I would like to welcome to the stage Professor Andras Buki from Hungary, and he's going to talk to us about biomarkers and TBI. Thank you for coming. Thank you very much. Thanks. Ladies and gentlemen, dear colleagues, dear chairman, it's a great honor to be here, so thank you very much for the opportunity. I have to talk about biomarkers in a nutshell, basically, and I would like to cover some successes and being more critical on the translational value of these research activities. And I can say that this work is a continuation of Professor Figaj's work as we are harshly criticizing the results in translational research, and it can be the summary of both folks. So, basically, what do we use biomarkers for? So we know that they are internal tools to measure the internal changes of the organism under pathological conditions and under normal conditions, and we can use them and classify them according to various reasons and goals, but we use them for diagnostic, prognostic, predictive, and so far, so on. And we basically can use biomarkers through the whole treatment at each phase of the treatment of the head-injured patient. But I will particularly highlight the issue of outcome prediction, and we're talking about developing countries where, like Hungary, where the healthcare system is in the level of Nigeria, and I'm not offending the Nigerians with that, probably. So where biomarkers can be used as adjuncts to outcome prediction and to audit of care to use them for quality control reasons. But globally, they are, for me, particularly important in aiding us to reduce the target population for randomized clinical trials, because they're a great asset to identify, to narrow down the subgroup of patients who may benefit from a particular treatment. So when we critically assess the field, we cannot deny that there are successes. We know that the Scandinavian guidelines, since five years, introduced S100 beta to the triage of mild traumatic brain injury patients. And if you are lucky enough to exactly know when you suffered your head injury, and you are lucky enough to get into the ER within six hours, then you may have a reliable S100 beta value to avoid a CT scan. Also from the track database or track records, nice studies were done and are being done, and we know that from a chairman's work, particularly, that the GFAP breakdown products are capable of discriminating patients who may have a CT positive lesion and also can discriminate patients on the basis of the number of their lesions. And further work with GFAP and UCHL1 also showed promising results, particularly in terms of the sensitivity of UCHL1 to herald CT positive lesions in patients. And with a biomarker addition to the core model of the impact calculator, we with others were able to demonstrate that, particularly with a multi-marker approach, we can significantly enhance the predictive power of the impact calculator. But if we are critical, we have to admit on the basis of the concept of Jeff Manley, I have stolen it, I'm very happy that he has not arrived yet, so I've stolen this concept from Jeff, but giving some credit to him at the bottom there, so that in cardiology the major success in this very demanding field was associated with advanced translation of research results. And we have to note that troponin, the field of biomarker research, is way ahead of what we have in neurotrauma. So when we critically assess neurotrauma and biomarkers in the field of neurotrauma, we definitely have to assess when and what marker to use and for which clinical question. And we have a very nice certification for various works, like from this work from Kevin Wang, where we know that at which phase, which biomarker should be assessed and for which subcellular compartment it is representative for. So when we make a critical step and analyze how actually researchers did in this field in the last decades, we may end up with really devastating and really disappointing results. So that's what we did under the framework of the FP7 funded center TBI trial with the lead of Stefania Mondello and with methodological aid from the Monash University, initiating a systematic review on biomarkers in the field. And the major question was, question number one, that in mild TBI, how do our markers perform in terms of basically identifying those patients who may have a CT positive lesion? And we assessed the literature, analyzed the literature, scrutinously with the head of – with the lead of Stefania Mondello. And you may say that these were two critical inclusion criteria, but I won't – I won't state that. I think these were general inclusion criteria, normal inclusion criteria, solid ones. But still, with these inclusion criteria, we were able to narrow from more than 5,000 records the scope to 26 relevant studies identified. And I think that's already a sad thing on its own. The very sad part of this, that you saw how many markers we assessed, but only S100 beta was bagged with sound studies to make conclusions relevant from the point of view of a systematic review. But when we crunched down the data and go into the details, it turns out that if we have 1,000 patients who were screened with S100 beta, more than 600 of the 770 – 717 who were positive with S100 beta, of those, more than 80 percent were basically false positives. So, basically, there was no lesion on the CT. More intriguing is probably this 4 percent where of the 283 who were S100 beta negative, four patients, basically, almost 1 percent were reaching a – were revealed to have a CT positive lesion. And you may state that it's not surgically relevant. On the contrary, we have data that this might be surgically relevant. Also, if you consider what we want to use our biomarkers, so let's assume that we use them at the playground to assess the return-to-play time, and we may say that in an athlete who may be injured very soon in the playground, we can let all the four guys go back to play because of the negative S100 beta. So, not only the surgically significant lesions can be significant in trauma, and that's very important. So, the results demonstrated that although there are absolutely positive results with other markers, they are just not there from the very scrutinous scientific point of view. And what the future comment from this, that we have to construct our studies in a different way. We have to focus on real-world clinical questions. We have to have the internationally constructed and approved reference standards. And what is very important, that it's not only in the field of neurotrauma and neuroscience, it's also in the field and relevant for the field of the performance and production of analytical performance and the laboratory standards. We also should add that the composite biomarker panels, also addressing structural damage as well as secondary pathogenetic processes, should be combined in the future, just as we did in our prognostic paper just mentioned before. And we hope that the involvement of comfort effectiveness research and the scrutinous application of common data elements, just in the INDBEER project, will lead to a result. And we are very proud to be part of this. PAGE is the center of the biomarker research, and we are now, three weeks ago we were about to collect 40 percent of the design centers. So the samples, so the number of the aliquots we have to collect at the end will be around 90,000 vials in our institution. And we really hope that the way, which is a little bit bumpy, will lead to the point of care devices and handheld devices. And there are some good signs. We saw that the FDA authorized marketing of the first blood tests in this field, although there are some questions about that. But let's say that this opened a really small door to this field. And for further information, I refer to the Lancet Neurology Comprehensive Manuscript of the INDBEER, particularly center research. So in conclusion, we know that biomarkers are important aids in this field, but we still lack a breakthrough, scientific breakthrough, despite of the promising results with S100 and beta GFEP and UCHR1. We hope that the polymarker approach and scrutinous preclinical studies should lead the way, and center TBI may open up new perspectives in this field. Thank you very much for your attention. Thanks for the invitation again. That was fantastic, Andras. I have a question. Who here is using biomarkers at home, blood-based biomarkers? Who measures S100B1? So we haven't yet seen the adoption, right? So we don't have any Scandinavian colleagues, I guess, or maybe the penetrance of the use of biomarkers is more in theory than in practice, even in Scandinavia. And I think one of the challenges is that it takes four or five hours to get the result back, and our emergency room colleagues and even the patients of a neurosurgeon isn't going to tolerate waiting four or five hours for a blood test to let us know whether to get a CAT scan, which is the current space. But I would just want to bring up one point and then get your feedback on this. If you look at the history of troponin for chest pain, the original FDA approval for that is not the modern application of the use of troponin. But once the biomarker was approved and it could be sold, then it was used in alternative ways that manifests itself in the modern use of troponin, which is you get an EKG and you get a blood test, and then you start making treatment decisions. So do you expect the use of these things outside of the context of their current approval? The approval is to get it to decide whether to get a CAT scan. But do you foresee, even though that's not the way you would use it, do you foresee measuring these things in your patients in the ICU? It's a very complex question, because first, and also to the second, as an international meeting, we have to appreciate that in some country the CT is very cheap. So in Hungary, a CT scan can be done for 25 US dollars in our department, while making a running an S100 beta test, at least, as you said, on the best circumstances, it takes four hours, and it costs about, let's say, 100 euro at least to do that, which is totally different than making the CT scan. I think that the real breakthrough, as you said, will be the off-label application. As the more and more clinical data will come with a more liberal use of the biomarkers, you obviously will not only use and compare your results with the CT scan, we will compare with the MR. And that's what I also want to comment on, the personalized use of advanced imaging in those institutions where it's available should be part of the protocol, particularly if there is any question about the imaging, I mean, about the monitoring results. So basically, putting together with the MR, putting together with outcome data, I think that the robustness of the biomarker data will get there to stratify this issue more clearly. Franco, you've been traveling the world these last few years. Do you have your finger on the pulse of where we stand? Are we ready for a biomarker to come into use where we can start figuring this out, or do you think that we're still quite a ways away from that? Second, we are quite a ways away from that. At the moment, it is, I think, important to research, and in perspective, what you say by yourself, the cost of a CT scan, and even a 4 percent pulse negative is unacceptable. In a mild and injury patient, where the alternative is a CT scan, how can we justify that we missed the surgical outcome until we arrive at the point in which we can use, for instance, biomarkers to predict the evolution of the CT scan, not the first CT scan. Sometimes we are predicting a CT scan. This is costly, takes time, and a lot of variation. If we can avoid repeating CT scans, for instance, in contusions, and instead rely upon biomarkers, this would be the right thing to do. So maybe not the first CT scan, but the subsequent CT scans. And I'm not sure what Jeff Manley, who has texted me that he has in fact landed, so he will in fact make it, I'm not sure what he's going to show, but I can tell you that we have data hot off the presses from the TRACK-TBI study where we think that there is a threshold of GFAP above which the mortality is almost certainly 100 percent. And so what would you say to a biomarker that gave you that kind of information? I think it's very important. It's very important, and as handheld devices will be more common, the data will be more robust to come up with that. It's like, you know, we will not deny treatment, but we will definitely guide your treatment intensity and your communication. So I think anything where biomarkers can add an exact and straightforward information on the top of the multimodality monitoring and clinical information would be very important and very welcome. I just want to add a couple of points about the product that was approved by the FDA on February the 14th of this year, and that's a kit that detects GFAP and the UHCL1. It's been noted, but this was largely funded, as you realize, by the Department of Defense. And I think the thought there is that in extremely austere environments, such as a combat zone where you may not be able to evacuate a patient for four hours, five hours, a patient has a concussion, you'd like to know the likelihood of that patient having a positive CT and thus committing resources to get them to the next level of care. I think that's what the military was sort of aiming at when they developed this. The fear, though, is once it's approved by the FDA, I am terribly afraid that the emergency rooms in the United States are going to order the test and get the head CT at the same time. And it's just going to increase our health care costs, which are ridiculous as it is. So I just want to add that caution that in very austere environments may be useful right from the get-go, but I think in your individual institutions, a little homework assignment for everybody here, go back and find out, does your institution, is this on their radar? Are they thinking about doing it? And it's the ER doctors that are going to be controlling this, and I think the neurosurgeons should really have some input. That's important. Any other questions? Thank you. Thank you, Andres. Then... APPLAUSE

biomarkers

traumatic brain injury

diagnosis

predictive power

clinical trials