Metastatic Spine Tumors: Minimally Invasive Fracture Risk Analysis and Treatment - Master

 描述(由申请人提供)：癌症转移到骨性脊柱的鉴定使治疗临床医生有义务做出手术决定。目前的脊柱稳定性决策是经验性的、定性的，即使是由经验丰富的脊柱临床医生做出的，也可能是不准确的。然而，这一决定的后果对患者来说意义重大，无论该建议是用于手术治疗还是非手术治疗。如果脊柱被认为不稳定，有骨折的危险，那么患者将接受一次重大的脊柱手术，通常会在余生的大部分时间里从中恢复。相反，脊柱被认为是稳定的，接受非手术治疗的患者，如果稳定性分析不正确，就有骨折和可能瘫痪的风险。这项研究计划涉及到三个关键问题涉及到的转移性脊柱缺陷患者的护理。我们建议开发定量的、可靠的和用户友好的方法来预测在生理相关负荷条件下转移性癌症椎体的骨折风险。我们将使用新型生物材料优化微创治疗技术，以重建包含(骨洞)或非包含(缺失的一段骨)缺陷的受影响椎体的承载能力。在第一个赠款周期中，我们成功地开发了用于非侵入性骨折风险预测的静态椎体结构分析(VSA)程序和用于微创治疗包含缺陷的椎体的可注射聚合物植入装置。我们已经使用在压缩载荷下测试的单个身体椎体对该程序进行了初步验证。在第二个周期中，我们计划开发和优化一种新型的、基于水凝胶的、可膨胀的聚合物复合治疗系统，用于治疗脊柱转移灶中的非包含性椎体缺陷(目标1)。由聚富马酸己内酯(PCLF)和低聚[聚富马酸乙二醇酯](OPF)水凝胶组成的生物相容性交联型中空管状支架将被制备。脱水的PCLF/OPF管可以绕着脊髓或马尾插入到非包含性椎体缺损处的前方位置。在重新水化时，聚合物植入物将膨胀回其预定的尺寸。然后，将聚富马酸丙酯(PPF)或聚甲基丙烯酸甲酯(PMMA)通过管壁注入，以填充中空管的内腔。在目标2中，我们将在身体上测试包含(目标2a)和非包含(目标2b)转移性脊柱病变的生物材料植入系统。三个节段功能脊髓单位包含的，模拟的溶骨性缺陷 中间椎体，无论是未经处理，使用PPF-co-PCL共聚物(在我们的第一个赠款周期中开发的可注射材料)处理，还是使用PMMA处理，都将在轴向压缩载荷和弯曲弯矩下进行力学测试。结果将用于在两种类型的加载条件下验证VSA程序。在Aim 1中开发的新型可扩展PCLF/OPF/PPF移植物重建了缺失节段的身体脊柱，将使用配套的后路脊柱内固定在屈曲弯矩下进行测试，以准确模拟这些类型脊柱重建中的常见临床情况。在目标3中，我们将在VSA程序中增加在特定日常生活活动(ADLS)期间相关生理负荷条件下的有限元分析(FEA)。静态VSA和VSA/FEA这两种方法在性质上是互补的。静态VSA使用基于图像的分析来提供静息条件下的是/否手术决定，而FEA模型在特定ADL负荷情况下分析椎体和后部元素，以允许临床医生向她/他的患者建议可以在低脊柱骨折风险的情况下执行ADLS。我们未来的计划是通过两种方式介绍脊柱VSA/FEA分析程序的初步临床实施。第一种实施方法将是通过我们在梅奥诊所的临床实践以及通过我们的顾问Brian Snyder博士在哈佛医院系统中对转移性脊柱患者群体的实施。我们将寻求每家机构的IRB批准，将VSA/FEA添加到这些患者的转移性脊柱病变的评估中，然后将这些数据纳入我们与患者的讨论，以确定我们对他们的护理建议。我们将研究这些建议的结果，根据这些结果调整必要的决策参数，然后通过肌肉骨骼肿瘤协会将分析扩展到更多的机构，就像斯奈德博士和我们过去通过转移性髋部骨折分析项目所做的那样。在第二种实施方法中，我们将包括VSA/FEA，作为我们现有的Mayo诊所骨质疏松症外部咨询服务的附加组件。与我们的骨代谢内分泌学同事一起，我们的实验室每年对大约50例过渡性骨活检进行定量骨组织形态计量学。我们符合良好实验室规范(GLP)，临床实验室改进修正案(CLIA)认证，美国病理学家学会(CAP)认证这项工作。我们将VSA/FEA结果添加到作为骨质疏松症评估的一部分进行的一系列研究中，方法是将病变大小设置为 零，从而根据用于患者的DEXA扫描的同一腰椎中的骨矿的数量和分布来计算脊椎的强度和硬度。

 DESCRIPTION (provided by applicant): The identification of cancer metastases to the bony vertebral column obligates the treating clinician to make a surgical decision. Current spinal stability decision-making is empirical, qualitative in nature, and can be inaccurate, even when done by experienced spinal clinicians. The consequences of that decision, however, are significant for the patient whether the recommendation is for surgical or non-surgical treatment. If the spine is deemed unstable and at risk for fracture, then the patient will undergo a major spinal operation, and will often spend much of their remaining life recuperating from it. Conversely, the patient whose spine is deemed stable, and who receives non-surgical treatment, risks fracture and possible paralysis if the stability analysis was incorrect. This research program addresses three critical issues involved in the care of patients with metastatic spine defects. We propose to develop quantitative, reliable, and user-friendly methodologies to predict the fracture risk of vertebrae with metastatic cancer under physiologically relevant loading conditions. We will optimize minimally invasive treatment techniques using novel biomaterials to reconstitute the load bearing capacity of an affected vertebra that has either contained (hole in a bone) or non-contained (a missing segment of a bone) defects. In the first grant cycle, we have successfully developed both a static vertebral structural analysis (VSA) program for non-invasive fracture risk prediction and injectable polymeric implant devices for minimally invasive treatment of vertebrae with contained defects. We have performed initial validation of the program using single cadaveric vertebral bodies tested under compression loads. In this second cycle, we plan to develop and optimize a novel, hydrogel-based, expandable polymer composite treatment system for non-contained vertebral body defects in spines with metastatic lesions (Aim 1). Biocompatible, crosslinked hollow tube scaffolds composed of poly(caprolactone fumarate) (PCLF) and oligo[poly(ethylene glycol) fumarate] (OPF) hydrogel will be fabricated. The dehydrated PCLF/OPF tube can be inserted around the spinal cord or cauda equina into an anterior position within the non-contained vertebral defect. Upon rehydration the polymeric implant will expand back to its pre-determined size. Poly(propylene fumarate) (PPF) or poly(methylmethacrylate) (PMMA) will then be injected through the tube wall to fill the lumen of the hollow tube. In Aim 2, we will test the biomaterial implant systems for both contained (Aim 2a) and non-contained (Aim 2b) metastatic spine lesions in cadavers. Three-level functional spinal units with contained, simulated lytic defects in the middle vertebra, either left untreated, treated with PPF-co-PCL copolymers (the injectable materials previously developed during our first grant cycle), or treated with PMMA will be mechanically tested under both axial compressive loads and flexion bending moments. The results will be used to validate the VSA program under both types of loading conditions. Cadaver spines with a missing segment reconstructed by the novel expandable PCLF/OPF/PPF graft developed in Aim 1 will be tested with concomitant posterior spinal instrumentation under flexion bending moments to accurately model the usual clinical situation in these types of spinal reconstructions. In Aim 3, we will add finite element analysis (FEA), under relevant physiological loading conditions during specific activities of daily living (ADLs) to the VSA program. The two methodologies, static VSA and VSA/FEA, are complementary in nature. The static VSA uses image-based analysis to provide a yes/no surgical decision under resting conditions, while the FEA model analyzes both the vertebral body and the posterior elements under specific ADL loading situations to allow the clinician to counsel her/his patient regarding ADLs that can be performed with a low risk of spinal fracture. Our future plans are to introduce the initial clinica implementation of the spinal VSA/FEA analysis program in two ways. The first method of implementation will be on the metastatic spine patient population in our clinical practices at Mayo Clinic and through our consultant, Dr. Brian Snyder, in the Harvard system of hospitals. We will seek IRB approval at each institution to add VSA/FEA to the evaluation of these patient's metastatic spinal lesions, and then incorporate these data in our discussion with the patients regarding our recommendations for their care. We will study the outcome results of those recommendations, adjust the decision parameters as necessary based on those outcomes, and then extend the analysis to additional institutions via the Musculoskeletal Tumor Society, as Dr. Snyder and we have done in the past with a metastatic hip fracture analysis program. In the second implementation method, we will include the VSA/FEA as an added component to our existing Mayo Clinic osteoporosis external consultation service. In conjunction with our bone metabolism endocrinology colleagues, our laboratory performs quantitative bone histomorphometry on ~50 transiliac bone biopsies per year. We are Good Laboratory Practices (GLP) compliant, Clinical Laboratory Improvement Amendments Act (CLIA) certified, and College of American Pathologists (CAP) certified for this work. We will add the VSA/FEA results to the battery of studies done as part of the osteoporosis evaluation by setting the lesion size to zero, and thus calculating the vertebral strength and stiffness based on the amount and distribution of bone mineral in the same lumbar vertebrae that are used for the patient's DEXA scan.