Biomarkers in Phototherapy of Barrett's Esophagus

这项研究旨在延续我们在上一期资助期间所做的独特观察，这些观察确立了p16在光动力疗法(PDT)治疗反应中的重要性。我们证明，PDT消融治疗能够消除治疗后大多数肿瘤的生物标志物。此外，我们发现，在预防食管腺癌相关死亡率方面，光动力疗法可与手术相媲美。在这项提案中，我们将研究针对Barrett‘s食道和具有p16异常的高度发育不良患者的替代治疗形式。为了研究这一假说，我们确立了两个具体目标。第一个是在随机研究中评估射频(RFA)和基于孔雀异构体的光动力疗法对p16完整的HGD患者的影响，每组患者20例。第二个目标是评估基于RFA和ALA的PDT在Barrett‘s食道和HGD患者中的效果，这些患者每支手臂有30名患者的p16异常。射频消融通过不同的机制产生损伤，可能不受p16丢失的影响。ALA PDT依赖于一种在粘膜内转化为活性形式的前体药物，与基于磷脂酰胺钠的PDT相比，ALA PDT还启动了一种不同的细胞死亡机制。在这份修订后的申请中，我们建议在两年内从最初提出的110人中招募100人，方法是缩短随访时间并增加人员编制，以增加患者招募。在接受PDT的患者中，我们将使用一种新型的反射探头来评估组织剂量学，该探头可以评估组织的散射和吸收系数以及血氧信息。我们还将使用一般和针对疾病的衡量标准来评估治疗后的生活质量。这项建议的新元素包括使用结合高分辨率窄带成像和自体荧光成像的成像技术来评估异型增生的程度。我们将继续用我们的生物标记物评估这些患者对消融治疗的反应，以增加我们对它们在预测疾病过程中的价值的理解。这些研究将提供关于Barrett‘s食道对消融治疗的反应的更好的理解。

This study is designed to follow through on unique observations made during our last period of funding which established the importance of p16 in treatment response to photodynamic therapy (PDT). We demonstrated that ablative therapy with PDT was able to eliminate most biomarkers of neoplasia after therapy. In addition, we found that PDT is comparable to surgery in its ability to prevent esophageal adenocarcinoma related mortality. In this proposal, we will be investigating alternative forms of therapy for patients Barrett’s esophagus and high-grade dysplasia that have p16 abnormalities. In order to investigate this hypothesis, we have established two specific aims. The first is to assess the effect of radiofrequency (RFA) and sodium porfimer based PDT in patients with HGD that have p16 intact in a randomized study with 20 patients per arm. The second aim will be to assess the effect of RFA and ALA based PDT in patients with Barrett’s esophagus and HGD that have abnormal p16 with 30 patients per arm. RF ablation produces injury through different mechanisms and may not be influenced by p16 loss. ALA PDT relies on a pro-drug that is converted to active form within the mucosa and also is known to initiate a different mechanism of cell death compared with sodium porfimer based PDT. In this revised application, we propose to enroll 100 out of the 110 we initially proposed within a two year time frame by decreasing the period of follow-up and increasing staffing to increase patient recruitment. In the patients who receive either for of PDT, we will be assessing tissue dosimetry using a novel reflectance probe that can assess tissue scattering and absorption coefficients as well as oximetry information. We will also be assessing the quality of life after therapy using general and disease specific measures. Novel elements of this proposal include the assessment of the extent of dysplasia using an imaging technique combining high-resolution narrow band imaging and autofluorescence imaging. We will continue to assess the response to ablation therapy in these patients with our biomarkers to increase our understanding of their value in predicting the course of the disease. These studies will provide an improved understanding regarding the response of Barrett’s esophagus to ablation therapy.