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

摘要/总结 背景：乳腺癌是女性最常见的恶性肿瘤，25-30%的患者累及腋窝淋巴结 案件。治疗通常包括手术前的全身治疗。新辅助治疗完全缓解 淋巴结正常化的全身治疗（NST）转化为不太广泛的手术， 发病率，有时强度较低的放射治疗。为了标记阳性淋巴结， 放置在NST前的正节点。NST后，标记的淋巴结通过超声、乳房X光检查， 或计算机断层扫描以植入外科医生用于淋巴结切除的定位器。超声是第一个- 线成像模式用于此任务。尽管如此，在~25%的病例中超声检查无法找到标记物， 在次优或中止的定位中，手术延迟，手术时间延长，患者不适增加 或不方便，以及增加的临床实践所吸收的成本。识别正确节点时出错 可能导致假阴性结果、过度/治疗不足和潜在的癌症复发。标记迁移 仍然存在另一个问题，可能导致错误的定位，将外科医生引导到不正确的节点。 该研究项目旨在解决这些未满足的关键需求，以开发可靠，易于使用的 超声波显着的标记，也是抗迁移。 方法：我们的初步数据表明，标记物的物理特征，如表面粗糙度，可能会导致 彩色多普勒超声闪烁伪影或“闪烁信号”与肾结石相关 血流成像凭借多元化研究团队的集体专业知识，我们开发了使用 聚甲基丙烯酸甲酯和增材制造（三维打印）。这些标记会产生 具有超声的稳健的闪烁特征，在多种成像模式下可见， 标记迁移我们将在六个月的猪模型中测试这些标记物的有效性和安全性。 模拟NST治疗与化疗的持续时间。最后，我们将进行第一阶段的临床试验， 在乳腺癌患者中使用我们优化的标记物来评估闪烁信号的长期强度 以及标记迁移的程度。为实现本项目的目标，我们提出以下具体目标： 目的1优化超声采集特性和信号处理链，以稳健地检测闪烁。 目的2优化乳房手术标记物的物理特性，增强基于多普勒的闪烁， 减少标记迁移。 目的3评估候选标记物在猪中的长期安全性、瞬时持久性和标记物迁移 动物模型 目的4在使用植入标记物的I期临床试验中评价优化标记物的闪烁和迁移 乳腺癌患者NST前腋窝淋巴结阳性。

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.