2015 Pituitary Network Association Conference
Dr. Daniel Kelly discusses the surgical management of pituitary tumors using the endoscopic
Good afternoon in the morning. So how many of you in the room have had pituitary surgery? Okay, so lots of you. So you you you know you know what it's like, potentially I'm gonna talk to you. This is gonna be a sort of a general talk on on the the use of endoscopic pituitary surgery. Um and and the objectives I think are two for you to understand the indications, um learned the goals of, of pituitary tumor removal, learn how the endoscope can help us in terms of visualization and then appreciate some of the nuances and then also realized the limitations and the potential complications of endoscopic pituitary surgery. So you've seen probably quite a few slides about the anatomy and I'd say by the afternoon, you probably all are experts on on pituitary anatomy. Um No, noting that the pituitary gland is really um surrounded by a lot of key structures, notably the carotid arteries, the nerves that that move the eyeball and for facial sensation. Um and then also the optic chasm which sits directly above the pituitary gland. Here's a side view showing how the carotid artery loops around on the outside of the gland here provides its blood supply, but can be very, very close and that's something that we have to pay a lot of attention to when you have a tumor. Um The uh the gland. These are mris looking straight on at the patient. So this is the right side and this is the left side, You can see the pituitary stock, you can see the gland here in a little micro adenoma, right next to the carotid artery. Those two dark circles are the carotid arteries. Um This is the heir and the spare annoyed sinus. And here's a slight somewhat bigger tumor, a macro adenoma that's pushing the gland way over to the right side here and the optical ASM is lifted up. And then here's a very big macro adenoma where the gland is extremely thinned out. Uh and a very large tumor that's going out over part of the carotid artery here. That tumor, if you were to image it right along here, you would have tumor out in this area behind the carotid artery. So the the imaging and understanding anatomy are obviously key. Um and we spend a lot of time looking at these images and trying to understand how the gland has been distorted. So there's obviously pituitary tumors are the most common tumor in the in the neighborhood. Um But there's other things wrath these cliffs, cysts which some of you may may have had or have where the gland is really surrounding this in this assist. Um Then there are cranial fringy aromas which are benign tumors but very invasive and get stuck to all sorts of things and the optic nerves, Blood vessels usually the gland is down here and the cranial friends aromas go back towards the brain and the hypothalamus and they often push the optic chasm forward and then there are many NGO Mazz which come from the coverings of the brain. And they often push in this region, they can push the pituitary gland down uh very common location. They often cause visual loss more than pituitary problems. And then there's some other tumors of the skull base. This is called a chordoma, a more of a malignant tumor. Um that often can get around and under the the pituitary gland. So in terms of what our management opportunity options are for pituitary tumors for the majority of them, it's transformational surgery as you know. Um And we really transitioned over to this indo nasal endoscopic approach. We do use radiation for some tumors. Um And we use medical therapy for many that we can't cure and we'll talk a little bit about that. Um But transformational surgery is the mainstay for most pituitary tumors. Um And there's many things that we see. So many people get MRI's for other reasons now. Um And then you may find something and there's many what we call incidental lomas are small lesions in the pituitary that we just don't operate on. So we looked specifically at pituitary adenomas. As I said for all of the major subtypes except prolactin omagh's surgery is the main state. So if you have a prolactin oma, most of the time those patients are treated at least initially with Bruno krypton or now cat burgling and has a very very high success rate and safety profile. But for all of these other things including bleeding into the pituitary from a pituitary tumor, so called pituitary apoplexy. The first line therapy we go to is surgery. So what are the goals? We want to selectively take the tumor out? Uh We to eliminate hyper secretion. So if you're making too much growth hormone, too much a c th too much prolactin, we make that normalize the rare thyroid stimulating hormone. Same goal. Get all the tumor out so that this hyper secretion syndrome goes away. We want to reduce mass effect. So the pressure on the optic nerves. Um We want that to go away the pressure on the gland. We want that to go away. Um And a lot of these larger tumors cause headaches and there's a pretty good rate of headache resolution by taking out large tumors. And of course we want to preserve the gland function or improve it or restore it and we can do that a fair amount of time. And obviously we want to avoid complications. And what I like to say to you all the patients, we like to sneak in and sneak out and not get caught. And we try to do that all the time. And so I would say certainly over the history of pituitary surgery, which now has been around for over 100 years. We've really come a long ways with the the use of the microscope dr hardy from Montreal was the first one to describe selectively removing a tumor and sparing the gland. Um So that hasn't actually been around for that long. We started going just through the nose instead of the sub labial approach under the lip Um extended approaches or what we call, where we go beyond the pituitary to say other other tumors out outside the realm of the Gland. And then this realm of endoscopic surgery which has been around now for for over 15 years, almost 20 years. The reason we switch to the endoscope is simply because we can see better. And this is a diagram of cartoon showing the view you get with the operating microscope which sits out the outside the nose. And you get this beam of light through a speculum going down to the cellar where the where the gland and the tumor is. And you get this very focused, very nice view right here. But you don't see a lot with the endoscope where you bring the scope in into the nasal cavity and then the solenoid sinus you get this very big much more panoramic view. And so to do that though you need a team approach and so someone has to drive the endoscope um to provide the view. And then that allows the surgeon to operate. So this is dr dr griffiths, my E. M. T. Partner many of you know um We have so we have um two monitors that we're looking at and our navigation in the middle. And the endoscope usually sits at the top of the of the nostril and the instruments are just underneath. Um So this sense of teamwork is key. And we we talked about this a little bit of a bit earlier today and and again this multidisciplinary approaches is really essential. So for most patients uh pituitary adenoma surgery, it's three or four hours of surgery. It's um this isn't considered not too much blood loss. Most people can handle this without an issue. We don't use nasal packing very often. Although sometimes we do we typically do some imaging and M. R. I. Often on day one. Sometimes we do a cat scan right after surgery. Most people are going home within two days of surgery and now more and more days we're sending people home on day one. Um And and that's a that's a nice thing for people to get out of the hospital quickly. We check up on electrolytes and their cortisol level after that and they come back and see us and C. R. E. N. T. Colleagues within the 1st 10 days. Um They usually have an endocrine follow up within about 2 to 3 weeks. Um We say, as you've all heard, we don't like you to do strenuous activity for about a week. You can typically fly after 7 to 10 days and after three weeks you can do whatever you want, anything goes. So um here's the the approach um that we do now. It's a mucosal uh sparing or preserving approach where we make a wide opening into the solenoid solenoid bone here and we make a wide bony opening of the seller here. This is showing the carotid arteries. We like to get right up to the edge of the carrots. Um And uh that's really important for adequate exposure. So this is the initial approach, basically an incision in the mucosa that gets pushed down. We remove the bone here, then we remove the bone here and that's our trajectory. Um And this is really the beauty of the microscope of the endoscope over the microscope. So this is an image looking in with the microscope. Um There's a speculum down the nostril. Um You can see some instruments here. That's the door, a pretty good view right here. But when we look at the same structures with the endoscope in we get this much more um panoramic view. You can see out beyond the bone edges. We can see where the carotid arteries are living under the bone, see where the optic nerves are hiding behind the bone. And this is really why we've switched over to this methodology of visualization. And so here's just this up close view. We get this is just opening the door of a very large tumor that's protruding out into the solenoid sinus here. Um And cutting away some of that involved dura there and then beginning the tumor removal. And you can see there's one instrument coming in from the left nostril one coming in from the right and the endoscope is held back here? I'm giving us that that beautiful view. So it is it does require some amount of teamwork and maneuverability. And so really this approach now has become the approach for many of these midline skull based tumors beyond the pituitary adenomas. So for cranial fringy aromas, meningioma, chordoma as um these are this is really the way we we go now. Um but the question is, are we doing a better job? Are we getting more tumor out? Are we preserving the gland function more? Are we having fewer complications? Just because we're using the endoscope. And the answer is, is a little complicated and I'll try and explain that to you in terms of complications, whether we go through the through a microscopic approach or an endoscopic approach, um there's there's many ways we can um get into trouble and the way we want to stay out of trouble. So, these are important factors. Are you operating on the right patients? Do you have the appropriate experience and instrumentation? There's things that can go wrong during the approach through the nose and into the solenoid sinus? Obviously working around the carotid artery is an important issue and something we keep in mind every time. And then how do we take the tumor out and how do we work to preserve the gland and make sure that the gland works well. And then finally our exit strategy, how do we get out? As you know, in many patients, we see some cerebral spinal fluid when we take the tumor out and this has to be repaired. Otherwise, people can get a postoperative spinal fluid leak. They can get meningitis and other problems associated with that. So there's a, there's a lot of potential things that can go wrong and have all been very uh well documented in the literature. And I've certainly had every one of these complications. Um, and we we learned from our errors and our mistakes and we're constantly trying to do better. Um, this is the use of the Doppler where you can see here, we're listening for the carotid artery before we open the dura here and the Doppler is essential, I think for, for safe wide exposure. And you can see here, we're looking um, and really mapping out where it is. So that when we open the dura, we know that we're not opening directly over the carotid artery. And so we do that on every case. And then this is what it looks like when we're actually, and then this topic doing here. So we know that this whole area is a safe zone here. And if you don't know where it is, you tend to be more conservative. Uh, if you don't have the doctor, you're going to say, well, I'm not sure where it is. Let's make sure, so you might do a lesser exposure. And ultimately that may mean that you get less tumor out. So the use of the doctor I think is very key. So let's look at some of the different tumor types. If we start with a nonfunctional or endocrine inactive tumors. Um uh We do quite well with those in in most cases. So this is an endoscopic approach removing this macro adenoma here you can see the gland is thinned out. That white band is the gland. And right here we're seeing the gland and we're pushing the gland up and we're doing what's called a pseudo capsule er dissection. There's a capsule of the tumor that's actually a rim of compressed normal gland and we can use that to grab on to it. Sometimes it's very soft and falls apart. But in a case like this um It's actually a great way to try and get the entire tumor out. So we're just gently pushing the tumor up. And then we're using an angled scope that's looking up more by 30° and we can see the top here, this is the Gland. This is the tumor. And then in some of these cases we can take the whole tumor out like this in one piece. Now of course they don't all come out that easily. That's the one I'm going to show you. Um But that is the beauty of the endoscope and we this is a view you can't get with the microscope because the microscope comes in like this. It's it's tunnel vision. Um And so this is again that the utility of the scope. Um This is putting some fat in from the abdomen to help prevent a spinal fluid leak. This is some synthetic collagen actually. It's not synthetic. It's bovine flexor tendon um that we put in on every case. It's a scaffolding for for scar tissue growth. And and then a a a buttress. And this is an absorbable plate that we put in now more and more. We actually use a bit of the posterior nasal septal bone that we have to remove anyway um for the exposure. And we use that. So we try to go on natural on this. Now, we don't like to use um things from from elsewhere. So that's a typical removal of a macro adenoma. And you can see the result here. So the gland was pushed way up here. Like so and now it's down here. This is actually the fat that we put in. And you can see the gland is thicker and you can see the pituitary stock now is longer because the glands come down. And so the gland is much much happier um Here's uh An invasive tumor. So the question is because we can see so well with these angled endoscopes, can we get tumor out of the cavernous sinus here. And in fact, we can we can get some of that tumor out. You can see here. This is a year after surgery. That tumor that was there is now appears to be gone. But we probably didn't get 100% of it. This is a nonfunctional tumor. So it's not such a big deal. But this is someone we're going to have to watch for years because the tumor that's out here may definitely grow. When we looked at our experience over um, a long time doing it with the microscope and then putting the endoscope in, going as far as we could with the endoscope, We looked at our results 140 patients. And what we found was that when we went as far as we could with the microscope in a in a given case. And then in that same code case we put the endoscope in. We found in over a third of patients. We we were able to see additional tumor that we couldn't see with the microscope. And it was very size dependent. And you can see with the smaller tumors. It was only about 20%. But as you get to these bigger tumors and over half the cases overall, we were seeing additional tumor that we couldn't see with the microscope. So that suggests that this enhanced visualization we get with the endoscope is really an important important thing. Another paper that came out a few years ago showed similar things when they compared their microscopic experience to their endoscopic experience. And they basically showed an increased rate from 50 Complete removal to 72% when they went from the microscope to using an endoscopic technique. But again the difference was bigger um with uh larger tumors. So we found similar things and others have found found the same. Now we can't take all tumors out completely. The big tumors. There's some we just can't take out. Here is an example of a patient with a very large what we would call a giant adenoma over four centimeters in size. Um It's this was a patient that I saw many years ago at U. C. L. A. She just refused to have surgery. Um She came back because the tumor kept growing. Her vision was getting worse And she eventually acquiesced and did the right thing. And as you can see here um we didn't get all the tumor out. We got probably about 90% or 85% by volume. But we left this part around the carotid artery. And because we knew this was going to keep growing. She got stereotype Actiq radiotherapy which is fractionated radiation that she got over about 30 treatments Over about six weeks. And she's now more than three years out and the tumor is very stable in size. And and that treatment has about a 95% or greater success rate. So it generally works extremely um extremely well for these tumors that we can't completely remove. And there's a fair amount of literature on giant pituitary adenomas um including work from us here and all of the studies show a similar thing. Um These are fairly recent papers And they all show that the complete removal rate in general is is under 70%. So we're gonna leave tumor around in a lot of these patients and probably microscopic tumor in the majority. And so sub total removal is probably the rule, not the exception. Um And many of these patients will need additional treatment like radiation or medical therapy and many of them will go on to develop pituitary gland problems that will require hormone replacement. So what about acromegaly? Well, there have been some recent studies comparing the endoscope to the microscope and this is from the University of Virginia where they have a very good pituitary program. That's where Ed Laws was my my mentor. Um And uh now john Jane Jr and at Oldfield are there, they're outstanding. Very seasoned pituitary surgeons And they compared their two results together. Um So they basically divided up with dr jane doing the endoscopic approach and dr Oldfield who is a little bit older and old school did the microscope. And all of the real advocates and fanatics about endoscopy would say well dr jane is clearly going to do better. Well the reality is he didn't do better. They basically did the same. Um They had similar rates of complications and remission rates. So um there was no evidence of increased tumor removal or remission in the patient's um, whether they were operated on endoscopic lee or microscopically. Um, so that's a very interesting thing. And it probably is because a lot of these tumors are invasive. They get out into areas where it's hard to see. And so you may look, it may look like the entire tumor was removed, but there's probably microscopic tumor unless you get 100% out. The patients don't go into complete remission. And so this is an interesting study in an important study. What we can say though about surgery and acromegaly is that the more tumor you get out, the more likely someone is to respond to Samantha status and logs like Austria tied or some actually. And I don't know how many of you are on these drugs, but these are the common drugs used to treat acromegaly. And this study clearly shows that if you can get At least 75% of the tumor out that the patients are more likely to have a good response to these medications. So this combination therapy is an important concept. Prolactin. Omagh's, As we said, most prolactin Omagh's, we don't operate on they get treated with Coburg line or Dawson X. Now. Um, and the reason being is because this is the typical response here's a patient who came in with visual loss from this large tumor And hypogonadism, meaning his testosterone was low, his prolactin level was over 8000. The normal prolactin level is less than 20. So 8000, that's pretty high, Very big tumor over four cm. He had visual loss um within two months of being on Dustin X. His tumor shrunk that much. So that's from january to March. And his prolactin level dropped by about 80%. More than 80%. Very impressive. We went up on his dose of Dawson X And by November 2013, you can see the tumor is really almost gone. Um, so nothing to do with surgery here. Um, He still doesn't have a completely normal prolactin, but this is a very good response to medication and that's why we don't operate on a lot of these. Um, so what are the indications um, for prolactin oma? Um, Ineffectiveness or intolerance of, of dopamine agonists, micro autonomous or a small, non invasive tumor. And some patients who just don't want to be on medical therapy. Some, some people say, I just don't want to take a medicine if you have an 80% chance of getting the tumor out and me being off medication, let's go with that. Um, The occasional prolactin oma during pregnancy. Um, these are known to get bigger during pregnancy. And so if we saw that, we would probably remove that, we've had to do that on occasion and then someone with bleeding into the tumor or rapid visual loss. Those are patients in whom we will do surgery. So here's a patient that had a mixed tumor, You know, not all these tumors are completely straightforward. This a patient who had high prolactin and high I. G. F. One a combination of a co secreting tumor, both prolactin and growth hormone. Um So a little bit of acromegaly, a little bit of prolactin oma. Um But because of this, we figured that this patient would do better. This is a large tumor also causing visual loss. We could immediately improve his vision with surgery. Um And we could get the vast majority of the tumor out. Probably not all of it, but it would likely make medical therapy better. Just the rest of his hormones showing his testosterone is low is thyroid was low. And here's the surgery. That's the Doppler. Um This was a tumor that as you can see, it's quite soft and under a lot of pressure here. I'm very typical looking of a of a growth hormone secreting tumor. Um Often sort of like um like custard I guess would be 11 texture you might think of. Um And these soft tumors are are nice remove this one didn't have a nice pseudo capsules, just sort of spilled out as you can see. And these can actually be more challenging because as you take the tumor out this membrane here starts to come down because of the normal pressure of the brain and we have to work around this sort of balloon of cerebral spinal fluid and make sure that we don't puncture it or put a hole in it and create a spinal fluid leak, which sometimes we do. But obviously we can avoid that. We want to, the normal gland is now way over here on the left side and we're working through all these folds to take the tumor out. Now, we're working up in this part over here where the tumor is a little bit more fibrous and rubbery. We're listening for the carotid there with the Doppler and just going as far as we can to try and get the maximum amount of tumor, knowing that we're probably not going to cure the patient with surgery. But if we can take the pressure off the gland, take the pressure off the optic nerves and get as much tumor out, good chance for gland recovery for vision recovery. And uh probably will respond better to medical therapy. And so that's the that's the finished product there. And he did do quite well. This is his immediate post op scan. You can see we put a fat graft in there, you can see the gland over here, There's probably some residual tumor around the parotid here that we couldn't get out. Um But on post op day one, his prolactin dropped by more than 95%. So from 1200 down to 53 had a normal cortisol levels, which means the gland is functioning well. So that's all good news. and here he is now 10 months out and he's just on a very low dose of destiny for Coburg line and his prolactin is normal at five. He's refusing testosterone therapy for some reason. Um And that's come up but it's still low. Um And his I. G. F. One which was high is right smack in the in the normal range. And this is his scan here, so his gland is recovered, his vision is recovered and he's on a very low dose of medical therapy. And this is where this team team effort with the endocrinologist and the neurosurgeons is so important. But if you look at the endoscopic data and there's not a lot of it basically patients with operate on fully endoscopic li we do very well with the micro autonomous and achieving remission 94%. But in the macro adenoma is only about 40% or less. So same as with the microscopic series. So you're not going to cure an invasive prolactin oma with just because you're using the endoscope and then finally cushing's disease. And I think the really important thing with cushing's um I think you probably all know the how it happens. The pituitary makes too much a c th causes excess cortisol and you get these progressive changes of of weight gain often in the face buffalo hump um street or stretch marks, you can get hypertension, diabetes. Um One of the big problems with cushing's for us is have we really made the diagnosis and this is where the endocrinologist comes in to really help us because it is a very hard diagnosis to make. Sometimes if you look at the prevalence of cushing's and some of these high risk populations, um you'd be surprised. But some people that happen to be heavy and have hypertension and diabetes. I think they may have cushing's and potentially Wanna have cushing's because it's very treatable. It'll make those things go away. Unfortunately, that's not the case. So in poorly controlled diabetics um 2-3 Um had cushing's disease. Okay, so that it does occur. Um 1% of patients with newly diagnosed diabetes had surgically proven cushing's almost 6% of of obese subjects referred to an endocrine clinic with all of these things had cushing's disease. Um and then patients, older patients with osteoporosis and vertebral fractures when they were done when they were evaluated for secondary causes. 11% of them had cushing. So they are out there but again, they're a minority. So we have to do the screening tests. Very important that the endocrinologist really confirms the diagnosis. Um And then of course surgery is the treatment of choice. Um And it involves selectively removing the tumor. Sometimes we have to take out a portion of the gland. We have to explore the gland in many instances because the majority of these tumors are small and about a third of them. We can't see on an M. R. I. So we literally have to go through the gland and slice the gland like a loaf of bread. Um to try and find uh an adenoma. Um Post operatively we typically don't give any steroids. We want to see the cortisol levels coming down very fast and we we monitor these things for the 1st 48 hours. Um And these patients for those of you that have cushions. You know that if if we're successful with your surgery, most people are on glucocorticoids or cortisol replacement for six months to a year. And if you don't require that early after surgery, it probably means we didn't get the whole tumor out. Um And we we we have not achieved a remission. So there's a long history of surgery with cushing disease. This has had laws here who trained me. Um It's been treated surgically for quite a few years. I'll just show you one case here of a patient, A man. The majority of patients with Cushing's 70- 80% are women. But here's a man with cushing's as all of the typical hallmarks of high blood pressure weight gain fatigue, low libido. Um He had a very small gland surrounded by the carotid arteries here and what looked like possibly a tumor right here. And this is where in fact we did find the tumor and we're doing that pseudo capsule er dissection separating it from the gland. Um But this was an invasive tumor growing into the surrounding structures growing into the dura here and into this area called the cavernous sinus. And so we did have to do a little bit more work here and getting this tumor out completely. We had to remove some of the dura. We had to um cauterized some of the dura. We pour hydrogen peroxide on it, we do everything we can to beat it up so that all the tumor cells die or go away and um this is really what what needs to be done. We have to take a fairly aggressive approach. Um And then you get this clean looking dura here but we still like to cauterize that two kill any microscopic cells. And he went on to do quite well. His cortisol level dropped to less than one on the first day after surgery and 32 months out. Um he's still in remission and there's the hydrogen peroxide going in straight out of the bottle cheap and it works. Hopefully it helps. But again, if you look at the endoscopic literature, this is a paper that came out of Europe. They had a remission rate overall of 72%. And that's right in line with what you get with the microscopic approach. Um and and again in patients with invasive tumors, only 40% of those went into remission. So um the endoscope is good but it's probably not any better than the microscopic approach for this particular disease. This is what we like to see before and after surgery here. Um this this sort of nice, nice recovery. So finally, on the issue of pituitary gland preservation uh and recovery of gland function. Again, we make a big point of this. Um We would like to preserve the master gland. Obviously it does so many things. And here here it is looking very pale from a very large tumor. That's the tumor there, that's the gland. And after we take the tumor out, the gland gets its blood supply back and in many instances we can improve gland function. And here is a gland that's very stretched out and here it is thickened up but down it's moved down. But these glands can often often recover. So we make a lot of effort to identify where it is in relation to the tumor before the surgery. Um and make sure that we do everything we can to to not harm the gland. Um in some instances, um this big descent of the gland life. So if we remove the large tumor like this, the gland is up here, it's gonna come all the way down here after we take the tumor out and you can see that here and that sort of stretching probably results uh in the development of some new pituitary gland failure and this is a case in which the patient lost their all their pituitary function even though it looks like the pituitary stock is still connected. Um the gland just did not sustain that amount of manipulation. And so it turns out that by far the most important predictor of, of gland of gland losses, the size of the tumor. So for tumors under 20 millimeters or two centimeters, the rate of new gland of failure, It's around 1-2%. It's very low. And as you get to the bigger tumors, it goes up significantly to about 15%. Um for the large the giant autonomous overall the risk is about 5%. So we don't do perfect. But in most instances we spare the gland function. And so um and then this is just a final case. This is a chordoma skull base tumor where the gland is is sort of writing the tumor here. And normally the gland would be down here. You can see there's very enormous tumor here pushing the gland up. This woman presented with visual loss and she had a Maria, She lost her menstrual periods because the gland is distorted. And so obviously we want to preserve the gland here. Um and get as much of the tumor out. And you can see here after the surgery on post op day one, the gland is down all of this is actually the flap. When we do these extended approaches, we have to use some of the nasal septal mucosa to reconstruct the skull base. But you can see here, her gland is is enhancing normally, it's looking pretty healthy. And then if we go here 23 months, the gland looks very normal here. Um And she went on to get what's called proton beam radiotherapy, which is what we use for these tumors. Um And right now she's got normal menstrual periods, normal vision, uh and resolution of her headaches. But we'll have because she's gotten the radiation, we're going to have to watch that As a potential source of loss of Gland function in the years to come. And there's probably at least a 50% chance within five years she'll lose gland function. So these are just some slides on the, on the outcome. So in general, the remission rates for the Functional tumors is around 60-80%. Depending upon the series that you read for the invasive tumors. The numbers go below 50% for the non invasive. The results are probably higher than 90%. Um And then again, similarly with the nonfunctional tumors, it really depends on how big they are. And if they're invasive or not, We do very well with resolution of visual deficits. About 80% of the time people's vision will recover, The pituitary Gland failure will recover in 25-50% of patients. And we do also very well with with headache resolution for the big tumors, Fortunately the rates of major complications are very low. And if you look at a bunch of series across the literature, it should be less than 1% for all these terrible things. Um new pituitary failure, as I said, it's about 5%. So overall it's a it's a pretty safe approach and experience hands whether you do it with a microscope or an endoscope. So I think in conclusion for for those of you and many of you already had your surgery, but you need to make sure that you really need surgery. Um and you you need to determine that from, from the experts, need to find an experienced team of pituitary doctors. Um, I think in terms of the approach, it's certainly becoming the endoscopic approach is becoming the method of choice and we have completely switched over and I don't think we'll ever go back to the microscope, although it still is a reasonable approach. Um the resection rates for large tumors and other paracel or tumors like cranial friends aromas are probably superior to the microscopic approach. Um but for the functional tumors like acromegaly and cushing's, they seem to be equivalent. And we don't see that the endoscope is really making a huge difference in remission rates and probably the histology or the pathology of the tumor. The anatomy of the tumor and the experience of the team are as important or more important than whether you use the microscope or the endoscope. Again, I would just stress this collaboration between the team members is really key. Thank you very much
