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 制定辅助全身治疗计划。这一决定是基于对以下风险的评估： 全身性疾病的复发，目前被告知的病理因素，如阶段，组织学 分级和淋巴结状态。提高个体患者风险评估的准确性是一项 认识到需要的领域。目前用于评估风险的大部分信息都集中在细胞内 肿瘤，包括其形态学特性。很少注意到细胞外基质， 转移细胞必须移动。二次谐波是一种光学散射现象 其方向性（由“F/B”比量化）受原纤维的直径、间距和无序度的影响 在胶原纤维中。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“聚焦于基质”的，因此是对当前“聚焦于细胞”的补充。 方法.在对44例I期结肠腺癌样本的初步研究中，我们发现原发性结肠癌的F/B比值在100%以下。 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局与III期患者无明显区别：15年 无进展生存率低于50%。换句话说，在这项研究中，F/B确定了一个子集， I期患者的生存统计数据与III期患者相似。I期患者很少被处方 辅助化疗，而III期患者几乎总是处方。这表明F/B可能 能够确定哪些患者将从辅助化疗中受益，哪些患者将离开 根据目前的预后指标未治疗。在一个72人的队列中， II期结肠腺癌样本，尽管不显著。因此，我们假设， F/B是结肠腺癌转移预后的一个临床有用的预测因子。该项目将 通过首先（目标1）使用存档样本和单独的随访数据， 训练和验证集，以开发和测试预测算法，包括F/B，以及临床和 基因组信息其次，它将（目标2）量化辅助化疗对预测性肿瘤的影响。 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分析将是一个有效的工具，可以迅速达到临床后，这项研究，以改善转移风险 考核提高个体患者风险估计的准确性将使临床医生能够治疗 那些注定发生转移的患者，改善结局，同时避免对那些 病人谁不是，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.!