Transcript
Good morning to everyone. I would like to start the first session this morning. Today, we have a different arrangement. It's a parallel session arrangement. This is the main session room here. If you would like to listen to the physics part, yeah, you have to go to the lecture next door. I don't mind if you leave. This is sort of...because quite interesting the talks over there. And anyhow, we also hope that we can present you a good session for AVMs, yeah. And that's the kind of situation. And we have 90 minutes' time. I urge everyone to keep to the time, including myself, otherwise, the power is cut. Yeah. So not like yesterday because we want with the parallel session arrangement, we want everything so that you can have the coffee together and everything else, yeah. And later on, there will be a closing ceremony, and that will be in this area.
So, okay. I have to advance. I'm all ready. "Management News for Patients with AVM." Is there any question of the right indication, true or false? For me is now I'm not really not going to present many of our own data. We have quite a big experience on that, but it's more or less I want to present a little bit food for thoughts. So, what we are really talking about is AVM risk of bleeding at diagnosis. You see the horizontal red line in this situation. And most interest for us is those AVMs that had a hemorrhage at presentation, deep location, deep drainage, and hemorrhage at presentation, plus the volume. And these questions will be all addressed during this meeting together with quite even so important questions about how do you target delineation, and everything else? Because a little bit the crux of that what we do is that quite often we don't really treat the nidus.
So this is the finished data that's almost now...there 1942 to 2005 showing again what is really matters and over that time. And I looked at natural history of brain AVM malformation, a long-term follow-up study of 238 patients, and they analyzed rapture, large size, deep location, infratentorial as risk factors for that, yeah, and the venous drainage that was not that conclusive. And then we had to face ARUBA, yeah, on that kind of situation. I also was part of this ARUBA study. And my neurological colleague who runs our neurological college, he analyzed and published about five papers about the database, the New York database. And so we also had a lot of discussion in our weekly rounds, yeah, when we talk about AVMs, yeah. And the ARUBA study did teach us, yeah, some important things. But there was already, yeah, quite kind of criticism about...And when we look at this, only certain percent of screen patients were randomized, imbalance in randomization of subtypes based on Spetzler Martin grade. Patients were followed up only for 33 months by that time, too short, lack of a standard plan for therapy, more than 10% for Spetzler Martin grade, 4, 25% Spetzler Martin grade, 3, underpowered and selection bias in the treatment modality, that's what we...neurosurgery alone, 5, embolization alone, 26%, that means 30, radiotherapy alone or radiation, 31. And there are multiple new studies evaluating ARUBA eligible patients showed better outcome with different situations.
These are the five-year results that we have in the moment, but the analysis has stopped because there's no more funding presented by Stapf, a randomized trial of unruptured, that means a little bit longer follow-up. The only thing where I would like to highlight to you on this is when we look for radiotherapy, any kind of radiotherapy, then we only had 12 patients, that means about 52 patients, and 50% of them or 40% had prior embolization and the short follow-up. So, the obliteration rate for radiation has been documented to be the lowest in this cohort. And that...yeah, a lot of colleagues did just take that face value, not taking into account really what it means. And also...we see that also later on, what in the literature, what is really obliteration, or close to obliteration, or anything like this, yeah.
And we have, from seeing here, kind of situation. I've brought this table out there. These are post-SRS data from seven centers with a mature follow-up. And based on 232 patients, which were ARUBA eligible, was marginal dose of 22.5 gray, and our hemorrhage rate after radiosurgery was 1% radiation-induced changes, symptomatic 8%, permanent 1%, and favorable outcome 76%. What does that mean, yeah? But on the other hand, okay, it shows, yeah, they do somehow better because we don't have obliteration in Europe, yeah. So in Germany, we have a national guideline. I would like to highlight that to you that the data acquisition for ARUBA, that means, for example, radiosurgery is not complete yet, long-term follow-up not available, no sub-group analysis available for complication risk factors if it is not possible to derive final treatment recommendation from this study. However, in the light of these so-called first results with so-called high evidence for ARUBA prophylactic treatment for non-ruptured AVMs should be restricted to careful selected cases with high cumulative hemorrhage risk.
We come to this, kind of, situation. You only should irradiate the nidus. And these are all observation, target delineation, which is inadequate, 2 vessels vs 4 vessels, super-selective angiography and obscuration of nidus by hematoma, but also embolization material, 26% to 67% of the failures due to targeting error. And what is quite important, and we have two speakers who will address that, is certainly optimal identification of the nidus, which is critical. And we always see that there's significant inter-clinician, yeah, contouring variability based on 3D only, and only 2D dynamic flow allowed to distinguish effluent and affluent vessels. That is somehow shown here. We will hear about that a little bit more later. And the localizer for co-registration of Angiographic 2D with 3D data. These are challenges. The nidus defined on 2D data transferred to this 3D image as ellipsoid, verification and fine-tuning on 3D data, and desired dose homogeneity through Dynamic Conformal Arcs and frameless positioning especially for Hypo-Fractionation, that means dose or volume-stage treatment for large AVMs.
And what we really don't know, and I already alluded to that a little bit adverse effects, we have imaging adverse effects that is shown, yeah, in about 72%. And we have so-called symptomatic adverse effects, and you can never count. And certainly the colleagues from Pittsburgh and the published data, and they showed also the V12, but also dependent on the area where you treat is almost unimportant. What kind of volume you treat, you may be facing symptomatic situations. This is one of my patients that I treated many years ago, just under 1 cube-centimeter, 8-year-old girl, and six months later after the treatment, left thalamic. She developed a thalamic hand, and we had to struggle at least for one and a half years, yeah, to get her better in this kind of situation that was two years the kind of and that state even for a longer time, but the thalamic hand luckily recovered. And that was simply easy radiosurgical case in terms of dose prescription, yeah. Marginal dose 18 gray, 18 gray to the 80%, and that was kind of situation.
Then we come to the kind of situation, "Multimodality Treatment of Giant Intracranial AVMs." And I've got here from the San Francisco group and Chang, Steinberg on there. And I looked at the kind of situation in these two...three paper cure in about only 36%, morbidity, 15%, mortality about 15% in the same row, and the mean size was about 6.8 centimeters in that study. So, and then the Antonio De Salles group's paper on hypofractionation, 20 patients, 50% prior embolization, no complete obliteration, but his data or his study was also not aimed at complete obliteration. It was more aimed to turn AVMs management by radiosurgery or surgery, AVMs, the volume decrease, he showed it quite nicely, 44%, 5% to 6% seemed to be better than 6% to 5%, and prior embolization seemed not to be beneficial.
So, and sometimes you're faced with this kind of situation about...yeah, that's 46 cubic centimeter, 12-year-old boy with recurrent hemorrhages, epilepsy, split-brain syndrome, and what to do in this case, just leave him alone or doing something? Okay. What is now? Okay. By that time, that was one of our first cases that we treated was hypofractionation as the only treatment. We have got a different aim. We want to obliterate at that time not to get it smaller. That means a complete result. What was new to us? This large AVM, yeah, showed at the follow-up of eight months MRI scan almost disappeared nearly completely, the draining veins and everything else, but what we did see here kind of situation? That means also the increased signal on the MRI scan. This was 48 months later, complete disappearance and also partial resolution of the neurological symptoms, especially split-brain.
This is another one in infratentorial AVM, yeah, also close to 50 cubed centimeters that were treated, also quite interesting because we did see the same increased signal in this kind of situation after 12 months. And this is the fastest response that I have ever seen in AVMs, yeah, even comparing small ones that were treated by radiosurgery and hypofractionation, at least in our hands, responds faster. The volume shrinks faster, somehow. This is only our observation, yeah, and in the moment, yeah. And this is the kind of situation at 60-months follow-up, yeah, complete resolution of the AVM, but it almost looks as if we have cut the cerebellar peduncle on that side. That's the left side in this kind of situation. He had some neurological symptoms. Initially, he had dysarthric speech, and later on, he recovered a little bit from dysarthric speech, but he had some other problems that means keeping balance and coordination. He learned it.
There's another way. So, I told you we do hypofractionation. We aim, at least in our group, for obliteration. There's again, group from Francisco here, San Francisco, they look for volume-stage SRS. And I have got two eras. The first volume stage was...the interval was 5.8 months, 50 ml per stage, and 15.5 gray, 29% complication. They, later on, made it smaller per stage and the interval shorter, 17 gray dose higher, and the complications went down. That's their observation. They tried also...they were also by the group from Virginia together with some others. They looked at the kind of situation at the literature and tried to derive something from it. These are typical papers on that, and, like, it did come up with the so-called complete obliteration in volume stage and dose staged, volume stage was higher, adverse radiation effects, same, re-bleeding, obviously, little bit lower in dose stage, mortality was similar in both of them.
So, yesterday, we heard already about this kind of situation. This is also what is going to happen, adverse effects. What do you do? Do you do steroids? Do we want to have steroids in this kind of situation? Or do you do Avastin? It also works in that. We published that. You can dig that out in literature. It's in the journal for "Pediatric Neurosurgery," yeah, because it was a pediatric patient, and that book went well. What is really now, and we don't...up to now, don't pay really attention to it is probably that immunotherapy will also reach the treatment of AVMs, and I really hope so because a lot of what we see and what we believe in the moment, for instance, the increased signal, we believe that that may have something to do with inflammation. We anyhow have got inflammation in AVMs, but there are certainly...there are factors, growth factors, experimental therapeutic, and genetic syndromes in this kind of situation.
This is also general of neurosurgery. And this is when you look at AVM thrombosis after radiosurgery plus the so-called lipopolysaccharide, and soluble tissue factor conjugate about 60%, 12% radiosurgery only, and 43% was the same factor. No systemic toxicity or intervascular thrombosis remote from targeting any of the animal groups. And here, the group from Australia, they identified also a fair number of factors which may play a role in vascular targeting and radiation-induced information, fibrosis, and autoimmunity. And I think this is probably, later on away that we will have to go and when we are treating AVMs and we are facing kind of situation. Thank you.
So, okay. I have to advance. I'm all ready. "Management News for Patients with AVM." Is there any question of the right indication, true or false? For me is now I'm not really not going to present many of our own data. We have quite a big experience on that, but it's more or less I want to present a little bit food for thoughts. So, what we are really talking about is AVM risk of bleeding at diagnosis. You see the horizontal red line in this situation. And most interest for us is those AVMs that had a hemorrhage at presentation, deep location, deep drainage, and hemorrhage at presentation, plus the volume. And these questions will be all addressed during this meeting together with quite even so important questions about how do you target delineation, and everything else? Because a little bit the crux of that what we do is that quite often we don't really treat the nidus.
So this is the finished data that's almost now...there 1942 to 2005 showing again what is really matters and over that time. And I looked at natural history of brain AVM malformation, a long-term follow-up study of 238 patients, and they analyzed rapture, large size, deep location, infratentorial as risk factors for that, yeah, and the venous drainage that was not that conclusive. And then we had to face ARUBA, yeah, on that kind of situation. I also was part of this ARUBA study. And my neurological colleague who runs our neurological college, he analyzed and published about five papers about the database, the New York database. And so we also had a lot of discussion in our weekly rounds, yeah, when we talk about AVMs, yeah. And the ARUBA study did teach us, yeah, some important things. But there was already, yeah, quite kind of criticism about...And when we look at this, only certain percent of screen patients were randomized, imbalance in randomization of subtypes based on Spetzler Martin grade. Patients were followed up only for 33 months by that time, too short, lack of a standard plan for therapy, more than 10% for Spetzler Martin grade, 4, 25% Spetzler Martin grade, 3, underpowered and selection bias in the treatment modality, that's what we...neurosurgery alone, 5, embolization alone, 26%, that means 30, radiotherapy alone or radiation, 31. And there are multiple new studies evaluating ARUBA eligible patients showed better outcome with different situations.
These are the five-year results that we have in the moment, but the analysis has stopped because there's no more funding presented by Stapf, a randomized trial of unruptured, that means a little bit longer follow-up. The only thing where I would like to highlight to you on this is when we look for radiotherapy, any kind of radiotherapy, then we only had 12 patients, that means about 52 patients, and 50% of them or 40% had prior embolization and the short follow-up. So, the obliteration rate for radiation has been documented to be the lowest in this cohort. And that...yeah, a lot of colleagues did just take that face value, not taking into account really what it means. And also...we see that also later on, what in the literature, what is really obliteration, or close to obliteration, or anything like this, yeah.
And we have, from seeing here, kind of situation. I've brought this table out there. These are post-SRS data from seven centers with a mature follow-up. And based on 232 patients, which were ARUBA eligible, was marginal dose of 22.5 gray, and our hemorrhage rate after radiosurgery was 1% radiation-induced changes, symptomatic 8%, permanent 1%, and favorable outcome 76%. What does that mean, yeah? But on the other hand, okay, it shows, yeah, they do somehow better because we don't have obliteration in Europe, yeah. So in Germany, we have a national guideline. I would like to highlight that to you that the data acquisition for ARUBA, that means, for example, radiosurgery is not complete yet, long-term follow-up not available, no sub-group analysis available for complication risk factors if it is not possible to derive final treatment recommendation from this study. However, in the light of these so-called first results with so-called high evidence for ARUBA prophylactic treatment for non-ruptured AVMs should be restricted to careful selected cases with high cumulative hemorrhage risk.
We come to this, kind of, situation. You only should irradiate the nidus. And these are all observation, target delineation, which is inadequate, 2 vessels vs 4 vessels, super-selective angiography and obscuration of nidus by hematoma, but also embolization material, 26% to 67% of the failures due to targeting error. And what is quite important, and we have two speakers who will address that, is certainly optimal identification of the nidus, which is critical. And we always see that there's significant inter-clinician, yeah, contouring variability based on 3D only, and only 2D dynamic flow allowed to distinguish effluent and affluent vessels. That is somehow shown here. We will hear about that a little bit more later. And the localizer for co-registration of Angiographic 2D with 3D data. These are challenges. The nidus defined on 2D data transferred to this 3D image as ellipsoid, verification and fine-tuning on 3D data, and desired dose homogeneity through Dynamic Conformal Arcs and frameless positioning especially for Hypo-Fractionation, that means dose or volume-stage treatment for large AVMs.
And what we really don't know, and I already alluded to that a little bit adverse effects, we have imaging adverse effects that is shown, yeah, in about 72%. And we have so-called symptomatic adverse effects, and you can never count. And certainly the colleagues from Pittsburgh and the published data, and they showed also the V12, but also dependent on the area where you treat is almost unimportant. What kind of volume you treat, you may be facing symptomatic situations. This is one of my patients that I treated many years ago, just under 1 cube-centimeter, 8-year-old girl, and six months later after the treatment, left thalamic. She developed a thalamic hand, and we had to struggle at least for one and a half years, yeah, to get her better in this kind of situation that was two years the kind of and that state even for a longer time, but the thalamic hand luckily recovered. And that was simply easy radiosurgical case in terms of dose prescription, yeah. Marginal dose 18 gray, 18 gray to the 80%, and that was kind of situation.
Then we come to the kind of situation, "Multimodality Treatment of Giant Intracranial AVMs." And I've got here from the San Francisco group and Chang, Steinberg on there. And I looked at the kind of situation in these two...three paper cure in about only 36%, morbidity, 15%, mortality about 15% in the same row, and the mean size was about 6.8 centimeters in that study. So, and then the Antonio De Salles group's paper on hypofractionation, 20 patients, 50% prior embolization, no complete obliteration, but his data or his study was also not aimed at complete obliteration. It was more aimed to turn AVMs management by radiosurgery or surgery, AVMs, the volume decrease, he showed it quite nicely, 44%, 5% to 6% seemed to be better than 6% to 5%, and prior embolization seemed not to be beneficial.
So, and sometimes you're faced with this kind of situation about...yeah, that's 46 cubic centimeter, 12-year-old boy with recurrent hemorrhages, epilepsy, split-brain syndrome, and what to do in this case, just leave him alone or doing something? Okay. What is now? Okay. By that time, that was one of our first cases that we treated was hypofractionation as the only treatment. We have got a different aim. We want to obliterate at that time not to get it smaller. That means a complete result. What was new to us? This large AVM, yeah, showed at the follow-up of eight months MRI scan almost disappeared nearly completely, the draining veins and everything else, but what we did see here kind of situation? That means also the increased signal on the MRI scan. This was 48 months later, complete disappearance and also partial resolution of the neurological symptoms, especially split-brain.
This is another one in infratentorial AVM, yeah, also close to 50 cubed centimeters that were treated, also quite interesting because we did see the same increased signal in this kind of situation after 12 months. And this is the fastest response that I have ever seen in AVMs, yeah, even comparing small ones that were treated by radiosurgery and hypofractionation, at least in our hands, responds faster. The volume shrinks faster, somehow. This is only our observation, yeah, and in the moment, yeah. And this is the kind of situation at 60-months follow-up, yeah, complete resolution of the AVM, but it almost looks as if we have cut the cerebellar peduncle on that side. That's the left side in this kind of situation. He had some neurological symptoms. Initially, he had dysarthric speech, and later on, he recovered a little bit from dysarthric speech, but he had some other problems that means keeping balance and coordination. He learned it.
There's another way. So, I told you we do hypofractionation. We aim, at least in our group, for obliteration. There's again, group from Francisco here, San Francisco, they look for volume-stage SRS. And I have got two eras. The first volume stage was...the interval was 5.8 months, 50 ml per stage, and 15.5 gray, 29% complication. They, later on, made it smaller per stage and the interval shorter, 17 gray dose higher, and the complications went down. That's their observation. They tried also...they were also by the group from Virginia together with some others. They looked at the kind of situation at the literature and tried to derive something from it. These are typical papers on that, and, like, it did come up with the so-called complete obliteration in volume stage and dose staged, volume stage was higher, adverse radiation effects, same, re-bleeding, obviously, little bit lower in dose stage, mortality was similar in both of them.
So, yesterday, we heard already about this kind of situation. This is also what is going to happen, adverse effects. What do you do? Do you do steroids? Do we want to have steroids in this kind of situation? Or do you do Avastin? It also works in that. We published that. You can dig that out in literature. It's in the journal for "Pediatric Neurosurgery," yeah, because it was a pediatric patient, and that book went well. What is really now, and we don't...up to now, don't pay really attention to it is probably that immunotherapy will also reach the treatment of AVMs, and I really hope so because a lot of what we see and what we believe in the moment, for instance, the increased signal, we believe that that may have something to do with inflammation. We anyhow have got inflammation in AVMs, but there are certainly...there are factors, growth factors, experimental therapeutic, and genetic syndromes in this kind of situation.
This is also general of neurosurgery. And this is when you look at AVM thrombosis after radiosurgery plus the so-called lipopolysaccharide, and soluble tissue factor conjugate about 60%, 12% radiosurgery only, and 43% was the same factor. No systemic toxicity or intervascular thrombosis remote from targeting any of the animal groups. And here, the group from Australia, they identified also a fair number of factors which may play a role in vascular targeting and radiation-induced information, fibrosis, and autoimmunity. And I think this is probably, later on away that we will have to go and when we are treating AVMs and we are facing kind of situation. Thank you.