (2009).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+isolated+nonresectable+liver+metastases+in+colorectal+cancer+patients:+a+case-control+study+of+isolated+hepatic+perfusion+with+melphalan+versus+systemic+chemotherapy.">Management of isolated nonresectable liver metastases in colorectal cancer patients: a case-control study of isolated hepatic perfusion with melphalan versus systemic chemotherapy.</a> Ann Oncol. 21 (8), 1662-1667 (2010).</li></ol>

The authors have nothing to disclose.

<html>不可切除肝转移患者可全身疗法进行治疗。然而，对于患者的转移性葡萄膜黑色素瘤，没有标准的全身性治疗是可用的和免疫或靶向治疗尚未能够显示出改进的生存。分离出的肝灌注已经被证明是一种有效的治疗患者局限于肝脏不能切除的葡萄膜黑色素瘤转移。9,28对于大肠癌转移多种治疗系统性可供选择，但一些患者这些方案下进展或不能耐受这种处理因为毒性。 2009年，范Iersel和同事报告25.0个月，与全身治疗治疗后与一个国际水文计划程序处理与21.7个月患者中位总生存期。虽然没有显著，这表明从一个国际水文计划的过程与全身化疗的开罗1个周期对利益的趋势。29 t"的&gt; IHP是一个复杂的外科手术和由于复杂性，住院时间和相关的发病率和死亡率从未获得了广泛的认可。由于有前景的结果的，较少侵入性的经皮系统的开发由于在手术过程中血液动力学pertubations的。和后程序血液学毒性，病人的选择是非常重要的。患者WHO状态0和1，没有或较少心肺危险因素，并可以选择PHP治疗。由于大剂量化疗保留肝功能，是有风险肝衰竭和肝脏体积因此不大于60％应该由肿瘤进行更换。PHP的方法的另一个重要方面是病人的麻醉管理，特别是高血压的控制30在手术过程中，瞬态低血压的发生是由于在预载的减少由于腔静脉闭塞和周围血管扩张血液通过量的通道小时chemofilters（血液滤过）和清除血管活性药物 （ 如去甲肾上腺素和肾上腺素）由chemofilters的。 Ravikumar 等人首先描述了经皮肝静脉隔离和化疗输液和手续79％球囊扩张后，随之而来的一过性低血压的重要性和预测这种情况的发生。14的流通过转移后发生低血压的第二期木炭激活的过滤器。这17,23是低血压持续时间短，并很好地响应流体和sympatico模拟物的管理。 虽然77％（第1代过滤器）过滤器提取率已经指出，美法仑还小全身发生泄漏，导致骨髓抑制。这已在多数文献病例被报道，是短暂性的，并与GCSF生长因子和/或血液制品以及管理的，主要是在门诊基础。16,17,19血细胞减少的最低点是PHP以后普遍达到10-14天。因此，在PHP后的头两个星期定期进行血液检查是强制性的。当前正在使用的第二代滤波器，希望通过增加滤波器萃取降低毒性。 在手术过程中，团队合作和清晰的沟通是非常重要的。该过程最好通过一个专门的团队，训练有素的成员执行。在我院的PHP程序，介入放射学家充当球队领袖。 PHP在治疗肝脏恶性肿瘤的当前状态还没有解决，但最近公布的III期临床试验结果显示改进的无进展生存期。未来的试验还必须证明的PHP是否可以集成在治疗策略的其它类型恶性肿瘤。短住院手术后，显示的耐受性此过程中，与管理的并发症支持PHP的癌症局限在肝脏处理正在进行的研究。 综上所述，PHP是治疗不能切除的肝癌转移的耐受性良好的局部治疗。生存和缓解持续时间在不同的试验进行了研究。

恶性肝肿瘤切除术是治疗原发性和继发肝脏恶性肿瘤的首选。然而，患者大部分是不是因为扩展性疾病或转移灶的位置的候选人进行手术。对于患有大肠癌转移无法切除，全身治疗往往是首选的治疗方法。从葡萄膜黑色素瘤肝转移通常很小，而整个肝脏弥漫性扩散。没有标准的全身治疗可用于本组患者。局部治疗可以是全身性治疗的替代方案中，在的情况下转移局限于肝脏。 因为肝脏的特定血管解剖的，这个机构可以从体循环中分离出来。这使得高剂量化疗（IHP，隔离肝脏灌注）肝脏灌注。此外，肝脏恶性肿瘤具有从hepati主导或独占血管供应Ç动脉，所述非肿瘤性肝实质的供给而70-80％是来自门静脉的。1,2这种技术二十多年前开发的，治疗患者以从不同的主起源不可切除的转移。3， 4特别是眼色素层黑素瘤患者在肝转移可以是候选人IHP因为转移通常很小，而在整个肝传播，并且目前没有标准全身治疗是可用的。5,6 IHP的原理是从全身循环暂时隔离肝脏和用高剂量化疗灌注器官，导致高的局部药物暴露与全身性副作用的限制。7这种高化疗剂量将是有毒的和导致并发症当全身施用。大多数国际水文计划的研究，用马法兰进行，调查了治疗肝metastasi的。期从大肠癌患者，以及患者的葡萄膜黑色素瘤转移的开放性手术过程中IHP 8,9一些研究表明，这种疗法可能是有效的:用于治疗50-59％的肿瘤缓解率（部分和完全反应）肠癌和治疗转移性葡萄膜黑色素瘤68％的肿瘤反应率的报道。8,10,11,12尽管有这些治疗的结果，该过程从未被广泛接受，因为该过程的复杂性，医院的持续时间留和相关的发病率和死亡率。 经皮肝灌注（PHP）的提供内容微创替代IHP和使用阿霉素13和人体试验的第一个被Ravikumar 等人进行的在猪模型首次证明1993。在1994年14由于缺乏有效性的证据，该技术主要被摒弃了，直到2000年初，当它W¯¯在美国国家癌症研究所（NCI）在美国15 PHP期间作为重新评估，将导管经由股动脉置于经皮到适当的肝动脉注入化疗剂。第二导管经由股静脉置于下腔静脉抽吸肝chemosaturated流出（参见图1中的PHP的电路）。隔离抽吸导管放置在腔静脉是双气囊导管，禁止泄漏进入体循环。的吸气chemosaturated血液由双木炭过滤器过滤，并通过放置在颈内静脉的第三导管返回到患者。病人在逗留〜3天的长度医院收治。 PHP的过程在全身麻醉下的血管造影室通过由专用的介入放射学家，麻醉师的一个训练有素多学科小组和体外perfusio执行NIST。一个肿瘤外科和肿瘤科医生也是这个多学科小组的成员，特别是集中在告知病人，病人的选择和术后护理。 <img alt="图1" src="/files/ftp_upload/53795/53795fig1.jpg" /> 图1 PHP的电路的原理图的图像。该图显示的PHP电路的设置。它显示了超有形的旁通管路隔离的肝脏灌注电路。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53795/53795fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 这个最小侵入性手术用少手术并发症相关联，并且可以被重复多次（至少4倍）。此外，它只有大约需要3至4小时，病人恢复快。的PHP的优点是，转移的所有尺寸可以治疗，和微转移正在汤治疗d以及。另外，转移，贴近血管结构和胆管的位置，是不是为PHP的禁忌证。最初的研究用的第一代滤波器执行的，用77％（平均）滤波器提取效率。16最近，III期试验的结果由Hughes 等人发布。表示在葡萄膜肝无进展存活的显著改善黑色素瘤患者与PHP相比，最好的替代治疗护理肝转移。17 自2012年4月2 第二代滤镜。在临床前研究中的第二代滤波器提取美法仑的98％。一些研究和案例研究系列为PHP多种适应症已公布，但除了最近出版的三期临床试验，生存还没有广泛地进行了分析。16,18,19,20在本次调查中，我们重点介入RAdiology程序，以及麻醉管理和被在此过程中，以促进在其他医疗中心采用这种治疗方法中使用的额外的体外循环。

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			<td height="42" style="height:42px;width:411px;">Delcath 2nd Generation Hepatic CHEMOSAT Delivery System&#160;</td>
			<td style="width:357px;">Delcath Systems Inc., New York, New York, USA</td>
			<td style="width:180px;">602001 and 602002</td>
			<td style="width:167px;">Item no. 1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Isofuse Isolation Aspiration Catheter (Double Balloon Catheter)</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
			<td rowspan="2">Item no. 1a</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">10F Venous Return Catheter</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Hemofiltration Cartridges</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
			<td rowspan="2">Item no. 1b</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Circuit components</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Level-1 rapid fluid management system</td>
			<td style="width:357px;">Smiths Medical</td>
			<td style="width:180px;"></td>
			<td>Item no. 2</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;">22G arterial line&#160;</td>
			<td style="width:357px;">Arrow International Inc. /&#160; Teleflex Inc.,Dublin, Ireland</td>
			<td style="width:180px;"></td>
			<td>Item no. 3</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Vigileo, Monitor</td>
			<td>Edwards Lifesciences Corp, Irvine, California, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 4</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">7.5F Triple lumen intravenous catheter, 20 cm&#160;</td>
			<td>Vygon, Valkenswaard, Nederland</td>
			<td></td>
			<td>Item no. 5</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">5F sheath&#160;</td>
			<td style="width:357px;"></td>
			<td style="width:180px;"></td>
			<td>Item no. 6</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">2.7 Progreat microcatheter&#160;</td>
			<td>Terumo, Tokyo, Japan</td>
			<td>MC-PP27131</td>
			<td>Item no. 7</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">18F sheath&#160;</td>
			<td style="width:357px;"></td>
			<td style="width:180px;"></td>
			<td>Item no. 8</td>
		</tr>
		<tr height="84">
			<td height="84" style="height:84px;">Auto-injector Medrad Mark V ProVis</td>
			<td>Bayer, Indianola, Pennsylvania, USA</td>
			<td style="width:180px;">Not available anymore, replaced by&#160;Medrad&#160;Mark 7 Arterion&#160;Injection System</td>
			<td>Item no. 9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Melphalan</td>
			<td>Alkeran, Aspen Pharmacare, Dublin, Ireland</td>
			<td style="width:180px;"></td>
			<td>Item no. 10</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Heparin LEO, 5000 IE/ml</td>
			<td style="width:357px;">LEO Pharma AB, Denmark</td>
			<td style="width:180px;"></td>
			<td>Item no. 11</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Centrifugal pump</td>
			<td style="width:357px;">Medtronic, Minneapolis, Minnesota, VS</td>
			<td style="width:180px;"></td>
			<td>Item no. 12</td>
		</tr>
		<tr height="21">
			<td colspan="2" height="21" style="height:21px;">Voluven colloid solution (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection)</td>
			<td style="width:180px;"></td>
			<td>Item no. 13</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Iopromide 300, Ultravist</td>
			<td style="width:357px;">Bayer, Indianola, Pennsylvania, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 14</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Detachable coil, Interlock</td>
			<td style="width:357px;">Boston Scientific, Marlborough, Massachusetts, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 15</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Vascular plug, Amplatzer 4</td>
			<td style="width:357px;">St. Jude Medical, St Paul,Minnesota, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 16</td>
		</tr>
	</tbody>
</table>

percutaneous hepatic perfusion (php) with melphalan as a treatment for unresectable metastases confined to the liver

结直肠癌的无法切除的肝转移可全身化疗进行治疗，旨在限制疾病，延长生存期或将无法切除的转移到可切除的。然而，一些患者患下全身治疗的副作用或进展。对于患者转移葡萄膜黑色素瘤没有规范的系统治疗方案。对于患者无肝外疾病，隔离肝脏灌注（IHP）可以使全身的副作用有限的地方疾病控制。以前，这是开放式手术过程中提供满意的结果进行，但发病率和死亡率有关的开放过程中，禁止一个广泛的应用。因此，经皮肝动脉灌注（PHP）并同时chemofiltration开发。除了降低的发病率和死亡率，此过程可以重复，希望导致更高的响应速率和改进的生存期（由疾病的局部控制）。在PHP，猫heters被放置在适当的肝动脉，注入化疗剂，并在下腔静脉以吸入chemosaturated血液通过肝静脉返回。的腔静脉导管是双气囊导管禁止泄漏进入全身循环。血液从肝静脉返回通过导管穿孔吸出，然后通过一个额外的有形过滤系统灌注。过滤后，将血液中的右颈内静脉返回到患者通过第三导管。 PHP期间美法仑的高剂量输注进入肝脏，其中是有毒的，当全身给药会导致危及生命的并发症。因为从腔静脉闭塞和chemofiltration，血液动力学监测和血流动力学支持体的组合得到的显著血流动力学不稳定的这一复杂过程中是非常重要的。

知识关于PHP是基于我小的相位和II期试验和案例系列和最近的大阶段III试验;公布的结果的概述示于表1中 。一个论述了麻醉过程，血流动力学和治疗的代谢方面的问题。然而，据报道没有生存的数据。所报告的22三个更大的试验，包括从不同的原发肿瘤转移肝脏疾病，因此，结果是难以解释。16,22第一手稿出版于1994年和5-FU和阿霉素是使用。20,23发布总体反应率变化对存活数据30和90％之间和有限的数据报告。最近的一项III期临床试验，患者的葡萄膜黑色素瘤的肝转移比较PHP最佳替代照料（BAC），报告为7个月改善肝无进展生存期1.6个月收到的BAC的组（p &lt;0.0001）。17在患者的PHP的组36％的患者有部分反应，另外52％的稳定的疾病。在中位总生存期无显著差异观察（10个月），可能是因为患者BAC组可以交叉到PHP处理。17 报围术期事件（该过程达72小时后的程序期间）包括血小板减少（74％）和贫血（60％），经常与输血治疗。同时手术相关低血压和肝动脉痉挛观察到，这可能与升压药及硝酸甘油分别进行处理。四人死亡（4％死亡率）的报道;两个骨，骨髓抑制相关，中性粒细胞减少和链球菌败血症-之一，因为渐进性肝功能衰竭，一名来自胃穿孔17 <strong&gt;的表1:经皮肝动脉灌注的结果发布<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53795/Table_1_JOVE.docx" target="_blank">，请点击这里下载该文件。</a>出版有报道患者局限于用PHP治疗的肝转移临床疗效。 ORR =总反应率; CR =完全反应; PR =部分缓解; SD =稳定的疾病。 HPFS =肝无进展生存期; NA =不可用。 其中，与第一代过滤器进行，以77％（平均）滤波器提取效率的初步研究。16过滤器设置和相关的协议，在响应中发生的并发症进行了调整。基于这些发现使用第一代滤波器研究还报道3级和4级凝血，可能通过过滤器有关的凝血因子的消耗。17,22，一个第二代滤器脱开发出来，这是自2012年4月可用在临床前研究中的过滤功效为98％。为PHP的程序选择的化疗剂是美法仑，因为它以前证明是有效的在不同类型的肝转移的治疗中，而不被肝毒性，即使当在清髓性剂量给药。7,22美法仑是烷化剂氮芥基团。它通过破坏原有的结构增加了的烷基的DNA，在快速分裂的细胞的干扰正常的有丝分裂。24添加其它化疗剂如5-氟尿嘧啶（5-FU）和甲酰四氢叶酸25，奥沙利铂26或TNF 11没有改善反应率与在大多数研究中观察到的增加的肝毒性。27 为了研究这个过程与第二代滤波器患者的有效性和安全性与unres葡萄膜黑色素瘤或大肠癌ectable肝转移，两相II试验已经在莱顿大学医学中心和伊拉斯谟MC癌症研究所（NTR4112分别NTR4050）启动。主要终点是根据对CT / MRI，扫描RECIST 1.1标准的响应速度。次要终点是根据CTCAE 4.0，（总体）生存和（肝）无进展生存期和缓解持续时间安全性，毒性。截至目前，27名患者经治疗后已一直没有PHP相关的死亡率。

Watch this Scientific Journal Video about Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver at JoVE.com

Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

在这个手稿中，我们描述了同时作为chemofiltration治疗不能切除的肝转移经皮隔离肝脏灌注。这个程序是在全身麻醉下在angiosuite由经验丰富的团队进行，包括介入放射学家，临床灌注师和麻醉师的。

经皮肝脏灌注（PHP）与美法仑作为囿于肝脏不能手术切除转移的治疗

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn ...

percutaneous-hepatic-perfusion-php-with-melphalan-as-treatment-for

Nanyang Technological University

Research

JoVE Journal

Medicine

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

11.8K 次观看.  Leiden University Medical Centre. 在这个手稿中，我们描述了同时作为chemofiltration治疗不能切除的肝转移经皮隔离肝脏灌注。这个程序是在全身麻醉下在angiosuite由经验丰富的团队进行，包括介入放射学家，临床灌注师和麻醉师的。 

视频: Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%1-3, the majority of cases being monocular2. Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.
Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself4,5 . Amblyopia is characterized by both monocular and binocular deficits6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions8. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia9,10 .
Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations.
In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15.

Amblyopia is a developmental disorder of the visual cortex that is often accompanied by strong suppression of one eye. We present a new technique for measuring and treating interocular suppression in patients with amblyopia that can be deployed using virtual reality goggles or a portable iPod Touch device.

测量和制止在弱视治疗

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current ...

科研

医学

Surgical Procedures for a Rat Model of Partial Orthotopic Liver Transplantation with Hepatic Arterial Reconstruction

Orthotopic liver transplantation (OLT) in rats using a whole or partial graft is an indispensable experimental model for transplantation research, such as studies on graft preservation and ischemia-reperfusion injury 1,2, immunological responses 3,4, hemodynamics 5,6, and small-for-size syndrome 7. The rat OLT is among the most difficult animal models in experimental surgery and demands advanced microsurgical skills that take a long time to learn. Consequently, the use of this model has been limited. Since the reliability and reproducibility of results are key components of the experiments in which such complex animal models are used, it is essential for surgeons who are involved in rat OLT to be trained in well-standardized and sophisticated procedures for this model.
While various techniques and modifications of OLT in rats have been reported 8 since the first model was described by Lee et al. 9 in 1973, the elimination of the hepatic arterial reconstruction 10 and the introduction of the cuff anastomosis technique by Kamada et al. 11 were a major advancement in this model, because they simplified the reconstruction procedures to a great degree. In the model by Kamada et al., the hepatic rearterialization was also eliminated. Since rats could survive without hepatic arterial flow after liver transplantation, there was considerable controversy over the value of hepatic arterialization. However, the physiological superiority of the arterialized model has been increasingly acknowledged, especially in terms of preserving the bile duct system 8,12 and the liver integrity 8,13,14.
In this article, we present detailed surgical procedures for a rat model of OLT with hepatic arterial reconstruction using a 50% partial graft after ex vivo liver resection. The reconstruction procedures for each vessel and the bile duct are performed by the following methods: a 7-0 polypropylene continuous suture for the supra- and infrahepatic vena cava; a cuff technique for the portal vein; and a stent technique for the hepatic artery and the bile duct.

Orthotopic liver transplantation in rats is an indispensable experimental model for biomedical research. Here we present our surgical procedures for orthotopic rat liver transplantation with hepatic arterial reconstruction using a 50% partial graft.

部分原位肝移植大鼠模型的肝动脉重建的外科手术

Orthotopic liver transplantation (OLT) in rats using a whole or partial graft is an indispensable experimental model for transplantation research, such as ...

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to stimulate microcirculation. The choice of delivery method for these agents is important because the route of administration profoundly affects the bioactivity and efficacy of these agents1,2. In this article, we demonstrate how to locally administer a substance in ischemic hindlimbs by using a catheterized osmotic pump. This pump can deliver a fixed volume of aqueous solution continuously for an allotted period of time. We also present our mouse model of unilateral hindlimb ischemia induced by ligation of the common femoral artery proximal to the origin of profunda femoris and epigastrica arteries in the left hindlimb. Lastly, we describe the in vivo cannulation and ligation of the infrarenal abdominal aorta and perfusion of the hindlimb vasculature with Microfil, a silicone radiopaque casting agent. Microfil can perfuse and fill the entire vascular bed (arterial and venous), and because we have ligated the major vascular conduit for exit, the agent can be retained in the vasculature for future ex vivo imaging with the use of small specimen micro-CT3.

We show here the in vivo insertion of an osmotic pump for constant local drug delivery and the creation of hindlimb ischemia in a mouse model. Moreover, the hindlimb vasculature is perfused with Microfil, a silicone radiopaque agent, to prepare for micro-computed tomography (micro-CT) imaging.

药物输送到微型计算机断层扫描成像缺血后肢血管灌注与微滤渗透

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to ...

Technique of Subnormothermic Ex Vivo Liver Perfusion for the Storage, Assessment, and Repair of Marginal Liver Grafts

The success of liver transplantation has resulted in a dramatic organ shortage. In most transplant regions 20-30% of patients on the waiting list for liver transplantation die without receiving an organ transplant or are delisted for disease progression. One strategy to increase the donor pool is the utilization of marginal grafts, such as fatty livers, grafts from older donors, or donation after cardiac death (DCD). The current preservation technique of cold static storage is only poorly tolerated by marginal livers resulting in significant organ damage. In addition, cold static organ storage does not allow graft assessment or repair prior to transplantation.
These shortcomings of cold static preservation have triggered an interest in warm perfused organ preservation to reduce cold ischemic injury, assess liver grafts during preservation, and explore the opportunity to repair marginal livers prior to transplantation. The optimal pressure and flow conditions, perfusion temperature, composition of the perfusion solution and the need for an oxygen carrier has been controversial in the past.
In spite of promising results in several animal studies, the complexity and the costs have prevented a broader clinical application so far. Recently, with enhanced technology and a better understanding of liver physiology during ex vivo perfusion the outcome of warm liver perfusion has improved and consistently good results can be achieved.
This paper will provide information about liver retrieval, storage techniques, and isolated liver perfusion in pigs. We will illustrate a) the requirements to ensure sufficient oxygen supply to the organ, b) technical considerations about the perfusion machine and the perfusion solution, and c) biochemical aspects of isolated organs.

Technique of Subnormothermic Ex Vivo Liver Perfusion for the Storage, Assessment, and Repair of Marginal Liver Grafts

Marginal grafts, such as fatty livers, grafts from older donors, or livers retrieved after cardiac death (DCD) tolerate conventional, cold static storage only poorly. We developed a novel model of subnormothermic ex vivo liver perfusion for preservation, assessment, and repair of marginal liver grafts prior to transplantation.

Subnormothermic的技术<em&gt;前体内</em&gt;肝脏灌注的存储，评估和修复边际移植肝

The success of liver transplantation has resulted in a dramatic organ shortage. In most transplant regions 20-30% of patients on the waiting list for ...

A Preclinical Murine Model of Hepatic Metastases

Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, murine pancreatic tumor model of hepatic metastases via a hemispleen injection of syngeneic murine pancreatic tumor cells is described. This model mimics many of the clinical conditions in patients with metastatic disease to the liver. Mice consistently develop metastases in the liver allowing for investigation of the metastatic process, experimental therapy testing, and tumor immunology research.

A preclinical, murine model of hepatic metastases performed via a hemispleen injection technique.

肝转移的临床前小鼠模型

Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, ...

Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

隔离肝脏灌注作为治疗葡萄膜黑色素瘤肝转移

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

MRI引导dmPFC-rTMS治疗作为治疗难治性抑郁症

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

Method of Direct Segmental Intra-hepatic Delivery Using a Rat Liver Hilar Clamp Model

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ischemia/reperfusion (I/R) injury with myriad negative consequences. Potential I/R injury in marginal organs destined for liver transplantation contributes to the current donor shortage secondary to a decreased organ utilization rate. A significant need exists to explore hepatic I/R injury in order to mediate its impact on graft function in transplantation. Rat liver hilar clamp models are used to investigate the impact of different molecules on hepatic I/R injury. Depending on the model, these molecules have been delivered using inhalation, epidural infusion, intraperitoneal injection, intravenous administration or injection into the peripheral superior mesenteric vein. A rat liver hilar clamp model has been developed for use in studying the impact of pharmacologic molecules in ameliorating I/R injury. The described model for rat liver hilar clamp includes direct cannulation of the portal supply to the ischemic hepatic segment via a side branch of the portal vein, allowing for direct segmental hepatic delivery. Our approach is to induce ischemia in the left lateral and median lobes for 60 min, during which time the substance under study is infused. In this case, pegylated-superoxide dismutase (PEG-SOD), a free radical scavenger, is infused directly into the ischemic segment. This series of experiments demonstrates that infusion of PEG-SOD is protective against hepatic I/R injury. Advantages of this approach include direct injection of the molecule into the ischemic segment with consequent decrease in volume of distribution and reduction in systemic side effects.

A unique rat liver hilar clamp model was developed for studying the impact of pharmacologic molecules in ameliorating ischemia-reperfusion injury. This model includes direct cannulation of the portal supply to the ischemic liver segment via a branch of the portal vein, allowing for direct hepatic delivery.

直接节段性肝内交付使用大鼠肝门部夹具模型方法

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ...

Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For inoperable patients, local ablation therapies, such as stereotactic body radiotherapy (SBRT), can provide effective local tumor control with minimal toxicity. Because of its high precision and accuracy, SBRT delivers a higher radiation dose per fraction, is more effective, and targets smaller irradiation volumes than does conventional radiotherapy. In addition, steep dose gradients from target lesions to surrounding normal tissues are achieved using SBRT; thus, SBRT provides more effective tumor control and exhibits fewer side effects than conventional radiotherapy. The use of SBRT is prevalent for treating intracranial lesions (known as stereotactic radiosurgery); however, it is now also used for treating spinal and adrenal metastases. Because of advancements in image-guided assistance and respiratory motion management, several studies have investigated the use of SBRT for treating lung or liver tumors, which move as a patient breathes. The results of these studies have suggested that SBRT favorably controls tumors in the case of moving lesions.
Four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) is clinically convenient for effective respiratory motion management. Because this method is noninvasive and allows free breathing, its use reduces complications. Furthermore, patients consider this method convenient. Moreover, it is considered more efficient than other methods of respiratory motion management by physicians and therapists. The use of 4D-CT with an AC for treating pulmonary lesions has also been widely investigated, and the technique is gaining acceptance for treating hepatic lesions. However, the protocols for using 4D-CT with an AC for treating hepatic lesions are different from those used for treating pulmonary lesions. In this article, we describe a new protocol for SBRT with 4D-CT and an AC for treating liver metastases.

Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.

内靶容积法治疗肝转移瘤的立体定向体放疗

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For ...

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, normothermic ex vivo liver perfusion (NEVLP) has been introduced as a method to evaluate and modify organ function. NEVLP has many advantages in comparison to hypothermic and subnormothermic perfusion including reduced preservation injury, restoration of normal organ function under physiologic conditions, assessment of organ performance, and as a platform for organ repair, remodeling, and modification. Both murine and porcine NEVLP models have been described. We demonstrate a rat model of NEVLP and use this model to show one of its important applications &#8212; the use of a therapeutic molecule added to liver perfusate. Catalase is an endogenous reactive oxygen species (ROS) scavenger and has been demonstrated to decrease ischemia-reperfusion in the eye, brain, and lung. Pegylation has been shown to target catalase to the endothelium. Here, we added pegylated-catalase (PEG-CAT) to the base perfusate and demonstrated its ability to mitigate liver preservation injury. An advantage of our rodent NEVLP model is that it is inexpensive in comparison to larger animal models. A limitation of this study is that it does not currently include post-perfusion liver transplantation. Therefore, prediction of the function of the organ post-transplantation cannot be made with certainty. However, the rat liver transplant model is well established and certainly could be used in conjunction with this model. In conclusion, we have demonstrated an inexpensive, simple, easily replicable NEVLP model using rats. Applications of this model can include testing novel perfusates and perfusate additives, testing software designed for organ evaluation, and experiments designed to repair organs.

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant liver donor shortage, and criteria for liver donors have been expanded. Normothermic ex vivo liver perfusion (NEVLP) has been developed to evaluate and modify organ function. This study demonstrates a rat model of NEVLP and tests the ability of pegylated-catalase, to mitigate liver preservation injury.

体外常温肝灌注的小动物模型

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, ...