Development of an ultrasound detectable, migration-resistant biopsy marker for improving care in patients with breast cancer

摘要/摘要 背景：乳腺癌是女性最常见的癌症，25%-30%累及腋窝淋巴结。 案件的数量。治疗通常包括手术前的系统治疗。对新佐剂的完全应答 全身治疗(NST)与正常的淋巴结转化为较小的手术范围，较低的相关性 发病率，有时还包括强度较小的放射治疗。为了标记阳性淋巴结，活组织检查标记物是 放置在NST前的正结节中。NST后，通过超声、乳房X光检查、 或者计算机断层扫描植入定位器，外科医生用来切除结节。超声波是第一个- 这项任务的直线成像模式。尽管如此，在大约25%的病例中，超声无法找到标志物，因此 在不理想或流产的定位中，手术延迟、手术时间较长、患者不适增加 或不便，并增加了临床实践的吸收成本。找不到正确的节点(S) 可能导致假阴性结果、治疗过度/治疗不足，以及潜在的癌症复发。标记迁移 仍然是另一个可能导致误导定位的问题，将外科医生引导到错误的结节。 这项研究项目旨在解决这些未得到满足的关键需求，以开发可靠、容易 超声波--也能抵抗迁移的显眼标记。 方法：我们的初步数据表明，标志物的物理特征，如表面粗糙度，可以导致 彩色多普勒超声闪烁伪影或与肾结石有关的“闪烁征象” 血流成像。凭借不同研究团队的集体专业知识，我们已经开发出了使用 聚甲基丙烯酸甲酯和添加剂制造(三维打印)。这些标记生成 强健的超声闪烁信号，可通过多种成像方式查看，并可抵抗 标记迁移。我们将在一个六个月的猪模型中测试这些标志物的有效性和安全性。 模拟NST化疗持续时间的周期。最后，我们将进行一期临床试验 在乳腺癌患者中使用我们优化的标志物来评估闪烁信号的长期强度 以及标记迁移的程度。为了实现这个项目的目标，我们提出了以下具体目标： 目的1优化超声采集特性和信号处理链，实现闪烁信号的稳健检测。 目的2优化乳房手术标志物的物理特性，以增强基于多普勒的闪烁和 减少标记迁移。 目的3评估候选标记在猪体内的长期安全性、闪烁持久性和标记迁移 动物模型。 目的在一期临床试验中评价植入标记的优化标记的闪烁和迁移 在乳腺癌患者NST前的阳性腋窝淋巴结中。

ABSTRACT / SUMMARY Background: Breast cancer, the most common cancer in women, involves the axillary lymph nodes in 25-30% of cases. Treatment usually involves systemic therapy before surgery. Complete response to neoadjuvant systemic therapy (NST) with normalization of the lymph nodes translates to less extensive surgery, lower related morbidity, and sometimes less intense radiation therapy. To mark a positive lymph node, a biopsy marker is placed in the positive node pre-NST. Post-NST, the marked node is identified with ultrasound, mammography, or computed tomography to implant a localizer, which the surgeon uses for node removal. Ultrasound is the first- line imaging modality for this task. Still, the marker cannot be found sonographically in ~25% of cases, resulting in suboptimal or aborted localizations, delays to surgery, longer procedural times, increased patient discomfort or inconvenience, and increased absorbed costs by the clinical practice. Errors in identifying the proper node(s) may lead to false-negative results, over/undertreatment, and potential cancer recurrence. Marker migration remains another concern that can lead to misguided localization, directing the surgeon to the incorrect node. This research project aims to address these unmet and critical needs to develop reliable, readily ultrasound-conspicuous markers that are also resistant to migration. Methods: Our preliminary data suggest that physical features of markers, like surface roughness, can cause an ultrasound twinkling artifact or “twinkling signature” classically associated with kidney stones using color Doppler flow imaging. With the collective expertise of a diverse research team, we have developed markers using polymethyl methacrylate and additive manufacturing (three-dimensional printing). These markers generate robust twinkling signatures with ultrasound, are visible with multiple imaging modalities, and are resistant to marker migration. We will test the efficacy and safety of these markers in a porcine model over a six-month period to mimic the duration of NST treatment with chemotherapy. Lastly, we will conduct a Phase 1 clinical trial in breast cancer patients with our optimized marker to evaluate the long-term strength of the twinkling signature and the degree of marker migration. To accomplish the goals of this project, we propose these Specific Aims: Aim 1 Optimize ultrasound acquisition characteristics and the signal processing chain to robustly detect twinkling. Aim 2 Optimize physical characteristics of breast procedure markers that enhance Doppler-based twinkling and reduce marker migration. Aim 3 Assess long-term safety, twinkling persistence, and marker migration of candidate markers in a porcine animal model. Aim 4 Evaluate twinkling and migration of optimized markers in a Phase 1 clinical trial using markers implanted in a positive axillary lymph node prior to NST in patients with breast cancer.