I am Costas Hadjipanais. Currently, our high-grade glioma standard of care relies on maximal safe resection. And at recurrence, repeat surg. Currently, our FDA-approved drug list for high-grade gliomas is quite small. Over multiple decades, really only six drugs and two devices have been approved. Temozolomide was approved in the late 90s. Our current paradigm really relies on maximal extent of resection of the. Most studies have really shown a patient benefit. The majority of patients do not undergo maximal extent of resection. And this is mainly due to the invasive biology of gliomas, where the infiltrated margin extends centimeters into the surrounding brain, where it is difficult to visualize this tumor for maximal resection. So there's really a large challenge in research. and the use of door navigation. We have newer technologies, which you'll hear about during this practical clinic, such as exoscopes, which... There is definitely an unmet need, though, for surgeons to really see that border well in real time and delineate it from the surrounding tissue, and this could impact how we can perform more maximal extent of resection of tumors. Fluorescence-guided surgery is a technology. tissue that can delineate that tumor tissue after being excited by a certain wavelength of light emitting a different color of light. Well, you may ask yourself, why fluoresce this guy? surrounding pathways that could be involved by the tumor, and of course, better resection of the tumor could result in better outcomes for our patients with improved overall survival. I'm just going to provide a short background of some of the other fluorescence-guided surgery agents that are being used and studied now for hydrogliomas. You can see here in this illustration just showing fluorescence emission wavelengths, and 1-fluorophore fluorescein can be seen in the visible light spectrum. and emission in the 635 nanometer. Fluorescein sodium was described in the late 40s by Dr. G.E. Moore for localization of brain tumors. It really relies on breakdown of the blood-brain barrier for accumulation of fluorescein into the tumor. It is an intravascular agent, so vessels can be imaged quite nicely with fluorescein, and the timing of administration is very important, and the effect is. Indocyanine green is the near-infrared agent we discussed that also is nonspecific and relies on blood-brain barrier disruption. Both fluorescein and indocyanine green are extracellular fluorophores, and they both are approved for ophthalmological treatment. used during ECIC bypasses, aneurysm treatment, and even AVM resection. There is interest with use of ICG in brain tumors where the accumulation of ICG can be found in brain tumors approximately 24 hours after being administered. And because of the near-infrared spectrum of the agent, better tissue We're going to focus on the 5-ALA compound for the course of this presentation. This is something that is now being used at many centers throughout the country and has been used throughout the world in a number of countries and really. Much of the work on 5A. study where in a randomized fashion. The trial was not powered for an overall survival study. There were some limitations of the study in that many patients did not undergo temozolomide chemotherapy, and there were centers that did not routinely use image guidance technology, period. However, even with these shortcomings, there was a significant The approval of 5-ALA in the U.S. and in the world has taken quite some, quite a long time. Really the first patient that was dosed with 5-ALA was in 1998. The randomized phase 3 study was completed in 2006, published in Lancet Oncology at that time and led to approval of the agent in Europe shortly thereafter in 2007. In the U.S. there was a large effort to get 5-ALA approved that took a number of years. First meeting occurred in 2011 and the initiation of the first 5-ALA IND in the U.S. occurred in 2011. Eventual 5-ALA approval occurred in However, it is being investigated for... And then there's new, there are new studies coming out now on whether 5-ALA can now be used as an intraoperative therapy agent with photodynamic therapy. There are other targeted fluorophores. No question that there's been a global rapid... In addition to the This is a publication we had several years ago just. A newer study by Dr. Witthelm from Vienna shows... Pediatric tumors are quite, are another brain tumor focus for fluorescence-guided surgery. Fortunately, there's limited data on the use of fluorescence-guided surgery in children where extended resection may have an even greater impact on outcomes in those patients. There are studies now. The combination of 5-ALA with other imaging modalities is now. Imaging with 5-ALA to perform more complete resections of GBMs. In Europe, a combination of FET-PAT imaging and 5-ALA has shown quite a benefit in patients with a greater extent of resection of high-grade gliomas. And of course, the combination of intraoperative imaging such as IMRI and fluorescence-guided surgery now is being studied at a number of different centers showing a possible benefit. There are even studies where multiple fluorophores are administered to patients. In this case, giving 5-ALA and fluorescein to the same patient may allow for better delineation of the tumor. 5-ALA is intratumoral, which fluoresces violet red. And then of course, if you give fluorescein, The heterogeneity of tumors is well-known, especially in high-grade gliomas. solid violet red fluorescence correlates with the tumor bulb. essence is visualized, despite the presence of smaller numbers of tumor cells. The intratumoral heterogeneity, as mentioned, is very well-known and probably accounted subpopulations, as well as within the tumor itself, there could be different regions. fluorescence pattern associated with tumor heterogeneity in high-grade gliomas. Lastly, I want to cover the—briefly cover One, as I mentioned, is in. Well, I'd like to just

high-grade glioma

maximal safe resection

fluorescence-guided surgery

visualization

tumor tissue

patient outcomes