## 4 Discussion  
Fluorescence-guided resection is a new field, first introduced in surgery for malignant gliomas and now in widespread use. In the context of malignant gliomas, visible residual 5-ALA-induced fluorescence identifies residual tumor, which may lead to more complete resections, as demonstrated in a prospectively randomized phase 3 study [3]. Surgical microscopes adapted for detecting fluorescence are widely available (Zeiss Meditech Blue400, Leica FL400). The range of available devices has recently been expanded by a lovet-based system (DVI Reveal), which has been validated as achieving the same diagnostic performance as the established microscopes [15]. Given regulatory approval for 5-ALA by the European Medicines Agency in 2007, followed by FDA approval in 2017 [16], 5-ALA, which is marketed as Gliolan in the EU and Gleolan(tm) in the US, there has been considerable interest in extending FGR to other brain tumor types. Among these, based on the literature, meningiomas may be a promising candidate [5; 6; 7; 8; 9; 10]. Apart from brain tumors, efforts are underway to extend FGR to other organ systems as well, not only using 5-ALA [17; 18; 19; 20], but also other fluorochromes, and study designs resulting in regulatory approval are being intensely discussed [21]. Any newly introduced agents or applications of available agents for intraoperative tumor imaging will have to be tested for toxicological safety and will require demonstrations of diagnostic accuracy and clinical usefulness. Such usefulness will be assumed when the agent helps to identify residual tumor in diseases where the extent of resection is accepted to be linked to patient outcomes but will not have to be linked to changes in outcome, i.e., longer survival or progression-free survival. On the other hand, simply showing that tumor is visualized by a fluorochrome, for example, will not be sufficient [14]. Prior to the present study, we have discussed several study designs for demonstrating the clinical usefulness of 5-ALA FGR in the treatment of meningiomas. Theoretically, usefulness could be linked to improvements in overall survival or progression-free survival as endpoints for a randomized study. In the context of meningioma, progression-free survival (PPS) is beyond 10 years [22], depending on degree of resection and tumor grade, so that PFS as endpoint would not allow a study to be completed in a meaningful period of time. A different approach may be a linkage of study endpoints to the completeness of resection with early post-operative MRI. However, even from very early studies [23], it is well accepted that there are differences in PFS that are related to whether the bulk tumor is removed with underlying dura and bone (Simpson Grade I), the dura is merely coagulated (Simpson II), or the tumor is removed without the dura being coagulated (Simpson III). It would be exceedingly difficult to objectively differentiate between Simpson Grades I to III resections on the basis of early post-operative MRI. Furthermore, in many complex meningioma cases, tumors are not completely removed if neurovascular structures are endangered, without cytoreductive surgery being viewed as being futile. Designing a study to demonstrate diagnostic accuracy in an unbiased fashion is highly challenging since surgeons cannot be \"blinded\" to an intra-operative imaging method. Even the most complex design for such a study that can be envisaged is not free from possible biases. Such a study could be randomized and placebo-controlled, with surgeons being blinded to study group allocation. Surgeons would first operate under white light. After declaring the end of resection under white light, surgeons would change to the fluorescence mode for detecting residual fluorescence, which is subsequentially addressed by resection of or biopsies from fluorescing tissue. A possible endpoint for this study would be the incidence of residual tumor detected under blue light.