这项研究是由大全癌症研究所的支持。

伦理声明：报告总结卫生系统机构审查委员会批准这项研究获得。 1.治疗咨询<ol><li>描述新肺SBRT治疗的病人。 注：新SBRT平台提供共面和非共面高辐射剂量的癌症靶，同时​​降低辐射剂量的非靶器官。 </li><li>讨论治疗的风险。 注：SBRT可能导致可能短期皮肤色素沉着或红斑，疲倦，咳嗽频繁，恶心，食管炎，以及罕见的内脏器官损伤。肺炎，或低烧和非生产性咳嗽的肺部炎症，治疗后可能会出现长达三个月。急性或迟伤到心脏，其他肌肉，周围神经或脊髓和骨是罕见的。有一个很小的危害为辐射诱发恶性肿瘤。 </li></ol> 2.基准标记布局<ol><li> PErform经皮CT引导下或单金涂覆标记的支气管镜放置插入肿瘤靶中心的质量。 <ol><li>问放射科医师执行患者胸部7的3-5毫米厚的连续轴向断层扫描成像。 </li><li>确定安全针的方法最大限度地减少加气的肺组织走过（避免大疱和裂缝）7。 </li><li>局部注射麻醉皮下注射（ 例如，1％利多卡因）。 </li><li>引入17或18G的同轴针来放置单个短（0.75×10毫米）或单长（0.75×20mm的）标记物10。 </li></ol></li><li>通过询问胸腔收购胸部断层成像支气管映射21做电磁导航支气管镜引导基准标记的位置。 <ol><li>楔形疑似支气管段支气管镜。 </li><li>引导支气管镜传感器探针与靶病灶。 </li><li>部署一个基准标记ER经支气管针。 注：在肺基准无放射技术被认为是研究性，并受到积极的研究22,23。 </li></ol></li><li>作为替代方案，为了至少三个短（1.6×3毫米），金涂覆标记可以定位在一个6厘米“框”在目标周围。如果一个以上的基准标记的放置位置，标记间2cm的物理分离，建议。 </li></ol> 3.治疗计划<ol><li>进行CT引导下模拟基准标记后放置4-7天（步骤3.2和3.3中所述）。 </li><li>让患者躺在上治疗机平板桌面仰卧，头先。 <ol><li>定位患者的手臂在他们头上，由上臂和手腕持有人或一个真空袋防盗支持。确保胸部和腹部都没有固定。 </li><li>或者，使用两针局部膝盖海绵索引。 </li><li>地方至少4个红外跟踪身体标记胸部本地化。红外跟踪呼吸标记过于本体区展现一致垂直呼吸运动（3mm以上的峰 - 峰运动建议）。 </li></ol></li><li>进行非连续的对比轴螺旋CT扫描（1毫米层厚，电压120 kVp的，350 MAS）。 注：治疗医生可以命令一个4D CT扫描胸部12或三维CT扫描的胸部，其中包括自由呼吸，吸气末和呼气末屏气图像设置24。 </li><li>获得18架F-FDG PET / CT扫描肺部肿瘤运动的增强型捕捉。 <ol><li>询问患者躺在一个头第一扫描位置的连续螺旋CT扫描（ 如电压120 kVp的，450 MAS）从orbitomeatal线大腿在平静呼吸。 </li><li>对平均18 F-FDG 11毫居里的在同一SC静脉内给药后获得18 F-FDG PET在平静呼吸安宁从orbitomeatal线大腿位置。如果采用这种方法，（18）F-FDG PET / CT扫描自动轮廓由软件设定在40％SUVmax值的阈值，然后，如所述1共同配准的CT模拟图像。 </li></ol></li><li>轮廓原发性肺总目标或多个卷（GTVp）由手绘图上的4D​​ CT数据集，最好的呼气阶段。扩大GTVp用5毫米的边距创建规划肿瘤体积（PTV）。辐射剂量规划发生了动态跟踪呼气末期扫描。 注意：作为替代，并使用三维CT数据集时，在自由呼吸CT模拟扫描是参考扫描。使用这种技术，所述治疗放射肿瘤学家轮廓GTV在自由呼吸（GTVfb），启示（GTVi），和到期日（GTVe）CT模拟扫描。在18F-FDG PET影像的阈值的40％的最大标准摄取值轮廓创建<suP&gt; 18F-FDG PET临床靶区（CTVpet）1。复合ITV表示GTVfb，GTVi，GTVe和CTVpet卷的补充总和。一个5毫米的利润率复合ITV的创建PTV。在这里，辐射剂量规划发生在自由呼吸扫描进行动态跟踪。 </li><li>轮廓附近的正常组织结​​构，由专人对4D CT数据集，最好呼气相拉伸。这可以包括正常肺，心脏加心包，食道，肝，双侧肾，臂丛神经和脊髓。可以产生气管，右主支气管和左主支气管的轮廓，扩展3毫米，并用作高优先级的规划约束，以避免后期毒性气道纤维化。 </li><li>点击在规划软件中的动态跟踪按钮。这个动作接合新SBRT平台上的万向平移和倾斜跟踪。 </li><li>规定的辐射剂量的PTV。考虑三种辐射蒙特卡洛剂量处方1S：3×17戈瑞= 51戈瑞每日周围型肺病灶; 4×12戈瑞= 48戈瑞在中央型肺癌病变和周围胸壁病变;或隔日5×10戈瑞= 50戈瑞。罕见当PTV体积约束（ 即，95％的覆盖）或器官高危约束不满足，可以使用8×7.5戈瑞= 60 Gy的处方。 </li></ol> 4.治疗交付和工作流程<ol><li>打造仰卧头第一校准后的安静的呼吸相关性模型。 <ol><li>放置4（或多达6个）红外线体标记在主体中鉴定在CT模拟相同的标记的位置。 </li><li>检查身体标记和病人对准通过红外摄像头和屏幕位置精度在治疗控制台。 注：身体标记位置作为一个波束上检查不规则运动，这样的咳嗽。 </li><li>获得跨平面双诊断千伏X射线或锥形束CT图像在治疗控制台来检测植入标记物内部positional精度。 </li><li>助理和关联身体标记运动（作为替代呼吸）和内部植入标记的运动与链接到新的平台SBRT工作流程的计算机软件。 注：另一种定位方法涉及病人根据前方和横向纹身CT模拟激光三角测量标记和使用标准化的参考阵列（星）有六个浸渍红外线人体标记的正交对准。 </li></ol></li><li>生成肺癌运动相关性模型。 <ol><li>得出一个万向平移和倾斜路径加速器使用链接到新SBRT平台的工作流程的计算机软件来跟踪肿瘤运动。 </li><li>视觉评估之前交付的辐射肺肿瘤运动相关性模型。 </li></ol></li><li>辐射在分娩过程中遵守的基准标记漂移。 </li><li>评估机器碰撞的患者由于机架旋转，O型圈支点，和万向节泛和倾斜动作事先计划交付。 注：辐射工作人员将执行此步骤。治疗可能需要八时五十五静态共面非共面治疗束，通过辐射传递工作人员手动和目视检查。治疗可能会持续15-30分钟，以完成大约每7分钟肺部肿瘤运动相关模型验证。 </li></ol>

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作者什么都没有透露。

有前途的早期立体定向放射治疗的临床经验驱使治疗肺癌25,26烧蚀辐射的临床试验研究。经验带领侦查员使用烧蚀辐射对多种肿瘤类型转移性肺27,28中。新SBRT平台引入了一个辐射光传输系统特别是切合移动肿瘤的治疗。 新SBRT平台提供由安装在一个旋转的O形环龙门直线加速器产生的看不见的X射线治疗。万向节机制使得直线加速器的泛和倾斜运动，提供即时动态肿瘤运动跟踪。双交叉平面千伏X射线之前和治疗过程中所获得验证自由度的6患者定位。共面和非共面的唯一的自由度提高输送高辐射剂量的癌症靶的同时最大限度地减少辐射剂量临界内脏器官。可以预料，处理消毒癌细胞目标而不对正常细胞的降辐射相关的毒性不可挽回的损失。新SBRT平台，今后的研究将记录在目标控制和副作用的减少任何收益。 新SBRT平台显示的初步经验保证10。肺肿瘤继续探讨动态跟踪的细微差别;然而，一些概括是显而易见的。肺肿瘤展示运动小于7毫米可以通过复合ITV加5毫米扩张的方式来对待最好。对于肺肿瘤表示7mm以上垂直平移，使用GTVp加5毫米膨胀可能是最好的用于治疗动态跟踪的方法。需要进一步研究确定这些限制。此外，在三维CT图像数据集叠加18F-FDG PET图像通常会增加复合ITV卷。这种方法假定容积EXPAN锡永在PET扫描仪的3-5分钟，时段时间由于18F-FDG信号涂抹发生。 40％的阈值18 F-FDG临床靶区进行了研究，并在我们的节目1人被使用。进一步的研究是否表征18F-FDG PET图像充分复制肿瘤滞后是必要的。最后，最多3个病灶在单个肺可以在一个时间被认为对于治疗。否则，顺序方法完成。 新SBRT平台上动态跟踪使用肺肿瘤运动相关模型来预测肺肿瘤运动长达40毫秒到未来。位置和红外身体和呼吸标记的速度被包括在模型中。的70％中获得的千伏X射线的标记检测率是一个必要条件动态跟踪。基准跟踪在三个维度（ 即，X，Y，Z）。由千伏X射线装置生成的图像自动注册和比较实时。 Ø在动态跟踪bserved延迟是由于在平移和倾斜万向节的硬件，软件的处理，和的千伏x射线单元的位置控制性能限制。研究调查人员正在从事改善跟踪延迟。 在使用新SBRT平台上动态跟踪辐射光传输，这是至关重要的，以观察基准标记漂移。趋势超出预定3毫米误差在任何方向上导致操作员启动处理暂停或自动束保持基准标记漂移。如果发生暂停的治疗，建议运营商之前的相关性模型允许恢复平静呼吸运动，在未来的几个病人呼吸，然后治疗恢复重建。如果暂停不成功，病人重新定位，红外呼吸标志运动检测，标记千伏检测，相关模型重建完成后恢复治疗。根据我们的经验，呼吸相关模型准确üP至7分钟，往往是由病人紧张或放松休息时对治疗桌面的限制。 悬而未决的问题依然存在。什么是放射生物学后果和细胞死亡的模式在正常细胞和癌细胞烧蚀辐射剂量后发生？为什么会如此难以融合高精度烧蚀辐射放射增敏化疗？而有必要调查提供烧蚀辐射在胸部的其他方式，目前还不清楚，以烧蚀辐射是否能提供等效的治疗效力开胸手术。事实上，胸外科是较常用的和验证的技术来实现肿瘤根除在肺当常规疗法已经得到了应用。在这里，新的SBRT平台提供了治疗的妇女和男子肺肿瘤显示运动中的创新的非侵入性的方式。

肺癌占癌症相关死亡的妇女和男子世界各地2的最大数量。最多的持续性或复发性肺癌63％涉及到已经通过征税或化疗之前照射肺组织3,4。在持续或反复的肺肿瘤位点进一步照射可能导致不能容忍的肺发病5,6，特别是当常规手术，化疗和放射疗法已经被尝试过。因此，在这样的情况下，临床上男性和女性都需要类似于本杂志7之前提出新的治疗癌症治疗策略。立体定向烧蚀体放射治疗（SBRT）可以通过精确的目标，高剂量辐射-8,9-灭菌肺肿瘤满足这种治疗的需要。 有一个新的SBRT平台，能够治疗这个任务10-12。它本身从其他SBRT平台通过分离积分双诊断Exactrac千伏x射线单元（能够锥束计算机断层摄影目标定位的）和红外线摄像机单元（能够体表标识跟踪作为替代内部运动），这两个允许的癌症立体开环反馈目标intrafraction运动。它也有一个独特的±4厘米万向平移和倾斜辐射加速器，具有其辐射束形60钨合金叶（0.25厘米物理宽度，11厘米物理高度）。它采用的是全过中心行程多叶准直为最多15×15cm的区域尺寸。它集成了一个机器人驱动的±60°转动O型环和±185°的旋转台架允许共面和非共面加速器束设置角度和独特的治疗自由度。最后，它具有亚毫米的精度（0.6毫米等角点）13。与此相反，其他SBRT放疗平台装入临床辐射加速器或者向工业机器人手臂14，或一个螺旋片逐片台架15，或者在一个传统的机器连接到图像引导调强放射治疗或动态弧传送软件16。每个平台从事各种机械部件的跟踪，从呼吸运动，心跳，消化或产生的运动。肺癌放射治疗已临床成功17,18，呈现方式放射肿瘤19,20一种新的治疗选择。该如何对文章提供了一种新的放射治疗协议，介绍动态肺肿瘤跟踪治疗目的。

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Vero SBRT Linac System 1.0</td>
			<td>Brainlab, Inc. (Munich, Germany)</td>
			<td>46300</td>
			<td>High accuracy first-of-its-kind gimbaled irradiation head with tilt function and gantry rotation</td>
		</tr>
		<tr>
			<td></td>
			<td>Mitsubishi Heavy Industries, Ltd. (Tokyo, Japan)</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Visicoil fiducial marker</td>
			<td>IBA Dosimetry America (Bartlett, TN, USA)</td>
			<td>67245</td>
			<td>0.75 mm x 10 mm marker -or- 0.75 mm x 20 mm marker</td>
		</tr>
		<tr>
			<td>Gold fiducial marker</td>
			<td>Civco Medical Solutions (Orange City, IA, USA)</td>
			<td>MTNW887860</td>
			<td>Sterile placement needle (14GA ETW x 20cm) with one 1.6mm &#215; 3mm marker</td>
		</tr>
	</tbody>
</table>

dynamic lung tumor tracking for stereotactic ablative body radiation therapy

医生考虑立体定向消融体内放射治疗（SBRT）为颅外癌症靶点治疗必须注意的正常组织损伤和相当大的风险的物理肿瘤小姐的危害。第一-的，其独一无二的SBRT平台通过多功能实时成像解决方案和先进的肿瘤跟踪功能的组合实现了高精度的消融放射治疗。它采用双诊断千伏X光机对癌症的目标intrafraction运动中发生呼吸运动和心跳的后果立体开环反馈。图像引导的反馈驱动万向辐射加速器（最大15×15cm的区域尺寸）能够实时±4厘米平移和倾斜动作。机器人驱动的±60°转动的集成±185°的旋转台架允许为共面和非共面加速器束设置角度，最终允许独特的治疗自由度。国家-的-ART辅助软件的实时六维定位，确保癌症靶点与亚毫米级精度（0.6毫米等中心）照射。使用这些特性使得能够治疗医生来引导辐射剂量的癌症肿瘤靶，同时降低辐射剂量对正常组织。通过加入呼吸相关计算机断层扫描（CT）和2- [18 F]氟-2-脱氧ᴅ葡萄糖（18 F-FDG）正电子发射断层扫描（PET）的图像转换成用于增强肿瘤靶轮廓规划系统，可能物理肿瘤小姐就变得少1。在这篇文章中，我们描述了移动肺肿瘤的治疗提供新的辐射计划。

SBRT新平台上当前涉及多个静态的辐射束会聚在单个或多个紧密相关的临床辐射目标，如在图1中描绘例如，一个代表良好的规划结果提供烧蚀辐射具有95％的覆盖率癌症靶体积和癌症靶的剂量一致性。 图1显示5共面和4个非共面的光束（ 即，环旋转+ 20°，波束2，4，6和8）用于治疗的单个PTV表示在右侧肺鳞状细胞癌。梁边距PTV是1毫米。辐射剂量，规定为95％的等剂量线，呈现95％的PTV覆盖率为1.48一致性指数。处方为50戈瑞五隔日10 Gy的分数。这里所示的结构包括规划靶体积（红），内部目标体积（白色），脊髓（绿），和食道（浅蓝色）。等剂量线所指示的。&lt;/ P&gt; <img alt="图1" src="/files/ftp_upload/52875/52875fig1highres.jpg" width="700" /> 图1：的右侧肺肿瘤肿瘤动态跟踪图为烧蚀辐射剂量（50戈瑞五10戈瑞隔日部分）传递到采用九静态梁单右侧肺部肿瘤为例（蓝/绿色，34°的）。 4规划软件窗口描绘：（A）一梁和临界结构碰撞地图，（B）的beam&#39;s眼视图（这里，波束1），（C）的三维CT和束重构地图，和（D）的轴向CT与剂量分布。 <table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td> 结构体 </td><td> 公 </td><td> 音量 </td><td> 可接受的变化 </td></tr><tr><td> PTV </td><td> V50Gy </td><td> ≥95％ </td><td> ≥90％ </td></tr><tr><td>最小剂量</td><td> 0.03厘米3 </td><td> ≥46戈瑞（92％） </td><td> ≥45戈瑞（90％）的</td></tr><tr><td>极量</td><td> 0.03厘米3 </td><td> ≤60戈瑞（120％） </td><td> ≤62.5戈瑞（125％） </td></tr><tr><td>脊髓</td><td> 0.03厘米3 </td><td> ≤15戈瑞</td><td> ≤22戈瑞</td></tr><tr><td>隆（减去GTV） </td><td> V20Gy </td><td> ≤10％ </td><td> ≤15％ </td></tr><tr><td></td><td>平均剂量</td><td> ≤8戈瑞</td><td> ≤10戈瑞</td></tr><tr><td>心脏/心包</td><td> 15厘米3 </td><td> ≤32戈瑞</td><td> ≤36戈瑞</td></tr><tr><td>食道</td><td>平均剂量</td><td> ≤18戈瑞</td><td> ≤20戈瑞</td></tr><tr><td></td><td> 0.03厘米3 </td><td> ≤27​​戈瑞</td><td> ≤30戈瑞</td></tr><tr><td>肱丛</td><td> 0.03厘米3 </td><td> ≤24戈瑞</td><td> ≤30戈瑞</td></tr></tbody></table> 表1：结构治疗计划的约束。

Watch this Scientific Journal Video about Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy at JoVE.com

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Stereotactic ablative body radiation therapy (SBRT) involves the precise delivery of high-dose radiation to cancer tumor targets. A novel SBRT platform offers a first-of-its-kind gimbaled radiation accelerator mounted within a pivoting O-ring gantry capable of dynamic image-guided tumor tracking. Here, we describe dynamic tumor tracking for lung targets.

动态肺肿瘤跟踪烧蚀立体定向放射身体治疗

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable ...

dynamic-lung-tumor-tracking-for-stereotactic-ablative-body-radiation

Research

JoVE Journal

Medicine

15.3K 次观看.  Summa Cancer Institute. Stereotactic ablative body radiation therapy (SBRT) involves the precise delivery of high-dose radiation to cancer tumor targets. A novel SBRT platform offers a first-of-its-kind gimbaled radiation accelerator mounted within a pivoting O-ring gantry capable of dynamic image-guided tumor tracking. Here, we describe dynamic tumor tracking for lung targets.

视频: Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model

It is well recognized that tumor hypoxia plays an important role in promoting malignant progression and affecting therapeutic response negatively. There is little knowledge about in situ, in vivo, tumor hypoxia during intracranial development of malignant brain tumors because of lack of efficient means to monitor it in these deep-seated orthotopic tumors. Bioluminescence imaging (BLI), based on the detection of light emitted by living cells expressing a luciferase gene, has been rapidly adopted for cancer research, in particular, to evaluate tumor growth or tumor size changes in response to treatment in preclinical animal studies. Moreover, by expressing a reporter gene under the control of a promoter sequence, the specific gene expression can be monitored non-invasively by BLI. Under hypoxic stress, signaling responses are mediated mainly via the hypoxia inducible factor-1&alpha; (HIF-1&alpha;) to drive transcription of various genes. Therefore, we have used a HIF-1&alpha; reporter construct, 5HRE-ODD-luc, stably transfected into human breast cancer MDA-MB231 cells (MDA-MB231/5HRE-ODD-luc). In vitro HIF-1&alpha; bioluminescence assay is performed by incubating the transfected cells in a hypoxic chamber (0.1% O2) for 24 hr before BLI, while the cells in normoxia (21% O2) serve as a control. Significantly higher photon flux observed for the cells under hypoxia suggests an increased HIF-1&alpha; binding to its promoter (HRE elements), as compared to those in normoxia. Cells are injected directly into the mouse brain to establish a breast cancer brain metastasis model. In vivo bioluminescence imaging of tumor hypoxia dynamics is initiated 2 wks after implantation and repeated once a week. BLI reveals increasing light signals from the brain as the tumor progresses, indicating increased intracranial tumor hypoxia. Histological and immunohistochemical studies are used to confirm the in vivo imaging results. Here, we will introduce approaches of in vitro HIF-1&alpha; bioluminescence assay, surgical establishment of a breast cancer brain metastasis in a nude mouse and application of in vivo bioluminescence imaging to monitor intracranial tumor hypoxia.

In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model

Bioluminescence imaging of hypoxia inducible factor-1&alpha; activity is applied to monitor intracranial tumor hypoxia development in a breast cancer brain metastasis mouse model.

在小鼠模型体内生物发光成像乳腺癌脑转移的肿瘤乏氧动力学

It is well recognized that tumor hypoxia plays an important role in promoting malignant progression and affecting therapeutic response negatively. There ...

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 ...

Stereotactic Radiosurgery for Gynecologic Cancer

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow 'pencil beam' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments.
Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient-independent abdominal compression.1-3 Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,4 patient mouthpiece active breathing coordination,5 respiration-correlated computed tomography,6 or image-guided tracking of fiducials implanted within and around a moving tumor.7-9 The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera-tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.10 Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.11-13
Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.7,8 Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET).8 Use of 18F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers.

Stereotactic body radiotherapy (SBRT) involves image-guided, ablative radiation delivered to cancer targets refractory to chemotherapy or to conventional radiation treatment. The robotic-armed Cyberknife SBRT system, using sophisticated target localization, delivers hypofractionated radiation doses capable of sterilizing cancer targets. This article will consider new therapeutic roles of SBRT for gynecological cancers.

妇科肿瘤的立体定向放射外科

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, ...

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy 1. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM 2. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments 3-5. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

We describe an integrated method for the precise, stereotactic implantation of human glioblastoma multiforme cells into the brains of nude mice and subsequent serial in vivo imaging to monitor growth and response to treatment of the resultant xenografts.

立体定向颅内植入和<em在体内</em生物发光成像的肿瘤异种移植的小鼠模型系统的多形性胶质母细胞瘤

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality ...

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 ...

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue.
Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules.
Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed.
Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 &mu;m from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads 5-7. In addition, the ICW provides many challenges when optimizing the imaging.

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We describe a novel in vivo imaging technique that couples fluorescent chimeric mice with intracranial windows and high-resolution 2-photon microscopy. This imaging platform aids studies of dynamic changes in brain tissue and microvasculature, at a single-cell level, following pathological insults and is adaptable to assess intracranial drug delivery and distribution.

一种新型的高分辨率<em&gt;在体内</em&gt;成像技术研究肿瘤生长及治疗颅内结构的动态响应

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a ...

In vivo 19F MRI for Cell Tracking

In vivo 19F MRI allows quantitative cell tracking without the use of ionizing radiation. It is a noninvasive technique that can be applied to humans. Here, we describe a general protocol for cell labeling, imaging, and image processing. The technique is applicable to various cell types and animal models, although here we focus on a typical mouse model for tracking murine immune cells. The most important issues for cell labeling are described, as these are relevant to all models. Similarly, key imaging parameters are listed, although the details will vary depending on the MRI system and the individual setup. Finally, we include an image processing protocol for quantification. Variations for this, and other parts of the protocol, are assessed in the Discussion section. Based on the detailed procedure described here, the user will need to adapt the protocol for each specific cell type, cell label, animal model, and imaging setup. Note that the protocol can also be adapted for human use, as long as clinical restrictions are met.

In vivo 19F MRI for Cell Tracking

We describe a general protocol for in vivo cell tracking using MRI in a mouse model with ex vivo labeled cells. A typical protocol for cell labeling, image acquisition processing and quantification is included.

在体内 19女性 MRI对细胞跟踪

In vivo 19F MRI allows quantitative cell tracking without the use of ionizing radiation. It is a noninvasive technique that can be applied to humans. ...

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

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 approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1.
Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians&#8217; choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10.
There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

A novel methodology that is employed for the treatment of recurrent glioblastomas is described. This treatment approach employs the application of alternating electric tumor treating fields (TTFields), known as TTF Therapy in combination with bevacizumab, a targeted agent that is currently FDA approved as monotherapy.

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 ...

Primary Tumor and MEF Cell Isolation to Study Lung Metastasis

In breast tumorigenesis, the metastatic stage of the disease poses the greatest threat to the affected individual. Normal breast cells with altered genotypes now possess the ability to invade and survive in other tissues. In this protocol, mouse mammary tumors are removed and primary cells are prepared from tumors. The cells isolated from this procedure are then available for gene profiling experiments. For successful metastasis, these cells must be able to intravasate, survive in circulation, extravasate to distant organs, and survive in that new organ system. The lungs are the typical target of breast cancer metastasis. A set of genes have been discovered that mediates the selectivity of metastasis to the lung. Here we describe a method of studying lung metastasis from a genetically engineered mouse model.. Furthermore, another protocol for analyzing mouse embryonic fibroblasts (MEFs) from the mouse embryo is included. MEF cells from the same animal type provide a clue of non-cancer cell gene expression. Together, these techniques are useful in studying mouse mammary tumorigenesis, its associated signaling mechanisms and pathways of the abnormalities in embryos.

The goal of this protocol is to study breast tumorigenesis. With this technique, mouse mammary tumors are removed and primary cells are prepared from tumors. A lung extraction protocol is included for studying lung metastasis. Furthermore, another protocol for analyzing mouse embryonic fibroblasts from the mouse embryo is included.

原发灶和MEF细胞分离，研究肺转移

In breast tumorigenesis, the metastatic stage of the disease poses the greatest threat to the affected individual. Normal breast cells with altered ...

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy.