Using Second Harmonic Generation to Predict Metastatic Outcome in Colon Adenocarcinoma

当治疗结肠腺癌(CA)患者时，在手术切除肿瘤后，临床医生必须 制定辅助系统治疗方案。这一决定是基于对以下风险的评估 全身性疾病复发，目前与病理因素有关，如分期、组织学 等级和淋巴状态。提高个体患者风险评估的准确性是一种 公认需要的领域。目前用于评估风险的大部分信息都集中在细胞内 肿瘤，包括它们的形态特征。对细胞外基质的关注较少，通过这些细胞外基质 转移的细胞必须移动。二次谐波是一种光学散射现象 其方向性(由“F/B”比率量化)受纤维直径、间距和无序的影响 在胶原蛋白纤维中。我们的初步数据表明，肿瘤样本的F/B分析提供了预后 关于未来转移的信息是“以基质为中心”的，因此是对当前“以细胞为中心”的补充 方法：研究方法。在对44例I期结肠腺癌标本的初步研究中，我们发现原发性结肠腺癌的F/B 肿瘤是无进展生存时间的重要预后指标。值得注意的是，第一阶段的四分位数 F/B比值最低的患者的临床结果与III期患者没有区别：15年 无进展存活率低于50%。换句话说，在这项研究中，F/B确定了 I期患者的生存统计数据与III期患者相似。I期患者很少被开出处方 辅助化疗，而III期患者几乎总是开这种药。这表明F/B可能会 能够确定哪些患者将从辅助化疗中受益，哪些患者将被留下来 根据目前的预后指标，未予治疗。在72人的队列中，预后趋势也很明显。 II期结肠腺癌标本，但差异不显著。因此，我们假设 F/B比值是预测结肠腺癌转移预后的有用指标。这个项目将 首先(目标1)使用存档的样本并在单独的情况下跟踪数据，从而使这一想法更接近临床 培训和验证集，以开发和测试预测算法，包括F/B，以及临床和 基因组信息。第二，它将(目标2)量化辅助化疗对预后的影响。 算法的能力，以及量化它们预测化疗疗效的能力。我们预测 F/B分析将是这项研究后能够迅速到达临床以提高转移风险的有效工具 评估。提高单个患者风险估计的准确性将使临床医生能够 那些注定要转移的患者，改善了预后，同时避免了那些 患者不是，减少过度治疗。！

When treating a colon adenocarcinoma (CA) patient, after surgical resection of the tumor the clinician must formulate a plan for adjuvant systemic therapy. This decision is based upon an assessment of the risk of systemic disease recurrence, and is currently informed by pathological factors such as stage, histological grade, and lymph node status. Improvement of the accuracy of risk assessment for individual patients is an area of recognized need. Much of the current information used to assess risk focuses on the cells within tumors, including their morphological properties. Less attention is paid to the extracellular matrix through which metastasizing cells must travel. Second harmonic generation (SHG) is an optical scattering phenomenon whose directionality (as quantified by the “F/B” ratio) is affected by the diameter, spacing, and disorder of fibrils within collagen fibers. Our preliminary data suggests that F/B analysis of tumor samples provides prognostic information about future metastasis that is “matrix-focused” and hence complementary to current “cell-focused” methods. In a preliminary study in 44 Stage I colon adenocarcinoma samples we found that F/B of the primary tumor is a significant prognostic indicator of progression free survival time. Significantly, the quartile of Stage I patients with the lowest F/B ratio had a clinical outcome indistinguishable from Stage III patients: a 15 year progression free survival percentage of below 50%. In other words, in this study F/B identified a subset of Stage I patients who had survival statistics similar to Stage III patients. Stage I patients are rarely prescribed adjuvant chemotherapy while Stage III patients are almost always prescribed it. This suggests that F/B might be able to identify individual patients who would benefit from adjuvant chemotherapy and who would be left untreated based upon current prognostic indicators. The prognostic trend was also evident in a cohort of 72 Stage II colon adenocarcinoma samples, although it was not significant. Consequently we hypothesize that F/B is a clinically useful predictor of metastatic outcome in colon adenocarcinoma. This project will move this idea closer to the clinic by first (Aim 1) using archived samples and follow up data in separate training and validation sets to develop and test predictive algorithms that include F/B, in addition to clinical and genomic information. Second it will (Aim 2) quantify the effect of adjuvant chemotherapy on the predictive ability of the algorithms, as well as quantify their ability to predict chemotherapeutic efficacy. We predict that F/B analysis will be an effective tool that can reach the clinic rapidly after this study to improve metastatic risk assessment. Improving the accuracy of risk estimation for an individual patient will allow clinicians to treat those patients who are destined for metastases, improving outcomes, while avoiding treatment for those patients who are not, reducing overtreatment.!