Specchia Francesco Maria Calamo, Monticelli Matteo, Zeppa Pietro, Bianconi Andrea, Zenga Francesco, Altieri Roberto, Pugliese Beatrice, Di Perna Giuseppe, Cofano Fabio, Tartara Fulvio, Bertero Luca, Cassoni Paola, Melcarne Antonio, Lanotte Michele Maria, Garbossa Diego
UOC Neurosurgery, Head and Neck Department, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
Neurosurgery Unit, AOC Città della Salute e della Scienza, Department of Neuroscience "Rita Levi Montalcini", University of Turin, 10124 Turin, Italy.
Brain Sci. 2021 Jun 16;11(6):795. doi: 10.3390/brainsci11060795.
Despite the aggressiveness of multimodal treatment, glioblastoma (GBM) is still a challenge for neurosurgeons, neurooncologists, and radiotherapists. A surgical approach is still a cornerstone in GBM therapeutic management, as the extent of resection is strongly related both to overall survival and progression-free survival. From this perspective, the use of photodynamic molecules could represent an interesting tool to achieve maximal and safe resection. Being able to trace the lesion's edges, indeed, could allow to improve the extent of resection and to minimize residual tumor while sparing normal tissue. The use of 5-aminolevulinic acid (5-ALA) as a photodynamic tracer is well established due to its strict correlation both with cellularity and metabolic activity of the GBM cell clones.
Our study aims to define whether a different molecular asset of GBM (especially investigating mutation, proliferation index, and MGMT promoter methylation) results in different fluorescence expression, possibly because of differences in metabolic pathways due to different genotypes.
Patients undergoing surgery for GBM removal at our Institute (Dep. Of Neurosurgery, Ospedale Città della Salute e della Scienza, University of Turin, Italy) were retrospectively reviewed. Patients with histological diagnosis confirmation and to whom 5-ALA was given before surgery were included. The whole surgical procedure was recorded and then analyzed by three different people (a medical student, a resident, and a senior surgeon with an interest in neurooncology and experience in using 5-ALA) and a score was assigned to the different degrees of intraoperative fluorescence. The degree of fluorescence was then matched with the genotype.
A trend of grade 2 fluorescence (i.e., "strong") was observed in the wild-type (WT) genotype, suggesting a more intense metabolic activity in this particular subgroup, while, no or weak fluorescence was observed more often in the mutated tumors, suggesting a lower metabolic activity. No relations were found between fluorescence grade and MGMT promoter methylation or, interestingly, cellularity. As a secondary analysis, more epileptogenicity of the mutated GBM was noticed, similarly to other recent literature.
Our results do not support the use of 5-ALA as a diagnostic tool, or a way to substitute the molecular profiling, but confirm 5-ALA as a powerful metabolic tracer, able to easily detect the pathological cells, especially in the IDH WT genotype, and in this perspective, further studies will be necessary to better describe the metabolic activity of GBM cells.
尽管多模式治疗手段积极，但胶质母细胞瘤（GBM）对神经外科医生、神经肿瘤学家和放射治疗师而言仍是一项挑战。手术方法仍是GBM治疗管理的基石，因为切除范围与总生存期和无进展生存期密切相关。从这个角度来看，使用光动力分子可能是实现最大程度安全切除的一个有趣工具。能够追踪病变边缘确实可以提高切除范围，并在保留正常组织的同时将残留肿瘤降至最低。由于5-氨基乙酰丙酸（5-ALA）与GBM细胞克隆的细胞密度和代谢活性密切相关，因此将其用作光动力示踪剂已得到广泛认可。
我们的研究旨在确定GBM的不同分子特征（特别是研究突变、增殖指数和MGMT启动子甲基化）是否会导致不同的荧光表达，这可能是由于不同基因型导致代谢途径不同所致。
对在我们研究所（意大利都灵大学城市健康与科学医院神经外科）接受GBM切除手术的患者进行回顾性研究。纳入组织学诊断确诊且术前给予5-ALA的患者。记录整个手术过程，然后由三名不同的人员（一名医学生、一名住院医师和一名对神经肿瘤学感兴趣且有使用5-ALA经验的资深外科医生）进行分析，并为不同程度的术中荧光评分。然后将荧光程度与基因型进行匹配。
在野生型（WT）基因型中观察到二级荧光（即“强”）趋势，表明该特定亚组的代谢活性更强，而在突变肿瘤中更常观察到无荧光或弱荧光，表明代谢活性较低。未发现荧光等级与MGMT启动子甲基化之间存在关联，有趣的是，也未发现与细胞密度有关联。作为次要分析，与其他近期文献类似，注意到突变型GBM的癫痫ogenicity更强。
我们的结果不支持将5-ALA用作诊断工具或替代分子谱分析的方法，但证实5-ALA是一种强大的代谢示踪剂，能够轻松检测病理细胞，尤其是在IDH WT基因型中，从这个角度来看，需要进一步研究以更好地描述GBM细胞的代谢活性。
