Authors thank Jeffrey Sellers to assist orthotopic pancreatic cancer mouse modeling. This work was supported by Research Initiative Pilot Awards from the Department of Radiology at UAB and NIH grants 2P30CA013148 and P50CA101955.

所有的程序批准的机构动物护理和使用委员会在阿拉巴马大学伯明翰分校。 1.原位胰腺肿瘤的老鼠模型<ol><li>在Dulbecco改良的Eagle培养基（DMEM）中培养的标准人胰腺癌肿瘤细胞系在补充有10％胎牛血清。保持所有培养物在37℃下在湿润的气氛中，用5％的CO 2。 </li><li>使用8-10周龄雌性重症联合免疫缺陷小鼠。放置动物笼子在12小时光照和12小时黑暗周期在RT（21±2℃）和60％的湿度。 </li><li>麻醉用通风所有动物用异氟烷与氧气（2L /分钟）在整个手术混合的2％。确认麻醉通过脚趾捏反射性的深度。上的加热垫（37℃）处的动物，以保持体温。取适量涂抹于眼睛兽医眼药膏，以防止干燥，而在麻醉下。 ＆＃160; </li><li>除去毛在各小鼠的腹部的左上象限，并给予止痛药（carpofen，5毫克/公斤体重皮下​​）进入该区。应用优碘解决暴露的皮肤。制备蒸压手术器械。 </li><li>使1cm的切口，在皮肤和腹膜使用虹膜直剪刀。轻轻地取出使用手术镊子腹部的胰腺。 </li><li>插入0.5 ml胰岛素注射器28克针入胰尾，然后慢慢注入2500000人胰腺癌细胞的溶液在30微升DMEM中。确认的小疱在胰头通过溶液创建。 </li><li>轻轻将胰腺回用手术镊子腹部。关闭腹膜和皮肤中1层2间断5-0普理灵缝线，然后终止麻醉。不返回已经历手术给其他动物的公司，直到完全恢复的动物。60; 7〜10日手术后取出缝合。 </li><li>给予止痛药（carpofen，5毫克/公斤体重皮下​​）的另一剂量在手术后24小时。 </li><li>检查肿瘤大小通过触诊用两个手指手术区域。肿瘤通常感觉比周围组织器官密度和颠簸。通常需要1〜 - 2周开始感觉肿瘤。 </li><li>每天监控动物疾病的迹象。当动物出现不适（缺乏正常的疏导和回避行为），我们终止它们使用颈椎脱位，而在麻醉下。 </li></ol> 2.磁共振成像<ol><li>适用的MRI当肿瘤大小为约5 - 7毫米直径通常在2〜4周后，细胞植入。使用磁共振扫描仪专门用于小动物成像或临床磁共振扫描仪配备了专门的线圈小动物成像。 注意：我们使用了9.4T小动物磁共振扫描仪有1小时容量谐振器的组合/发射机和表面线圈接收器（30毫米直径）（布鲁克BIOSPIN股份有限公司，比尔里卡，MA）中。表面线圈提供更好的信噪比（SNR），14。 </li><li>制备钆基MRI对比剂注入〜0.1 - 0.2毫摩尔/千克，以每只动物在〜0.1 - 0.2毫升的PBS（磷酸盐缓冲盐水）。 注意：我们使用钆特醇，并在一段持续15秒（0.1毫升/秒）注入0.2毫摩尔/千克0.15毫升的PBS。 </li><li>制备微聚乙烯管（长度：7.62毫米，内径：0.45毫米，外径0.64毫米）。插入地下30针（12.7毫米长）插入管的一端，和一个地下30的钝头针头（9.5毫米长）到另一端。连接1ml注射器含有MR造影剂的钝头针头，并慢慢地推注射器填满整个管与MR造影剂。 </li><li>在整个制备和成像异氟烷与氧气（2L /分钟）混合的2％ - 麻醉用通气〜1动物。确认ANEST的深度hesia由脚趾捏反射。取适量涂抹于眼睛兽医眼药膏，以防止干燥，而在麻醉下。扩张尾静脉用烤灯针头插入前。抢用凯利镊子地下30针的中间，并且将其插入到尾静脉。胶带二者的尾管上的一块塑料或纸板纸（10毫米宽×100毫米长），以保持尾直。 </li><li>放置在仰卧位的动物在装有循环热水（或暖空气）成像期间调节体温的动物床。设置在床的温度至37℃。插入直肠温度探头监控成像期间的体温。 </li><li>应用的垂直弯曲的塑料板到腹部。确保肿瘤位于板的上端身后，然后拉下板略（〜2毫米），确保肿瘤被捉住由董事会。大盘董事会动物睡觉坚决。 </li><li>大盘呼吸垫转导R（SA仪器公司，石溪，NY）的胸部成像过程中监测动物的呼吸。放置在肿瘤区域的顶部表面线圈，并将其用胶带动物床牢牢。推动物床进入MR扫描仪放置肿瘤区域中心处的体积线圈（内径72毫米）。 </li><li>为接收器和发射器进行匹配和调整，其次是垫补。 </li><li>开头的解剖磁共振序列来定位肿瘤。使用T2加权（T2W）快速自旋回波序列，以获得轴向图像与下列采集参数。重复时间（TR）/回波时间（TE）= 3000/34毫秒，128×128矩阵，图30×30mm的场，平均值的数= 1，回波串长度= 4，和20个连续1mm厚的片在隔行模式，以覆盖整个肿瘤区域（总扫描时间：1.6分钟）。 注意：由于原位胰腺肿瘤更难位于比皮下的人，常规locali具有较低分辨率图像ZER未必有用。 </li><li>获得T1加权（T1W）与各种翻转角度的图像检索T1的地图。为了这个目的，可使用回波使用以下参数multiflip角的方法的梯度：重复时间（TR）/回波时间（TE）=三分之一百一十五毫秒，128×128矩阵，来看一个30×30mm的场，数平均值= 4，〜5 - 7个连续1mm厚的片在交错模式以覆盖肿瘤区域，和10个7翻转角，20，30，40，50，60，和每翻转角70（总扫描时间：1分钟）。 注意：不过，multiflip角度的方法是有效的，只有当B1场均匀性是很高的。如果没有，T1的地图可以与多个TR方法，而不是15获得。 </li><li>之前基于钆磁共振造影剂注射后，即可获得T1W图像。使用相同的采集参数和几何形状为T1的映射，但与30使用线性编码的固定的翻转角，以确保获得的k空间的中心时稳定状态下，尤ecially当短TR和低度翻转角被使用。收购注射造影剂前5的基准图像。那么收购后注射造影剂40张图片（共扫描时间：45分钟）。使用注射泵以恒定速率（0.01毫升/秒）注入造影剂。 </li><li>持续监测动物的呼吸，并调整异氟醚浓度，保持呼吸频率50 - 每分钟100次呼吸。监控整个成像动物体温。 </li><li>完成DCE-MRI之后，脱下针和其他探测器，并把动物层状用纸巾空笼子。轻轻按摩下腹部区域。笼应放置在热灯下一半，以允许动物进出，因为它恢复移动的热量梯度。不要让动物无人看管，直到它恢复足够的意识，保持胸骨斜卧。 </li></ol> 3.图像处理与分析<ol><li>段肿瘤REGI<html>在T2W图像。在T2W成像，在肿瘤区域中的信号强度比周围组织更亮，所以肿瘤边界可以手动圈定。 注：如全局阈值或活性轮廓半自动分割技术可以用来16,17，但不均匀背景强度应当纠正特别是当一个表面线圈被使用。 </li><li>创建T1和质子密度图。在用梯度回波序列获得T1W图像，假定回波时间（TE）比T2 *值，像素值由下式确定要少得多 <img alt="式（1）" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq1.jpg" /> 其中S 0是质子密度，T 1为T 1弛豫时间常数，TR为重复时间，θ是一翻转角。公式（1）可重写为 641eq2.jpg“/&gt; 当S（θ）/SINθ替换为Y，和S（θ）/tanθ被替换的X.等式（2）是线性方程，其斜率和截距可用于检索的T1和S 0的值，分别为。 </li><li>计算DCE-MR图像的磁共振造影剂浓度。当基于钆MR对比剂注射，T 1弛豫时间常数随时间变化。所以，方程（1）可重写为 <img alt="公式3" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq3.jpg" /> Ť1（t）的相关与MR对比浓度C（T），如下， <img alt="公式4" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq4.jpg" /> 其中 ，r 1是磁共振造影剂的纵向弛豫。这样，通过结合方程式（3）和（4），MR造影浓度由下式确定 <img aLT =“式5”FO：内容宽度=“3英寸”SRC =“/文件/ ftp_upload / 52641 / 52641eq5.jpg”/&gt; </li><li>发起对比度注射后定量的MR造影剂。 中c p（t）的呈现在血浆MR造影浓度的药代动力学参数在时间 t。 中c p（t）被所谓的动脉输入功能（AIF）。如果AIF是可用的，MR造影剂的药代动力学参数可通过计算 <img alt="方程6" fo:content-width="4in" src="/files/ftp_upload/52641/52641eq6.jpg" /> 其中，C T（t）是MR造影剂浓度在靶组织，V p是小数血浆容量，V e是分数血管外细胞外液容量， 和 K 跨量是转移常数。通量速率常数，k EP，等于 k TRANs除以V 即如果AIF不可用，则参考区模型可以用来代替18,19。基准区域模型是基于所述流限制凯蒂模型20，并且使用对比度浓度在基准区域如下来除去的必要性AIF中， <img alt="公式7" fo:content-width="5in" src="/files/ftp_upload/52641/52641eq7.jpg" /> 其中，C T，投资回报率 （T），K 反，投资回报率 ，以及v E，ROI是造影剂浓度，体积转移常数和分数血管外，细胞外液容量，分别在感兴趣区域（ROI）的区域，而C T，RR （吨），K 反式，RR和 v 即，RR是那些在该基准区域。椎旁肌常被选择为基准区域， 和 v 即，RR小鼠巴ravertebral肌肉被假定为恒定在0.08 21。我们使用的参考区域模型。 </li></ol>

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Authors do not have any conflicts of interest to declare.

我们已经介绍了原位胰腺肿瘤模型使用免疫缺陷小鼠，小鼠的DCE-MRI腹部肿瘤，以及其动力学参数量化的具体方法。在原位胰腺肿瘤模型中，必须将针插入胰尾时服用。如果成功的话，将细胞将被转移到胰头创建一个小疱。当施加一个垂直弯曲的塑料板，关键是要确认肿瘤位于下方板的上端。由于胰腺肿瘤附近至该膜片，所述基板也可以是不能够牢固地保持它，特别是当肿瘤大小小于5毫米的直径?...

该方法的总的目标是要应用动态对比增强磁共振成像（DCE-MRI）对小鼠原位胰腺肿瘤异种移植物。 DCE-MRI是一种非侵入性的方法，通过监测MR对比的变化超过一定时间内注射后，以评估微脉管的目标组织。 DCE-MRI已经被用于诊断恶性肿瘤，并评估肿瘤对各种疗法1-4。定量DCE-MRI已经呈现高重复性5。定量的靶组织的磁共振造影剂的药代动力学参数，在注射造影剂前获得不同的时间点和T1地图获得的所有DCE-MR图像必须配准6。然而，由于在腹部呼吸和蠕动运动，定量的DCE-MRI已经具备了胃肠道肿瘤应用有限。 原位胰腺肿瘤模型已被用于评估胰腺肿瘤反应下的生物治疗和化疗7,8。原位肿瘤模型被认为是优于传统的皮下模型中，由于在原来的肿瘤部位的微环境被反射并由此人肿瘤对治疗的反应，可以更准确地预测。然而，小鼠胰腺位于腹部的左上象限，在小鼠中，以便定量的DCE-MRI的原位胰腺肿瘤异种移植物还未容易地实现。 我们已经建立了小鼠腹部肿瘤中的DCE-MRI的协议通过使用正交弯曲的塑料板，以防止从胸部区域9运动传递定影的肿瘤。通过这款主板所施加的压力是局部的腹部，并没有导致呼吸困难。一种自动化图像配准技术已经被验证为在自由呼吸模式腹部器官的DCE-MRI，但它执行effectivelY仅在目标地区缓慢移动，并定期10。动物的呼吸速率成像期间可变的，在腹部区域，以便物理约束将是必要的，以检索在原位胰腺肿瘤小鼠模型可靠的药物动力学参数。我们已经使用正交弯曲的塑料板DCE-MRI中11-13成功定量在原位胰腺肿瘤异种移植物的MR造影剂的药动学参数。在这里，我们提出了原位胰腺肿瘤模型的详细过程，对移植瘤小鼠和药代动力学参数量化的DCE-MRI。

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	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:245px;">Name of Material/ Equipment</td>
			<td style="width:199px;">Company</td>
			<td style="width:119px;">Catalog Number</td>
			<td style="width:712px;">Comments/Description</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">DMEM</td>
			<td>Invitrogen</td>
			<td>11965-118</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Fetal bovine serum</td>
			<td>Harlan Laboratories</td>
			<td>BT-9501</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Betadine</td>
			<td style="width:199px;">Purdue products</td>
			<td style="width:119px;">67618-153-01</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">5-0 Prolene sutures</td>
			<td style="width:199px;">Ethicon</td>
			<td style="width:119px;">8720H</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;">9.4T MR scanner</td>
			<td>Bruker Biospin Corporation</td>
			<td style="width:119px;">BioSpec 94/20 USR</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;">Gadoteridol</td>
			<td>Bracco Diagnostics Inc</td>
			<td style="width:119px;">NDC 0270-1111-03</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Micro-polyethelene tube</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
			<td style="width:119px;">#PE-10-25</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">30G blunt tip needle</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
			<td style="width:119px;">89134-194</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Monitoring and gating system</td>
			<td style="width:199px;">SA instruments, Inc</td>
			<td style="width:119px;">Model 1030</td>
			<td>This is an MR compatiable system to measure resiratory rating and body temperature of small animals at the same time.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Syringe pump</td>
			<td>New Era Pump Systems, Inc.</td>
			<td>NE-1600</td>
			<td></td>
		</tr>
	</tbody>
</table>

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.

人类胰腺肿瘤细胞在小鼠胰腺创建实体瘤成功生长。 图1显示（A）的正常的胰腺，其中肿瘤细胞溶液被注入，和（B）的照片的代表性小鼠附有是胰腺肿瘤异种移植物原位（MIA PACA -2- ）。肿瘤位于腹部的左上腹，旁边的脾脏。它通常需要2 - 4周的肿瘤长到5 - 后细胞植入直径7毫米。 原位胰腺肿瘤异种移植的议案被大幅抑制，尽管运动伪影存在于MR图像有一定幅度?...

Watch this Scientific Journal Video about Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model at JoVE.com

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

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.

原位胰腺癌小鼠模型的动态对比增强磁共振成像

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

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15.0K 次观看.  University of Alabama at Birmingham. 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. 