The authors are grateful to Dr Liesbeth Boersma and colleagues at the Maastro Clinic for their advice on the voluntary breath-hold technique. The authors are also very grateful to the Pink Ribbon Foundation for funding the dissemination of the VBH technique. This article presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-1010-23003). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The work was undertaken in The Royal Marsden NHS Foundation Trust which receives a proportion of its funding from the NHS Executive. We acknowledge NHS funding to the NIHR Biomedical Research Centre and the support of the NIHR, through the South London Cancer Research Network.

通过此协议实施这项研究是由英国皇家马斯登委员会临床研究（英国Sutton）和研究伦理委员会（伦敦 - 滨江，英国）批准（ISRCTN 53485935）。 1，放射治疗诊所<ol><li>评估病人是否适合在门诊自愿屏气法：建议放射肿瘤学家左乳房或胸壁放疗（无淋巴结照射）。 </li><li>查看病人的一般状况和合并症（特别是肺癌相关的）。 </li><li>让患者练习屏住呼吸在家里，而躺着，最初为5秒，并建立在5秒间隔20秒。 </li></ol> 2，放射治疗计划-CT会话<ol><li>放置在标准治疗地位在CT沙发上的病人。 </li><li>定义纹身和地方的CT标志（十字架）上的FR病人中线的位置EE呼吸，沿可能的领域边缘约一半。加横向标记到患者在自由呼吸的每一侧，在与中线的标记线。 </li><li>让患者练习深呼吸并持有它，最初为5秒，建立在5秒的时间间隔20秒前。要求他们屏住呼吸长达20秒前指导患者呼吸，呼吸两次。这种放松的病人，帮助他们为屏气准备，并帮助屏气一致性。 </li><li>记录，病人可以舒适地屏住呼吸的最长持续时间。 </li><li>重复屏气并标记前的位置和横向纹身就激光器屏气，以帮助建立可重复性。在进行CT扫描之前，记录的横向纹身上述期间屏气沙发上方的高度。 </li><li>给标准屏气指示病人，并开始扫描一旦检测到Satisfied病人在屏气。 </li><li>一旦CT扫描已经完成，检查并记录在CT扫描的横向纹身的高度，以确认执行了一致屏气。如果横向榻高度差为大于3毫米的初始床的高度，重新测量的前部和侧面的参考点。 </li></ol> 3，放射治疗计划注：放射治疗计划的过程是一样的标准乳房患者。 <ol><li>按照当地协议适用切线放疗领域。 </li><li>生产出符合标准的ICRU临床放射治疗计划。 </li><li>记录除了（根据本地协议）记录标准的治疗计划数据的前束源到皮肤的距离（SSD）。注：前束固态硬盘是用来检查在治疗室的前后设置。 </li></ol> 4，放射线治疗herapy处理设置<ol><li>对齐纹身在自由呼吸。马克从左侧的纹身，并在患者的皮肤前正中线纹身（从信息记录在规划-CT会话）后下方的测量。 </li><li>指导患者采取深呼吸并保持前呼吸进出两次。在患者的皮肤上的参考标记应上升到激光的水平。要求患者重复屏气过程几次在进行病人安装程序之前进行确认的重现性。 </li><li>要求患者进行屏气并对准中线纹身等中心位置上/下，并设置焦点到表面距离（FSD）在中线。 </li><li>在自由呼吸，搬床横向到等中心。 </li><li>测量和标记在自由呼吸的内侧和外侧领域的边界。 </li><li>将所有其他的机器参数（ 如 。，字段大小和GAn请，准直器，和沙发角），头梁（左前斜）。要求患者进行屏气，检查内侧缘对齐步骤4.5做标记。 </li><li>标记字段边缘（由光场的定义）用钢笔在每个级分：这有助于患者的屏气的可视化。 </li><li>对于后斜束重复步骤4.6和4.7，并把第一个使用这种光束。 </li><li>如果病人的设置是出公差（根据当地公差等级为标准的乳房放疗患者），请参阅故障排除算法（ 图2）。 </li><li>如果有足够的摄像头监控领域的优势，以及相对于沙发龙门从控制室的位置，评估机架旋转离开治疗室，以避免碰撞之前。 </li></ol> 5，放射治疗交货<ol><li>一旦在控制室内，缩放疗程室M相机，使标记在病人的皮肤领域的边界是在控制室监控可见。 </li><li>一旦准备开始治疗，要求病人通过对讲系统进行一次屏气（如4.2中详述）。检查光场圆满对准标记字段边框上，然后开始治疗（ 图3）。 </li><li>治疗分娩过程中监测病人的屏气。如果有担心，有在屏气深度的变化治疗应中断。 </li></ol> 6，放射治疗验证<ol><li>执行病人体位（如电子门户成像（EPI）或锥束CT）成像验证，以下为成像和公差等级类型/频率的本地协议。 </li><li>正确用于与根据标准乳房放疗的病人本地协议等角点移动的系统误差。病人＆＃标记的调整8217;皮肤不应该是必要的。 </li></ol>

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The authors have nothing to disclose.

在协议中的关键步骤包括：1）检查在规划，CT和处理设置屏气的一致性; 2）检查在CT上测量的水平沙发高度与测量前的CT一致; 3）使纹身在自由呼吸，但屏气设置消防处; 4）确保光场与对齐开始治疗前显着田地边界。 数屏气处理分娩过程中需要变化从病人到病人，而且主要是依赖于段交付的数量。治疗分娩过程中适当的中断点（以使病人重复一次屏气前放松）应在个人基础上根据交货的方法来确定。我们强烈建议，对于VBH的，一个稳定的球队是用来初步实施。这使有关人员更快速地成为主管，并帮助维持治疗的质量。问题在哪里都带处理安装过程中反驳，病人可能会被要求修改自己的屏气（如需要更深或更浅）。如果失败，以提高设置，患者应重新设置。向量沙发上移动应该作为最后的手段。故障排除的算法如图2所示。 <img alt="图2" fo:content-width="5in" src="/files/ftp_upload/51578/51578fig2highres.jpg" width="500" /> 图2。故障诊断算法自愿屏气技术处理设置。该算法可用于辅助治疗的设置，其中病人不设置在公差范围内（根据当地的公差等级）。作为一个例子，我们中心采用5毫米的公差等级。该算法应遵循从上到下。在大多数情况下，安装程序都可以在公差范围内通过询问病人来修改他们的屏气深度（更深或更浅的带必需的）。 人口系统和随机治疗摆位误差小于那些出现在自由呼吸切线野放疗乳腺癌24，并 ​​与屏气技术，25,26等公布的数据是一致的。 VBH了25-58％，与标准自由呼吸乳房放射治疗在我中心（ 表1）相比，平均降低正常组织的剂量。心脏剂量与VBH比看到在屏气技术11,16,17,26,27等发表的作品低，但记录的剂量数据的方法，这些研究之间变化。 正如引言中所述，所有屏气技术使用一个代理来衡量间和intrafraction重复性。该VBH技术使用光场对准标记场的边界开始治疗前和治疗分娩过程中，以检查一致性。虽然还没有正式报道，我们发现intrafrac化的再现性是非常好，很少，如果有的话，intrafraction运动（使用多个intrafraction环境绩效指标来衡量）。这与以前发表的著作26一致。鉴于观察到的一致intrafraction重复性，放射治疗系统，其中光场处理分娩过程中不要留在不必是一个障碍，实现VBH的。在房间内的激光器，可以使用作为替代光字段检查该屏气的治疗递送过程中维持。此外，从该屏气再现性进行监测的基准点可以适合;例如，使用非对称场技术中心，不妨利用优越的切线野边界。 VBH提供超过其他心脏稀少的技术，其中的一些已经提到的显著优点。它最大限度地减少目标和OAR妥协之间的权衡往往需要使用MLC时，它减少了低剂量的我心脏的rradiation和少得多的资源密集型的调强放射治疗相比，它比俯卧照射而造福乳房大小不一的女性更具有可重复性。相对于其他屏气技术，VBH给出可比重复性和心脏备用，而被更便宜的实施，因为没有专门设备是必需的。该技术的低成本意味着有一个非常现实的机会，它有利于其他的医疗保健系统，尤其是那些资源有限。 目前已经发表的作品展示了使用红外线反射标记17和肺活量为基础的14个系统提供淋巴结照射除整个乳房/胸壁照射的可行性。我中心现进行进一步的工作，以确认使用VBH在乳腺癌患者淋巴结照射的可行性。反调强放射治疗计划很可能有利于在选定的病人，尤其是当DELIV化工e圈同时集成升压，并且在这些患者中使用VBH的可行性需要被评估。最后，治疗其他肿瘤，包括肺癌28，肝脏29，和胃的癌症30时屏气技术可能是有益的。需要进一步开展工作，以评估使用VBH技术治疗部位比其它丰胸的适用性。

癌症是人类死亡的首要原因，占7.6万人死亡，2008年1。所有癌症中，乳腺癌是拥有超过1380万世界各地的发病率是最常见的，而这发病率正在上升1。然而，改善乳腺癌的诊断和治疗意味着妇女的生存乳腺癌的人数也在不断增加，预计到2040年，在英国独自2到高音到1.7亿美元。乳腺癌放疗形成了许多妇女的乳腺癌治疗的重要组成部分，减半乳腺癌复发的风险及3.8％3降低乳腺癌死亡的风险。通过改进乳腺癌生存，任何长期的副作用引起乳腺癌的治疗变得越来越重要。在乳腺癌放疗一个无辜的旁观者是心脏，这是暴露在有害的辐射邻近辐射场的结果，尤其是在左侧乳房照射。正是这种不必要的剂量是占在乳腺癌放疗4相关的非乳腺癌死亡人数增加1％的心脏。最近的证据表明，有没有剂量阈值，低于该乳腺癌放疗的晚期强心作用不会发生5，使其成为关键的肿瘤学界建立技术，这不影响乳腺组织覆盖减少心脏剂量。然而，由于乳腺癌放疗占所有放射治疗6约30％，任何新的技术必须是简单和廉价，为了可持续发展，并且避免医疗资源无法接受的负担。 还有一些可以使用的乳房放疗期间，以减少心脏剂量技术。多叶准直器（MLC）被广泛应用于英国[放射科的皇家学院&#39;（英国）审计2012]虽然在不遗余​​力的心脏组织有效，它的风险同时屏蔽乳房组织。逆计划调强放射治疗（IMRT）提高靶组织保形7，但也可能增加心脏，肺和对侧乳腺7,8的低剂量照射。在心脏的低剂量照射的增加是不可取的，尤其是在光美等 5中的数据。此外，反调强放射治疗计划更是资源密集型的，需要更大的物理和质量保证（QA）的时间和专业知识。俯卧（面朝下）的位置对待妇女可能会降低心脏剂量较大胸女9，但是，问题仍然在该技术10的位置可重复性。屏气技术，其中，放射治疗在分娩过程中患者屏住呼吸，导致心脏被推向下并远离放射治疗领域，并且可以最小化的需要靶组织覆盖和器官在风险之间的折衷（OAR）不遗余力（ 图1）11。 目前在临床上使用的两个主要屏气技术。第一类包括连接到一个气球阀数字肺活量计的。呼吸的患者通过喉舌和剪辑放在自己的鼻子，以免鼻腔呼吸。肺活量跟踪可视化显示器上，和灵感中断，在预定的肺容积举行。第二种方法主要设计用于作为一个呼吸门控系统，尽管它也有一个内置的屏气设置。这个系统使用一个摄像机来记录一个反射红外线的标记放置在病人的胸部的运动。该标志的垂直运动被显示在监视器上进行实时和治疗递送开始一次标记移动到一个预先指定的阈值区域。这两种系统都显着降低心脏的剂量在接受左侧乳房放疗的病人。肺活量为基础的技术，显着地降低心肌的照射量12-14，以及比标准的仰卧自由呼吸乳房放疗15展示了类似的区域内和跨部分的重现性。同样，使用红外线反射标记处理50％以上11,16,17降低了平均剂量的心脏，同时维持目标组织覆盖11。这样的剂量节约预计将等同于在心脏病死亡18一10倍减少。 这些系统中，但是，一个障碍广泛实施的一个缺点，就是其成本。这两个系统需要投资在设备本身，但是，在肺活量测定系统的情况下也有作为吹嘴是一次性的持续费用，需要对规划-CT以及用于治疗的各组分的新咬嘴。成本，再加上缺乏员工培训，解释了为何使用β只执行4％的英国乳腺癌的治疗reath控股在2012年的技术[的放射科&#39;（英国）审计皇家学院。屏气技术在更广泛的使用在欧洲的其他地方，使用这些技术，2010年19个中心的20％。一种解释，这是一个简单，价格低廉，设备无屏气技术的开发和实施，自愿屏气（VBH）。直到最近，然而，数据缺乏的的VBH技术的可重复性。在皇家马斯登医院（英国Sutton），英国HeartSpare研究，进行了一项随机研究表明，interfraction重复性与VBH技术相媲美，与肺量计为基础的装置。此外，VBH技术提供了时间上的优势在规划，CT和处理设置和是首选的患者和放射技师都20。该VBH技术目前正在推广到10英国放射治疗中心，以确认该技术是可行的一项多中心本身拟合和心脏，备用维持（HeartSpare二）。预计这将铺平道路心脏稀少乳房放疗的全英国的摄取，并有可能导致英国之间的乳腺癌幸存者一个显著降低心脏疾病。

<table border="0" cellpadding="0" cellspacing="0" width="604">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Name of Material/ Equipment</td>
			<td style="width:71px;">Company</td>
			<td style="width:119px;">Catalog Number</td>
			<td style="width:167px;">Comments/Description</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Brilliance CT big bore oncology</td>
			<td style="width:71px;">Philips</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">MT350 breastboard</td>
			<td style="width:71px;">Med-Tec</td>
			<td style="width:119px;">MT-350-N</td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:247px;">Dorado virtual simulation laser system</td>
			<td style="width:71px;">LAP Laser</td>
			<td style="width:119px;">Dorado CT-1-3-Wall</td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="45">
			<td height="45" style="height:45px;width:247px;">Pinnacle3radiation therapy planning system v9.2</td>
			<td style="width:71px;">Philips</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Synergy linear accelerator</td>
			<td style="width:71px;">Elekta</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Intuity XVI Release&#160;4.5.1&#160;</td>
			<td style="width:71px;">Elekta</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:247px;">Iview Electronic Portal Imaging Release 3.4&#160;</td>
			<td style="width:71px;">Elekta</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Apollo room lasers</td>
			<td style="width:71px;">LAP Laser</td>
			<td style="width:119px;"></td>
			<td>Other makes/models compatible with VBH technique</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:247px;">Active breathing coordinator (ABC)</td>
			<td style="width:71px;">Elekta</td>
			<td style="width:119px;"></td>
			<td>Commercially available breath-hold system, not required for VBH technique</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:247px;">Real-time position management (RPM) system</td>
			<td style="width:71px;">Varian</td>
			<td style="width:119px;"></td>
			<td>Commercially available breath-hold system, not required for VBH technique</td>
		</tr>
	</tbody>
</table>

voluntary breath-hold technique for reducing heart dose in left breast radiotherapy

屏气技术，减少在切向场左侧乳腺放疗收到的心脏结构的辐射量。有了这些技术，患者屏住呼吸，而放疗交付，推动心脏下来，并远离放射治疗领域。尽管有明确的剂量学优势，这些技术还没有被广泛使用。其中一个原因是，市面上的解决方案需要专门的设备，因此需要不仅显著资金投入，但往往也招致持续的成本，如需要每天一次性烟嘴。这里所描述的自愿屏气技术不需要任何额外的专门设备。所有屏气技术需要一个代理来监控屏气一致性和屏气是否保持。自愿屏气使用由前部和侧面的参考点（纹身）远离治疗室激光器呼吸浩移动的距离LD监测的CT规划和治疗设置的一致性。光场然后被用来监测屏气稠度之前和放疗在分娩过程中。

实时电子门户图像（EPI）进行匹配上线，数字重建X光片（DRRS）23例（172处理部分）。 EPI位移为右前进行了分析和留在（U，V）平面内后斜梁（V方向平行的头尾向轴和U方向垂直于该）21，而对于VBH技术安装错误估计。 EPI-基于人口系统误差范围（每束光在每个平面）为1.5-1.8毫米和随机误差范围1.7-2.5毫米。 表格剂量体积直方图（DVH）的数据被用来导出新台币平均 （总剂量的生物加权平均来组织使用标准的线性二次模型22，α/β= 3GY归2戈瑞分数）的心脏，左前冠状动脉前降支（LAD），同侧和整个肺部。此外，通过在LAD（LAD 最大 ）接收的最大剂量估计。 Ñormal组织的剂量示于表1中 。 被记录的时间进行规划，CT会话，治疗设置，提供治疗和总疗程，并示于表2。的数据表明，规划-CTS可以在标准的30分钟会话内完成。处理时间包括CBCT成像，这是对每第三个级分进行。治疗的设置和总会话时间，因此，预计将短于此处报告的中心，让CBCT成像进行不规范治疗的一部分。然而，即使使用CBCT成像，处理可经20分钟处理会话内完成。 患者和放射技师被要求自己的治疗过程中，完成有效问卷23日在其规划-CT会议以及两次。六十五名病人问卷和64技师问卷进行分析。该份问卷汇总患者的舒适度分数（PCS）和放射技师满意度评分（RSS）（出9，得分越高=更舒适/满意）。 PCS中位数为8（四分位间距8-9）和中位数的RSS为7（四分位间距6-8）。 <img alt="图1" fo:content-width="5in" src="/files/ftp_upload/51578/51578fig1highres.jpg" /> 图1。VBH。轴向和矢状CT片的从在相同的胸壁水平在自由呼吸（A和C），并使用VBH技术（B和D）相同的病人的心脏保护效应 。需要注意的是心脏（黄色概述）已被按下，远离使用VBH技术的放疗领域。 <a href="https://www.jove.com/files/ftp_upload/51578/51578fig1highres.jpg" target="_blank">请点击这里查看这个数字的放大版本。</a> <imgALT =“图3”FO：内容宽度=“5英寸”SRC =“/ files/ftp_upload/51578/51578fig3highres.jpg”/&gt; 图3。检查从控制室屏气一致性 。控制室央视剧照展示场相对光的位置为右前斜梁在自由呼吸（A）和光场的校准和标记字段边框标记字段边框一旦病人在屏气（ B）。 <table border="0" cellpadding="0" cellspacing="0" ><tbody><tr ><td ></td><td colspan="2" >平均剂量（Gy） </td><td colspan="2" >最小剂量（Gy） </td><td colspan="2" >最大剂量（Gy） </td></tr><tr ><td ></td><td > VBH </td><td > FB </td><td > VBH </td><td > FB </td><td > VBH </td><td > FB </td></tr><tr ><td >心脏新台币意思 </td><td > 0.6 </td><td > 0.8 </td><td > 0.4 </td><td > 0.4 </td><td> 0.9 </td><td> 2.1 </td></tr><tr > &lt;TD&gt;法援署新台币意思 </td><td > 2.5 </td><td > 6 </td><td > 1.3 </td><td > 1.2 </td><td> 10.0 </td><td> 22.6 </td></tr><tr ><td >法援署最大 </td><td > 28.6 </td><td > 43.7 </td><td > 9.7 </td><td > 4.6 </td><td> 41.8 </td><td> 51.3 </td></tr><tr ><td >患侧肺新台币意思 </td><td > 4.1 </td><td > - </td><td > 2.8 </td><td > - </td><td> 5.6 </td><td > - </td></tr><tr ><td >全肺平均新台币</td><td > 2.0 </td><td > - </td><td > 1.3 </td><td > - </td><td> 2.7 </td><td > - </td></tr></tbody></table> 表1。正常组织的剂量为自愿屏气（VBH）技术。中位数，最小值和最大值新台币平均 （戈瑞）对心脏，法援署，同侧和整个肺部都显示，因为是中位数，最小值和最大值法援署最大 （戈瑞）。此外，中位数，最小值和最大值心脏剂量为标准自由呼吸（FB）的左乳房放射治疗在我中心显示进行比较。 <table border="0" cellpadding="0" cellspacing="0" ><tbody><tr ><td ></td><td colspan="3" >时间（min） </td></tr><tr ><td >事件</td><td >中位数</td><td >最低限度</td><td >最大</td></tr><tr ><td >规划-CT会话</td><td > 22 </td><td > 14 </td><td> 44 </td></tr><tr ><td >处理设置</td><td > 9 </td><td > 6 </td><td> 15 </td></tr><tr ><td >治疗交付</td><td > 7 </td><td > 5 </td><td> 12 </td></tr><tr ><td >总疗程</td><td > 18 </td><td > 14 </td><td> 27 </td></tr></tbody></table> 表2。规划，CT和疗程时间为自愿屏气技术。中位数，最小值和最大值规划，CT，治疗设置，提供治疗，总疗程时间显示（分钟）。

Watch this Scientific Journal Video about Voluntary Breath-hold Technique for Reducing Heart Dose in Left Breast Radiotherapy at JoVE.com

Voluntary Breath-hold Technique for Reducing Heart Dose in Left Breast Radiotherapy

在乳腺癌放疗目前的当务之急是减少心脏剂量不影响目标组织覆盖。这里所描述的自愿屏气技术是一种简单，廉价的解决这个问题，并能够被广泛地实行，而不需要专门的设备。

自愿屏气技术减少心脏剂量的左乳房放射治疗

Breath-holding techniques reduce the amount of radiation received by cardiac structures during tangential-field left breast radiotherapy. With these ...

voluntary-breath-hold-technique-for-reducing-heart-dose-left-breast

Research

JoVE Journal

Medicine

46.4K 次观看.  Royal Marsden NHS Foundation Trust. 在乳腺癌放疗目前的当务之急是减少心脏剂量不影响目标组织覆盖。这里所描述的自愿屏气技术是一种简单，廉价的解决这个问题，并能够被广泛地实行，而不需要专门的设备。 

视频: Voluntary Breath-hold Technique for Reducing Heart Dose in Left Breast Radiotherapy

Quantifying Cognitive Decrements Caused by Cranial Radiotherapy

With the exception of survival, cognitive impairment stemming from the clinical management of cancer is a major factor dictating therapeutic outcome. For many patients afflicted with CNS and non-CNS malignancies, radiotherapy and chemotherapy offer the best options for disease control. These treatments however come at a cost, and nearly all cancer survivors (~11 million in the US alone as of 2006) incur some risk for developing cognitive dysfunction, with the most severe cases found in patients subjected to cranial radiotherapy (~200,000/yr) for the control of primary and metastatic brain tumors1. Particularly problematic are pediatric cases, whose long-term survival plagued with marked cognitive decrements results in significant socioeconomic burdens2. To date, there are still no satisfactory solutions to this significant clinical problem.
We have addressed this serious health concern using transplanted stem cells to combat radiation-induced cognitive decline in athymic rats subjected to cranial irradiation3. Details of the stereotaxic irradiation and the in vitro culturing and transplantation of human neural stem cells (hNSCs) can be found in our companion paper (Acharya et al., JoVE reference). Following irradiation and transplantation surgery, rats are then assessed for changes in cognition, grafted cell survival and expression of differentiation-specific markers 1 and 4-months after irradiation. To critically evaluate the success or failure of any potential intervention designed to ameliorate radiation-induced cognitive sequelae, a rigorous series of quantitative cognitive tasks must be performed. To accomplish this, we subject our animals to a suite of cognitive testing paradigms including novel place recognition, water maze, elevated plus maze and fear conditioning, in order to quantify hippocampal and non-hippocampal learning and memory. We have demonstrated the utility of these tests for quantifying specific types of cognitive decrements in irradiated animals, and used them to show that animals engrafted with hNSCs exhibit significant improvements in cognitive function3.
The cognitive benefits derived from engrafted human stem cells suggest that similar strategies may one day provide much needed clinical recourse to cancer survivors suffering from impaired cognition. Accordingly, we have provided written and visual documentation of the critical steps used in our cognitive testing paradigms to facilitate the translation of our promising results into the clinic.

Cognitive impairment resulting from the radiotherapeutic management of brain tumors represents a clinically intractable condition that adversely impacts quality of life. The capability to critically evaluate potential interventions for ameliorating radiation-induced cognitive decrements ultimately depends on the capability to undertake rigorous quantitative assessments of cognition.

量化颅放疗引起的认知递减

With the exception of survival, cognitive impairment stemming from the clinical management of cancer is a major factor dictating therapeutic outcome. For ...

科研

医学

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 &mu;l every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

The purpose of this article is to describe the use of an orthotopic glioblastoma model for chemoradiation studies. This article will go though cell processing, implanting, and radiotherapy of the mouse using an intracranial model.

在原位小鼠脑肿瘤模型结合放疗

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the ...

The WATCHMAN Left Atrial Appendage Closure Device for Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States 1. Since AF affects primarily elderly people, its prevalence increases parallel with age. As such, it is expected that 15.9 million Americans will be affected by the year 2050 2. Ischemic stroke occurs in 5% of non-anticoagulated AF patients each year. Current treatments for AF include rate control, rhythm control and prevention of stroke 3.
The American College of Cardiology, American Heart Association, and European Society of Cardiology currently recommended rate control as the first course of therapy for AF 3. Rate control is achieved by administration of pharmacological agents, such as &beta;-blockers, that lower the heart rate until it reaches a less symptomatic state 3. Rhythm control aims to return the heart to its normal sinus rhythm and is typically achieved through administration of antiarrhythmic drugs such as amiodarone, electrical cardioversion or ablation therapy. Rhythm control methods, however, have not been demonstrated to be superior to rate-control methods 4-6. In fact, certain antiarrhythmic drugs have been shown to be associated with higher hospitalization rates, serious adverse effects 3, or even increases in mortality in patients with structural heart defects 7. Thus, treatment with antiarrhythmics is more often used when rate-control drugs are ineffective or contraindicated. Rate-control and antiarrhythmic agents relieve the symptoms of AF, including palpitations, shortness of breath, and fatigue 8, but don't reliably prevent thromboembolic events 6.
Treatment with the anticoagulant drug warfarin significantly reduces the rate of stroke or embolism 9,10. However, because of problems associated with its use, fewer than 50% of patients are treated with it. The therapeutic dose is affected by drug, dietary, and metabolic interactions, and thus requires detailed monitoring. In addition, warfarin has the potential to cause severe, sometimes lethal, bleeding 2. As an alternative, aspirin is commonly prescribed. While aspirin is typically well tolerated, it is far less effective at preventing stroke 10. Other alternatives to warfarin, such as dabigatran 11 or rivaroxaban 12 demonstrate non-inferiority to warfarin with respect to thromboembolic events (in fact, dabigatran given as a high dose of 150 mg twice a day has shown superiority). While these drugs have the advantage of eliminating dietary concerns and eliminating the need for regular blood monitoring, major bleeding and associated complications, while somewhat less so than with warfarin, remain an issue 13-15.
Since 90% of AF-associated strokes result from emboli that arise from the left atrial appendage (LAA) 2, one alternative approach to warfarin therapy has been to exclude the LAA using an implanted device to trap blood clots before they exit. Here, we demonstrate a procedure for implanting the WATCHMAN Left Atrial Appendage Closure Device. A transseptal cannula is inserted through the femoral vein, and under fluoroscopic guidance, inter-atrial septum is crossed. Once access to the left atrium has been achieved, a guidewire is placed in the upper pulmonary vein and the WATCHMAN Access Sheath and dilator are advanced over the wire into the left atrium. The guidewire is removed, and the access sheath is carefully advanced into the distal portion of the LAA over a pigtail catheter. The WATCHMAN Delivery System is prepped, inserted into the access sheath, and slowly advanced. The WATCHMAN device is then deployed into the LAA. The device release criteria are confirmed via fluoroscopy and transesophageal echocardiography (TEE) and the device is released.

The accompanying video describes a procedure for percutaneous placement of the WATCHMAN Left Atrial Appendage (LAA) Device. The WATCHMAN is a nitinol device designed to be permanently implanted at, or slightly distal to, the opening of the left atrial appendage (LAA) to trap blood clots before they exit the LAA, preventing thromboembolic stroke.

守望的左心耳封闭装置心房颤动

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States 1. Since AF affects primarily ...

Reduction in Left Ventricular Wall Stress and Improvement in Function in Failing Hearts using Algisyl-LVR

Injection of Algisyl-LVR, a treatment under clinical development, is intended to treat patients with dilated cardiomyopathy. This treatment was recently used for the first time in patients who had symptomatic heart failure. In all patients, cardiac function of the left ventricle (LV) improved significantly, as manifested by consistent reduction of the LV volume and wall stress. Here we describe this novel treatment procedure and the methods used to quantify its effects on LV wall stress and function.
Algisyl-LVR is a biopolymer gel consisting of Na+-Alginate and Ca2+-Alginate. The treatment procedure was carried out by mixing these two components and then combining them into one syringe for intramyocardial injections. This mixture was injected at 10 to 19 locations mid-way between the base and apex of the LV free wall in patients.
Magnetic resonance imaging (MRI), together with mathematical modeling, was used to quantify the effects of this treatment in patients before treatment and at various time points during recovery. The epicardial and endocardial surfaces were first digitized from the MR images to reconstruct the LV geometry at end-systole and at end-diastole. Left ventricular cavity volumes were then measured from these reconstructed surfaces.
Mathematical models of the LV were created from these MRI-reconstructed surfaces to calculate regional myofiber stress. Each LV model was constructed so that 1) it deforms according to a previously validated stress-strain relationship of the myocardium, and 2) the predicted LV cavity volume from these models matches the corresponding MRI-measured volume at end-diastole and end-systole. Diastolic filling was simulated by loading the LV endocardial surface with a prescribed end-diastolic pressure. Systolic contraction was simulated by concurrently loading the endocardial surface with a prescribed end-systolic pressure and adding active contraction in the myofiber direction. Regional myofiber stress at end-diastole and end-systole was computed from the deformed LV based on the stress-strain relationship.

This article describes procedures for implanting a novel hydrogel in failing hearts and quantifying its effect on left ventricular wall stress and function. These procedures have been successfully applied in dogs and humans.

左室壁应力和改进功能衰竭心脏使用Algisyl LVR减少

Injection of  Algisyl-LVR, a treatment under clinical development, is intended to treat  patients with dilated cardiomyopathy. This treatment was recently ...

A Murine Model of Myocardial Ischemia-reperfusion Injury through Ligation of the Left Anterior Descending Artery

Acute or chronic myocardial infarction (MI) are cardiovascular events resulting in high morbidity and mortality. Establishing the pathological mechanisms at work during MI and developing effective therapeutic approaches requires methodology to reproducibly simulate the clinical incidence and reflect the pathophysiological changes associated with MI. Here, we describe a surgical method to induce MI in mouse models that can be used for short-term ischemia-reperfusion (I/R) injury as well as permanent ligation. The major advantage of this method is to facilitate location of the left anterior descending artery (LAD) to allow for accurate ligation of this artery to induce ischemia in the left ventricle of the mouse heart. Accurate positioning of the ligature on the LAD increases reproducibility of infarct size and thus produces more reliable results. Greater precision in placement of the ligature will improve the standard surgical approaches to simulate MI in mice, thus reducing the number of experimental animals necessary for statistically relevant studies and improving our understanding of the mechanisms producing cardiac dysfunction following MI. This mouse model of MI is also useful for the preclinical testing of treatments targeting myocardial damage following MI.

We introduce a surgical method to induce experimental ischemia/reperfusion (I/R) injury to simulate myocardial infarction (MI) in mouse models that allows for more clarity in positioning of the ligation on the left anterior descending artery (LAD) to increase the reproducibility of MI experiments in mice.

心肌缺血再灌注损伤的通过左前降支结扎小鼠模型

Acute or chronic myocardial infarction (MI) are cardiovascular events resulting in high morbidity and mortality. Establishing the pathological mechanisms ...

Murine Heterotopic Heart Transplant Technique

It is now over forty years since this technique was first reported by Corry, Wynn and Russell. Although it took some years for other labs to become proficient in and utilize this technique, it is now widely used by many laboratories around the world. A significant refinement to the original technique was developed and reported in 2001 by Niimi. Described here are the techniques that have evolved over more than a decade in the hands of three surgeons (Plenter, Grazia, Pietra) in our center. These techniques are now being passed on to a younger generation of surgeons and researchers.
Based largely on the Niimi experience, the procedures used have evolved in the fine details - details which we will endeavor to relate here in such a way that others may be able to use this very useful model. Like Niimi, we have found that a video aid to learning is a priceless resource for the beginner.

The manuscript describes the steps required to perform the heterotopic heart transplant in the mouse.

小鼠异位心脏移植技术

It is now over forty years since this technique was first reported by Corry, Wynn and Russell. Although it took some years for other labs to become ...

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure.
Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload. Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure. A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion. In contrast, the infarct area at 24 hr after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling.
Besides the model of permanent ligation of the left anterior descending coronary artery, the technique of invasive hemodynamic measurements in mice is presented in detail.

Heart failure is the leading cause of hospitalization and a major cause of mortality. A model of permanent ligation of the left anterior descending coronary artery in mice is applied to investigate ventricular remodelling and cardiac dysfunction post-myocardial infarction. The technique of invasive hemodynamic measurements in mice is presented.

左冠状动脉前降支的小鼠结扎：对心肌梗死后重塑和心衰模型

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It ...

In Vivo and Ex Vivo Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose

High-grade serous ovarian cancer (HGSC), the cause of widespread peritoneal metastases, continues to have an extremely poor prognosis; fewer than 30% of women are alive 5 years after diagnosis. The omentum is a preferred site of HGSC metastasis formation. Despite the clinical importance of this microenvironment, the contribution of omental adipose tissue to ovarian cancer progression remains understudied. Omental adipose is unusual in that it contains structures known as milky spots, which are comprised of B, T, and NK cells, macrophages, and progenitor cells surrounding dense nests of vasculature. Milky spots play a key role in the physiologic functions of the omentum, which are required for peritoneal homeostasis. We have shown that milky spots also promote ovarian cancer metastatic colonization of peritoneal adipose, a key step in the development of peritoneal metastases. Here we describe the approaches we developed to evaluate and quantify milky spots in peritoneal adipose and study their functional contribution to ovarian cancer cell metastatic colonization of omental tissues both in vivo and ex vivo. These approaches are generalizable to additional mouse models and cell lines, thus enabling the study of ovarian cancer metastasis formation from initial localization of cells to milky spot structures to the development of widespread peritoneal metastases.

In Vivo and Ex Vivo Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose

We outline a protocol that implements both in vivo and ex vivo approaches to study ovarian cancer colonization of peritoneal adipose tissues, particularly the omentum. Furthermore, we present a protocol to quantitate and analyze immune cell-structures in the omentum known as milky spots, which promote metastases of peritoneal adipose.

在体内和体外途径研究银河系结构现货卵巢癌转移定植腹膜脂肪

High-grade serous ovarian cancer (HGSC), the cause of widespread peritoneal metastases, continues to have an extremely poor prognosis; fewer than 30% of ...

Technique of Minimally Invasive Transverse Aortic Constriction in Mice for Induction of Left Ventricular Hypertrophy

Transverse aortic constriction (TAC) in mice is one of the most commonly used surgical techniques for experimental investigation of pressure overload-induced left ventricular hypertrophy (LVH) and its progression to heart failure. In the majority of the reported investigations, this procedure is performed with intubation and ventilation of the animal which renders it demanding and time-consuming and adds to the surgical burden to the animal. The aim of this protocol is to describe a simplified technique of minimally invasive TAC without intubation and ventilation of mice. Critical steps of the technique are emphasized in order to achieve low mortality and high efficiency in inducing LVH.
Male C57BL/6 mice (10-week-old, 25-30 g, n=60) were anesthetized with a single intraperitoneal injection of a mixture of ketamine and xylazine. In a spontaneously breathing animal following a 3-4 mm upper partial sternotomy, a segment of 6/0 silk suture threaded through the eye of a ligation aid was passed under the aortic arch and tied over a blunted 27-gauge needle. Sham-operated animals underwent the same surgical preparation but without aortic constriction. The efficacy of the procedure in inducing LVH is attested by a significant increase in the heart/body weight ratio. This ratio is obtained at days 3, 7, 14 and 28 after surgery (n = 6 - 10 in each group and each time point). Using our technique, LVH is observed in TAC compared to sham animals from day 7 through day 28. Operative and late (over 28 days) mortalities are both very low at 1.7%.
In conclusion, our cost-effective technique of minimally invasive TAC in mice carries very low operative and post-operative mortalities and is highly efficient in inducing LVH. It simplifies the operative procedure and reduces the strain put on the animal. It can be easily performed by following the critical steps described in this protocol.

The aim of this protocol is to describe step-by-step the technique of minimally invasive transverse aortic constriction (TAC) in mice. By elimination of intubation and ventilation which are mandatory for the commonly used standard procedure, minimally invasive TAC simplifies the operative procedure and reduces the strain put on the animal.

小鼠横主动脉狭窄诱导左心室肥厚的技术研究

Transverse aortic constriction (TAC) in mice is one of the most commonly used surgical techniques for experimental investigation of pressure ...

Laparoscopic Radical Left Pancreatectomy for Pancreatic Cancer: Surgical Strategy and Technique Video

Radical resection margins, resection of Gerota&#8217;s (perirenal) fascia, and adequate lymph node dissection are crucial for an adequate oncological resection of left-sided pancreatic cancer. Several surgical techniques have been described in recent years, but few were specifically designed for minimally invasive approaches. This study describes and demonstrates a standardized and reproducible technique for an adequate oncological resection of pancreatic cancer: laparoscopic radical left pancreatectomy (LRLP).
A 61-year-old woman presented with an incidental finding of a 3 cm mass in the left pancreas suspect for malignancy. Imaging did not reveal distant metastases, central vascular involvement, or morbid obesity, hence the patient was suitable for LRLP. This study describes the main steps of LRLP for pancreatic cancer. First, the lesser sac is opened by transecting the gastrocolic ligament. The splenic flexure of the colon is mobilized and the inferior border of the pancreas including Gerota&#39;s fascia is dissected down to the inferior border of the spleen. The pancreas is tunneled and hung, including Gerota&#8217;s fascia with a vessel loop. At the pancreatic neck, a tunnel is created between the pancreas and the portal vein, likewise a vessel loop is passed. The pancreas is then transected using the graded compression technique with an endostapler. Both the splenic vein and artery are transected before completing the resection. The entire specimen is extracted in a retrieval bag via a small Pfannenstiel incision.
Duration of the surgery was 210 min with 250 mL blood loss. Pathology revealed a R0-resection (&#62;1 mm) of a well-to-moderately differentiated adenocarcinoma originating from an intraductal papillary mucinous neoplasm. A total of 15 tumor-negative lymph nodes were resected. This is a detailed description of LRLP for left-sided pancreatic cancer as is currently being used within the international, multicenter randomized DIPLOMA (Distal Pancreatectomy Minimally Invasive or Open for PDAC) trial.

Oncologically safe left pancreatectomy requires radical resection (R0), Gerota&#8217;s (perirenal) fascia resection, and adequate lymph node dissection. This study describes the technical details of laparoscopic radical left pancreatectomy (LRLP), used in the first international multicenter randomized trial comparing minimally invasive with open left pancreatectomy for pancreatic cancer, the DIPLOMA trial.

胰腺癌的腹腔镜根左造影切除术：手术策略与技术视频

Radical resection margins, resection of Gerota&#8217;s (perirenal) fascia, and adequate lymph node dissection are crucial for an adequate oncological ...