Biomarkers in Phototherapy of Barrett's Esophagus

本研究旨在通过我们在最后一个资助期间所做的独特观察，该观察确定了p16在光动力疗法（PDT）治疗反应中的重要性。我们证明了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PDT在预防食管腺癌相关死亡率方面与手术相当。在本提案中，我们将研究有p16异常的Barrett食管和高度发育不良患者的替代治疗形式。为了研究这一假设，我们确立了两个具体目标。第一个是在一项随机研究中评估射频（RFA）和基于聚硫脲钠的PDT对p16完整的HGD患者的影响，每组20例患者。第二个目的是评估RFA和ALA为基础的PDT对Barrett食管和HGD患者p16异常的效果，每组30例。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依赖于在粘膜内转化为活性形式的前药，并且与基于卟啉钠的PDT相比，已知其启动的细胞死亡机制不同。在这个修订后的申请中，我们建议在两年的时间框架内通过减少随访时间和增加人员来增加患者招募，从最初提出的110名患者中招募100名。在接受PDT或PDT治疗的患者中，我们将使用一种新型反射探针来评估组织剂量学，该探针可以评估组织散射和吸收系数以及氧饱和度信息。我们还将使用一般和疾病特异性措施评估治疗后的生活质量。该建议的新颖元素包括使用结合高分辨率窄带成像和自身荧光成像的成像技术来评估发育不良的程度。我们将继续用我们的生物标志物评估这些患者对消融治疗的反应，以增加我们对其在预测疾病进程中的价值的理解。这些研究将对Barrett食管对消融治疗的反应提供更好的理解。

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.