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Neurosurgical Innovation in the Academic Ecosystem

Alexander Khalessi

May 31, 2021

Transcript

- Colleagues and friends, thank you for joining us for another session on the virtual half of the Neurosurgical Atlas. My name is Erin Cohen. Our guest today is Dr. Alex Colossi from UC San Diego. He's the chairman of neurosurgery there. He's also one of the members of the executive committee of the Congress of neurological surgeons. In addition, he's one of the members of board of governors, of the American College of Surgeons. And finally, and I'm sure the only one, is, he's the vice chairman of the Stru Consortium for the UC system, UC California system, in that state. He will be a chairman there in a coupla years, he's truly being, really a unique innovator in many ways, really a strong academician and a superb colleague and I'm so honored to have him with us today. He will talk to us about an extremely important topic, which is neurosurgical innovation in the academic arena. Alex, cannot thank you enough. Very excited to listen and learn from you, please go ahead.

- Well, thank you very much, Erin, for the generous invitation and introduction and congratulations on what's been, really a tremendous platform for our specialty. I've planned an ambitious hour for us together, to really provide the best perspective I can, on the opportunities we have as practicing surgeons to innovate and to highlight some specific infrastructure, I believe to be required, to move our specialty forward in a systematic way. I can't have any conversation around innovation without acknowledging the distinguished group of partners that really have allowed me the flexibility to think in broad ways about these issues. And as you'll see through some of my slides, were really great role models for innovation within their respective subspecialties. It's my strong feeling that as a specialty, we really are, in what I would consider an Apollo moment, for neurosurgery. In 2019, it was the 50th anniversary of the moon landing and I believe there are many object lessons for our specialty, as we contemplate that bicentennial. I would note that as a specialty over the course of the next hour together, I'm going to basically outline six major opportunities, I think that we have, to innovate. I'll start in general terms, thinking about how as surgeons, we make scientific progress. It happens that as both an open cranial and endovascular surgeon, I've had a front row seat, to some of the material science advancements in endovascular technology specifically. And so I think there's some object lessons, I think that could apply across surgery. And then as you mentioned in my role here at UC San Diego, I have a responsibility to think about, from a system standpoint, what are the necessary and sufficient conditions for surgical innovation. And then over the course of the last 15 years, as you can imagine, as a vascular specialist, I'll share my personal journey through its five neurovascular conditions that we'll walk through, I think some of the practical elements of introducing new technology into your practice, and then we'll conclude with two sections. One of which demonstrates how these areas and opportunities apply outside of vascular neurosurgery and then talk a little bit about where the future of our specialty lies in terms of mentorship and the next generation of surgeons. And so I'm fond of saying, that in William Holstead's time, who's inset here on the upper left, that you had to have a real command of anatomy to, for example, take out your mother's gallbladder with a candle and a kitchen spoon. And so when we think about how surgery's moved forward, it really has been due to procedural advances involving iteration in devices, imaging and visualization and operative technique. We also as surgeons are obviously the best first observers of physiology and natural history and there's important lessons that we can draw from that. And then there's this whole third mature area of inquiry around health services research, And that is once you know the right thing to do in the care of a given patient, how do you make sure that you actually get that mark, every single time? And lastly, that leads into developing highly reliable systems, systems engineering processes of care and surgical training. And I'm fond of saying, that our skull-based program with Rick Friedman and Mark Schwartz are great exemplars of that high fidelity system. And so if you have the ambition to innovate or leave a specialty better than you found it, it's very important, I think, to look at the lessons from history. And so Charlie Drake, in my view, was a tremendous innovator in the treatment of basilar tip aneurysms. At that time, that disease carried a very unforgiving natural history and 85% mortality rate with a two year rupture rate greater than 40%. And so it was very important, I think, to think about the physiology of that disease and way stop, potentially interrupt that natural history. And he made that fundamental observation. And I think that when we look at that disease entity, we see how there's been this massive advancement in device iteration and practice adoption. And when we think about commodity devices versus transformative devices, it's very helpful to use the Drake model, because transformative devices allow us to treat conditions, I mean, we weren't previously able to, and what I hope to show as we walk through our endovascular journey, is that we've reached, essentially the technical limits, of what we can achieve, with material science alone and so we now are running into barriers around Biology, Rheology and Pharmacology. And any talk about innovation really requires a discipline on the part of the surgeon to have a meticulous scrutiny of complications. Because it's really when we achieve our technical goals, but are unable to alter the natural history and let the real opportunities to innovate by. And so, I'm fond of showing this inset image, this is the first patient that Drake treated, with a Giant Basiliar Aneurysm. This is an Angiogram by Alcock and a rendering by Drake of that aneurysm. And the patient underwent an awake Hunterian Ligation, a clip in the mid basil segment with the verts, picking up the SEA and the AIKAs, and relying on flow from the PCOMS to pick up the PCA and you can see no residual filling of that aneurysm. That same aneurysm today is very straightforward, for an interventionalist to treat with standalone coiling or with adjuncts. Similarly, skull-based aneurysms in the cavernous segment, the chronic cave, or the Optomix segment used to be a test of a vascular surgeons metal. But initially with a coil and stent coiling techniques, and then ultimately, with the advent of flow diverters, these cases have become routine. The flow diversion story, in my view, is a particularly interesting one because I was admittedly a slow adopter on flow diversion. In no small part, because I felt that there was a challenge in permanently surrendering endovascular access to an aneurysm and committing that much hardware to the parent artery. And so when there was this advent of a flow diversion for aneurysms, that in my view, had a forgiving natural history like cavernous aneurysms, I didn't rush to introduce those things into my practice. This case, however, I think demonstrated the opportunity that comes with flow diversion. This was a patient who was going progressively blind, where a well-intentioned interventionalist, serially coiled this aneurysm. You can actually see here, the enterprise stent that had actually been placed in a well intentioned way to allow for some flow diversion, this obviously was not successful in this particular case. And we actually used a balloon to go through and through, to make sure we were in the true limit of that enterprise stent and a telescoped in an off-label way of flow diversion because of the previous stent. And the reason I show this case, you can actually see the very nice stasis in the aneurysm after that flow diversion procedure. Is the goal of this procedure was actually to protect the patient from a hemorrhage. What we didn't anticipate, is the patient's vision, dramatically improved from light perception in the right eye and 2,400 in the left side to 2030 and 2040 with the loss of that pulsatile insult to the optic chiasm. And so this was a physiologic insight that came in a serendipitous way, from an application of this technology. Similarly, I'm fond of calling the low-profile two millimeter self-expanding stents, the Elvis junior and the Atlas as an endovascular Sonic boom, because the protection of a two millimeter artery, really was a barrier in terms of definitively treating from a technical standpoint, aneurysms arising from small parent arteries. This is just an example of a patient who was one of the early Elvis Junior cases. You can actually see this a fusiform P1, P2 segment aneurysm, and you can see that the reliable visualization, self-expansion of this aneurysm, excuse me, of this stent, really allowed for definitive treatment of this aneurysm in a difficult to access surgical location. It's important, however, when we think about these two millimeter stents, excuse me, that we don't just apply them in a way that neglects the fact that there is an exploratory component to open surgery and so this case really makes that point. A 61 year old patient with a refractory jaw pain, serial tooth extractions by well-meaning dentist. And the source was actually this wide neck pike aneurysm. And so this is what the operative view was , from a CP angle approach. We determined that surgical decompression of her ninth and 10th nerve was the best option. We could have incorrectly applied the lessons from that flow diversion case and thought of stent coiling with an Elvis Junior, would achieve the same result by removing the pulse talon salt on the ninth cranial nerve. We would've missed, however, the fact that, this lower nerve root, was also badly compressed by an entatic V4 segment, you can see the brain stem and the depth here. And so you had CD instead of Magellan there, I do think it's very important for us to not neglect the fact that open surgery provides a defended visualization that you don't necessarily achieve with endovascular techniques. Similarly, there were times where the diagnosis is in doubt and so this was a 68 year old gentleman who presented with a rapid and progressive cognitive decline from a significant phellamic edema here. One of my interventional partners, astutely shot an angiogram and identified this tentorial based fistula. This is a non-trivial thing for the non-interventionalists to calf this festival, he was successful in doing that, but recognized this was not a safe embolization position due to the potential for reflux into the internal carotid. And so we took this patient to the operating room and from a sitting position, identified the fistula and was able to ligate it. I show this case because this is an example of flow through the operative microscope. And this is in my view, another transformative technology, because while we have a very low threshold for intraoperative catheter angiography here at UC San Diego, performing a catheter angiogram from the sitting position is a bit of a technical challenge. And so this provided an opportunity to make sure that we left the operating room, knowing that we had definitively treated this patient's problem. We then did a definitive post-operative angiogram demonstrating no residual fistula. I had mentioned in my introductory comments, how important it is, that we are meticulous and rigorous in scrutinizing our complications. And so, there are times where, when we stray from our strategic principles, there's no amount of technology that will save you. And so this is a 51 year old who had, what in my view, remains the most challenging aneurysm for us to treat, which is a fusiform M1 segment aneurysm involving lenticulostriates. The standard treatment here should be a bypass and clip sacrifices as this patient had. However, there are times where the lure of technology can lead you to talk yourself out of a potential intervention. And so this was a 75 year old with a known progressive giant aneurysm, who came in with Progressive Aphasia and Hemiparesis, it was unclear whether this was from Ischemia or if it was from Mass Effect. And so, because of our success with flow diversion, we actually telescoped serial pipelines. You can actually see the result here, and we're very happy with the stasis and the aneurysm. Of course, on postoperative day one, this construct promptly thrombosed and the patient required an emergent, a resection of that aneurysm that we were actually able to resect on block. And we then put it in a prostate slicer and relied on our phenomenal Humana-pathologist to help us learn that mechanism of thrombosis. And it became clear to us that the acute plate ruler response implies that there is almost certainly a certain length of construct where the diameter is not sufficient to maintain flow. And this definitely clotted essentially from the outside in, as demonstrated by these graphs. And so what this picture shows and a terrific review by G. Thomas, is really we are living in a golden age of material science and with nitinol and braiding technology, we were able to fashion all manner of devices for intrasaccular or parent vessel applications. So there is no longer a question of whether we can engineer a reliable device. And so now the question remains is why hasn't this intrasaccular device of revolution eliminated the need for open surgery? And the answer is, when you actually have an aggregation of material at the neck of an aneurysm, it hasn't obviated the need for dual antiplatelet therapy. The goal of intrasaccular devices was always to eliminate the need for antiplatelet therapy, and to allow their broad application in ruptured aneurysms, for example. And so it's clear when we think about what's next in endovascular technology, it's going to rely on a better command and understanding of Rheology, Pharmacology, and even the potential for bioabsorbable or non-permanent implants that will not necessitate the need for a long-term anti-platelet therapy. And so that's a cycle of evolution that happens over, five to ten years, as opposed to the two to three year cycle of innovation that comes with new devices. And so now to take a step back, when we think about what are the necessary and sufficient conditions to innovate, we require as Drake did, a competing natural history that's unforgiving, full availability of standard of care alternatives, you shouldn't be flow diverting aneurysms that can be easily coiled, for example, and an unmet clinical need, the transformational devices allow you to treat something that wasn't treated before. And the sufficient conditions really provide an eye to the FDA and regulatory processes that allow you to make sure these technologies are available to patients. They'll need health system, innovative care policies that will allow you to support first inpatient, sort of procedures. And then obviously need access to still biomedical engineers that'll help you iterate in terms of device design and applications. And we've been fortunate here at UC San Diego to be involved in the FDA regulatory process of every major interventional device in the last decade, and more importantly and then taking the additional health services research step to make sure that the introduction of that technology, for example, flow diversion can be cost-effective. And those efforts then ultimately will allow you to inform national guidelines in the neurovascular space and other areas of neurosurgery, and to involve your nursing tech or surgical partners, to make sure that you develop highly reliable systems of care as we were able to do in these ischemic stroke space. So I'd like to pivot now, to one of my role models in innovation, Thomas Edison, who was fond of saying that he's never failed, he's only found 10,000 ways that that haven't worked and so part of the spirit of innovation is recognizing quickly an unsuccessful strategy and moving on. And so I thought there were a lot of practice adoption object lessons that come, in the five Cerebrovascular conditions that have defined my own personal career to date. And when I think about one of the most Ischemic changes that's taking place in medical care in my career date, it's really that we're living in, what I'm fond of saying, is the penicillin era of Ischemic stroke and the promise of thrombectomy for stroke was always, as depicted on this slide, that you're able to open an artery that's essentially depriving the blood, half the brain. And if you could do that in a high fidelity way, you're saving a patient's hemisphere. And the opportunity was really the recognition that the systemic use of IV rt-PA had a progressively poor revascularization rate, as you were more proximal in the super vasculature. So the better technical endovascular target, was the worst systemic target. So that's an opportunity for obviously complimentary application of endovascular and IV rt-PA. And this is I think, in my view, one of the most important lessons when it comes to innovation, in the sense that, it was really the defining moment in the end of vascular treatment of ischemic stroke, was actually a negative clinical trial and that was the IMS III trial, because this was the first trial that essentially demonstrated that if you achieved a TICI 2b or TICI 3 results, which on an angiogram means that you got at least half the distal distribution open or the entire distribution open for an occlusive vessel, then more than half of those patients actually were modified ranking zero to two, meaning they were functionally independent at three months for a disease large vessels occlusion for stroke that had a much less forgiving natural history than that. And so for the first time interventionalists realized how good do we have to be in the angio suite, to get a patient a clinical benefit. And it gave us a good technical target. The reason IMS III was not a successful trial, was because we didn't actually select the correct patients with a confirmed large vessel occlusion with preoperative angiograms or CT angiograms, excuse me. And we didn't get the artery open high enough percentage of the time. But now that we actually had a technical target to drive for, we were able to actually borrow from the cardiology literature and recognize that stents were very good at solving the technical problem with opening blood vessels. And so Stent retrievers were predicated on keeping the best elements of sense, but not committing the patient to permanent intracranial hardware. And so not surprisingly, the first stent retriever trials actually demonstrated that we were able to achieve that modified ranking of zero to two greater than 50% of the time, with a comparable mortality and an acceptable symptomatic ICH rate. And that advanced work at that time, a contemporary case, really allowed for the development and treatment of stroke systems. And what you see on these slides, where that avalanche of trials that came in 2015, that essentially demonstrated that the number needed for independence, the number needed to treat was between three and four. Which really was comparable to the use of penicillin for infection. And so that rational progression of inquiry that led something that was exceptional and miraculous, meaning thrombectomy for ischemic stroke to become routine in such a short period of time, really, I think, is a great story of innovation. Similarly, once we actually achieve a benefit, it's critically important to understand the biological implications of our intervention. And so I'm grateful for my partners Shi Chen, Dai Teng and Albert Chao in Radiology, who've really helped us cycle that way. And as an interventionalist, there's a temptation to think about the super vasculature as plumbing, but as this slide demonstrates, the endothelium is a very dynamic biological system, which toggles between static and laminar flow and what was interesting, and this is definitely applied to other disease states like flow diversion for aneurysms, is, there is clearly, as inset on this slide, a use it or lose it phenomenon, that if you look at the bottom series of panels, under disturbed or oscillatory flow, you can see the progressive loss of tight junctions and leakiness of the blood brain barrier among endothelial cells. Whereas under organized or pulsatile flow, those tight junctions persist. Similarly, if you have an endothelial injury, let's say during a thrombectomy procedure, and you have persistent disturbed flow, as in the lower set of images, you don't see endothelial migration and healing across that injury. Whereas under pulsatile flow, you can see in 24 hours, in the middle panel here on the right, excuse me, the middle row on the far right panel, you actually can see very nice endothelialization. And so we actually developed a system that essentially characterized, the three-dimensional pattern of injury across an artificial blood vessel. We then had a poor sign model that essentially validated this model, you can see on the cross-sectional images here, and you can actually see, this is for example, a TREVO in a three-and-a-half millimeter vessel. Next slide please, and then in a canine model demonstrated with a balloon occlusion in the MCA, that you are able to actually change the overall stroke volume as a function of the amount of endothelial injury. So how traumatic you are in disrupting the endothelium, the vessel, does have implications for the end organ. We then demonstrated in human patients, these are three T-MRI images in human stroke patients that we can identify those areas where endothelial injury had taken place from instrumentation. And so when we talk about innovation, what ultimately matters is, does it reach patients? And so, this progression of inquiry, from an artificial vessel model and 3D patterns of injury, all the way through animal validation of that pattern of injury and looking at a human stroke patient, really allowed us to inform our industry partners of how they could actually improve their device design. And so that led for the TREVO, which was originally tapered and machined from a tube, to develop a more open flare design. Similarly, we used to dramatically oversize these devices, but the lead stent retriever at that time, the Solitaire by Medtronic, intermediate sizes were developed in order to actually limit the amount of endothelial injury. And so we clearly were able to inform the design of the devices that go into patients now. And so similarly, we are now translating that work to the treatment of aneurysms. And you can actually see here, in a parallel plate model, that we were able to actually use tracers to understand the flow in a half dome model. And that actually has led to better understanding under pulsatile flow conditions, on what the flow conditions are in these aneurysms. And that leads to significant biological implications for these lesions. Because as we look at these more complex flow patterns in aneurysms, you can actually see, we were able to develop confluent layers of endothelium in these cells. And so after two days of pulsatile flow on the right inset, you actually see an ulcer develop in the endothelium, as outlined here. And so that ulcer could become an excrescence or a rupture point in an in vivo example. And so this is just an inset that highlights that point. Similarly, we saw differences between the inflow and outflow track of these aneurysms, and you see, interestingly, the area of vulnerability or progression of aneurysms tends to occur at the outflow track because that's the area where the stress response leads tend endothelial cell loss. And interestingly, like in the previous set of examples, what you see here is a flow simulation on the left and the MRI Flow imaging of our model on the right. And so we were able to validate this using our current MRI Diagnostic techniques in practice. And so you can just see this, this is just a different angle demonstrating that same point. And so the obvious implication for this, is we can then titrate the porosity of different flow diverters, to better understand, how we can actually improve and harness the Biology of flow. And so this is, we can imagine, we can take from, this is from the of a patient, and` plan the complex flow patterns here and select our devices to make sure that, for example, we protect the outflow track of this ACOM aneurysm, on the right side. So as I hope I've shown in the kind of sequence of ischemic stroke and the treatment of aneurysms, that our progressive understanding of the Biology of these lesions can actually inform further treatment. But as I turn now, to what I think, is in my view, kind of the next frontier in cerebrovascular care or what is essentially the ischemic stroke of the current time. It really is spontaneous basal ganglia hemorrhage and the potential surgical management of that lesion. And the reason I say that is because MISTIE III, in my view, is really the opportunity that IMS III presented for ischemic stroke. In the sense that in the MISTIE III results, we actually found that there was signal, in terms of functional independence, meaning ending up in these light blue, blue, or yellow bars, if we were able to achieve a certain technical target in terms of ICH evacuation. Unfortunately the MISTIE III procedure, meaning the introduction of a catheter in the parenchymal administration of Ib tPA or intraparenchymal tPA, excuse me, didn't achieve that volumetrical high enough percentage of the time. But what we did find, and you'll see in the left inset there, that if you were able to get a volumetrically to less than 10 CCS of residual clot, or between 10 and 20, there was a very strong signal in terms of the potential for functional independence and the direct evacuation of that clot, as opposed to indirect ICP management, led to substantial reductions in length of stay and overall cost. And so that, in conjunction with a similar procedure, in the clear trial, which looked at intraventricular hemorrhage evacuation, demonstrated an opportunity to innovate. And so this was the first case in a patient done using, at the time it was called the Apollo and is now called the Artemis by Penumbra. This was a 53 year old patient, who'd actually come in with this devastating intraparenchymal hemorrhage and through what is now commonplace, a super orbital eyebrow incision, in the direction of a sheath along the long axis of a clot, you can actually see the controlled evacuation of this clot and what's required of the surgeon, as you see in terms of the inset movements on the right, very modest hand movements and this is a very controlled process to progressively evacuate this clot. You can see that the collapse of the contused surrounding brain tissue and very good visualization. About 25% of the time, there is an arterial bleeding source, that you have to manage, that likely explains the roughly 25% bleeding rate, we actually saw in other cases. And we can go ahead and move to the next slide, and you can actually see this is that patient. So as opposed to being in the ICU for two weeks, intubated, maybe with a trach and a bolt, this is him on the floor postoperative day two. And we put in EBDs at that time, because we didn't necessarily know, what the perioperative management should look like, that's no longer necessary or the case so this is his immediate postop scan. We obviously can't undo the primary insult to his brain and so he did have a left sided hemiparesis but otherwise was able to make a good recovery. And so that led to a series of cases, that really demonstrated there may be value to this potential approach. And it was really that MISTIE III trial, which really provided us substantial insights into the optimal trajectory and the potential evacuation of these clots. And so I'm fond of saying, the MISTIE III essentially helped us. We lost the battle but it helped us win the war, Even though there was a failure of the primary endpoint, it really demonstrated on what our technical targets should be and provided a lot of surgical pearls for the Endoscopic Evacuation of ICH. More than that, there was a real interest in the Biology, the disease and the demonstration in a very elegant way by the investigators. Why was that 15 CC threshold so important? And what these slides essentially show, is there was a dramatic reduction, particularly in this lower right slide. You can actually see, the peri-lesional edema reduction was dramatically different if you were able to get under 15 CCs. And so, that essentially demonstrated, that you got, essentially an additional 8 CCs, of volumetric benefit of the surrounding tissue by removing enough clot burden that there wasn't that direct team hematotoxic effect. And so that is our second condition and our third condition, in my view, really outlined what was kind of like a commonplace, of physiologic observation, that I remember very well from my training. And that is that chronic subdural hematomas essentially recur, because of neovascularization of those membranes and bleeding of those leaky valley vessels into that potential space. And so, very similar to the story around flow diversion, the idea of middle meningeal artery embolization for these lesions seemed somewhat farfetched to me initially. And what allowed me to introduce this into my practice was really the fact that there were certain patients who weren't candidates for borehole or surgical evacuation because of their need for anticoagulants or the fact that they had another bleeding diathesis. And so that's what pushed me for the first time to consider selective embolization of the middle of a meningeal artery. And as this right image demonstrates, I was surprised at the very exuberant angiographic blush you can actually see from these membranes. And so that provided a very attractive technical target as demonstrated on these slides. And so, we use in our practice, serial DMSL, and then chase that with a permanent embolic, as opposed to the initial cases that were described by PVA and we use Onyx. And so that membrane ends up marinating in a chemical sclerosing with the MSO. And you can actually see, we have very good involution of those subdural hematomas over time. And so this is a situation, where again, a physiologic observation informed a treatment that we didn't actually have a very satisfying technical treatment for. And so there are two ongoing trials now, one of which, by way of disclosure, I'm a member of the steering committee of the embolize trial for Medtronic. That essentially is, I think going to answer this question as either an adjunct or standalone to surgery, excuse me, or as a standalone therapy. Another area where I think there's been a huge opportunity to leverage observations around physiology, is in the treatment of carotid stenosis. If we could start the video. The gold standard treatment for Carotid disease has always been an endarterectomy as shown here, but because the treatment of carotid disease is essentially, a collision of different specialties, in general terms, the criteria for designating someone symptomatic versus asymptomatic has always centered around the presence of a referable neurologic deficit without a consideration of systemic blood pressure. In addition, many patients are taking to surgery or to intervention with really only an image of the cervical carotid and no consideration given to the intercranial collateral circulation. And so it was always my feeling that was a missed opportunity in assessing either the existing literature for both symptomatic or asymptomatic disease. Next slide please. And so our group essentially recognized that if you had what A-class criteria would be asymptomatic disease, that by definition, there was collateral flow, that was actually responsible for providing blood flow to that compromised hemisphere. And we further recognized there was anecdotal evidence, the carotid artery stenting in a subset of patients actually had a durable anti-hypertensive benefit. And so if we put those two observations together, there's an opportunity to innovate. And so by definition, the collateral circulation would exist in one of two ways, either in the top set of panels through either the ACOM or PCOM, low resistance Circle of Willis collaterals or through high resistance pial collaterals, as seen here with the PCA back filling the ACA on the left and the MCA on the right through high resistance pial collaterals. And so we looked at 74 patients in our practice who essentially either had a competent or incompetent circle of Willis. And unsurprisingly, the patients who had high resistance pial collaterals that were responsible for protecting their hemisphere, had a dramatic durable improvement in their mean arterial pressure after intervention. And most interestingly, we were able to find that a pre-procedural mean arterial pressure of greater than 96, was actually quite predictive of not having a competent circle of Willis. And so this argued for the idea of when you're selecting patients for carotid revascularization, you really shouldn't be thinking about just a referable, a neurologic deficit, you should also be thinking about the mean arterial pressure and in patients who actually don't have a competent circle of Willis, that would be a strong argument for carotid intervention in an effort to treat their secondary hypertension. And this is obviously the forerunner of an existing trial through stroke net, of which I'm a CIPI the crest age trial. That doesn't however, eliminate the need for being judicious in applying our technical lessons to surgery. And so you can actually see here, this is a patient who had a highly mobile, in the lower right picture, tear drop plaque and we were able to remove that in an unblock way. Next slide please. And so how do we bring this all together? I've walked you through four conditions. And in my view, as a dual trained vascular surgeon, I've always felt the most satisfying way to bring that all together, is around the treatment of ABMS. And so we in our practice recognize that as you progressively embolize ABMS, they become more and more dangerous, in terms of the potential loss of outflow. And so, I've done our combined final stages of ABM immobilization and resection in tandem. And so this is just, a kind of three cases, that bring together what I believe, is the continued artisanship in our specialty and leveraging these engineering advances. And so this was a 32 year old who came in with this ruptured ABM. And what was interesting, this was the initial angiogram, we sometimes, in the setting of a rupture, we'll wait and manage these in delayed way, but the reason this case is selected, is you can actually see, due to the extrinsic compression of the clot, there's stasis in the venous outflow here, just on the diagnostic angiogram. And so in our experience of venous outflow obstruction, is a harbinger of potential re-rupture. And so we very quickly, embolize two branches from the MCA and then took the patient immediately to surgery. And you can actually see these inset red triangle and a green circle, you'll see in the surgical video. And if we can start the video. And so what you actually see here is the embolic state, which is a good, critical boundary as an entry point, you immediately can see the MCA feeder here, which we were able to take. And once we taken that MCA feeder, we then turned our attention immediately to the evacuation of the clot. So you can actually see the clot evacuation here and then right on cue the identification to the PCA feeder. And we're able to take that and remove the AVM, and then once we've disconnected the AVM, we remove the deflated Venous Varix as well, with the exposure all the way to the faults and ICG essentially confirms our resection. Next slide please. And this is just the post procedure. Similarly, this is a 20 year old, who had an intervention through a hemorrhage due to this complex cradle AVM. Patient actually had a posterior cerebral artery and interior cerebral artery supply. We were able to embolize from both the PCA and the ACA distribution as actually shown here. This is the PCA embolization from two different catheter positions. And then this, in my view, case is being shown, because it really shows, that the advances that we've made, aren't just in the angio suite, they are also in the operating room. And leveraging, navigation, visualization and illumination at depth to really allow us in a controlled way, to take these cases on. And so this is an inner hemispheric contralateral approach, you can actually see the initial mobilization of a draining vein, the division of the faults here and then we'll be looking at the exposed mesial surface of the left hemisphere and the ABM will actually come into view. You can actually see the arterialized Venus Varix here and the embolic state from our previous embolization, and we opening the faults a little bit further and then begin our core discectomy to get a good gliotic plane around the ABM. And what's attractive about this contralateral approach is there are sometimes residual choroidal fears that you can extend into the potential space of the ventricle. And so what's attractive about this is we're looking along the long access to the ventricle, to make sure that we maintain control, then work around our embolic state from our ACA embolization procedure, divide that and divide the PCA embolic state and then all that's left is essentially this now bluish draining vein, which we're able to divide and cut, one last feeder that we have to disconnect there and then we're left with a very nice clean resection cavity. Next slide please. And this is just the post angiogram demonstrating the absence of residual. And then lastly, one of the real advantages in patients with complex Anglia architecture of combining, these different modalities is you're really able to parse a sympathetic draining venous drainage from involved nital AVM. And this case really makes that point. And so this was a very complex pradel ABM here, you can start the video, and what, just to orient you on the right side of the strain is anterior and so we begin posteriorly to identify these residual MCA branches along the sulcus and our initial subarachnoid dissection is really designed to demarcate the boundaries of the ABM and to spare the surrounding tissue. And so what you actually see here, is anteriorly a lot of these vessels are vessels that are not involved in the AVM. And so you need to do that microdissection to separate those things out, and then you're able to actually develop, see this is peninsula around the ABM and preserve those things. And we now actually see the blue of the vein we want to preserve, and then we can continue that microdissection and serially divide the radial feeders that are actually coming in to the ABM, and then it becomes relatively straightforward to remove that. And you can actually see the actual resection cavity is substantially smaller than the original profile of the ABM, which essentially looked like a mushroom draped over what can be eloquent areas of the brain. Next slide please. And this is just the patient's postoperative scan an angiogram. And so, I hope in this initial two sections of the presentation, I've shown you essentially, that really the key to innovation is to be a discriminating observer of pathophysiology. And we're quite fortunate now zooming out to kind of assisting Stanford here at UC San Diego. We really developed the full continuum of infrastructure, from obviously having all the major subspecialty services at our flagship hospital in LA Jolla, to having a CTSA funded clinical translational Institute to do phase zero through phase four trials, and then having a GLP service surgical laboratory, where we can do that animal validation work and training overall. And that really allows us to take advantage of the fact that there was over 650 million of Biotech VC in San Diego, is one of the three major hubs of innovation nationally. And we're fortunate that our chancellor, in particular, has really recognized that opportunity and develop that infrastructure on the campus side. And so what's next for us, is the development of a GMP facility for medical device, to really take that back into the napkin idea and develop a commercial grade product. We're additionally, leveraging our center for novel therapeutics to look at the development of a GMP facility for biologics, for the development of stem cell therapies, carticel therapies and other things that will be important for neurosurgeons to deliver to the neural access. And so one example of that technology from start to finish and how these industry partnerships can work, was really around the development of the Sony now Olympus or by or 4k, 3d exoscale. And so initial prototype was actually brought to our center for future surgery, that was iterated over time to the point that we were able to do validation work with cadavers, looking at, you can see on the left here, a conventional microscope versus the exoscope with standard interhemispheric retro SEG and orbital-pterional approaches. And then that allowed us, to essentially, take on first inpatient cases. And so this was a frame of magnum and angioma, and the advantage of this outside of the ergonomics and the posterior fossa, was the depth of focus. And so we were able to maintain the arachnoid in the depth, maintain this high cervical nerve roots, maintain the vert and remove this tumor in a definitive way and spare that patient quadriparesis. So we've come really a long way, I think, from the visualization days of William Halston. Next slide, please. Similarly, our intrinsic tumor colleagues have really allowed the concentration of data at their finger pits in fingertips, excuse me, in a very unique way. So you see on the left inset here, we have a magnetoencephalogram, which allows us to marry structural imaging, at neural stimulation into the green dot in this upper-left inset, demonstrates the tibial nerve response in this patient with a new onset seizure and a ruptured cavernoma so we can plan a trajectory to that lesion that would potentially spare them a footprint, footdrop. And we're able to take what used to be in the upper left and upper right, kind of artistic images 10 years ago, around tractography. We now have post-processing that allows the integration of tractography into the heads up display of the operating microscope and so you combine that with florescence and it really allows for a controlled resection of intrinsic tumors. And so this is a video, courtesy of one of my partners, which essentially just demonstrates this technology. You can actually see a toggling between fluorescence, observing the outline of the ventricle and critical tracts in a very controlled opportunity to resect where there's never really any doubt on the part of the surgeon between normal and abnormal and the protection of eloquent structures. And so we've really come a long way in the treatment of intrinsic tumors, you can see the florescence here really allows for the controlled the resection of that last bit at the end and improves your gross total resection rate. Next slide, please. Similarly, if you could start that video. Similarly, the use of intra-operative MRI, has really allowed us to apply laser interstitial thermal therapy to deep-seated lesions and plan trajectories that prevent the clot. And it's my feeling, that not just in the application of energy, this is going to allow us to deliver in a controlled way, our biologics in the future for other conditions. Our next slide, please. I already highlighted the luxury of having a magnetoencephalogram, which allows you to, what I like to call, true functional imaging, which is marrying electrophysiologic response to a particular region of the brain. If we start that video. Similarly, there've been massive advances in endoscopic visualization techniques and recall that definition of transformative technology, transformative technology really allows you to treat problems you weren't able to treat before. And so, a large skull based lesion like this one and the panoramic view that you're able to achieve of the ventral surface of the brainstem and the basilar is really something that's quite unique and wasn't possible even as recently as a decade ago. And so it's a really exciting time in neurosurgery, in my view, where things that were once kind of bleeding edge, become a routine in such a quick cycle time. Next slide, please. And lastly, I'd mentioned, in the neuro-oncology space that I used to believe a combined or complex case, was one that required embolization, resection, and potential sacrifice of the sinus. But there's no question that as our understanding of the systemic treatment of cancer has grown, it used to be that a craniotomy for tumor was really reserved for intrinsically almost, but we've had such advances in the systemic treatment of cancer, that now the predominant craniotomy for tumor are really in treatment of metastasis. And that's because if you are able to get them good intracranial disease control. What you're able to do, thanks to our neuro-oncology, radiation oncology, neuroradiology, neuropathology, and your anesthesia colleagues, is really buy that patient a lot of functional life. And so I opened the talk, talking about this Apollo moment in neurosurgery, and I hope I've shown that in addition to the leveraging of advancements we've made in material science and computational power, there also is this kind of astronaut model to the surgeon. That is leveraging the efforts of many different people at the point of patient care. The other thing I wanted to emphasize though, in JFK's inspiring talk to send us to the moon, was this middle inset portion of his quote, which is, 'that the goal will serve to organize and measure the best of our energies and skills. And one of the exciting things about developing an innovative system, is really that you don't want to limit the participants in that system with your own imagination. And so it's been a real source of pride for me, that partners like Joe Chachi have taken this environment and led things like, first in patient, a stem cell therapy for chronic spinal cord injury, and he's really demonstrated through painstaking animal work solving that mechanical problem of getting stem cells in metromatic area with a way into the substance of the spinal cord. And then demonstrating is seen on the lower left here, in an animal model, how you actually get those stem cells to their biological target. And so in addition to that, I'm embarrassed to say that, prior to a better understanding, Joe's work, and you can start this video, I hadn't really thought about what would be required in terms of a floating cannular system and infusion rate to actually perfect that delivery, as you can see here in a first inpatient video. Next slide, please. And so, and if you could start the animation, this to me, is what innovation looks like. And when you actually have a very good material scientists, like our colleague Shadi Daja in Engineering, you can take a 64 contact lead, get good confirmation with a 10, 24 contact lead, and you see a much richer picture of electrophysiologic activity at the cortical surface. And so now deconstructing the function of the brain and our subjective experience of the mind, becomes possible with this degree of resolution, a temporal spatial resolution, and the computational power to interpret these signals. Similarly, Dr. Ben-Haim in our department, has actually piggybacked a research electrodes on SEG depth electrodes to better understand limbic circuitry for pain. Next slide. And Dr. Osorio, our director of spinal oncology and surgical deformity, has really demonstrated the processes and workflow around surgical instrumentation and verification has taken the simple geometry of a PGK and really used tailored rods and other things, to really achieve really dramatic corrections. Similarly, we've had a lot of work done combining navigation and robotics to make the placement of instrumentation, a minimally invasive and highly reliable process. So I'd like to conclude, what I hope has been a progressive consideration of innovation from endovascular techniques to five cerebrovascular conditions, to systems of care and to how this would apply across the subspecialties in neurosurgery, to really conclude with a section that focuses on the surgeons of tomorrow, and that is our trainees. It happens that Sir William Osler who, in my view, was the father of American Medicine, in a formative manner to Harvey Cushing. There's a broader story that Bill Caldwell tells well of the relationship in Cushing, sort of that involves Osler's son. But I think for the purposes of this talk, I'll focus on the fact that Osler really first went to pathology and did a thousand autopsies with Virchow, who was a destination pathologist at the time, and described a lot of historically neurosurgical conditions like the tropism of cerebral aneurysms for the circle of Willis. Cushing was so touched by Osler's mentorship that you could actually see in the upper right here, that he used Osler's profile as an ohmage in looking at the pterional craniotomy, and I rarely read quotes in their entirety, but I actually believe that Osler's quote, in Aequanimitas bears reading, 'the successful teacher is no longer on a height, pumping knowledge at a high pressure into passive receptacles. When a simple honest spirit animates a college, there is no appreciable interval between the teacher and the taught, both were in the same class, the one a little more advanced than the other. So animated, the student feels that he has joined a family whose honor is his honor, whose welfare is his or her own and use interest should be his or her first consideration.' I share that because part of the spirit of providing a perspective on innovation, is really because, to provide a toolkit, for those who'll push our specialty even greater heights. And I'm fond of Voltaire's admonition, as I think about the things in neurosurgery that we need to combat, and that is anilinism in the treatment of what seemed like untreatable diseases. And so this is the moment we are trying to prepare our residents for. A patient who comes in with a dominant left hemispheric clot, a blown pupil, a ruptured MCA aneurysm and you can start the video. You can see the evacuation of the clot here, and then what you'll see in the upper left, is a remote from the dissection due to the gap in transmural pressure between the atmosphere and the mean arterial pressure of the patient, a spontaneous rupture of the aneurysm. And so, this is the training moment, that we're trying to prepare our trainees for. And so, I'll confess that some of the videos I've shown today are sped up, but this is a real time video. And so this is, three simultaneous things happening at once, the patient's exsanguinating, all the blood that's coming out of the head, should be going to the brain, so the brain is beginning to stroke and as the brain strokes, it will swell and so you'll lose your surgical corridor. So you have a short period of time, to secure this aneurysm. And so you can see here, just the use of stacking clips to secure that rupture point, the removal of the initial clip placement, to demonstrate the deflated dome and then it becomes straightforward, to that inspect and make sure you have a good preservation, obviously of the parent MCA trunk here in the MCA of bifurcation and you can see the deflated dome. Next slide, please. And you can play both videos. What I liked about this, is this is that patient 10 days later and so she's a hemiparetic on the right, you can see her inset CT, and I don't think we have sound, but one of the reasons I really liked this video, is because the therapist at the end of the video asked her, would you like to sit down? And she looks at him and smiles and says, please. And so not only is she not a phasic, but 10 days out from this event, in a way that I wouldn't have personally anticipated, she's observing social decorum. And so this really shows us, our patients as people before their disease, and the fact that if there was anything that we need to fight against and innovating, it really is the idea that the nihilism in treating untreatable conditions. Next slide, please. And so part of what we're doing to prepare our trainees for that moment, and I wanna acknowledge Clare, one of our residents leadership here, is through the society of neurological surgeons, running a sagittal sinus, a simulator course, you can start the video. And while this doesn't seem as immersive, as that initial surgical video, I just showed, next slide, please. What we were able to find, is that the training works and that is heart rate monitors for residents. This was sufficiently immersive that there was a drug spike in the heart rate of the attendings. And while there was a response it's much less of a spike in the heart rate of the attending. And so I would conclude with one of my favorite quotes from Teddy Roosevelt. I would acknowledge this is the person in the arena now, not the man in the arena, but the idea is, that our specialty is a small guild-like community. And if I leave you with one thought, it really is that there should be an urgency in coming up with new, innovative, and better solutions to the treatment of neurologic disease. Because in the absence of our specialty leading in this area, our patients don't have the luxury of waiting around for someone else to do it. So I hope for the audience of this talk, you're thinking about how you can be applying these lessons in your own practice. And so I thank you again for the invitation. I hope this has provided a good roadmap and Aaron will welcome your comments and questions.

- Alex, beautiful lecture, really tremendous accomplishment. I'm so proud and to see that immense leadership and vision that has led to such a great department at UC San Diego neurosurgery. If I may please ask you to comment, what would you, sorta, advice young neurosurgeons in the residency who wanna become innovators in our field? What are the top priorities that would be important to them? If you could talk about that? I think all of us would appreciate.

- Yeah, well thank you again Erin for the invitation and really appreciate the question. What I would say is, I share with my own residents here, is the first thing to do is to identify that subset of patient, where are our current technical solutions are not enough. And so I'm fond of saying, out of 500 cases, I'm delighted for us to celebrate the 498 times things go everywhere you hoped it would. But not to be too self-congratulatory, I think we do have that challenge in our space because as a surgeon, it's your job to do the surgery, pilots don't high-five when they land the plane, it's their job to land the plane. But there are maybe two times where we did everything we wanted to do, but it really wasn't enough. And I think that's really your first opportunity to innovate because there is a forgiving competing standard. And then the next question, as I hope it showed, in the thrombectomy and now the endovascular evacuation of ICH examples, is the question is, well if you do wanna move the needle clinically, how technically good do you have to be? Because part of the challenge of innovating is really understanding of what your target is. And so if it's getting a clot down to less than 15 CCs, you can then work to engineer that technical problem. If it's getting a large vessel occlusion in the brain, open greater than 85% of the time, that gives you a target. And then once you have that, then you need to actually say, how do I get at engineering that problem? And it starts with kind of access to artificial or simulation models, then doing important animal validation work. We've gotten so good within vivo imaging now, that that's a very direct bridge to patients. And then you're in a position, I think, to start to move care. And then lastly, if I had to say one thing that really allows ideas to languish, it's, I think there's a preoccupation with kind of entrepreneurship and IP. And the idea that sharing your idea is going to lead someone to steal it. And I think for a young person with a good idea, I'd be very clear that innovation is very much as I hope I've shown, a team sport. And so, I would encourage you in the same way, as surgeons were subject matter experts in certain things, there is a whole set of professionals whose job it is to help you with every stage of that process. And your idea will never reach a patient unless you bring other people with you. And so being able to lead a team, as you do in the operating room, no less important to do that as you hope to actually advance a new idea. And then, lastly, I'd say that the distinction between innovating in the device space and in the biologic space are very different and the cycle time is actually quite different. And so, it's much more challenging, I think, without a large-scale funding support and the benefit of access to kind of basic science and translational laboratories to innovate in the biologic space. But if you asked me what what's next for our specialty, it's really is being the gatekeepers, the living brain in spinal cord is really gonna be around the delivery of those biologics.

- Very nice, I really appreciate it and I agree with you, Alex, and you already answered my question about the next level of innovation in neurosurgery, which is delivery of biologics. I can't agree with you more. So with all of those thoughts, I really want to congratulate you Alex, in such a young age, really tremendous accomplishments, such a role model you have been for so many of us and younger neurosurgeons. So again, my sincere congratulations, look forward to hear about your future successes, which I have no doubt will be soon and frequent and again, thank you for your extremely valuable time.

- Thank you and I appreciate the invitation.

- You're welcome, thank you.

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