C-Met targeted fluorescence molecular endoscopy in Barrett's esophagus patients and identification of outcome parameters for phase-I studies
C-Met targeted fluorescence molecular endoscopy in Barrett's esophagus patients and identification of outcome parameters for phase-I studies
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DOI：
10.7150/thno.42224
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Nagengast, Wouter B.
中科院分区：
文献类型：
--
作者：
de Jongh, Steven J.;Voskuil, Floris J.;Nagengast, Wouter B.
荧光分子内镜（FME）是胃肠病学领域的一项新兴技术，作为一种“红旗”内镜成像技术，有可能改善诊断和指导治疗。在这里，我们调查的安全性，可行性和管理的EMI-137，靶向c-Met，在FME在巴雷特食管（BE）和报告的早期阶段FME研究的几个结果参数的最佳方法：FME进行了15巴雷特肿瘤患者。将EMI-137给予三组五名患者：0.13 mg/kg静脉内（IV）; 0.09 mg/kg IV或局部，剂量为200 μ g/cm BE（n=1）或100 μ g/cm BE（n=4）。荧光在体内可视化，在体内定量使用多直径单纤维反射，单纤维荧光（MDSFR/SFF）光谱和相关的组织病理学和免疫组织化学。EMI-137定位进行了评估，使用荧光microscopic.Results：FME使用不同的IV和局部剂量的EMI-137似乎是安全的，并正确识别16/18病变，虽然适度的目标-背景比观察（中位数范围为1.12-1.50）。C-Met过度表达在病变之间变化，而在胃型上皮中观察到生理表达。显微镜下，EMI-137聚集在肿瘤细胞膜周围。我们确定了几个对EMI-137用于FME的验证很重要的结果参数：1）最佳给药途径; 2）最佳剂量和安全性; 3）体内FME对比度; 4）内在荧光的定量; 5）荧光、组织病理学和靶表达的离体相关性;以及6）显微示踪剂分布。使用EMI-137的C-Met靶向FME可能不是改善BE监测内窥镜检查的理想组合，然而，所确定的结果参数可以作为设计和执行未来早期临床FME研究的有价值的指导，而与研究的荧光示踪剂无关。
Fluorescence molecular endoscopy (FME) is an emerging technique in the field of gastroenterology that holds potential to improve diagnosis and guide therapy, by serving as a 'red-flag' endoscopic imaging technique. Here, we investigated the safety, feasibility and optimal method of administration of EMI-137, targeting c-Met, during FME in Barrett's Esophagus (BE) and report several outcome parameters for early phase FME studies.Methods: FME was performed in 15 Barrett's neoplasia patients. EMI-137 was administered to three cohorts of five patients: 0.13 mg/kg intravenously (IV); 0.09 mg/kg IV or topically at a dose of 200 mu g/cm BE (n=1) or 100 mu g/cm BE (n=4). Fluorescence was visualized in vivo, quantified in vivo using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy and correlated to histopathology and immunohistochemistry. EMI-137 localization was assessed using fluorescence microscopy.Results: FME using different IV and topical doses of EMI-137 appeared to be safe and correctly identified 16/18 lesions, although modest target-to-background ratios were observed (median range of 1.12-1.50). C-Met overexpression varied between lesions, while physiological expression in the stomach-type epithelium was observed. Microscopically, EMI-137 accumulated around the neoplastic cell membranes. We identified several outcome parameters important for the validation of EMI-137 for FME: 1) the optimal administration route; 2) optimal dose and safety; 3) in vivo FME contrast; 4) quantification of intrinsic fluorescence; 5) ex vivo correlation of fluorescence, histopathology and target expression; and 6) microscopic tracer distribution.Conclusions: C-Met targeted FME using EMI-137 may not be the ideal combination to improve BE surveillance endoscopies, however the identified outcome parameters may serve as a valuable guidance for designing and performing future early phase clinical FME studies, independent of which fluorescent tracer is investigated.