CN102843959A - 表征组织对治疗方案的病理反应的方法 - Google Patents
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Abstract
一种表征组织对治疗方案的病理反应的方法包括:获得所述组织的一组连续形态透视图,其中每个透视图对应于在所述治疗方案期间的特定时间点;对该组透视图产生所述组织的生物力学性质的一组代表性值,其中每个代表性值基于相应的透视图;基于该组代表性值确定所述生物力学性质的趋势;以及基于所述生物力学性质的趋势预测所述组织对所述治疗方案的反应。
Description
相关申请的交叉引用
本申请要求2011年2月14日递交的美国专利申请第13/027,036号和2010年2月12日递交的美国临时申请第61/304,256号的利益,这两个申请通过该引用被全部并入。
技术领域
本发明一般涉及医学领域,且更特别地涉及癌症治疗领域中表征组织对治疗方案的病理反应的改进方法。
背景
常见的癌症治疗包括从患者去除癌性肿瘤组织、放射治疗、化疗或切除介入,但最有效的治疗或治疗的组合通常因患者而异。例如,并不是所有的癌症患者都对某些治疗例如化疗和放射治疗反应,且此外并不是所有反应的癌症患者都对这些治疗有同等成功。常常直到治疗结束时或在治疗后的随访期(follow-up period)之后才知道对患者的治疗的成功。然而,能够准确地预测患者是否会对治疗良好地反应——特别是在治疗方案中的早期——以指导替代疗法的实施和/或中止不成功的治疗方案是有利的。准确并频繁地评估肿瘤对治疗的反应允许医师优化对患者的治疗方案,并可能使不反应的患者免受来自该治疗的不必要的副作用,例如化疗引起的副作用的身体和精神损伤。理论上可通过重复使用核磁共振成像(MRI)或正电子发射断层摄影(PET)来进行患者体内肿瘤组织的状态监测。然而,这些技术是昂贵的且在社区中可能不能获得重复使用,使它们不适合于肿瘤组织的频繁评估。其他技术例如X-射线利用了排除频繁使用的电离辐射。因此,在医学领域中存在对创建表征组织对治疗方案的病理反应的改进方法的需要。本发明提供了这样的改进方法。
附图简述
图1是优选实施方式的方法的示意图;
图2是在优选实施方式的方法中获得组织的一组连续形态透视图(morphology rendering)的步骤期间可使用的扫描仪的示意图;
图3A-3D是在优选实施方式的方法中获得组织的一组连续形态透视图的步骤的示意图;
图4是在优选实施方式的方法中产生一组代表性值的步骤的示意图;
图5和6是在优选实施方式的方法中基于生物力学性质的一组代表性值来确定该生物力学性质的趋势的变化形式的示意图;
图7是在优选实施方式的方法中基于生物力学性质的趋势来预测组织对治疗方案的反应的一个变化形式的示意图。
优选实施方式的描述
以下对本发明的优选实施方式的描述并不用来将本发明限制到这些优选实施方式,而是使本领域的任何技术人员能够实施和使用本发明。
如图1所示,优选实施方式的表征组织对治疗方案的病理反应的方法100包括以下步骤:获得组织的一组连续形态透视图(S110),其中每个透视图对应于在治疗方案期间的特定时间点;对该组透视图产生组织的生物力学性质的一组代表性值(S120),其中每个代表性值基于相应的透视图;基于该组代表性值确定该生物力学性质的趋势(S130);以及基于该生物力学性质的趋势预测组织对治疗方案的反应(S140)。优选地,方法100被用来预测和/或监测癌症例如乳腺癌对化疗或放射治疗的病理反应(或治疗的副作用),而且另外地和/或可选地可用来预测或监测任何癌症或良性肿瘤对任何合适的治疗的反应。另外地和/或可选地,方法100可用来预测化学预防(降低癌症风险的药理途径)的成功。预测并表征癌症患者将如何对特定的癌症治疗反应允许医师区分开对治疗可能获得成功的患者与不太可能对治疗获得成功的患者,从而允许医师指导替代疗法的实施和/或中止该特定的治疗。关于患者对治疗的反应的这种知识使医师能够例如使不反应的患者免于遭受化疗或放射治疗的副作用及免于将可能有限的财政手段应用于无效治疗,并向着优化治疗方案的疗效前进。优选地使用在治疗方案中早期的肿瘤的生物力学性质的趋势例如变化率来预测完全的治疗反应,但另外地和/或可选地可使用在治疗方案中任何阶段的生物力学性质的趋势。方法100可便于准确且频繁地评估肿瘤对其他治疗的反应例如以评估新的治疗剂或疗法的临床疗效。
获得一组连续形态透视图的步骤S110起作用来获得来自患者的数据。该数据形成在表征组织对癌症治疗的反应中的分析的基础。形态透视图优选地包括肿瘤组织的透视图,且另外地和/或可选地可包括健康组织例如肿瘤组织周围的组织的透视图。另外地和/或可选地,形态透视图可包括断裂的骨骼或任何合适的组织。每个透视图优选地对应于治疗方案过程中的特定时间点,使得该组透视图表示在治疗方案期间的不同时间点处的组织的连续的按时间顺序排列的快照。例如,获得透视图可每小时、每天、每隔几天、每隔1-3周或任何合适的频率被执行,或相应地在治疗阶段例如化疗治疗(例如,之前立即和/或之后立即)被执行。获得一组透视图(S110)优选地在治疗方案的早期阶段(例如最初几个月内)被执行,但可选地可在治疗方案的任何合适的阶段期间被执行。可在治疗方案期间以大致有规律的时间间隔或以无规律的时间间隔(例如,透视图的时间选择可取决于化疗治疗的具体时间安排)获取该组透视图。在优选的实施方式中,获得一组透视图(S110)优选地包括用超声扫描仪扫描组织以获得声音数据(S112)及使用该声音数据创建表示组织的声音参数的图像(S114)。每当获得单个透视图时,扫描组织和创建图像的步骤每个优选地被执行至少一次,使得扫描组织和创建图像的步骤可重复多次。另外地和/或可选地,获得一组透视图(S110)可包括从存储设备例如硬盘驱动器或在线服务器或任何合适的存储库例如硬拷贝患者记录中取回一组图像或透视图。
扫描组织的步骤(S112)优选地包括用发射并接收穿过组织的声波的传感器包围组织。例如,如图2和3A中所示,为了用具有环形传感器的超声波断层扫描仪扫描乳腺癌患者的乳房组织,患者将自己的脸朝下置于在床的胸部区域中具有孔的柔性床上。患者的乳房穿过床中的孔并置于浸没到水浴中的传感器内。在扫描步骤S112期间,环形传感器优选地被固定到台架,并在垂直路径中移动以在前后方向上在胸壁和乳头区域之间穿过,从而优选地对整个乳房成像(可选地,乳房的所选部分)。优选地,该扫描仪与通过该引用被全部并入的名称为“Method and apparatus forcategorizing breast density and assessing cancer risk utilizing acousticparameters”美国专利公布第2008/0275344号中描述的扫描仪相似。然而,环形传感器可用来扫描任何合适的组织,例如手臂、手、腿或脚。优选地,该扫描仪是相对便宜、快速且对于患者更舒适的且易于安装和操作。扫描步骤优选地收集了声音数据,包括来自组织的声反射、组织内的声衰减和/或组织内的声速。然而,另外地和/或可选地,扫描步骤可收集组织的任何其他声音数据或合适的生物力学性质。可选地,该方法可包括使用核磁共振成像(MRI)和正电子发射断层摄影(PET)或产生组织的透视图的任何适合的设备获得一组形态透视图。例如,可使用PET评价组织的代谢变化以产生组织图像。
创建表示组织的声音参数的图像的步骤S114优选地包括从在扫描步骤期间获得的声音数据中产生一个或多个二维(2D)图像,且可包括产生组织的一个或多个三维(3D)图像。在优选的实施方式中,如图3C中所示,产生一个或多个2D图像包括产生组织的多个2D横截面图像(例如,冠状面或任何合适的面中的“片”)(S116)和将组织的2D横截面图像组合成组织的3D图像(S118)。优选地,这些图像是断层摄影图像,且更优选地是超声波断层摄影图像,虽然它们可选地可以是任何合适的断层摄影图像。将数叠2D图像组合成3D图像的一般方法是本领域技术人员已知的,但美国专利公布第2008/0275344号中描述了一种可能的方法。可选地,2D和/或3D图像可以以任何合适的方式产生。如图3D中所示,在获得一组连续形态透视图的步骤S110中,优选地重复扫描和创建图像的步骤,直到获得组织的一组按时间顺序排列的透视图(优选地3D)为止,使得该组透视图包括在时间t1、t2、t3...tn处的形态透视图。这些图像优选地表示来自组织的声反射、组织内的声衰减和/或组织内的声速中的至少一个。然而,另外地和/或可选地,这些图像可表示组织的任何合适的生物力学性质。例如,这些图像可表示多普勒雷达下的组织或组织与造影剂的相互作用(例如,吸收或流动动力学)。如图3B中所示,优选地在单独的一叠2D图像中对每个声音参数成像,使得在该叠内的每个横截面水平处,声反射(Ir)、衰减(Ia)和/或声速(Is)的图像可被叠加或组合成合并的2D图像。
产生生物力学性质的一组代表性值的步骤S120起作用来量化或以其他方式表征该组透视图中的生物力学性质。如图4中所示,产生一组代表性值的步骤S120优选地包括对每个透视图计算生物力学性质的平均值(S122),从而产生该组织的生物力学性质的一组连续的或按时间顺序排列的体积平均值。产生一组代表性值(S120)还可包括标准化该组代表性值,例如以从所测量的数据除去统计学误差。该组透视图的所产生的代表性值优选地是声速,而另外地和/或可包括声衰减、声速、组织密度和/或任何合适的生物力学性质。在优选的实施方式中,平均值是患者体内原发肿瘤的生物力学性质的体积平均值。优选地通过当肿瘤块出现在声反射图像的形态透视图上时找出肿瘤块的轮廓来定义原发肿瘤,且该肿瘤轮廓可被复制在声衰减和/或声速形态透视图上以显示原发肿瘤的边界。体积平均值优选地合并由透视图表征的原发肿瘤的体积内的生物力学性质的平均值。例如,可如美国专利公布第2008/0275344号中描述的计算平均体积声速。然而,体积平均值可以是以任何合适的方式计算的原发肿瘤中的生物力学性质的代表性值。例如,另外地和/或可选地,体积平均值可包括其他方面,例如被遍布原发肿瘤的生物力学性质的值的空间分布加权。在另一个实施例中,体积平均值可考虑遍布原发肿瘤的多种不同种类的生物力学性质的组合。
在一个变化形式中,平均值可以是多个肿瘤的多个体积平均值的平均值或其他统计平均数,或多个肿瘤的多个体积平均值的最大体积平均值。在另一个变化形式中,平均值是所再现的组织的任何合适的健康或不健康部分的平均值或其他统计平均数。然而,可选地,平均值可以是任何合适的平均值。
对每个透视图计算生物力学性质的平均值(S122)优选地包括计及肿瘤组织内生物力学性质的值与该肿瘤组织周围的背景组织中生物力学性质的值之间的差异(S124)。计及差异起作用来忽略背景组织中的生物力学性质的值。优选地,计及差异(S124)包括从肿瘤组织的生物力学性质的体积平均值中减去背景组织内的生物力学性质的平均值(S126),但可以以任何合适的方式计及该差异。可以以多种方式中的一种或多种界定每个透视图中背景组织相对于肿瘤组织的边界。在一个变化形式中,背景组织可被界定为超出有轮廓的肿瘤组织的边界的距离阈值(例如,2厘米)之外的区域。在另一个变化形式中,背景组织可被界定为生物力学性质的梯度满足差异阈值的边界之外的区域。然而,可以以任何合适的方式界定背景组织相对于肿瘤组织的边界。
在另一个变化形式中,产生一组代表性值(S120)包括确定生物力学性质的初始值或基准值或生物力学性质的任何合适的奇异值。例如,初始值可从在步骤S110中获得的第一透视图获取。另外,确定生物力学性质的趋势(S130)可包括表征多种生物力学性质的初始值或多种生物力学性质的任何合适的奇异值。
可选地,产生一组代表性值(S120)可包括在该组透视图的每一个中表征生物力学性质的空间分布。表征可以是定性的,或可以例如通过产生描述生物力学性质的空间分布的参数是定量的。产生一组代表性值(S120)可包括在声学透视图中表征声速的空间分布,而且另外地和/或可选地可包括表征声衰减或任何合适的生物力学性质的空间分布。
确定生物力学性质的趋势的步骤S130起作用来基于可被分析以预测或以其他方式表征患者对治疗方案的反应的声音数据产生度量。确定趋势(S130)优选地包括计算该组平均值中的变化率(S132),这可以是多个变化形式中的一个或多个。在第一变化形式中,如图6所示,确定生物力学性质的趋势(S130)包括绘制生物力学性质的该组平均值相对于时间变量(例如,治疗天数或治疗次数)的曲线(S134)。该组平均值中的每个值可被表示成绝对值,被表示成该组的第一平均值的百分比或以任何合适的方式表示。在该变化形式中,计算变化率(S132)优选地包括计算拟合到曲线的至少一部分的最佳拟合曲线的斜率。换句话说,生物力学性质的所计算的变化率可以是拟合到该组体积平均值中的两个或更多个值的最佳拟合曲线的斜率。可选地,所计算的变化率可以是第一个和最后一个平均值之间的斜率、相邻平均值对的子集之间的斜率的平均值或中位数、曲线上的两个或更多个点之间的百分比差异或曲线中的变化率的任何合适的统计学度量。所计算的变化率可以或可以不被显示在曲线上。
在第二变化形式中,确定生物力学性质的趋势(S130)包括在数学上计算变化率。该计算可以与第一变化形式相似,除了计算在不将该组平均值绘制在曲线上的情况下被执行之外。
在第三变化形式中,确定生物力学性质的趋势(S130)包括确定多个生物力学性质的趋势。例如,多种生物力学性质的初始值可相对于彼此例如通过绘制一种生物力学性质的初始值相对于另一种生物力学性质的曲线(或以任何合适的方式例如通过计算比率来比较)来表征。例如,在确定多种生物力学性质的趋势中,组织的声速的初始值可与组织的声衰减的初始值比较。此外,如图6中所示,例如在具有一个轴上的声速的时间相关的值、另一个轴上的声衰减的时间相关的值和可能第三个轴上的时间变量的多维曲线图上,或具有在一个轴上的两种生物力学性质的比率和在另一个轴上的时间变量的曲线图上,一种生物力学性质的多个时间相关的代表性值(例如,按时间顺序排列的平均值)可与另一生物力学性质的时间相关的代表性值进行比较。
在可选实施方式中,确定生物力学性质的趋势(S132)可包括绘制该组生物力学性质的平均值相对于时间变量的曲线图,与第一变化形式的曲线图相似,并表征由该曲线图形成的曲线的总体形状。可定量和/或定性地表征曲线的总体形状(例如,平坦区域)。例如,曲线图上示出的生物力学性质的趋势可被描述为具有分别指示梯度或平坦度的大致程度的某个类型的斜率或平坦区域。
基于生物力学性质的趋势预测组织的反应的步骤(S140)起作用来表征组织对治疗方案的反应。在预测步骤期间,可评价生物力学性质的趋势以获得组织特性变化,例如长期的多阶段介入例如化疗和放射治疗,或细胞死亡,作为切除介入例如冷冻疗法、射频(RF)切除或电穿孔的结果。如图7中所示,预测组织的反应(S140)优选地包括比较变化率与阈值(S142)。该阈值可以是定量的或定性的。该阈值优选地基于表征先前患者对治疗方案的反应的数据,使得经历该治疗方案的先前患者形成目前患者可以比较的基准。例如,可使用根据优选方法扫描和分析的患者的先前实验数据来确定阈值。这些先前患者中的一些或全部可能已完成该治疗方案,且另外的方法例如MRI或PET扫描可用来确定这些患者对该治疗方案有反应还是没有反应以及反应的患者对该治疗方案的什么成功程度。先前患者的实验数据的分析可产生多个阈值,其指示对治疗方案的预测的反应度(例如,“完全”、“部分”或“不反应”)的变化的阈值。
在优选的变化形式中,阈值可以是“成功”阈值,使得如果生物力学性质的变化率(或任何奇异值,例如初始基准值)在成功阈值处和/或之上,则患者被预测为对继续的治疗方案积极反应。此外,在该变化形式中,如果变化率不满足成功阈值,则患者被预测为不对治疗有利地反应。变化率或其他趋势相对于阈值的精确比较取决于具体的生物力学性质。例如,如果特定患者体内原发肿瘤的声速变化率是比成功阈值的斜率更陡的下降斜率,则该特定患者被预测为对继续的治疗方案积极反应。然而,对于其他生物力学性质,如果变化率是比成功阈值的斜率更陡的倾斜斜率,则患者可被预测为积极反应。可选地,该阈值可被认为是“失败”阈值。
另外地和/或可选地,预测组织的反应(S140)可包括生物力学性质的该组平均值的任何合适的特征。例如,在一个可选的变化形式中,预测组织的反应(S140)包括分析由该组平均值相对于时间变量的曲线图所形成的曲线的总体形状。在另一个变化形式中,预测组织的反应(S140)包括分析该组平均值中的生物力学性质的起始初值。在又一个变化形式中,预测组织的反应(S140)包括分析一种或多种生物力学性质和/或形态特征相对于另一种生物力学性质和/或形态特征的趋势。例如,分析该趋势可包括分析具有在一个轴上的一种生物力学性质(例如,声速)的值、另一种生物力学性质(例如,声衰减)的值和可能第三轴上的时间变量的多维曲线上的散布或分布。在另一实施例中,分析该趋势可包括分析两种生物力学性质之间的比率的趋势(或由这些比率相对于时间变量的曲线图形成的曲线的总体形状)。
该方法还可包括基于预测的反应修改治疗方案(S150),S150起作用来利用组织的所预测的反应以使患者最大程度地受益。例如,如果预测是患者将对治疗方案有利地反应,则基于所预测的反应修改治疗方案的步骤S150可包括维持目前的治疗方案和/或继续监测患者的身体反应。作为另一个实例,如果预测是患者不会对治疗有利地反应,则修改治疗方案的步骤可包括:改变治疗方案的特征(例如剂量类型、给药量、给药频率或辐射的分布图案或切除),施用不同种类的治疗或中止该治疗方案。如本领域技术人员已知的,根据具体性质和患者的状态,其他合适的修改可由医师自由决定。
如本领域技术人员将从之前的详细描述和从附图及权利要求书中认识到的,可对本发明的优选实施方式进行修改和改变而不偏离以下权利要求书中所定义的本发明的范围。
Claims (37)
1.一种表征组织对治疗方案的病理反应的方法,包括:
·获得所述组织的一组连续形态透视图,其中每个透视图对应于在所述治疗方案期间的特定时间点;
·对该组透视图产生所述组织的生物力学性质的一组代表性值,其中每个代表性值基于相应的透视图;
·基于所述一组代表性值确定所述生物力学性质的趋势;以及
·基于所述生物力学性质的趋势预测所述组织对所述治疗方案的反应。
2.根据权利要求1所述的方法,其中获得一组连续形态透视图包括获得肿瘤组织的一组形态透视图。
3.根据权利要求1所述的方法,其中获得一组连续形态透视图包括扫描所述组织以获得声音数据及使用所述声音数据创建表示所述组织的声音参数的图像。
4.根据权利要求3所述的方法,其中扫描所述组织包括使用超声扫描仪扫描。
5.根据权利要求3所述的方法,其中创建图像包括创建表示来自所述组织的声反射、所述组织内的声衰减和/或所述组织内的声速中的至少一个的图像。
6.根据权利要求4所述的方法,其中创建图像包括产生一个或多个二维图像。
7.根据权利要求6所述的方法,其中创建图像包括产生所述组织的多个二维横截面图像以及将所述横截面图像组合成所述组织的三维图像。
8.根据权利要求7所述的方法,其中扫描所述组织包括使用环形传感器包围乳房组织以及使所述环形传感器沿相对于所述乳房组织的前后方向通过。
9.根据权利要求3所述的方法,其中扫描所述组织和创建图像在所述治疗方案期间以规律的时间间隔重复。
10.根据权利要求1所述的方法,其中产生生物力学性质的一组代表性值包括对每个透视图计算所述组织的所述生物力学性质的体积平均值,从而产生所述组织的所述生物力学性质的一组连续体积平均值。
11.根据权利要求10所述的方法,其中计算体积平均值包括对每个透视图计算所述组织内的声速的体积平均值。
12.根据权利要求10所述的方法,其中计算体积平均值包括对每个透视图计算所述组织内的乳房密度的体积平均值。
13.根据权利要求10所述的方法,其中计算体积平均值包括计算肿瘤组织的所述生物力学性质的体积平均值,从而产生所述肿瘤组织的所述生物力学性质的一组体积平均值。
14.根据权利要求13所述的方法,其中计算所述肿瘤组织的所述生物力学性质的所述体积平均值包括计及所述肿瘤组织内的所述生物力学性质的值与所述肿瘤组织周围的背景组织中的所述生物力学性质的值之间的差异。
15.根据权利要求14所述的方法,其中计及所述差异包括从所述肿瘤组织的所述生物力学性质的所述体积平均值中减去背景组织中的所述生物力学性质的平均值。
16.根据权利要求14所述的方法,其中计算所述肿瘤组织的所述生物力学性质的所述体积平均值包括计算所述肿瘤组织内的声速的体积平均值。
17.根据权利要求1所述的方法,其中产生一组代表性值包括确定所述生物力学性质的初始值或基准值。
18.根据权利要求1所述的方法,其中产生一组代表性值包括在该组透视图的每一个中表征所述生物力学性质的空间分布。
19.根据权利要求1所述的方法,其中确定所述组织内的所述生物力学性质的趋势包括计算所述一组代表性值中的变化率。
20.根据权利要求19所述的方法,其中计算变化率包括计算拟合到所述一组代表性值中的两个或更多个值的最佳拟合曲线的斜率。
21.根据权利要求19所述的方法,其中预测所述组织的反应包括比较所述变化率与阈值。
22.根据权利要求21所述的方法,其中比较所述变化率与阈值包括将所述变化率与基于表征先前患者对所述治疗方案的反应的数据的阈值进行比较。
23.根据权利要求1所述的方法,其中确定所述组织内的所述生物力学性质的趋势包括分析由所述一组平均值相对于时间变量的曲线图所形成的曲线的总体形状。
24.根据权利要求1所述的方法,其中预测所述组织的反应包括比较所述生物力学性质的趋势与阈值。
25.根据权利要求1所述的方法,其中预测所述组织的反应包括分析一种或多种生物力学性质相对于另一种生物力学性质的趋势。
26.根据权利要求1所述的方法,其中确定趋势包括在所述连续形态透视图中确定所述组织内的声速的趋势。
27.根据权利要求1所述的方法,其中确定趋势包括在所述连续形态透视图中确定所述组织内的声衰减的体积平均值的趋势。
28.根据权利要求1所述的方法,其中确定趋势包括在所述连续形态透视图中确定所述组织内的声反射的趋势。
29.根据权利要求1所述的方法,其中确定趋势包括在所述连续形态透视图中确定多普勒测量结果的趋势。
30.根据权利要求1所述的方法,其中确定趋势包括在所述连续形态透视图中确定造影剂吸收测量结果的趋势。
31.根据权利要求1所述的方法,还包括基于所预测的反应修改所述治疗方案。
32.一种表征患者组织内的肿瘤对治疗方案的病理反应的方法,包括:
·获得所述组织的一组连续超声形态透视图,其中每个透视图对应于在所述治疗方案期间的不同时间点;
·对该组透视图产生所述肿瘤内的声速的一组体积平均值,其中每个体积平均值基于相应的透视图;
·基于所述一组体积平均值计算所述肿瘤内的声速的变化率;以及
·基于所述肿瘤内的声速的变化率预测所述肿瘤对所述治疗方案的反应。
33.根据权利要求32所述的方法,其中获得一组连续超声形态透视图包括产生所述肿瘤的多个二维横截面图像以及将所述横截面图像组合成所述肿瘤的三维图像。
34.根据权利要求33所述的方法,其中获得一组连续超声形态透视图包括使用环形传感器扫描所述肿瘤组织以及使所述环形传感器沿相对于所述乳房组织的前后方向通过。
35.根据权利要求32所述的方法,其中计算所述肿瘤内的声速的变化率包括计算拟合到所述一组体积平均值的两个或更多个值的最佳拟合曲线的斜率。
36.根据权利要求32所述的方法,其中预测所述肿瘤的反应包括将所述变化率与基于表征先前患者对所述治疗方案的反应的数据的阈值相比较。
37.根据权利要求32所述的方法,还包括基于所预测的反应修改所述治疗方案。
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CN102843959B (zh) | 2014-11-12 |
US9144403B2 (en) | 2015-09-29 |
US10278672B2 (en) | 2019-05-07 |
WO2011100691A1 (en) | 2011-08-18 |
JP2013519454A (ja) | 2013-05-30 |
US20200015775A1 (en) | 2020-01-16 |
US20110201928A1 (en) | 2011-08-18 |
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