我们希望这个手稿的准备过程中承认安吉拉·戴维斯博士对她有见地的意见。

注：该协议包括两部分：用于施加TTF系统和方法对于贝伐单抗输注8-11的详细方法。只有经过培训的处方由制造商美国FDA授权可以规定该设备。患者符合TTF疗法是那些22岁以上的老年人复发性胶质母细胞瘤，通常手术，手术和放疗方案已经用尽，但应该已经收到至少一个前化疗后。禁忌使用TTF治疗的包括灵敏度的导电水凝胶，有源植入型医疗装置的存在（深脑刺激器，脊髓刺激器，迷走神经刺激器，心脏起搏器，除颤器和可编程分流），颅骨缺损或子弹的片段（ S）。而TTF治疗一般耐受性良好，最典型的器械相关不良事件是皮肤发红，有时皮肤破裂，由于日的长时间接触ë换能器阵列，以在皮肤表面。为了尽量减少这种潜在的副作用，该阵列通常每周更换两次，并且如果皮肤反应观察到，则阵列可移离皮肤发红或炎症部位。这些皮肤反应还可以通过局部类固醇和/或如果需要的话1外用抗生素治疗。 在TTF系统的应用1 注：该系统由以下部分组成：一个电场发生器（设备），连接电缆和盒子，便携式电池（多个），一个充电器为便携式电池，插入式电源，以及一组换能器的阵列（4）（ 图1）。 <ol><li>装配系统 注意：为了使电场发生器提供的电场的肿瘤块，该组件具有以下面的方式进行互连： <ol><li>通过将它的力量共同使用充电电池充电器电池（S）RD上的充电器背面的电源按钮，一个标准的墙壁电源插座和开关。 注：电池机架最多可容纳3电池的时间。 </li><li>使用充电电池来驱动的电场发生器或“设备”，这又提供了电场到换能器阵列。 </li><li>通过它的连接器在插入电池到标有“DC IN”的设备的前面板上的一个插座中。确保将电池连接器上的箭头朝上向着“DC IN”的标志，而在连接器的堵塞。 </li><li>打开电源按钮，将电池插入设备后。 </li><li>连接的四个换能器阵列的连接器，使用颜色编码插头，以在连接电缆盒匹配的彩色编码的插座。 注意：例如，用红色环的换能器阵列连接器被插入到红色插座（标有“N1”）上的连接电缆盒（ 见图1）。 </li><li>盘绕连接线连接到一端的箱子和设备的另一端。 </li><li>将电池连接到设备，以提供必要的功率的装置，以产生交变电场。 </li><li>将设备连接到所述连接电缆和盒子使用匹配附连到换能器阵列的颜色编码的电缆，该彩色编码的套接字。 </li></ol></li><li>应用该传感器阵列向头皮<ol><li>准备病人头阵列的应用。刮脸用的电动剃须刀整个头皮。确保无茬遗骸和擦拭用70％的医用级酒精的头皮。 注：如果头皮受刺激的过度的非处方氢化可的松（类固醇）的奶油都可以使用。 </li><li>根据对一个病人清洁，剃头皮预先确定的特定的阵列布局布置的换能器阵列。 注意：磁盘阵列布局使用，利用头部和肿瘤MEAS专用软件计算为了产生最佳的电场强度在肿瘤部位，以达到最大的结果，从患者的磁共振成像（MRI）urements。 </li><li>剥去信封并取出数组，然后根据特定阵列布局配色方案应用到头皮。 注意：根据在那里它们被放置在头皮上前方（蓝色），背面（红色），右（黄色），左（白）：换能器阵列的位置和颜色。 注：换能器阵列提供清晰的无菌袋中。 </li><li>扣插头插入连接器。 </li><li>放置颜色编码插头上的四个换能器阵列的换能器阵列的连接器。 注意：这些颜色相匹配的已产生针对每一个病人用的专用软件（1.2.2）的帮助下，换能器阵列布置图的颜色编码。 </li><li>请将阵列电缆插入颜色匹配的连接线和框，上面提到的（参见1.1节）。 </li><l我&gt;打开电源开关上的设备，一旦阵列中的位置，系统完全连接。 </li><li>开关上的TTF字段按钮，系统现在准备电场交付。 注：没有标准的时间延续TTF疗法，然而，在笔者看来TTF疗法可以持续到的疾病或不可接受的毒性的发展，临床和/或影像学进展的时间。以达到最佳的反应，转录因子治疗，应使用在连续基础上进行最少每天18小时。每天不少于18小时的治疗时间已经与次优反应有关。每月合规日志可以从设备的软件由Novocure技术人员下载。 </li></ol></li></ol> 2.并发贝伐单抗管理注：贝伐单抗是靶向血管内皮生长因子（VEGF）蛋白的人源化单克隆抗体。通过阻断VEGF的相互作用与其受体，贝伐单抗施加一个强效的抗血管生成作用6,7。通常贝伐单抗的给药如静脉滴注（通常在30分钟内），每2个星期。然而，TTF设备被设计成在连续基础上使用，或者至少为每天18小时，以达到最佳的结果10。 <ol><li>小心，以尽量减少对药物的严重并发症的可能性，选择患者。 注：排除标准包括贝伐单抗近期颅内出血，近期中风或心肌梗死（1年以内），4周内大手术，未控制的高血压，妊娠或哺乳期和成像显示很少或没有对比增强疾病。另外，必须注意在患有肾疾病，包括蛋白尿，出血性疾病，深静脉血栓形成的历史，不受控制心绞痛，心律失常，充血性心脏衰竭，事先胸壁辐射，现有的蒽环类博览会行使URE，患者抗凝剂，近期（6个月以内）动脉血栓事件及其他严重内科疾病。 </li><li>预先筛选的患者的基线测试，包括全血计数及分类，肾和肝功能检查，血电解质，尿试纸的蛋白质和前，后输液血压测量。 </li><li>施用贝伐单抗输注一次，病人使用10毫克/千克体重的剂量水平被认为合适的候选，并与贝伐珠单抗输注同时启动TTF系统。 注：给初次输注60分钟，混合100毫升生理盐水。只要没有并发症的发展，贝伐珠单抗可考虑在后续输注30分钟。 </li></ol> 3.监测患者输液后<ol><li>监测病人的输液反应，如发热，寒战，瘙痒，皮疹或血管神经性水肿。如果这些发生停止贝伐单抗输液，和TR吃了用基于其严重程度8,9,11程度的标准方法的反应。 注意：需要调整剂量或停药贝伐珠单抗治疗的其他并发症包括蛋白尿和高血压，这两者都已经观察到在临床试验中使用贝伐珠单抗8,9,11。 </li><li>如果急性高血压（20毫米汞柱或以上的舒张血压上升或一百分之一百五十〇毫米汞柱以上正常基线值的血压）发生时，扣压贝伐珠单抗。如果按照输液的保持血压随后返回到正常1h内，重新启动输液半的初始速度。如果发生持续性高血压则高血压修饰剂，如钙通道阻断剂，ACE抑制剂或利尿药（氢氯噻嗪）。 </li><li>如果尿蛋白（+ 2，+ 3或4 +尿试纸），然后发生蛋白进行24小时尿液收集。如果24小时尿蛋白revea的ls小于2克/ 24 hr的蛋白质水平，然后施用贝伐单抗在充分的力量。为之间2-4克/ 24小时的水平，施用贝伐单抗以5mg /公斤体重（½标准剂量）。中止贝伐单抗为大于4克/ 24小时，蛋白水平。 </li><li>执行钆-DTPA增强磁共振成像每隔8-12周一次，以评估肿瘤反应。 注：FLAIR序列也是尤其是在服用贝伐单抗特别有帮助，因为偶尔增强了对比度成分可能会减少，而FLAIR信号的变化可能会出现恶化的迹象。 </li><li>评估使用NeuroOncology（RANO）标准的最新修订出版的评估（从老麦克唐纳标准修改）16胶质母细胞瘤的影像学改变。 </li></ol>

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这项研究是由来自Novocure有限公司的资助，以支付出版费用的支持。

本文介绍了一种新的方法用于治疗复发性胶质母细胞瘤。该方法涉及合并的只有两个FDA批准的治疗方式病情反复发作。这涉及使用连续强度低，中频电场处理与TTF系统结合的抗血管生成剂贝伐单抗。虽然每个这些治疗方式被FDA批准作为单一疗法，给定的GBM的预后不良，在复发的时间，组合方法可能被证明优于单一疗法，但是这仍然正在进行临床试验的受试者。这个过程从来没有被文献报道，但临床试验目前正在研究这个组合是否会导致更好的中位总生存期的标准放化疗后17谁复发的患者。 故障排除： 有几个问题可能潜在地出现杜响TTF装置的操作。例如，该设备的电源指示灯可能会失败，尽管转向“ON”的设备开机。可能的原因包括电池没电，发生故障的电池，充电器或设备。第一步将是一个充满电的备用更换电池没电。否则，该设备应转向“OFF”的技术支持热线联系。电缆可以从换能器阵列，其连接电缆或设备本身分离。这可能表明在电缆上过多的物理力或可指示与系统部件有故障的连接。更换传感器阵列可以解决问题，但如果没有固定的问题，然后再次TTF治疗应转向&#39;OFF&#39;和制造商联系。该器件还具有一个内置的报警系统，指示有问题的设备或它的操作方式。如果设备报警激活这可能表示电池电量不足，松动或断线电缆，堵塞设备侧通风口，可怜的换能器阵列的接触或者干脆设备故障。因此，故障诊断应包括更换电池（尤其是当电池电量不足指示灯亮起），或者电池电量不足指示灯不亮，则所有连接应进行检查，以确保没有连接松动，侧通风口应检查是否堵塞和换能器阵列也应进行检查，以确保他们得到适当的应用也是如此。如果问题仍然存在，然后再次制造商应该联系。从换能器阵列，以头皮的应用副作用也可能出现，并且包括瘙痒，发红或不太常用的水泡。如果发痒或发红，0.1％氢化可的松软膏可应用的阵列转移一寸通过¾远离瘙痒或红肿的部位。另一方面水泡可以指示感染，并且可能需要抗生素治疗。 该技术的局限性： 除了使用相当有限的范围内，交流电场的应用程序不是一个已知的治疗复发性GBM虽然2和3年生存率分别为8％（95％CI：4％-13％）和4 ％（95％CI：1％-8％）与5％（95％CI，3％-10％）和1％（95％CI，0％-3％），为TTF与主动控制10它的使用。已被证明是EQUivalent到医生的选择，化疗，但用的标准方法失败后较少的副作用，如手术辐射和第一线化疗方案。随着治疗继续在未来加以提炼，交流电场可能被证明有效的一线治疗胶质母细胞瘤。 相对于现有方法的意义： 正如上面提到的，TTF治疗是目前FDA批准用于复发性GBM而不是为一线治疗新诊断的GBM。照顾新诊断的GBM的治疗标准是目前的“Stupp”协议，其中涉及同步放疗（60 Gy的6周以上），替莫唑胺化疗后的辅助替莫唑胺在一起的管理。尽管这种治疗方案的中位总生存期的延长显著，GBM仍然是一个高度抗病各种形式提供的treatment方式和保持均匀的致命伤。加入四分之一的治疗方式，即在交变电场的医疗设备为GBM的治疗是非常需要的，在这一点上。使用各种组合和TTF疗法与其他目前批准的治疗方式排列今后的研究可以证明非常有益的。 在协议中关键的步骤： 在TTF系统的正确操作是成功治疗的关键。应当精确地跟随在协议部分中描述的步骤，但应注意的是，通过对谁打算使用的设备医疗服务提供者的设备的制造商美国FDA授权的适当培训。的关键步骤包括对电池进行充电适当，正确地组装该部件中的协议部分所指出的，正确的剃须和清洁头皮，施加导电的水凝胶，最后施加每次治疗布局的换能器阵列的剃的头皮。这有助于确保在交变电场的适当传导至其预期的大脑区域。后确保TTF系统和应用换能器阵列的相应组件，电源按钮接通时，最后的TTField按钮打开时，开始治疗。 未来发展方向： 在GBM中的治疗中使用的TTF疗法，无论是在复发和新诊断的设定很可能在将来得到改进。未来的研究与TTF疗法特别是在新诊断的设置可能特别有前途。由于其独特的作用和良好的安全性的机制，它是可能的转录因子疗法中的各种化学治疗的组合以及分子靶向药物将在未来的临床试验中被采用。目前有一个正在进行的试验测试TTF疗法的安全性和有效性结合辅助替莫唑胺的患者中18岁以上初诊GBM（EF-14），25。从本试验阳性结果，可能会导致扩大TTF疗法的指示，包括新诊断的GBM患者。此外，转录因子疗法也将适用于多种其他癌症包括转移性脑疾病的测试。我们希望，作为技术是精制，这些方法会对这种均匀地致命疾病显著影响。

这种新颖的TTF系统是FDA批准的设备，可提供中间频率，低强度直接交变电场的脑复发性胶质母细胞瘤1的治疗。它被认为是四分之一的治疗方式对癌症除了手术，放疗和化疗的治疗。在临床前试验，其结果表明，肿瘤细胞暴露于肿瘤治疗领域或TTFields导致细胞分裂的破坏，并随后凋亡20。 成胶质细胞瘤是胶质瘤中最常见的类型，也是最积极的。在新诊断的设置，标准的治疗方法包括并发辐射和替莫唑胺加辅助替莫唑胺6个月13。最近完成的一项III期临床试验结果显示中位总生存期的延长显著的并发和辅助治疗的RA患者替莫唑胺diation作为单独而不是辐射。该试验导致通过该协议作为护理的新诊断胶质母细胞瘤13的管理的新标准。不幸的是，这些患者总是复发和治疗选择变得有限，在这一点上。有复发性胶质母细胞瘤的治疗没有标准的办法;然而，有两种FDA批准的治疗方式，即贝伐单抗和新颖的TTF系统。贝伐单抗，一种单克隆抗体针对VEGF蛋白导致VEGF蛋白/受体相互作用的阻断。这导致抑制血管增殖是肿瘤脉管系统的一部分。在TTF系统的工作原理，通过一个完全不同的机制，即通过输送连续的交变电场，其导致抑制细胞分裂和细胞凋亡的1,6,7,20的。尽管所有可用的治疗方法，预后复发性胶质母细胞瘤仍然ðismal 4。 在这里，我们描述了一种新的方法对复发性胶质母细胞瘤的使用传送两个TTFields的以及同时的贝伐珠单抗输注治疗。希望的是，结合的办法将证明优于单药治疗，但是这仍然是一个大规模的临床试验来验证。 对于TTF系统的电磁基础 为了理解电场为基础的治疗的抗有丝分裂作用的GBM（肿瘤治疗领域的治疗或TTF疗法），必须审查有关电磁理论的几个概念。这一理论在1800年制定的法拉第并指出一个源电荷通过电磁场18所包围。这会对被放置在该领域内的一个检验电荷的力量。电场可以是均匀的或不均匀的。在一个均匀的电场，场强留制服贯穿始终。这可以通过力的平行线表示。在非均匀电场中，电场强度是不均匀的，并且改变从场的一端到另一边。这反过来又可以通过会聚或发散的力量，其中的力量汇聚成线代表更高的场强，反之亦然领域线条来表示。测试费用将迈向这一领域内的高场强的区域。另一方面，电场可以是恒定的或随时间变化的（交变）。在一个恒定电场的源电荷将保持相同，而相同电荷将产生振荡/正与负之间交替的随时间变化的场作为时间19的函数。 在电场测试电荷运动方向取决于多个参数。首先，一个测试电荷可以是电荷或偶极。的电荷是正的或负的，而偶极我S上一端正负另一方。电荷将朝相反的电荷移动，而偶极子的旋转速度。在TTF系统提供了一个交变电场，因此，两种电荷和偶极移动或旋转在相反的电荷和高电场强度的方向。在子细胞中末期的形成，对细胞产生非均匀电场的形态和场梯度导致介电电泳19。介电电泳被定义为向着的最大磁场强度的非均匀场的位置不带电粒子的迁移。 肿瘤的抗有丝分裂作用的机制处理，字段 使用TTFields（肿瘤治疗领域），用于治疗癌症的概念最初是由约拉姆帕提20教授概念化。帕提推测，癌细胞的有丝分裂活性会被APPL被打乱英适当调整电场。假设随后在各种癌细胞的细胞培养物进行测试，其中它被证明电场破坏微管蛋白亚基的聚合，因此，防止了所需的细胞分裂20有丝分裂纺锤体的形成。例如， 在体外高级别胶质瘤模型中，示出的最佳TTField频率施加而没有过度的组织刺激或加热的最大细胞杀伤测定为200千赫20。低频率（&lt;1千赫兹）电场的应用是已知的导致通过膜去极化的生物组织的刺激。随着频率的增加远远高于1千赫兹，刺激作用大大削弱，因为膜的超极化和去极化周期被集成和净效应变得更接近于零。在显著较高频率（MHz范围内）时，电场由于介电损耗导致组织加热。牛逼他的概念已在临床实践中的应用，如电疗和射频肿瘤消融应用。最佳的效果也依赖于电场强度，其中在1-3伏/厘米的愤怒领域是不引起组织加热最有效的。另外，由于该领域的应用是中频（200千赫在神经胶质瘤细胞的情况下），它们并没有导致生物膜的刺激。因此，低强度（1-3伏/厘米），中频（200 kHz）的肿瘤治疗领域对细胞进行有丝分裂的应用导致了更高的电场强度的方向上的高度带电的微管蛋白亚单位的取向，在这种情况对细胞分裂沟。这导致有丝分裂的破坏，形成质膜小泡并最终凋亡性细胞死亡（见手稿的视频部分）20。 Kirson和他的同事还发现​​，观察到最大效应时，现场粗略加人翁相同的方向进行有丝分裂的细胞。以这种方式，并在至少24小时连续的基础上施加的电场被证明导致阻滞细胞的增殖和杀伤细胞发生有丝分裂20。使用这些临床前的数据，在应用TTF系统阵列的当前方法是这样的，两个连续的场方向被施加到肿瘤，以优化细胞杀伤率。正因为如此，在阵列的布局是使用肿瘤MRI数据，实现所需的生物活性的最大计划。 贝伐单抗和理由行动的结合电场治疗RGBM机制 贝伐单抗是一种人源化单克隆抗体靶向VEGF的分子，并防止其相互作用与VEGF受体。它获得了美国食品和药物管理局（FDA）的批准，2009年经常性胶质母细胞瘤的治疗基于两个II期，开放标签，非ST对比udies。在大脑研究中，客观缓解率为28％（85分之24），与5.6个月响应的时间中位数。在PFS-6速度与单药贝伐单抗为42.6％（95％CI，29.6％-55.5％），中位OS为9.2个月（95％CI，8.2-10.7个月）8。第二项研究（NCI 06-C-0064E）的客观缓解率为19.6％（11/56; 95％CI，10.9％-31.3％）。中位PFS为16周（95％CI，12-26周），对PFS-6率为29％（95％CI，18％-48％），中位OS​​为31周（95％CI，21 -54周）21。总之，这两项研究发现，当与历史对照相比，使用贝伐珠单抗与较高的无进展生存率和疾病的缓解率相关联。在另一方面，没有强有力的证据表明，作为前期治疗新诊断的GBM患者使用时，贝伐单抗能延长中位总生存期。贝伐单抗已被合并审理与几个Chemotherapeutic代理了过去。复发性GBM患者的回顾性分析与处理含贝伐单抗治疗方案，并随后用不同的含贝伐单抗方案后进展的结论是，与以下肿瘤进展27延续贝伐单抗没有好处治疗。此外，尽管基础上减少了加强疾病贝伐单抗治疗后看到了有利的影像学反应，最近的一项研究得出结论，非增强疾病进展是贝伐单抗治疗后常见的，可能与不良预后有关。28 几个临床前和早期临床数据表明，肿瘤的组合治疗与化疗剂可能更有效（和潜在的协同作用）比单独22,23,24化疗领域。例如，一个研究评估TTFields的影响单独或与各种化疗（紫杉醇，doxor组合ubicin，对人乳腺癌细胞（MDA-MB-231）和人神经胶质瘤（U-118）细胞系24环磷酰胺和达卡巴嗪）。同样的研究调查TTFields的效果结合在动物肿瘤模型，并在试点的临床试验中，这些经常性的化疗药物和新诊断的GBM患者。这项研究的结论是，对化疗治疗的敏感性提高了1-3个数量级，加入TTFields的。在涉及患者初诊和复发性GBM试点临床试验，该组合的方式产生了显著改善PFS和OS（中155周无进展生存期和39+个月，总生存期），与历史对照相比，26。 在另一方面，大量的III期试验比较TTF治疗医师的选择化疗RGBM（EF-11）的处理表明，两种治疗方法产生了类似的生存结果WHI乐TTF治疗得到更好的副作用与化疗相比，10。鉴于二者贝伐单抗和TTF疗法已显示活动和当前FDA批准尽管作为单一疗法用于RGBM，我们推测这两个治疗方式的组合可以得到优于单独使用任一种药剂。为何组合贝伐单抗与化疗可能提供小的优点在患者总存活方面的一个假设是化疗对血脑屏障妥协的依赖性。当贝伐单抗校正血脑屏障，它也影响化疗有效地到达肿瘤的能力。 TTF疗法作为一种物理形态是假设不依赖于血脑屏障对于它的功效。有限制利用这种新的治疗方法。一方面，患者的选​​择可能是困难的主要原因是受禁忌对于每个治疗模式。目前还不清楚是否有禁忌症的组合方式也同样的，当作为单药治疗，或是否有与组合方式额外的预防措施，个体治疗模式。从我们这个新方法的经验有限，患者耐受治疗好。在另一方面，它仍然是在大规模临床试验可以看出这种方法是否能提供任何附加的优点（总存活或无进展生存期），在目前可用的治疗方案。目前，有相当大的未满足的需要制定有效的治疗方法为RGBM其预后仍不顾一切可用的治疗方式惨淡。这一方法将需要在大规模的临床试验进行评估，以确定它是否可以解决这一尚未满足的需要这一不幸的患者群。

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			<td style="width:167px;">Comments/Description</td>
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			<td height="21" style="height:21px;width:216px;">NovoTTF-100A System&#160;</td>
			<td style="width:157px;">Novocure Limited</td>
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			<td>Haifa, Israel</td>
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			<td height="21" style="height:21px;width:216px;">Bevacizumab (Avastin)&#160;</td>
			<td style="width:157px;">Genetech Corporation</td>
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			<td>South San Francisco, USA</td>
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</table>

tumor treating field therapy in combination with bevacizumab for the treatment of recurrent glioblastoma

一种新型设备，它采用TTF疗法最近开发并正在使用中经常性胶质母细胞瘤（RGBM）的治疗。这是FDA批准的2011年4月为患者22年或以上的RGBM治疗。该设备提供了交流电场，并进行编程，以确保最大的肿瘤细胞杀死1。 胶质母细胞瘤是胶质瘤中最常见的类型，并具有大约每年10,000例新病例中仅在美国就有2估计发病率。这种肿瘤的治疗特别耐并且是均匀地致命特别是经常设定3-5。在此之前的TTF系统的批准，唯一被FDA批准用于治疗RGBM是贝伐单抗6。贝伐单抗是靶向血管内皮生长因子（VEGF）蛋白，其驱动肿瘤血管生成7人源化单克隆抗体。通过阻断VEGF途径，bevacizumaB可导致显著放射线照相响应（pseudoresponse），改善无进展存活和减少在RGBM例8,9的皮质类固醇的要求。然而，贝伐单抗未能延长总生存期在最近的第三阶段试验26。一个关键的III期临床试验（EF-11）表现出医生的选择化疗和TTF疗法，但更好的生活质量进行了在TTF臂10之间观察比较的总生存期。 目前尚未满足的需求，开发设计，延长总生存期和/或提高生活质量在这个不幸的患者群新方法。一个富有吸引力的办法是将二者结合起来目前批准的治疗模式，即贝伐单抗和TTF疗法。这两种治疗方法目前被批准作为单一疗法11,12，但它们的组合从来没有在临床试验中被评估。我们已经开发了一种方法来合并这两个治疗方法和治疗2 RGBM患者。在这里，我们描述了详细的方法，概述从治疗的患者之一，这种新的治疗方案和现在的有代表性的数据。

上述协议是用于治疗2例谁没有传统的手术，放疗和化疗治疗复发性胶质母细胞瘤。来自这些患者中的一个所获得的数据进行了讨论。患者为一名56岁女性，标准的化疗，放射根据“Stupp协议”13谁是最初治疗。在疾病进展的时间里，她当选根据先前报道的“救援研究”14中所使用的协议，以追求剂量密集替莫唑胺。她的病情保持稳定数月的剂量密集的替莫唑胺，但其后除骨髓抑制（3级血小板减少症）开发的第二个放射学进展。然后，她决定继续与该组合的方式表示关闭标签使用贝伐单抗和NovoTTF治疗的知识上述协议，因为它们都是美国FDA批准作为单药治疗复发性设置。该患者共ntinued用约1个月这样的组合方式。她使用TTF疗法平均10〜12小时的一天，但后来逐渐激动，并拉动设备电缆。病人家属则选择停止治疗，追求临终关怀。 跟进成像，肿瘤呈显著影像学反应。有趣的是，无论是增强（如由MR后钆为代表）和非增强性疾病（MR FLAIR序列）显示放射线照相回归（参见图2）。当阿瓦斯汀施用作为单一疗法治疗复发性GBM，这是不寻常观察的减少肿瘤的增强组分的同时观察FLAIR信号变化的进程。此肿瘤反应背后的确切机制尚不清楚但是它是通过减少血管“泄漏”推测，贝伐珠单抗和透气性可导致在可不象下降olinium外渗而不影响非增强的疾病15。不论这种组合方法导致一个真正的减少两者的增强和肿瘤的非增强组分保留在将来​​大规模的研究，以进行验证。不幸的是，病人已过期约2个月后该协议的开始。患者有胸痛和呼吸急促（每女儿的帐户）紧接她的死亡，因此，（虽然通过调查，没有得到证实），我们认为，死因是灾难性的肺栓塞，而不是直接关系到她根本GBM。如前面所指出的，贝伐珠单抗治疗与肺栓塞6,11的风险增加相关联。 <img alt="图1" fo:content-width="5in" src="/files/ftp_upload/51638/51638fig1highres.jpg" width="500" /> 图1：NovoTTF-100A系统COMponents和组装。 （A）中的换能器阵列被示为它们应用到头皮（1）与连接到所述彩色编码的插座上的连接电缆和箱阵列电缆（2）。反过来箱连接到所述电场发生器与电池作为电源（3）。（B）的换能器阵列的示出陶瓷盘和连接器。 <img alt="图2" fo:content-width="5in" src="/files/ftp_upload/51638/51638fig2highres.jpg" width="500" /> 图2：经常性GBM的射线响应并发NovoTTF治疗和贝伐单抗预处理轴向MR图像后钆DTPA管理（一），冠后钆DTPA（b）和FLAIR（三）一名57岁的女性，反复发作。 GBM。后处理MR扫描（1个月并发处理后）表示显著减少两者的提高，轴向（d）和冠状（五）以及没有增强（六）FLAIR信号变化。

Watch this Scientific Journal Video about Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma at JoVE.com

Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

所采用复发成胶质细胞瘤的治疗的新型方法进行说明。这种治疗方法采用交流电肿瘤治疗领域（TTFields），与贝伐单抗，有针对性的代理，目前FDA批准作为单药治疗组合被称为TTF疗法的应用。

肿瘤治疗领域的治疗与联合贝伐单抗治疗复发性胶质母细胞瘤的治疗

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA ...

tumor-treating-field-therapy-combination-with-bevacizumab-for

Research

JoVE Journal

Medicine

26.9K 次观看.  Southern Illinois University School of Medicine. 所采用复发成胶质细胞瘤的治疗的新型方法进行说明。这种治疗方法采用交流电肿瘤治疗领域（TTFields），与贝伐单抗，有针对性的代理，目前FDA批准作为单药治疗组合被称为TTF疗法的应用。 

视频: Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

Catheter Ablation in Combination With Left Atrial Appendage Closure for Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide 1-3. The rapid, irregular, and disordered electrical activity in the atria gives rise to palpitations, fatigue, dyspnea, chest pain and dizziness with or without syncope 4, 5. Patients with AF have a five-fold higher risk of stroke 6.
Oral anticoagulation (OAC) with warfarin is commonly used for stroke prevention in patients with AF and has been shown to reduce the risk of stroke by 64% 7. Warfarin therapy has several major disadvantages, however, including bleeding, non-tolerance, interactions with other medications and foods, non-compliance and a narrow therapeutic range 8-11. These issues, together with poor appreciation of the risk-benefit ratio, unawareness of guidelines, or absence of an OAC monitoring outpatient clinic may explain why only 30-60% of patients with AF are prescribed this drug 8.
The problems associated with warfarin, combined with the limited efficacy and/or serious side effects associated with other medications used for AF 12,13, highlight the need for effective non-pharmacological approaches to treatment. One such approach is catheter ablation (CA), a procedure in which a radiofrequency electrical current is applied to regions of the heart to create small ablation lesions that electrically isolate potential AF triggers 4. CA is a well-established treatment for AF symptoms 14, 15, that may also decrease the risk of stroke. Recent data showed a significant decrease in the relative risk of stroke and transient ischemic attack events among patients who underwent ablation compared with those undergoing antiarrhythmic drug therapy 16.
Since the left atrial appendage (LAA) is the source of thrombi in more than 90% of patients with non-valvular atrial fibrillation 17, another approach to stroke prevention is to physically block clots from exiting the LAA. One method for occluding the LAA is via percutaneous placement of the WATCHMAN LAA closure device. The WATCHMAN device resembles a small parachute. It consists of a nitinol frame covered by fabric polyethyl terephthalate that prevents emboli, but not blood, from exiting during the healing process. Fixation anchors around the perimeter secure the device in the LAA (Figure 1). To date, the WATCHMAN is the only implanted percutaneous device for which a randomized clinical trial has been reported. In this study, implantation of the WATCHMAN was found to be at least as effective as warfarin in preventing stroke (all-causes) and death (all-causes) 18. This device received the Conformit&eacute; Europ&eacute;enne (CE) mark for use in the European Union for warfarin eligible patients and in those who have a contraindication to anticoagulation therapy 19.
Given the proven effectiveness of CA to alleviate AF symptoms and the promising data with regard to reduction of thromboembolic events with both CA and WATCHMAN implantation, combining the two procedures is hoped to further reduce the incidence of stroke in high-risk patients while simultaneously relieving symptoms. The combined procedure may eventually enable patients to undergo implantation of the WATCHMAN device without subsequent warfarin treatment, since the CA procedure itself reduces thromboembolic events. This would present an avenue of treatment previously unavailable to patients ineligible for warfarin treatment because of recurrent bleeding 20 or other warfarin-associated problems.
The combined procedure is performed under general anesthesia with biplane fluoroscopy and TEE guidance. Catheter ablation is followed by implantation of the WATCHMAN LAA closure device. Data from a non-randomized trial with 10 patients demonstrates that this procedure can be safely performed in patients with a CHADS2 score of greater than 1 21. Further studies to examine the effectiveness of the combined procedure in reducing symptoms from AF and associated stroke are therefore warranted.

Catheter ablation is combined with placement of the WATCHMAN Left Atrial Appendage Closure Device to prevent ischemic stroke in a patient with non-valvular atrial fibrillation.

结合消融房颤左心耳封堵

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide 1-3. The rapid, irregular, and ...

科研

医学

Human Neuroendocrine Tumor Cell Lines as a Three-Dimensional Model for the Study of Human Neuroendocrine Tumor Therapy

Neuroendocrine tumors (NETs) are rare tumors, with an incidence of two per 100,&#x200A;000 individuals per year, and they account for 0.5% of all human malignancies.1 Other than surgery for the minority of patients who present with localized disease, there is little or no survival benefit of systemic therapy. Therefore, there is a great need to better understand the biology of NETs, and in particular define new therapeutic targets for patients with nonresectable or metastatic neuroendocrine tumors. 3D cell culture is becoming a popular method for drug screening due to its relevance in modeling the in vivo tumor tissue organization and microenvironment.2,3 The 3D multicellular spheroids could provide valuable information in a more timely and less expensive manner than directly proceeding from 2D cell culture experiments to animal (murine) models.
To facilitate the discovery of new therapeutics for NET patients, we have developed an in vitro 3D multicellular spheroids model using the human NET cell lines. The NET cells are plated in a non-adhesive agarose-coated 24-well plate and incubated under physiological conditions (5% CO2, 37 &deg;C) with a very slow agitation for 16-24 hr after plating. The cells form multicellular spheroids starting on the 3rd or 4th day. The spheroids become more spherical by the 6th day, at which point the drug treatments are initiated. The efficacy of the drug treatments on the NET spheroids is monitored based on the morphology, shape and size of the spheroids with a phase-contrast light microscope. The size of the spheroids is estimated automatically using a custom-developed MATLAB program based on an active contour algorithm. Further, we demonstrate a simple method to process the HistoGel embedding on these 3D spheroids, allowing the use of standard histological and immunohistochemical techniques. 
This is the first report on generating 3D spheroids using NET cell lines to examine the effect of therapeutic drugs. We have also performed histology on these 3D spheroids, and displayed an example of a single drug's effect on growth and proliferation of the NET spheroids. Our results support that the NET spheroids are valuable for further studies of NET biology and drug development.

We present a simple agarose overlay platform to grow 3D multicellular spheroids using neuroendocrine cancer cell lines. This method provides a very convenient way to examine the effect of therapeutic drugs on the neuroendocrine tumor cells. It could also help us establish human neuroendocrine tumor spheroids for cancer therapy.

人类神经内分泌肿瘤细胞株为研究人类神经内分泌肿瘤治疗的三维模型

Neuroendocrine tumors (NETs) are rare tumors, with an incidence of two per 100,&#x200A;000 individuals per year, and they account for 0.5% of all human ...

Adjunctive Diode Laser Therapy and Probiotic Lactobacillus Therapy in the Treatment of Periodontitis and Peri-Implant Disease

Periodontal and peri-implant diseases are plaque-induced infections with a high prevalence, seriously impairing people&#39;s quality of life. The diode laser has long been recommended as adjunctive therapy in treating periodontitis. However, the optimal combination of usage mode (inside or outside periodontal pocket) and application regimen (single or multiple sessions of appointment) has not been described in detail. Meanwhile, probiotic Lactobacillus is regarded as a potential adjuvant in the management of the peri-implant disease. Nonetheless, a detailed protocol for an effective probiotic application is lacking. This article aims to summarize two clinical protocols. For periodontitis, the optimal collaboration of laser usage mode and application regimen was identified. Regarding peri-implant mucositis, a combined therapy containing professional topical use and home administration of probiotic Lactobacillus was established. This updated laser protocol clarifies the relationship between the treatment mode (inside or outside the periodontal pocket) and the number of laser appointments, further refining the existing diode laser therapy. For inside pocket irradiation, a single session of laser treatment is suggested whereas, for outside pocket irradiation, multiple sessions of laser treatment provide better effects. The improved probiotic Lactobacillus therapy resulted in the disappearance of swelling of the peri-implant mucosa, a reduced bleeding on probing (BOP), and an obvious reduction and good control of plaque and pigmentation; however, probing pocket depth (PPD) had limited improvement. The current protocol should be regarded as preliminary and could be further enhanced.

Adjunctive Diode Laser Therapy and Probiotic Lactobacillus Therapy in the Treatment of Periodontitis and Peri-Implant Disease

This article describes two protocols: 1) adjunctive diode laser therapy for treating periodontitis and 2) probiotic Lactobacillus therapy for treating peri-implant disease, with emphasis on the laser usage mode (inside or outside pocket), laser application regimen (single or multiple sessions), and a probiotic protocol of professional and home administration.

辅助二极管激光治疗和益生菌 乳酸杆菌 治疗牙周炎和种植体周围疾病

Periodontal and peri-implant diseases are plaque-induced infections with a high prevalence, seriously impairing people&#39;s quality of life. The diode ...

Surgical Treatment of an Endolymphatic Sac Tumor

Endolymphatic sac tumors (ELST) are low-grade papillary adenocarcinoma originating from the endolymphatic sac. Usually slow-growing, with local aggressiveness and a low risk of distant metastases, ELST can be sporadic but also frequently associated with von Hippel Lindau disease. The current treatment of ELST is primarily surgical resection. A 55-year-old woman accessed our otologic tertiary level referral center for a sudden worsening of hearing loss in her left ear and vertigo. A magnetic resonance (MRI) and computer tomography scan study subsequently showed a mass in the petrous bone; hence, the presence of an ELST was hypothesized. After embolization of the mass, the patient underwent surgical removal of the lesion. The resection of the mass was done through a translabirinthine approach, with an uneventful procedure. No residual disease remained after surgery. After 24 months of radiologic follow up with MRI, there are no signs of recurrence disease. This paper reports the management of this sporadic ELST, as well as the follow up results, providing clinicians this protocol for the handling of such a challenging otologic skull base surgery and rare disease.

Here, we discuss clinical and radiological features of endolymphatic sac tumors and report the methodology and results of a surgical removal in a case in care at our otologic referral center.

内淋巴囊肿瘤的手术治疗

Endolymphatic sac tumors (ELST) are low-grade papillary adenocarcinoma originating from the endolymphatic sac. Usually slow-growing, with local ...

小针刀治疗肩周炎的疗效

Clinical Efficacy of Small Needle Knife Therapy on Stage I-II Frozen Shoulder

Frozen shoulder is a kind of aseptic inflammatory disease of the shoulder caused by strain, trauma, and other reasons, resulting in shoulder joint pain and limited function. The protocol presented here demonstrates the operation of a small needle knife in treating frozen shoulders, including patient management, material preparation, positioning, operation, and postoperative care. The purpose of this protocol is to relieve the pain and functional limitations and improve the living ability of patients with frozen shoulders. In our study, 76 stage I-II frozen shoulder patients who met the inclusion criteria were randomly divided into a control group and a treatment group (n=38). Patients in the control group received functional exercise, while the treatment group received small needle knife therapy with functional exercise. The visual analogue scores (VAS), the Constant and Murley scores (CMS), and the thickness of the coracohumeral ligament (CHL) under ultrasound were evaluated. After small needle knife therapy, the VAS score was significantly lower in the treatment group (5.11 &plusmn; 0.89) than in the control group (5.49 &plusmn; 0.65; t=-2.065, p&lt;0.05); the CMS score was significantly higher in the treatment group (64.72 &plusmn; 4.78) than in the control group (60.97 &plusmn; 6.00; t=2.947, p&lt;0.05); the CHL thickness was significantly decreased in the treatment group (2.38 &plusmn; 0.36) than in the control group (2.57 &plusmn; 0.42; t=-2.117, p&lt;0.05). These results indicate that the small needle knife significantly relieved the pain symptoms, improved the shoulder function, reduced the CHL thickness, and improved the quality of life and, therefore, had significant therapeutic efficacy in stage I-II frozen shoulder patients.

作者聚焦：用小针刀疗法治疗肩周炎 

The protocol presented here describes the detailed operation method and proves the effectiveness of a small needle knife in the treatment of frozen shoulders.

小针刀治疗I-II期肩周炎的临床疗效

Frozen shoulder is a kind of aseptic inflammatory disease of the shoulder caused by strain, trauma, and other reasons, resulting in shoulder joint pain ...

用氨甲环酸和微针疗法加强黄褐斑治疗

Roller Microneedle Combined with Tranexamic Acid Solution in Treating Melasma

Melasma, a common, acquired facial pigmentation skin disorder, presents a straightforward clinical diagnosis but poses challenges in terms of effective management. The precise underlying causes of melasma remain elusive, and the current therapeutic approaches predominantly encompass pharmaceutical and laser interventions, with limited efficacy. Transdermal administration stands as a prevalent treatment method for melasma, often facilitated by the application of microneedles. Among these, tranexamic acid emerges as a frequently employed therapeutic agent. A subset of microneedles, known as roller microneedles, plays a significant role in this approach by delicately puncturing the epidermis with multiple fine needles, synergizing with drug delivery. This methodology not only enhances drug absorption but also augments treatment efficacy while minimizing tissue trauma. These attributes forecast promising avenues for the treatment of melasma. This article primarily introduces the combination of roller microneedle and tranexamic acid solution in the treatment of melasma and demonstrates the efficacy of roller microneedle and tranexamic acid solution in the treatment of melasma through clinical cases.

作者聚焦： 黄褐斑的非手术治疗 – 氨甲环酸微针

This article presents a protocol to conduct the treatment of melasma by using roller microneedles in combination with tranexamic acid solution and evaluate the efficacy.

滚筒微针联合氨甲环酸溶液治疗黄褐斑

Melasma, a common, acquired facial pigmentation skin disorder, presents a straightforward clinical diagnosis but poses challenges in terms of effective ...