In Reply: Novel Urokinase-Type Plasminogen Activator Receptor-Targeting Optical Imaging Agent ICG-Glu-Glu-AE105 for Visualization of Malignant Glioma During Surgery: First-in-Human Study in 35 Patients With Brain Cancer

To the Editor: We thank the author of the “Letter: Novel Urokinase-Type Plasminogen Activator Receptor-Targeting Optical Imaging Agent ICG-Glu-Glu-AE105 for Visualization of Malignant Glioma During Surgery: Firstin-Human Study in 35 Patients with Brain Cancer”1 for their interest in our publication.2 The author addresses some of the strengths of our study and we thank them for their acknowledgement hereof, and also raises some questions to be further enlightened. We are aware that some issues could have been discussed in more detail, but the limited space available meant that prioritization was necessary. In the question of resection of tumor in eloquent areas, the authors raise a fundamental question. It is well known that tumor may grow in eloquent areas and fluorescence is NOT restricted to noneloquent areas and this limitation also holds true for both 5-ALA and intraoperative MRI scan that are comparable tools for visualization during surgery for complete resection. Balancing the resection, the so-called oncofunctional balance3,4 to do no harm is the other approach that needs attention. To aid in this delicate intraoperative decision-making process, intraoperative mapping should be contemplated in both asleep and awake settings, considering tumor location and patient selection. Said that we agree that resection of tissue not harboring tumor cells due to false positivity is of great importance, and false negative tissue is of concern. We did, however, find a high positive predictive value2 supporting the safety profile, at the expense of performing a noncomplete resection. Again, balancing the extent of resection is the art of the neurosurgeon never to be underestimated and careful patient and method selection is as always important. Although uPAR is also expressed by activated immune cells, its levels under normal physiological conditions are low and is only transient expressed at high levels in the process of inflammation,5 eg, microglia. In addition, our immunohistochemistry data demonstrated that this does not mislead the delineation of the tumor. The value of uPAR as a marker is underscored by its involvement in multiple functional roles related to tumor progression, including tumor proliferation, metastasis, and angiogenesis and that the expression is highly prognostic, including in glioma cells.6 Regarding induction of immune response by FG00, we have not observed this after a single dose of FG001 and do not have data from patients who have received multiple doses. So to conclude from our study, we believe FG0001 could a surgical aid for excision of human gliomas that is safe and reliable.