Purpose

Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA.

Procedures

Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and H&E images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence.

Results

In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75–85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence.

Conclusion

Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections.

Clinical Trial

NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1).

中文翻译：

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在啮齿动物和人类胶质母细胞瘤中同时使用 Delta-氨基乙酰丙酸和第二窗口吲哚菁绿后的诊断准确性评估。

目的

荧光引导手术提供了肿瘤组织的术中可视化。δ-氨基乙酰丙酸 (5-ALA) 靶向肿瘤细胞中的酶促异常，是唯一获准用于荧光引导神经外科手术的药物。最近，我们描述了第二窗口吲哚菁绿 (SWIG)，它通过增强血管通透性来靶向肿瘤组织。我们假设与 5-ALA 相比，SWIG 在识别高级别胶质瘤方面具有相似的临床效用。

程序

雌性 C57/BL6 和裸/无胸腺小鼠分别接受了 300,000 个 GL261 和 U87 细胞的颅内植入。在施用 5-ALA（200 毫克/千克腹膜内）和 SWIG（5 毫克/千克静脉内）后，荷瘤小鼠被安乐死。对脑切片进行原卟啉-IX 和 ICG 荧光成像。荧光和 H&E 图像使用半自动脚本进行注册以进行分析。患有 HGG 的人类受试者接受了 SWIG（静脉注射 2.5 毫克/千克）和 5-ALA（口服 20 毫克/千克）。术中，对肿瘤进行 ICG 和原卟啉-IX 荧光成像。

结果

在非坏死性肿瘤中，5-ALA 和 SWIG在 U87 肿瘤中显示出 90.2% 和 89.2% 的肿瘤准确度（p值 = 0.52），在 GL261 肿瘤中显示出88.1% 和 87.7% 的准确度（p值 = 0.83）。5-ALA 和 SWIG 分布之间最明显的差异出现在肿瘤相关坏死区域，通常显示弱/无原卟啉-IX 荧光，但 SWIG 荧光强。在来自四名 HGG 受试者的 20 个活检标本中，SWIG 显示出 100% 的准确度，而 5-ALA 显示出 75-85% 的准确度；SWIG 和 5-ALA 荧光之间有 90% 的一致性。

结论

我们的结果首次直接比较了 SWIG与5-ALA 在啮齿动物和人类 HGG中的诊断效用。鉴于 SWIG 与 5-ALA 相比具有更广泛的临床效用，我们的数据支持在肿瘤手术中使用 SWIG 以提高安全切除的程度。

临床试验

NCT02710240（美国国家医学图书馆注册处；https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1）。