Transcript

- Dear colleagues and friends, thank you for joining us for another session of the Virtual Operating Room from Neurosurgical Atlas. Our guest today is Dr. Phil, Phil Theodosopoulos from UCSF Neurosurgery. Phil is a dear friend, an amazing surgeon, technically superb, especially around the area of the skull-base and acoustic neuromas. He is in fact, the program director, the vice chairman of neurosurgery, as well as the director of skull-based surgery at UCSF. Phil it's an honor to have you with us, and I'm really excited to listen to you, especially about the algorithm of managing these challenging tumors. Technical expertise of yours will be much appreciated with your videos. And before we start, I just wanna get some personal reflection of yours regarding what makes a good skull-based surgeon and specifically an acoustic neuroma surgeon. Please go ahead.

- Thank you Aaron. It's been great to see you, and it's been great, this project that you have championed here is top-notch, high quality, this is really what we need a lot more of and maybe this is the silver lining of the whole pandemic thing that we actually can be even closer when we can't really be in-person closer and educate everybody close and far in a different way. And maybe I hope we're generating something that will have some staying power, something that will last into the next generations. And then I, as you said, I help direct the residency here and I've been involved with resident training for a long time and fellow training and I think it's such an important part of, as I get older, I find that, it's such a huge part of what we do. Not because I want my name remembered, but because whatever we learn, the hard way that we learn it, as you know and many of our listeners know, it's so critical to not be wasted, let's pass it on. Let's really have a formulation where this art that we all practice is more cohesive and it's more, a big family that we are. Now, I knew you're gonna ask an easy question. So it's pretty easy to answer. I think a couple of things come to mind. The first and foremost, in my opinion, is willingness to fail. And I think failure is what I've seen throughout my career. And today I'll talk about acoustic neuromas and I think we are a few steps forward from where we were when I started and we were standing on the shoulders of giants then, but now we're a little bit further ahead and I hope to share some of this with you, and certainly opened a lot of horizons that for young people, for the new people going into it, they can push it further. But this wasn't a rosy road, this was not knowing, and failing, and seeing that what we do is actually detrimental despite what we wanted to make it better for patients. So this quest for better outcomes and better technical abilities and better, better, better is defined solely by failure. And hand-in-hand I think failure goes with honesty. Unless you can say that I messed this one up, I remember when I was a fellow at the Brigham, I didn't obviously I have an office, but I had a little desk and the little desk was in the library of the old offices at the Brigham. And that was where they had up above, this was the actual room that Cushing used to have as his office and they had made it a library, Peter had made it a library. And I remember up above, it was like all the volumes of Cushing's operative reports. And I know what a huge history buff you are, as I am. And you know, when I had some time, I would just pull random volumes down and I would open it up and it would be his operative report. And the comments that you would see that he would write, the honesty there, I messed this one up. I mean, paraphrasing, but I missed this one up because X, Y, and Z. This patient never woke up because I was incompetent in doing this. I mean, this was the kinds of things that Cushing would write. And of course we idolize him and I'm sure he was a human being with plenty of issues but... When you look at that, I think that's what we owe to our patients, that's what we owe to one another. And I think that's what we need to be discussing more. How did we fail, why, and how can we get better? Instead of the opposite, which sometimes we tend to do in this difficult field of test something. So I think, if one wants to be a good skull-based surgeon prepare to lose, prepare to be in for the longterm, 'cause only then, do you justify, especially for the younger of all of us, do you justify hurting somebody when somebody else could have done it better. It's the commitment you have to keep on doing it, and doing it, and doing it, and doing it so that many more folks down the line will benefit from you. And the honesty, that if you have a great idea, great, do it. And if it fails and falls on its face and it's completely not the right thing, say it, and get out and say, "Okay, well, we tried this, that didn't work out well." And so those two things, I think are the cynical unknowns for skull-based. And I think for academics, there's a lot more, there's intellectual curiosity, and perseverance, and kindness. And then on top of that, we gotta be physicians, right? I mean, we gotta be healers. We got to be patient with all of this. And I think as you and I, and many of our listeners know, it's a journey. And it's a journey that never ends. And I think, now as a 20 years plus after I started in my independent practice, I can say that I feel a lot more comfortable in a lot more things, and I feel that I control a lot less, but that I am okay with that. And I think that equanimity is, as we all attain that or come closer to it, is what to strive for for all the younger folks, especially in this hard technical disciplines.

- Thank you so much. Well said, let's go ahead and jump into the lecture.

- All right, well, thank you. And I will speak today, as it was allowed for me to choose my own topic, I will speak today on acoustic neuromas 'cause it's the thing that I enjoy the most in skull-base surgery, I am blessed to having a quite busy practice in skull-base and doing a lot of different things, but acoustic neuromas, I think, are the thing that I enjoy the most, and now for different reasons than 20 years ago. But now for intellectual integrity here, I have no disclosures really, but a lot of the stuff that I will show you, especially things that are research oriented are funded by the Chair and by the other chairs we have here and by the program grant that we have from the NIH. And I do, I should say, I do practice both radiosurgery and microsurgery. And so I am kind of, I'm biased that way because I make my living by treating these tumors. However, I do end up following probably about half of the acoustic neuromas that I see for a while. So what's the problem? Let's define the problem. Here on the right-hand side is a 20-something year old, 28, I think 29. When I first saw him a few years ago, he was a law student and he came with no symptoms other than some ringing in his ears, and he has a four centimeter acoustic neuroma. This is the problem, that these tumors are in a bad spot, they often present with very little issues, and we can hurt a lot of things in trying to treat them. And it's between a rock and a hard place, 'cause even if you try not to treat them in a very aggressive way, then they, as a tumor, recur to become problems. So, what we know, and this take from me, and you can go back to the original literature, but what we know is that gross total resection of acoustic neuroma, especially the big ones, carries a significant morbidity, that is mostly on cranial nerve morbidity, however, other morbidities as well. Subtotal resections of large tumors have other potential problems, particularly because they can cause, number one, equal or more morbidity to cranial nerves, and we'll talk about why that happens, and number two, that then you have a tumor that can regrow, and some do significantly, and we'll talk about that as well and what we understand of that now. The idea of hybrid treatment, and this originally started with, almost 20 years ago, with a trial that we had started a few of us around the country, then others got involved, then the other person who held the Khatib Chair Andy Parsa, the late Andy Parsa, a good friend, coined in fact, if I remember correctly, and now it's been many years, the concept of hybrid treatment, meaning that we combine surgery and radiosurgery. And that now has advanced in a significant way and I'll try to take you through that journey as well, a little bit in this. Now, things that... I can't see the entire slide, but I assume that you guys can see the titles as well. But things that we have assumed that are probably not correct, that these tumors always have low proliferation, that they're always slow growing, that gross total resection equals a cure, and that stereotactic radiosurgery controls growth. And it is a low dose, it's the lowest of doses that we give to anything, 12 and a half gray, and that's based on a lot of work that was done mostly early on, about 25 years ago, about the dose that controls and doesn't hurt the cranial nerves. And I say this because there's now data to suggest that all of these statements are incorrect. In fact, all of these statements factually are incorrect. So, this is the best data that we have. Madjid Samii's data, I think very few people will ever come close to his experience, now having done more than a thousand of these, I can tell you that the amount of work that professor Samii had done is just mind boggling, especially at that time. This was the most recent of his papers, a few years ago now, but the last 200 of them, and what you see is that, when you take everybody, it's 66%, and the idea from it was always that we should take all the tumor out, and in fact, in all of these, almost all of them had all the tumor out. And only about 66% of them had House-Brackmann one and two, meaning good facial nerve function in the longterm. And in fact, when we go into the larger tumors, as you can see, is a lot less. It's almost up to 50%. And in a very appropriate fashion, Professor Samii, saying that you never stop learning how to do this better. And now 20 years later, and I'm nowhere close to his experience, but I can say that that is so true now that I still see things for the first time when I'm in the OR with these tumors. So Christian Raftopoulos from Brussels now did this paper back in 2005. This is kind of where this whole idea of treatment started. And if you see this is, you don't have to read this, but every line is a different series of the big names, the , everybody who ever did significant acoustic neuroma surgery for big tumors. And you'll see that House-Brackmann one and two, is this thing on the right, let me just get this, yeah. This column on the right here, and you see that it's 40%, 50%, 60%, but not really great numbers this day and age. And at the bottom is their study, and their study was on the premise that maybe we'll leave some tumor behind and we see what happens. And 15 out of 15 people had good outcome. Well, that started the whole idea of, well, maybe we should be leaving some tumor behind 'cause really, most of the morbidity of this, if you know what you're doing, most of the morbidity comes from trying to dissect the tumor from the facial nerve. Now, that's not the layer and sometimes it's the entire width of the tumor, et cetera. But can we leave some tumor behind? Schematically speaking, this, take the tumor, leave some tumor along the facial nerve, once you find the facial nerve. This was the first of the papers that we did on this perspective trial, the first trial ever to introduce that, we got a lot of flak by the way, for any aspiring folks who try to change the world, you probably know this already, but we got a lot of flak for doing things like that 'cause back then it was anathema to say that you're gonna leave any tumor behind. And honestly now, 20 years later, I can tell you that it is so much easier for me to have hurt somebody's face than to have residual tumor that regrows. And take that and understand it as acoustic neuroma surgeons. A lot easier for me to hurt somebody's face and take all the tumor out than to keep some tumor behind. It's a lot harder for them. So this is part of where the healing comes in. You have to be patient together with your patient. You have to co-manage this over the years. And that's a different concept that we have. Anyways, this is the first part of the trial, the trial was about bigger tumors that we did subtotal resection. We didn't even know how much we should be taking out, but we tried to take out all of it, if not most of it and then next some timber behind. And this was when we reported the one year data on 66 patients. This was multiple centers. And basically you would go to the place where this is the brainstem, this is the tumor here on the right side of tumor, but this is just to show that you go to the place where basically as you're dissecting, it becomes really sticky. And naturally, based on experience, this point maybe different for different people. This was the one point that was the end point of how much you should dissect. And then you would thin out whatever tumor remained behind. The second point that you should stop was the point where, or the alternative point that you should stop is the point where you would lose some stimulation of the facial nerve, meaning that the response of the facial nerve to stimulation would become weaker and weaker. And you absolutely should stop there according to the trial. In fact, the way we had during the trial was that as soon as you find the facial nerve, stop dissecting off of the facial nerve, but what does that mean? I can tell you, I'm still, I'm writing a paper now what that means, 20 years later, and I'm not exactly even sure how to put all my thoughts together. So, that was the idea. And so this was the data. The data, and it's the length of follow-up that we had and the data of how many head gross total resection on the post-operative MRI and on the surgeons perception, how many ended up having subtotal resections and near total resections and we determined the near total resection as below four millimeters, et cetera. That's mostly defined in different ways by different people. However, here, I would say this, that what we found was that the optimal place to be was this in the longterm. And this was the near total resection, not so much the subtotal resection. 'Cause as you can see, the gross total resection, a lot of people had facial nerve dysfunction, late and early. But really the best outcome, and it's the light gray thing, it's almost 90% of the people in near total resections had grade one and two, had grade one and two facial nerve function. So that seems to be the sweet spot. Well, how do we get there? Now, that's kind of the million dollar question, right? Now, these were, in that original cohort, my patients that I include 22 patients back then, this was years ago, and basically, so this is just to understand, I left about 16% of the tumor behind on average. And three of those patients of 22, almost 10% or a little bit more, 15%, progressed in the period of time that we had followed them, and that was an average of at least one year. And it was, I mean followup for my patients was about two years, but this was the data that we produced. And here's the example. So this was really, and the good thing about trials like that is that they're centrally administered all the data, all the scans are done in a very specific way. There's minimal bias 'cause basically they're centrally reviewed. So these are big tumors, this was a young woman, a banker, and this was actually what we termed the gross total resection and was lucky to get a facial nerve function that was normal afterwards. This was another patient from the trial from my patients who, big tumor here and had a small amount of tumor here, left in the eye, seen along the facial nerve. And that was immediate, and then longterm, this was the same. And so this is kind of how we do that. This is the debulking of the tumor, this is a right-sided tumor, the debulking of the tumor, the dissection off of the brainstem. Actually, I'm sorry, this is a left-side tumor, dissection off of the brainstem, and then finding, that was the facial nerve down below, that's the trigeminal nerve right here that we're gonna be dissecting the tumor off of stimulating the nerve comes from below to right about here, which is the anterior part of the capsule. A lot of times the facial nerve crosses in this kind of an orientation. And so it starts right here, this is facial nerve here, and it goes up like that behind the tumor and then comes up along the IAC to go there. So it's important to remember that this is now a distal in the IAC after, this is rather a distal in the IAC after we had taken all the tumor out of the IAC. So basically, you're left with this piece of tumor, the tumor that is remaining is this. This is a piece of gelfoam down in the brainstem. And the nerve crosses like this, and then like this, and comes behind it and goes into the IAC. This is the optimal thing, and this is actually by the way the most common anatomy that you get the nerve down below, then you get the nerve up above, and then the part of the tumor, and in general, the nerve splays, not when it exits the brainstem, but really when it hits that vertical segment from here to here to go up to the IAC. Next slide please. So this is the tumor, this was the tumor, the one that you just saw, and this is what remains, this is a little bit. Remember that laterally out there that path that we took the tumor out of there, we took the tumor out of here, there's a little bit of muscle that we put as a plug on there, I always do that in the drilled IAC, but this is the tumor that's left there. That's, really, I would call the optimal and near total resection of a tumor. Here's another example and these are, actually the next two cases are from last week. This is the 11th of April of this year. A tumor in a young guy, 42 year old guy. And what you see here is the fifth nerve up here we're dissecting, right here is the fifth nerve, petrosal vein here. And we will find the facial nerve stimulating in this area. Again, this is a common thing then the superior aspect of the tumor, you will find the facial nerve stimulating. And you can do the sub-dissection to go down and expose the capsule of the facial nerve. And again, most of the sub-dissection is important, the instruments, by the way, for all of you who do this, the instruments I use are obviously the micro scissors and the number six dissector, but mostly the Crabtree, the Jimmy, named after Jimmy Crabtree. See, I'm stimulating up here, this is trigeminal nerve, and this is where the facial nerve is and I stimulated. And it comes around right back here, right underneath the capsule, is splayed out here. This is how it's about to get up to the IAC. And then if you're look inferiorly now, I'm visualizing right here, down here is where the nerve is. And in general, this area is the secondary, you'll be looking for the facial nerve and that's right as it comes off of the brainstem, you see the Crabtree right here that I'm using, Crabtree is a hockey stick, and the actual, in magnification, its blade is flat like this. So it allows you to pull the tumor and dissect the plane better than a six or a two or a one or whatever else you can use. And so basically yet again, the story is the same. The nerve goes from here to the brainstem, around the left-hand-side, goes underneath the capsule, goes up here and up there. And in general, it's this piece of tumor that, it's not so much that it's stuck on the brainstem although sometimes it can be. But if it's not stuck on the brainstem, the nerve comes out compact and then splays from here to here, and all the way, really up to the IAC. So basically the nerve comes out compact and it becomes big. And that's where you lose the nerve if you push it. And here is the result. You take this tumor and you leave this little bit behind. So this was Monday's case, this is Wednesday's case. Here's a bigger tumor, but both of these are actually exactly the same age, 42 year old men, both having hearing imbalance dysfunction. Now, the things I look for, and this is more of an expert kind of thought, but you should start thinking about that is, when I look at a tumor like this, I say, well, why does it have the shape that it has? Some tumors are oblong like this, some tumors are fat like this, some tumors are just round, and some tumors have this indents. And the indents almost invariably are blood vessels, major blood vessels that somehow are stuck there. Usually the AICA or some kind of big brands. Rarely it's also a compact facial nerve, a compact facial nerve can do this. So you have to be very careful. So coming down here, debulking with acoustic, if there is a big vessel here, it's not going to be a good situation. So you have to be really careful and always read it like that. Now here's what we see on this tumor. And this is now trying to find the facial nerve, down in here is the inferior aspect of it. I'm trying to pull this tumor away. It's a more complex tumor and in fact, this ended up being more stuck, but again, sub-dissection, try to leave all the thinned out capsule of the eighth nerve behind 'cause in front of it then it would be again, we're pulling away from brainstem. I don't know what that was, but we're pulling away from the brainstem. And so here's brainstem, here's tumor, facial nerve is right down here. I don't know if you can see but right down here, that's where facial nerve is, and we'll stimulate in a second. Now this allows me to obviously debulk more of this tumor, and keep going. And next slide please. going in the further down, so this is again, now, I'm pulling the capsule away from the thinned out part of the eighth nerve, and the facial nerve is in front of it, it doesn't stimulate right here. The facial nerve stimulated right down here, and then again, up here. This is the vein, dorsal vein, and this is brainstem here, it's pristine. And you should always have that pristine pia plane. If you don't, then you should stop dissecting. So this is the thinned out pia and arachnoid off the eighth there being splayed out. And right in here where I find again, stimulation of the facial nerve. So the facial nerve goes from here, goes from here to there. Here is the origin of it, and it comes along and as it comes here, and usually, as the facial nerve starts turning, starting here and turning like that and going up, when it starts turning along the front of this capsule is where it becomes really thinned out. That is where most facial nerves have been lost. And as you are pushing this tumor away, you're actually decompressing, obviously the brainstem. So then once we do all this proximately, now we're up above again, petrosal vein. Thankfully, these are all left-sided tumors so you're not confused in the orientation. So petrosal vein here. And this is where the facial nerve stimulates down here, right down in here, facial nerve stimulates. And when I say stimulate, that's at 0.1 volt or a 0.1 milliamp, by the way the resistance of the system is usually one kiloamp so basically either volt or milliamps is the same. And this is where in the depth here, the tumors really dug into the brainstem, and I'm trying to debulk it more and cut it away from the petrosal area so I can roll it down. But I also know that a tumor like this that has indents and blood vessels that are trapped, et cetera, the chance of me being able to peel it completely clear off the brainstem are not very high. And that's okay because that is, the goal of the surgery is to be, the goal of the surgery is to debulk it maximally and be safe to the nerve. So once we mobilize all of this, look, can you advance it a little bit, or if not, that's okay. Now this is by the way after we drill the IAC, so the IAC, yeah, here we go, that's perfect. So this is the trigeminal nerve, right here, this is the facial nerve turning around, this is the facial nerve distal in the IAC that I can see, and this is the trigeminal nerve and brainstem down here. Where I just stimulated is the proximal facial nerve. So again, you try to really minimize this tumor to be able to tell where the facial nerve is proximally and distally. This is really critical because otherwise you're going blind. And the going blind is where subtotal resections don't work. The main limitation of a subtotal resection is that you just don't know where the facial nerve is. You have to find the facial nerve and you're putting it at risk by trying to find it. So this is the whole idea. And then it's the classic sharp dissection away from a thin pad of tumor left of the facial nerve here, off of the brainstem and the trigeminal nerve. Now, I'm gonna cut this tumor away to get this all gone. And look, here you just advance the very end of this clip. So we're gonna cut this little remnant of tumor here. And so here's your trigeminal nerve down here, the facial nerve is protected by this pad right up here, the origin of the facial nerve is right here, and the nerve goes like this and like that. And then we also have distally the facial nerve in the area of the IAC. This is gelfoam right on the brainstem. So basically, here you go, you're gonna have this little bit of tumor left behind. And what this looks like is, let's go to the next slide please. And what this looks like is this. So you take this tumor, and you leave this little bit of tumor right down here, and this thing, which was a bit of, I couldn't show it to you in this, it was in the long video, but there was a bit of tumor that was really stuck into the brainstem and I had all the pia of the brainstem all around it exposed but I could not really pull this thing out. So I amputated and left it there. So that's the optimal near total resection. The facial nerve goes along like this. You gain nothing by taking this bit of tumor out, tumor control-wise, so we think, based on data, and you gain a lot in terms of morbidity. And both of these guys had facial nerve function that was normal after the surgery, both of them from last week. So after the original data that we had, a lot of people did a lot of studies on this. I did one of all the tumors that I did include in the trial originally, and many others have. And basically, what everybody has shown is that, well, is that the data is not as, facial nerve data is better than it used to be when we tried to do gross total resections but it's not as obvious as you think that what Christian had shown initially 15 out of 15, all have good facial nerve function, that is not true. That these trials that show subtotal resections have an equal morbidity of the facial nerve, why? This is another study that we did, 52 patients outside of the trial. And basically what you see again is that the near total resection here is the sweet place where we wanna be, and the subtotal resection pretty much everybody progresses and needs more treatment. And this was, again, the difference between subtotal and near total was the size. Now you would say, well, what is so different between less than four millimeters and more than four millimeters? So, I can tell you it's not really the size. For simplicity it's the size, we don't really understand exactly what it is quite yet. But what do you see here, also in another paper by Mike Link, is that near total resection is pretty much as good as gross total resections and subtotal resections are the ones that leave us wanting more. Now, so let's go into the meaning of this. Why do we have subtotal resections that are not obviously so much better than gross total resection in outcomes? Well, the tumor capsule can be hard, the adhesions can be hard to visualize, monitoring the facial nerve function is difficult at times, because if you don't find the facial nerve on the brainstem, you're not gonna be monitoring anything. And that's really critical, tumors that are big and they have moved ventrally the facial nerve origin are really difficult to find the facial nerve 'cause you get stuck on that brainstem and that tumor is not gonna move over. Well, then you're risking it. And this suboptimal to optimal transition of how much tumor we leave behind is difficult. I mean, obviously if you took just the bite and closed, it's nothing, and if you took it all out, again, you skip the point. So this is an example of, and this is actually a video that is twice, I think, or three times the speed of how I operate. So this is not like my normal operating speed, but I think it helps to visualize it. And again, I'll show you, it's a very similar thing that we've been seeing a lot over these videos, but I want it to stay in your mind. This is again, the facial nerve root entry zone down here, again, another left-sided tumor for purpose of making it easy for everybody to figure it out. Take these tiny little things and sharply divide them, little feeders of the tumor. And then as you can see in a second here, we'll focus more over here. Here's the nerve, the facial nerve, you see it very compact here, same here. Very compact at the beginning, gets thinned out right here. Always right here is where it gets thinned out as it goes up, and I'll show it to you know, in there. So here's the facial nerve, you can see it as big as Dallas is, Larry Pitts used to say. And then it gets really thinned out from here to here. And it will be going up to the IAC. So, you can keep on going here sharply, and again, you see the Crabtree is a really perfect instrument for this 'cause it allows you to do what used to say, of how do you split the facial like you peel an orange. That's another place where there's significant adhesion. And in general, by the way, let me just say also this for the benefit of all the Japanese influence I have, I almost never take the veins here, the petrosal vein I almost never take because I think venous insufficiency is something that hurts the brainstem and the recovery, especially even on the facial nerve end. And here's what I would call the dissection that is optimal in this area, because you allow it to, again, for these arachnoid and pia planes to open up by themselves, see them. You can cut them sharply, and don't certainly do the duck dissection, unless you have done this a few hundred times. But whatever is there is stuck, you can cut it but it's, this is the plane between the pia of the brainstem and the capsule of the tumor. The nerve is not here, the nerve is over here and over here and over here. So, I have the space, I wanna take this knuckle of tumor that in general insinuates itself right at the origin of the trigeminal nerve. And this is usually what the trigeminal dysfunction that folks have with acoustic neuromas is caused by. It's not just compression of the trigeminal nerve it's compression of the people. The plane deeper is better than the plane more superficial. So doing again, the idea of going from the inside out, this is why a Crabtree is good 'cause he can hook this tumor here as long as you know that there is no facial nerve and allow you to dissect this plane from the inside out. Dissecting this plane from the outside in is not as easy. Now, once you do this, then you can actually eventually pull this knuckle of a tumor. This is again, the facial nerve right here, knuckle of the tumor and the brainstem here, you can try to shrink it, and debulk it, and cut it. And eventually, and this is, by the way, we're done with all of that and now this is the lateral aspect, this is the IAC that has been drilled. I'm taking the tumor out of the IAC and I will, you'll see I'm stimulating the facial nerve on the brainstem is right down here, the facial nerve is also up here, that trigeminal nerve here, and so this is the last bit of the tumor. This is the last bit of the tumor, it goes from here. This is the last bit of... That's really what, if I were to define a near total resection, I would define it as such, that the tumor that remains is mostly out here, and that the IAC connection of this tumor to the dura of the IAC has been interrupted. And that's important because most of the blood supply of this part of the tumor comes from the dura of the IAC. Again, IAC cleared, the nerve right in here cleared of tumor. This is the tumor that vertical segment. And once we cut this out, and again, this is the corneas where it gets blood supply from the dura of the IAC. It's important to cut these, coagulate and cut them once you stimulate them so that whatever you leave behind is a dead piece of tumor. This is the facial nerve again, right in here, and it goes down there, and it comes around, and goes down here, okay, that's the facial nerve. It just ends up being very widened here and very thinned out. All right, next slide please. And so this is what you end up having. A tumor like this that ends up being this tumor left right in here, along this facial nerve, barely see it, right? This is the idea. And again, this patient had normal facial nerve function at the end. I think this is really the elusive good thing to do. So, what are the tools we have? Well, so understanding intraoperatively where you are is not the most obvious thing, especially if the tumor doesn't come away from the normal structures. If you see the brainstem, or you see a trigeminal cell et cetera, it's all good, but doesn't always happen that way. Here's a good example. An older lady who had a tumor that grew very significantly. And so we decided to take her to the OR and we left this behind, right? Perfect, I would say, for a subtotal near total resection, but how do we do this? Well, in this case, this is an example of how you can use intraoperative guidance for this. And this is the original kind of volume that this with a brain lab. And this is what the brain lab by the end was suggesting that is residual tumor. Okay, this. Now, as you can see this, and this is flipped, but this and this are different. In reality, this was less. And the reason being that the brainstem actually comes back at you. In fact, there was a little bit of tumor that I thought was here. So the brainstem kind of shifts. So, what the system thinks that you've left behind, oftentimes actually ends up being bigger than what you actually leave behind because the brainstem has shifted and taken over. But you have to be, this is a way that some people do it. I don't think it's a very accurate way, but it is a way you can do it when you can't see all the anatomy. Now, it's not always easy to do. It's not always as good as I showed you. So here's an example of a young guy who is from Argentina. He had surgery there when he was, I think, 17 years old and he had a big tumor, they left some behind. Great outcome, one would say, they decompressed his brainstem. But you know, though, unless you really treat this with radiation, it's gonna come back, it ain't dead. He came to see me with this two years later. I took him to the OR and left this little line of tumor right there. However, in doing this, and given it was a re-operation, I gave him a weakness of his face. And this was almost, I don't know, seven years ago. And now he still has weakness. He is a lot better, but he still has weakness and we did radiosurgery to it and stable, did this little residual and it's stable since then. But this is a 25 year old person who now has some tumor left behind and weakness. And that's really tough. But the bottom line is that if you can't really tell the plane, you can't tell the plane and you wanna actually do the best for these people and not hurt them on purpose. This is an awful case that came to me with this tumor after she had had two operations, two subtotal resections, and fractionated, a fully fractionated radiation treatment. So here is how the whole idea of, I-don't-wanna-hurt-you, goes exactly the opposite direction. Anybody who argues that could use this case to really, to their benefit because this tumor, well, you clearly didn't help this person. You might have as well cut that facial nerve to begin with and take all the tumor out instead of this. By the time she came to see me she had hydrocephalus, she was blind, her face was out and she didn't have any hearing. So, great. And you can get it down to this, but this, I can tell this was a 12-hour surgery and it was a piece of concrete stack on her brainstem surface. And thankfully since then it can stay stable, but this is kind of really what to avoid. This is why this bigger tumors should really not be done by people who don't do many of them, because you can end up in this, trying to not hurt somebody with all the good intentions, but they ended up having a huge problem. Or even this, and it's easy for all of us, I said earlier on that we need to be honest. I mean, this is my doing, and this was a patient who came to me, this scan October 13, it's a 20 something year old woman who was found to have this, somebody did a subtotal resection. And this was the post-op scan that they had. They took, I don't know, 20% or 30% of the tumor out. They gave her a stroke in her cerebellum in her brainstem. She still can't walk straight and this was years ago, you know, eight years ago. And I finally had to take her and do more surgery. And this is what I was able to do without hurting her lower cranial nerves. And you may say, well, I took a lot more tumor out, but there's still a lot more tumor there. And this tumor has stayed stable since then. However, functionally, she hasn't improved really that much. Since she has a facial nerve function that's good, and she has lower cranial nerve function that is fair, but this is the kinds of things that you may think that all of them end well, but they don't. And this is why these are difficult tumors. And eventually longterm, it has stayed stable, and even more recently, it has. Now, the other thing, and maybe I should have said that in terms of Aaron's question of, what does it take to be a good acoustic neuroma surgeon or a skull-based surgeon, don't believe everything you think. And that's probably a good dictum for life in general, but degree of resection correlates with outcome, not so true. Residual tumors, if they grow, they grow slowly, not so true. And that the data really answers things, well, I don't know that it does. So here's what we know about residual tumors. 20% progression, no question about this, all the prospective trials have shown this. I remember Robert Ojemann used to say that 25, 30 years ago. And they can solidly grow or form cysts. And of course, remember, the capsule you leave behind will collapse and look different. And the timing can be pretty quickly of all of this. And so this is a patient who started with this pre-op, went to this post-op, this is patient from the trial. Went to this post-op, went to this 22 months later. And this was not a malignant tumor or anything different than the standard acoustic neuroma. And 30 months after the fractionated radiation and needed to have surgery again. This is within two years. The tumor is as big as it used to be. And this tumor was perfectly treated according to the trial, it was less than 10% of tumor left. So for anybody who says that these tumors don't grow, you're just wrong. As simple as that. For anybody who says that remnants don't grow, you're just wrong. 20% of these will grow. And for anybody who thinks that they grow slowly, you're also wrong. And this is not the only case, I've seen plenty. Andy and the group from here with Larry Pitts, had looked at all the cases of Larry's , there's 707 cases. And what they had found is that the degree of resection didn't matter longterm. This was past 7, 8, 9 years. And basically gross total resection subtotal near total resection all ended up at 80% control. Mind-boggling, nobody believed this data when it came out. I didn't believe this data when it came out. Lo and behold Mike Link comes out and does this trial of 22 years of followup up-to, from the Mayo clinic data. And this is the data of all the huge names from Mayo clinic way before Michael. And here's the actual truth. Subtotal resection, and this slide I show, not because of the subtotal resections, pretty much all of them fail. I'm showing this because the gross total resections, about 40% of them fail. Gross total resections, 40% of them fail. I'll say it again. So anybody who thinks that gross total resections is the solution to acoustic neuromas is also dead wrong. This is where you shouldn't believe everything you think, 'cause we have thought about these things a lot and we're just wrong. And what are the predictors of that? Well, tumor volume we leave behind is a predictor of recurrence, and recurrent operation, re-operation versus the primary operation is also a predictor. And it turns out that about, in volume, about a little over a centimeter cubed is the predictor of where there is goes up. Now, is it really a centimeter cubed? Well, I don't know, but this is what we did in our trial. And what we found was that 1.4 centimeters was the sweet spot in terms of the logistic regression that we did. So subtotal resections, folks who had less than 1.4 centimeters cubed, in the longterm, and this is in 12 years follow-up, this is a lot of people for a lot of data, and more than that. Now, again, I will say it again and again, is it really that 1.4, or 1.27 or whatever the sweet spot? Well, it obviously logistically and statistically is, but it is not anything special that 1.4 centimeters cubed does. It is the overall volume, the location of the volume, and probably other things we don't really understand well. But this is where the trick lies in optimizing this big quest that I, at least I have felt my entire career in acoustic neuroma surgery, how do we optimize subtotal resection? This is big part of it. And when you look at tumors that are radiated, primary tumors that are radiated, just try to understand also the radiation bit in this. We all know the pseudo progression that from date of treatment, two years down the line, the first two or three years, tumors can swell and then eventually go down. And when you break it down it's somewhere between six months and a year and a half, really, that most of that peak is. And most tumors kind of can, they're growing, this is the average line, the growing time of treatment, and then they can go up and down, but then eventually they come down, they become smaller or stable, and there's some that go, whoa, look at all that swelling, there's this bump here the first two years, and then they go down. And of course there's a small cohort of these tumors that keep on growing. So not all of these tumors will be controlled with radiation but, and what we see now, and this has not been published yet, but it will be coming out at some point soon. This is a kind of 68 folks from the original acoustic neuroma trial that we did, now with seven year followup, and many with up to 10 years of follow-up. And again, the extent of resection, gross total resection, maybe a third of them or a quarter of them. Well, what really, and I'm not gonna give up all the data from the trial as we are gonna publish it. But what you find is that early facial nerve improved function doesn't necessarily hold true for the longterm. Why? Well, because there's recurrences. And recurrence in subtotal resections is three times as high as in gross total and near total resection. Again, indicating that near total resection probably is the sweet spot. How do we define that, that's where the money is? And remember, and this was another thing that we learned very well from this trial, was that we all started by saying 20 years ago that, well, let's follow these residuals. And it was part of the trial, part of the protocol. And if they show growth, then we treat them with radiosurgery. Well, lo and behold, what ended up happening is that salvage radiosurgery was not at all as good at controlling these tumors as upfront radiosurgery. And the truth is that this has been shown by Doug Kondziolka and Dade Lunsford and others, and the Cleveland folks. And the bottom line is that the control with radiosurgery is not as good at salvage. And why we say this, it's because, not all acoustics are created equal. I say this, and I mean this. Not all acoustics are created equal. For any of you who do a lot of skull-based surgery, heck, for any of you who do a lot of brain surgery or tumor surgery, you know meningiomas are not all created equal. And I'm not talking about a typical versus atypical, I'm talking about typical meningiomas, a meningioma along the skull-base, versus a meningioma along the . And if they're grade one, they can function differently, and so do these tumors. So what does this mean? Well, large tumors in young patients. I mean, the 23 year old who had the four centimeter tumor, that's not growing a millimeter a year, he hasn't lived long enough, even if it started growing in utero, or two millimeters, they grow five and eight millimeters a year and they're still grade one acoustics. The development of quick symptoms of hydrocephalus, that's not very common. And that is also a sign of faster growing tumors. And of course, post-treatment progression. And to remember this, that anybody who talks about the natural data, the Danish study, the French studies, the study, all of the studies that we have of the natural history of these tumors, totally don't apply to this, these are not those tumors. All natural history data obviously is biased because it is the tumors that we choose not to treat for whatever reason, obviously, whether it's not like some kind of a randomized thing, it is the you're old, or the tumor is not that big, or you don't have symptoms, et cetera. But really, nobody randomizes a 20 year old with a four centimeter tumor on the natural history data on following them, we don't. So, when we say, when people say, that maybe 30% of these tumors grow, that's absolutely dead wrong. 20% or 30% of intracanalicular tumors grow, yes. 50, 60% of all comers who are chosen to follow grow. So majority of tumors that we think they may not grow, grow. And all of the tumors, I would pause this to you, all of the tumors that are big and that we wanna treat at the beginning grow, all of them. Some, very fast. So, natural history, the question of natural history is not very well defined 'cause the natural history of big tumors, we have no clue. And I can tell you that based on data and based on understanding it, and based on seeing these folks, those tumors grow a lot faster than anybody thinks that they do. And they're still benign. So this tumor, this was a 26 year old guy who works for a big company, a big tech company here in town. He came to me, he just was having a little bit of imbalance. This is not a one millimeter a year, or two millimeters a year, or even 5 millimeters a year of growth. This is a five centimeter tumor. And the yes, you can take it out with good, no morbidity really, if you're lucky, and leave a little bit of tumor on the facial nerve and he had normal facial nerve function. That's better lucky than good. But look at this, and coming back, this was one of the blessings of coming back to my alma mater for being faculty. This is a tumor that I had done when I was chief resident here with Larry Pitts. Gross total resection, or one would say, I mean, this is a good quality MRI scan. Nine years down the line, there's another tumor here. This is what Mike has shown with the Mayo data, this is what we're showing. We don't look necessarily long enough, but anybody who says that gross total resections don't reoccur is just dead wrong. And this is why I was saying at the beginning, be open-minded and be ready to be wrong, because we have been wrong at almost everything that we have argued about acoustic neuromas over a long period of time. And then of course up 2007 gets radiosurgery, and I'm still following this patient with a reduced size tumor, and look at how it shrunk. So it was clearly a growing tumor. Tumors that are not growing don't shrink with radiosurgery, and this did. And who knows what's gonna happen to this person. But this is a 20-year journey of this person through acoustic neuroma. And he's not the only one. Or this tumor, 2004, was taken out, gone. Andy, I think did this or Larry, I can't remember. Regrowth. And there was no tumor left behind. Regrowth. And then I took it out and I had to leave a little bit behind, thankfully again, good facial nerve function. But again, this is just one little bit of the world where these tumors don't grow any faster. I hear differently in San Francisco and everywhere else. We maybe a center of excellence and people come here, but this is not, these are people who originally were treated here. These are not the big failures and salvage things that come to me. This is just run of the mill. You follow enough, you have a long enough follow-up and a big enough practice, you see this. So, that's for people who think algorithmically, and I, since my title was an algorithm, I think I should show this before going to something a little bit more interesting. And we're coming to the close here soon, but symptomatic tumors in young people should have surgery, period. In my opinion, after a lot of thinking, and studying, and operating on this. Asymptomatic tumors, you can do anything you want, but the large ones basically should go into surgery. I think there's no question in my mind that all of that is true. Older folks with vestibular dysfunction, for sure surgery is better in vestibular dysfunction treatment than not. Radiosurgery sure, failure or radiosurgery, certainly you should go into this group of facial nerve preservation surgery. And again, this is the whole concept of the hybrid treatments, subtotal resections. Facial nerves should trump gross total resection, no question about that. And of course, progression from radiosurgery, et cetera, should go again into facial nerve preservation. Cutting a facial nerve, I don't think there's any reason to do that, period. And here is the exciting part. I will leave you with this because I think that we need to start thinking like oncology surgeons. Charlie Wilson once told me that they feel there's no benign and malignant tumors in the brain, all brain tumors grow. Back then, I wasn't so sure that he was accurate. I mean, the guy of course, was the first person who got NIH funding for neurosurgery and that brain tumor research center we have here and we're so proud of has been continuously funded from the NIH for the past 50 years with a lot of money. So maybe there was something to it, and now in my older days, also, I figured out that yes, he probably was right in this. So this, obviously everybody knows Bevacizumab, Avastin, works for, well in this case, NF2 tumors that are recurrent, and this was the original study that the guys from, Plotkin, et cetera, from MDH did. But also there's a lot of other small molecule inhibitors. Lapatinib, imatinib, nilotinib, all of these had been tried with some effect on sporadic tumors. When you look at the data on meningiomas, and I do this on purpose, you see that the NF2 is the, the Merlin mutation is the most common mutation for all grade one meningiomas and for most grade two meningiomas, and this is the exact same mutation that vestibular schwannomas have. And then there's a host of other thing, the SMO and the AKT1, et cetera, and this is what we are doing. The trial we just kind of concluded here, multicenter trial for meningiomas. I think we need more of this. We need to really figure out what chemotherapy is actually, what small molecule inhibitors work on these things. And then we need to get away, frankly, from the just 30,000-foot level genetic alterations of mutations and go into the epigenetics. And that will bring me in a second to the next slides. But I want you to remember also this, it turns out the big part of the puzzle of failure of acoustic neuroma surgery is the following, and this is an important thing. Tumors that fail one treatment fail all treatments. Tumors which grow after your surgery, tend to not do very well with surgery. Tumors that grow after surgery, if you leave some residual tumor, don't do very well with radiosurgery either. So here's Doug's data and dates from Pittsburgh, tumor control rate with prior resection, 60%. Original tumors have more than 90%. In fact, more than 95% in most trials control rate longterm, why? So this goes back to the thing, well, not all these tumors are the same originally, or something happens with treatment. Now this was a thought that we have had, my group has had for a very long time. And I have pondered on this throughout this entire journey that I showed you here that I've been involved with. What happens to these tumors? Now, we know with glioblastomas, the work that Mitch and others have done here, that the bottom line is that, treatment say with tumor docking, hypermethylate the tumor and make them grow faster, et cetera. Something happens in this, and it could not be that treatment, either with surgery or radiation, genetically altered these tumors. I mean maybe, but it is just not very likely. These are not tumors likely, or blastomas that we see 30 and 50 and 60 different mutations in their genetic material by the time they recur in six months or eight months. So this gotta be something different. And the idea then, based on this, based on the fact that again, these are not, all these tumors are created equal. Then this, and you know, of course there's PDL1 expression in this, and this is the original study that Mike had done. So all of a sudden, we're starting to see an immune response in these tumors, just like we've seen other tumors and maybe it's an epigenetic change. And of course this is important, this was some data that we had for PDL1 with meningioma. Why it's important, because there's blockers of these tumors, like nivolumab, and others, pembro, et cetera. These are blockers of PDL1 and could be used. And this brings us kind of to where I will kind of conclude here. We looked at a number of acoustic neuromas, and this is David Raleigh's lab, he's one of my colleagues, also helps the Wolfe Chair on meningiomas now, radiation oncologist. Where we looked at many, 70 something tumors, that we had, which we resected and then we followed for a long time. And it turns out these acoustic neuromas, when you even look at it genetically in methylation profiles, they're very different. There is a group that has there is a group that has neural crest genes hypermethylated, and there's a group that has immune cells hypermethylated to the point that we have post-treatment. We find cells that become basically, tumor cells that become immune cells. That secrete immune IgGs. And so when you look at this, all of a sudden, the story starts being well, maybe, and this is now under review by nature, but maybe, just maybe, when you look at this, and I'm not gonna go into these details 'cause you can't even really read it. But what I want you to see is that maybe, and this is part, a small bit of it, of the radiation, radiation turns, post-microsurgical radiation turns on genes that had not been turned on before in these tumors. So epigenetic changes, that treatment incites in these tumors. Now, is it really treatment or is it the immune response of the treatment? Or are these tumors inciting this immune response to protect themselves like other tumors do? Who knows? But the bottom line is that these tumors, at the time of ending all these treatment, they look epigenetically different, different parts of them are hypermethylated and this is obviously key for what proteins are expressed. So even if they don't have genetic mutations, which never made sense that genetically we're changing these tumors by surgery or radiation in the short-term 'cause such low radiation never has done anything genetically to any cells really, but epigenetically, that makes sense. And such hormonal epigenetic locally, immunologically. And what we also did is when we look at this, we find out that there's two different groups of tumors, the tumors that are, that have the neural crest genes hypermethylated and the tumors that have the immune cells hypermethylated 'cause that can also happen originally before any treatment. These are two groups of tumors. And I think now the hypothesis we have is that you can take a neural crest derived tumor, neural crest enriched tumor, and switch it into the immune enriched tumor, which is actually the ones that are the bad actors, the ones that regrow quickly. In other words, it's an immune response within the tumor itself that causes these tumors to grow quickly, the remnants. Well, they look differently on imaging, and maybe, and this is an important paper when it comes out, because maybe, just maybe, we could predict this before surgery. Obviously after surgery, we know what they are, 'cause we can study their genome and epigenetics but how about before surgery, if we could do that. And when you look at it, they do separate quickly into two sets of tumors. And when you look at GPER methylation, and GPER is a protein in breast cancer that has been shown to be associated with recurrence. Well, when you look at that, and this was again, a fishing expedition originally, but it really gives data to understand what is different in these tumors? You see that there's very significant difference between the two groups, the groups that are immune enriched and neural crest enriched. So, I will conclude here, and I will say that what we've learned over the past 20 years on acoustic neuromas is a lot. But certainly, that if you take this entire experience with surgical treatment of acoustic neuromas is that as we went into the lesson, gross total resections of tumors, we have had higher rates of tumor progression, no question about that. Functional preservation surgery, which is leaving some tumor behind, on the facial nerve to prevent it's degradation of function, and hybrid treatment paradigms, which is basically to do that and then treat the remnant with something else, usually the radiosurgery, may upfront provide better facial nerve outcomes. However, we need longer term data. The longer term data often will suggest that it's a mixed bag for now. And that may be, because the subtotal or near total resection is not optimized, then I think that's the one bit that we as technical surgeons need to really focus on, how do we optimize that? And it may be because the timing of adjuvant treatment or radiosurgery is critical, and maybe it shouldn't be radiosurgery, or maybe we should be pre-treating these people before radiosurgery with immune mediators, who knows. It is no question that radiosurgery can turn these tumors epigenetically, no question. So can surgery. So tumors, as a conclusion, can and do grow post-treatment and post two treatments, and they can do that quickly. That there is now ample evidence from our data that molecular and epigenetic subtypes of acoustic neuroma, there's at least two of them, the neural crest one and the immune one, the immune enriched one. And finally, again, I would focus on this. I hope you got from this, that there's not one thing that is less than gross total resection, there's a lot of them. How do we get to that is our quest for acoustic neuroma surgeons. I think the quest is really that, the holy grail is where do you do it? What are the very specific technical aspects of it, of treating an acoustic neuroma micro-surgically, that optimize the surgical treatment of it. And then the downstream thing is, what are the aspects that optimize any adjuvant or salvage treatment that we have for them? And with that, I would like to say, look, this is 20 years or more worth of work that I certainly have not done on my own whatsoever. I've stood on the shoulders of some giants, John Tew, I mean, these are really very, very close people to me, Mitch, Mike, and of course, a lot of EMT folks, this is a mixed group of people that we need to continue these collaborations. And of course, a lot of fellows and residents and folks who are now big, good surgeons on their own, who I've had the pleasure of having them spend time with me. And I would end in that, and say that the story is certainly not complete. We understand a few more things than we understood before. Certainly our group here is pushing this to the next level. And I sure hope that we have collaborators around the world, probably, maybe some of you that will continue to do good work on that. And with that again, Aaron, this is an amazing forum, I think. I hope everybody utilizes this, I'm looking forward to actually learning for a lot of these things from others. And thank you for the kind invite.

- Thank you so much, Phil. Great talk, very worthwhile perspectives. For the sake of time, I'm gonna go ahead and just finish by thanking you for really a great perspective. The fact that functional preservation remains a critical part of acoustic neuroma surgery. And really the experience allows you to maximize resection, and minimize the amount of residual tumor, and preserve maximum amount of function. And that experience is so critical in acoustic neuroma surgery, and a gross total resection is not the first goal, it's functional preservation. So with that in mind, I wanna again thank you, and I look forward to having you with us in the near future.

- Absolutely. Thank you all.

- Thank you. Thank you.

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